Fight Aging!

Life expectancy, mortality, and risk of age-related disease are well known to correlate with a complicated web of socioeconomic factors. Educational attainment correlates with life expectancy, but so does intelligence. The relationship with intelligence might have underlying genetic causes, in that more intelligent people may be more physically robust. Or it may be that intelligence and education are inextricably linked - smarter people are better educated or better educated people do well on tests of intelligence - and the effect on life expectancy has little to do with genetics.

Further, educational attainment correlates with wealth, both of the region, and of the individual. Is it thus a proxy for greater access to medical technology purely due to greater wealth? What about the education and intelligence needed to use that access well? Or perhaps it has little to do with medical technology for most of the life span, and education and intelligence tend to lead to better lifestyle choices? Trying to peel apart these relationships is a complex task, and one that has not yet succeeded in any meaningful way, I would say.

The various epigenetic clocks are measures of age based on an algorithmic weighting of patterns of DNA methylation on the genome that appear to be a characteristic reaction to the damage and dysfunction of aging, occurring in very similar ways in every individual. The underlying molecular damage that causes aging is, after all, the same for everyone. It is as yet unknown as to exactly which underlying processes correspond to which DNA methylation sites on the genome, but the correlation is quite good overall. People in groups with higher risk of mortality or exhibiting age-related diseases tend to have higher assessed DNA methylation age than their healthier peers, which provides a way to determine pace of aging to some degree. Can this be useful as a tool to start dissecting the complicated relationships between aging, lifestyle, and socioeconomic status in populations? Perhaps.

Socioeconomic position, lifestyle habits and biomarkers of epigenetic aging: a multi-cohort analysis

Aging is characterized by a gradual and constant increase in health inequalities across socioeconomic groups, an association based on strong epidemiological evidence known as the social gradient in health. On average, individuals with lower socioeconomic position (SEP) have lower life expectancy, higher risk of age-related diseases, and poorer quality of life at older ages compared with less disadvantaged groups. Although lifestyles differ by SEP, unhealthy habits only partially explain this association.

The role of epigenetic mechanisms in response to trauma, and evidence for their involvement in intergenerational transmission of biological impacts of traumatic stress have been proposed to explain how social adversity gets biologically embedded, leading to differences in biological functionalities among individuals in different social conditions, especially at older ages. Epigenetics, specifically DNA methylation (DNAm) has been proposed as one of the most powerful biomarkers of biological aging and as one of the plausible biological mechanisms by which social adversities get 'under the skin' and affect physiological and cellular pathways leading to disease susceptibility.

Two measures of epigenetic clocks have gained considerable popularity, and the concept of epigenetic aging acceleration (EAA) has been introduced as the difference between predicted DNAm age and chronological age. EAA has been associated with all-cause mortality, cancer incidence and neurodegenerative disorders, as well as non-communicable disease risk factors such as obesity, poor physical activity, unhealthy diet, cumulative lifetime stress and infections.

Given the above, it can be assumed that the various epigenetic clocks describe different aspects of the biological (epigenetic) aging process. We previously showed a dose-response relationship between SEP and EAA. Further, our results suggest that the effect could be partially reversible by improving social conditions during life. In addition, ours and two more recent studies indicate that childhood SEP might have a stronger effect on EAA than adulthood SEP.

Despite extensive research in the field, to date no studies have compared the effect of SEP on epigenetic aging biomarkers with those of other lifestyle-related risk factors for age-related diseases. We aimed to systematically investigate the association of education level, as a proxy for SEP, with the total number of SEMs and 'accelerated aging' as assessed using the three epigenetic clocks, and to compare the independent effect of low education with those of the main modifiable risk factors for premature aging: smoking, obesity, alcohol intake, and physical inactivity, by conducting a meta-analysis including data for more than 16,000 individuals belonging to 18 cohort studies from 12 different countries worldwide.

Epigenetic aging biomarkers were associated with education and different sets of risk factors independently, and the magnitude of the effects differed depending on the biomarker and the predictor. On average, the effect of low education on epigenetic aging was comparable with those of other lifestyle-related risk factors (obesity, alcohol intake), with the exception of smoking, which had a significantly stronger effect. Our study shows that low education is an independent predictor of accelerated biological (epigenetic) aging and that epigenetic clocks appear to be good candidates for disentangling the biological pathways underlying social inequalities in healthy aging and longevity.

This popular science article discusses at length the chronic inflammation that is characteristic of the old, and its role as a proximate cause of age-related disease. Inflammation is a necessary part of the immune response to injury and pathogens, and when present in the short term it is vital to the proper operation of bodily systems. But when the immune system runs awry in later life, and inflammatory processes are constantly running, then this inflammation corrodes metabolism, tissue function, and health.

The causes of excess, constant inflammation are both internal and external to the immune system. Internally, the supply of new immune cells falls off with age as the thymus atrophies and hematopoietic stem cell populations decline; this leads to an immune system made up of increasingly damaged, malfunctioning cells. Externally, much of the inflammation of aging is the result of signals secreted by lingering senescent cells, and removal of this inflammation is a primary reason why senolytic therapies produce rejuvenation and longevity when tested in animal models. Addressing these causes of inflammation will be an important aspect of rejuvenation therapies in the years ahead.

In 2007, researchers already knew that exercise reduces the risk of cardiovascular disease as much as cholesterol-lowering statin drugs do. By analyzing biomarkers in the blood of 27,055 women participating in a long-term study, and other objective measures, they hoped to tease out how much of the benefit was attributable to improved blood pressure, to lower body weight, or to something else. "We were actually surprised that reduced inflammation was the biggest explainer, the biggest contributor to the benefit of activity, because we hadn't hypothesized that. We knew that regular exercise does reduce inflammation over the long term, but we also knew that acute exercise transiently increases inflammatory biomarkers during and immediately after exertion." About a third of the benefit of regular exercise, they found, is attributable to reduced inflammation. The anti-inflammatory effect of exercise was much greater than most people had expected. That raised another question: whether inflammation might also play a dominant role in other lifestyle illnesses that have been linked to cardiovascular disease, such as diabetes and dementia.

In 2017, two cardiologists, who suspected such a link, published the results of a human clinical trial which involved more than 10,000 patients in 39 countries, and was primarily designed to determine whether an anti-inflammatory drug, by itself, could lower rates of cardiovascular disease in a large population, without simultaneously lowering levels of cholesterol, as statin drugs do. The answer was yes. But the researchers went a step further, building into the trial additional tests seeking to clarify what effect the same anti-inflammatory drug, canakinumab, might have on illnesses seemingly unrelated to cardiovascular disease: arthritis, gout, and cancer. Only the researchers themselves, and their scientific colleagues, were unsurprised by the outcome. Lung cancer mortality dropped by as much as 77 percent. Reports of arthritis and gout also fell significantly.

In medicine, believing something is true is not the same as being able to prove it. Because the idea that inflammation - constant, low-level, immune-system activation - could be at the root of many noncommunicable diseases is a startling claim, it requires extraordinary proof. Can seemingly unconnected illnesses of the brain, the vasculature, lungs, liver, and joints really share a deep biological link? Evidence has been mounting that these common chronic conditions - including Alzheimer's, cancer, arthritis, asthma, gout, psoriasis, anemia, Parkinson's disease, multiple sclerosis, diabetes, and depression among them - are indeed triggered by low-grade, long-term inflammation. But it took that large-scale human clinical trial to dispel any lingering doubt: the immune system's inflammatory response is killing people by degrees.

Now the pertinent question is why, and what can be done about it. The pharmaceutical industry is deeply interested in finding ways to stop inflammation with medicines like canakinumab, an orphan drug that blocks a specific pro-inflammatory pathway called IL-1beta. But some researchers suggest that the inflammatory process - a normal and necessary part of the natural immune response - has itself has been misunderstood. Scientists know that the process can be turned on and off, but have only recently understood that this doesn't mean normal physiology will resume once the inflammation caused by infection, injury, or irritant has been shut down. Instead, the restoration of health is an active phase of the inflammatory process itself, facilitated by a little-known class of molecules called pro-resolving mediators - the protectins, resolvins, maresins, and lipoxins - brimming with marvelous, untapped, regenerative capacities.

Link: https://harvardmagazine.com/2019/05/inflammation-disease-diet

In atherosclerosis, fatty deposits form in blood vessel walls, narrowing and eventually rupturing or blocking them. It is one of the largest causes of death. The majority of efforts to treat atherosclerosis are focused on reducing the input of LDL cholesterol. This means statins and other, more recent approaches to lower levels of LDL cholesterol in the bloodstream, such as PCSK9 inhibitors. It is possible to reduce blood cholesterol to very low levels indeed, far below normal, and this actually has comparatively little effect on existing atherosclerotic lesions. Patients still die. The disease still progresses, just more slowly.

Atherosclerosis isn't a condition of cholesterol, for all that this is how it largely discussed in the medical profession, but rather a condition in which the macrophages responsible for clearing cholesterol from blood vessel walls become dysfunctional. The focus should be on the macrophages. Nonetheless, the research community remains largely focused on LDL. The work here is illustrative of attempts to find yet more ways to reduce LDL cholesterol in blood vessel walls, this time somewhat more specifically than by simply lowering levels everywhere. Still, I suspect it will be unlikely to produce benefits significantly greater than those of PCSK9 inhibitors and their general reduction in LDL cholesterol in the bloodstream.

Since low-density lipoprotein, or LDL, cholesterol entry into the artery wall drives the development of atherosclerosis, or hardening of the arteries, and atherosclerosis leads to heart attacks and strokes, future treatments preventing the process may help decrease the occurrence of these life-threatening conditions. A new study reveals for the first time how a protein called SR-B1 (short for scavenger receptor class B, type 1) ferries LDL particles into and then across the endothelial cells that line arteries. The study also found that a second protein called dedicator of cytokinesis 4, or DOCK4, partners with SR-B1 and is necessary for the process.

In the early stages of atherosclerosis, LDL that has entered the artery wall attracts and is engulfed by important immune system cells called macrophages that ingest, or "eat," LDL particles. LDL-laden macrophages become foam cells that promote inflammation and further the development of atherosclerotic plaques. The plaques narrow the artery and can become unstable. Plaques that rupture can activate blood clotting and block blood flow to the brain or heart, resulting in a stroke or heart attack. In studies of mice with elevated cholesterol, the investigators determined that deleting SR-B1 from the endothelial cells lining blood vessels resulted in far less LDL entering the artery wall, fewer foam cells formed, and atherosclerotic plaques that were considerably smaller.

In their studies, the researchers compared SR-B1 and DOCK4 abundance in areas of the mouse aorta that are prone to plaque formation compared with regions less likely to become atherosclerotic. They found higher levels of SR-B1 and DOCK4 in the disease-prone regions long before atherosclerotic plaques formed. This finding suggests that atherosclerotic lesions may be more common in particular artery sites because of more SR-B1 and DOCK4 present there. To determine if these findings might apply to people, the researchers reviewed data on atherosclerotic and normal arteries from humans in three independent databases maintained by the National Institutes of Health (NIH). In all three databases, SR-B1 and DOCK4 were more abundant in atherosclerotic arteries compared with normal arteries. The researchers are now exploring the possibility of using gene therapy to turn off or reduce the function of SR-B1 or DOCK4 in the endothelial cells that line arteries in order to prevent atherosclerosis.

Link: https://www.utsouthwestern.edu/newsroom/articles/year-2019/how-bad-cholesterol-enters-artery-walls.html

OneSkin Technologies is one of the few companies in the present community of startups focused on rejuvenation and slowing aging to adopt a serious cosmetics focus on development. Here "cosmetics" is a regulatory term, not an indication of something used for the purposes of looks: it is perfectly possible for a topically applied product that is regulated as a cosmetic to have therapeutic effects, just like a drug. Nonetheless, cosmetics and drugs have entirely distinct paths of regulation, very different from one another, and each with their own costs and challenges. In regulated cosmetics development there is no animal testing at all, everything proceeds to human trials on the basis of tissue models of skin. The trials themselves are quite different. It is arguably easier to run a rejuvenation therapy through the cosmetics regulatory pathway than to try to introduce it as a drug, provided that has a significant effect on skin aging.

This is the direction taken by OneSkin, where the staff are working on a line of senolytic compounds to selectively destroy senescent cells in aged tissues, and that will be developed as cosmetic products at the outset. I met the OneSkin founder earlier this year, and had a chance to pose a few questions about the work being carried out at the company. I think that this approach to the challenge of medical development is worth watching, particularly given that the next major area of rejuvenation research to take off may be cross-link breaking. Cross-links are influential in the age-related loss of elasticity in tissues such as skin and blood vessels. I imagine that companies analogous to OneSkin will emerge quite quickly in that space, once it has reached the same level of maturity as presently exists for senolytics research and development.

How did OneSkin Technologies come about? What led you into cosmetic senolytics?

OneSkin's initial proposal was to validate the effectiveness of "anti-aging" skincare products available in the market, in order to meet the needs of consumers for science-validated products as well for the companies that are looking to differentiate their products from competitors. Our approach for this validation was to test a given molecule in 3D human skin equivalents and analyze changes in the methylation pattern by running age-predictor algorithms, such as the Molecular Clock developed by Steve Horvath in 2013. Since this and other algorithms used at the time largely failed to predict skin age accurately, we decided to develop our own skin-specific molecular clock, in which the average difference between predicted age and chronological age is lower (approximately 4.6 years) than the currently available molecular clocks. Later on, we realized that we could create more value and offer a scalable solution by developing new and more effective products for skin rejuvenation, instead of limiting ourselves to validating third party products. We also realized that there wasn't any initiative for targeting senescent cells focused on our body's largest organ, the skin.

We believe the skin will be the first tissue to benefit from a senotherapeutic approach since it allows for topical application, virtually no contact with the bloodstream, and possibly a faster route to the market, if categorized as a cosmetic. We also love the proposal to develop senotherapeutics for skin because their effects will be visually perceived by consumers. Finally, the International League of Dermatological Societies (ILDS), a global, not-for-profit organization representing 157 dermatological societies worldwide, has identified the consequences of skin aging as one of the most important grand challenges in global skin health. Reduced functional capacity and increased susceptibility of the skin with development of dermatoses such as dry skin, itching, ulcers, dyspigmentation, wrinkles, fungal infections, as well as benign and malignant tumors are the most common skin conditions in aged populations worldwide and may be prevented with the use of technologies that have been designed to promote skin age reversal, like ours.

The audience here is more familiar with the FDA process for new drugs. How does cosmetics development differ from that?

Here in the US, the law does not require cosmetic products to have FDA approval before they go on the market, but there are laws and regulations that apply to cosmetics on the market, including the voluntary cosmetic registration program. Despite the general feeling that cosmetics are hardly regulated by FDA, safety is the number one rule, accompanied by the important observation that cosmetic products must be properly labeled. This means that any cosmetic product in the market should do no harm to the skin. For this purpose, there are guidelines to be followed when introducing a new molecule in a cosmetic product.

Basically, the company should provide data regarding mutagenesis and chromosomal changes by performing tests such as the Ames test (which uses bacteria to analyze the potential of a given compound to cause DNA mutations), cytotoxicity (using human cells) and karyotyping analysis (using human cells). Since OneSkin does not use animals to develop products, additional safety studies using the complete formulation to assess skin irritation, corrosion, and sensitization are performed in human skin equivalents (in vitro) and also in human subjects. Additional tests, such as ocular toxicity are desirable and even mandatory according to the cosmetic product. At OneSkin, we performed most of the cited tests, including cytotoxicity in human fibroblasts and keratinocytes derived from different donors, mutagenesis (Ames) and chromosomal aberration (karyotyping), toxicity through human skin equivalents, and, finally, we have already performed the Repeated Insult Patch Testing (RIPT) in 54 human subjects, provided by an independent contract organization. All of them came out clear and in accordance with the parameters required, guaranteeing safety for our future clients.

Tell us something about your development. What is your candidate molecule, and how far along are you in the process of validation leading to human use?

Our lead candidate molecule is a new synthetic peptide, which was initially screened in a synthetic library for antimicrobial peptides (AMP). AMPs have multifunctional behavior and accumulate several interesting properties for skin applications, including tissue repair, antioxidant activity, collagen synthesis, anti-inflammatory activity and we decided to evaluate their senotherapeutic potential. From our initial 200 library, we selected 4 hits - the 4 compounds which were most effective in decreasing senescent cells in human skin. Then, we used an algorithm to create variations of such sequences, leading to hundreds of possible leads. Among those leads, we selected the two best peptides, deemed OS-1 and OS-2, which have consistently shown the ability to decrease human cellular senescence caused by aging, ultraviolet light, and other types of genotoxic stress by 25-50%.

It is worthy of mention that we chose to build a human cell-based platform in order to close the gap between preclinical and clinical scenarios and to mimic skin aging as closely as possible. Indeed, our valuable technological platform is proprietary and has been patented. To briefly outline our pipeline, first, we evaluate the ability of new compounds to decrease cellular senescence through two markers. The classical senescence associated-β-galactosidase (SA-β-Gal) marker is analyzed, as it has been consistently used in the aging field for a least 30 years and is considered an easily identifiable marker of cellular senescence. Nevertheless, since SA-β-Gal also has important limitations, we complement our analysis with a more recent and sensitive marker of cellular senescence, ATRX foci formation.

For each compound, we test both markers in cells obtained from at least three different healthy and aged donors. As positive controls, we have used senolytic and senomorphic molecules, such as fisetin and rapamycin. We also have tested most of senolytics described in the literature and most have failed to induce apoptosis in senescent cells in those cell types or show nonspecific effects, causing a significant toxicity to non-senescent cells. To date, our peptides are the molecules that have performed the best, considering safety and efficacy endpoints. We have been able to replicate human skin aging in vitro by growing skins with cell donors of diverse ages, ranging from a neonatal (0Y), to young (approximately 30Y) to aged (over 50Y). We have characterized these models according to skin equivalent structural organization, gene expression, and accumulation of senescent cells. Using aged skin equivalents, we test compounds by adding them into the culture media for 5 days. At this time, histological, SA-β-gal staining and qPCR analysis are performed to evaluate the skin health and the senotherapeutic and age reversal potential of such molecules. Additionally, we have formulated our main peptide in a topical cream and have applied onto skin biopsies of aged donors, and we could observe an improvement in epidermal thickness after 5 days of treatment.

Importantly, OS-1 is performing better than retinoic acid, currently considered the gold standard molecule for anti-aging skincare products. It is also worth mentioning that we have consistently seen an increased expression of p16 and inflammatory cytokines like IL-6 and IL-8, along with the "peeling effect" of retinoic acid, which is usually perceived in human use.

Finally, after performing these in vitro studies and clearing the safety (including an IRB approval) of our lead candidate, we have improved our own topical OS-1 formulation and began testing it on a group of 23 healthy volunteers, ranging from 32 to 84 years old. This experiment was initially focused on safety assessment only, but we already consider it a first validation of OS-1 effectiveness in humans, since our preliminary data is extremely promising, with 100% safety and a significant visual improvement observed in most patients within the first month of continuous use. Later this year, we will proceed to a randomized, placebo-controlled clinical study provided by an independent contractor organization.

Why can't one just use dasatinib, or other established senolytics, in some form and spread it on skin? Why something new?

Despite major proofs of concepts generated in the longevity field recently, the clinical use of senolytics must be carefully evaluated. We initially tested several senolytics like dasatinib and unfortunately, the majority that we tested on our platform were either very toxic even to non-senescent cells, or are not effective in decreasing the relative percentage of cellular senescence. Initially, we were disappointed by the lack of reproducibility in our hands, but since we have tested such compounds consistently, we believe that the discrepancies observed may result from different experimental settings, since most papers are based on animal models or genetically-modified cell lines, while we work with healthy and normal aged human cells.

Furthermore, when tested in skin equivalent models, senolytics continued to be highly toxic, compromising skin equivalent general structure, and decreasing the thickness of the epidermis. ABT-263, A1331852 and Dasatinib + Quercetin are but a few senolytics we have already tested. We have tested other molecules which are safer and effective like fisetin, but this molecule has the limitation of requiring high concentration to be effective (i.e. 20 μM), due to its low bioavailability. Fisetin's natural color (yellow to orange) also impairs its use in a topical product.

If your product works topically on skin, why not administer it systemically to clear out senescent cells throughout the body?

As mentioned before, we believe skin health is an important and highly overlooked target to rapidly promote drastic improvement of wellness, self-confidence, and prevention of aging-related skin disorders. Therefore, we have chosen skin as a starting point to validate our lead molecule and start bringing its benefits earlier to consumers. Once OS-1 ́is proven to be well-tolerated and effective at reducing skin senescence when applied topically, it will then open several avenues to explore other indications of the peptide throughout the body, which would fall in the regular FDA pathway for drug development. In this regard, one basic assay we performed in order to assess the potential application of OS-1 for longevity purposes was the evaluation of healthspan improvement and lifespan extension in C. elegans worms. In this experiment, parameters of healthspan (thrashing and esophageal pumping - which basically indicates how well the worm moves and eats) were improved, and the treated worms lived longer (median life extension increased approximately 12%).

This is comparable to other age reversal strategies published in the literature, and reflects the potential of OS-1 to be used for other therapeutic applications in the future. The positive result surprised us, because we have not yet optimized our candidates by applying any medicinal chemistry. However, this will soon be performed once the mechanism of action is elucidated. On this subject, we have shown that OS-1 promotes a decrease of cellular senescence levels of cells and tissues by promoting apoptosis (decrease in phosphorylated Akt on Ser473), increasing DNA repair capacity (induction of BLM and SIRT6 gene expression) and preventing DNA-damage induced senescence (UVB exposure induction model).

What other areas of rejuvenation research do you think would benefit from a cosmetics approach, to speed adoption?

Most strategies targeting one of the hallmarks of aging could be useful for a cosmetic approach. The main limitation we see is the delivery of whatever rejuvenation technology through the stratum corneum, the outermost layer of the skin, which is very well designed to work as a barrier to protect the skin from potential harm or infections. Our peptide, as a reference, is considered small (10 amino acids) and we were fortunate to validate its ability to penetrate through the stratum corneum barrier and into the dermal layer. Larger molecules may face additional challenges in penetratration and to promote their effects in deeper skin layers.

Importantly, to be able to validate any technology to promote skin rejuvenation it is not a trivial process. Previous experience has shown that skin aging is a little bit different from aging in other tissues. Therefore, it will be important to validate other strategies while considering the important drivers for skin aging by testing on aged models that replicate chronological aging such as UV exposure, oxidative stress, and pollution, and not on less important drivers such as oncogene-induced and chemically-induced senescence. The ability to replicate these models required years of optimization and it is an ongoing process when you start considering not only the influence of age, but also how the diverse genetic background plays a significant role in this matter.

What is the future of OneSkin Technologies beyond your first senolytic product?

OneSkin's main goal is to build the first skincare line targeting cellular senescence and bring its own products to the market. We believe there is no proposal out there, focusing on skin, that tackles aging from its cause as we do. This makes us confident in the value our products will bring to consumers. After the first validation for aesthetic skin rejuvenation, we are going after other age-related skin disorders and eventually, age-related disorders beyond the skin. An oral application of our peptide is another avenue to be explored. As we intend to keep our focus mainly towards skin applications, we envision to explore these additional indications through partnerships with pharma or other longevity companies. Finally, OneSkin's main asset is our screening and validation platform, which will constantly screen and identify new leads, be them small molecules, peptides, natural compounds or combinations thereof, to target cellular senescence and senescence-associated diseases. We are determined to work to position our technologies in the forefront of the future therapies for aging and longevity.

A number of approaches to tissue engineering and regenerative medicine have focused on providing a supporting structure for native cells, to steer their behavior towards regrowth rather than scarring or inactivity. The results here are an example of one class of minimally invasive approach, in which an artificial extracellular matrix material can be injected rather than implanted. In addition to providing a structure that cells favor, this sort of material can be laden with a mix of signal molecules that will aid cell survival and activity. Better repair following damage such as that of a heart attack is a poor second best to preventing the heart attack from occurring in the first place, but it is an incremental improvement over the present state of affairs.

Tissue engineering strategies to replace or supplement the extracellular matrix that degrades following a heart attack are not new, but most promising hydrogels cannot be delivered to the heart using minimally invasive catheter delivery because they clog the tube. Researchers have now demonstrated a novel way to deliver a bioactivated, biodegradable, regenerative substance through a noninvasive catheter without clogging.

When a person has a heart attack, the extracellular matrix is stripped away and scar tissue forms in its place, decreasing the heart's functionality. Because of this, most heart attack survivors have some degree of heart disease, the leading cause of death in America. "We sought to create a peptide-based approach because the compounds form nanofibers that look and mechanically act very similar to native extracellular matrix. The compounds also are biodegradable and biocompatible. Most preclinical strategies have relied on direct injections into the heart, but because this is not a feasible option for humans, we sought to develop a platform that could be delivered via intracoronary or transendocardial catheter."

Peptides are short chains of amino acids instrumental for healing. The team's approach relies on a catheter to deliver self-assembling peptides - and eventually a therapeutic - to the heart following myocardial infarction, or heart attack. The team's preclinical research was conducted in rats and segmented into two proof-of-concept tests. The first test established that the material could be fed through a catheter without clogging and without interacting with human blood. The second determined whether the self-assembling peptides could find their way to the damaged tissue, bypassing healthy heart tissue. Researchers created and attached a fluorescent tag to the self-assembling peptides and then imaged the heart to see where the peptides eventually settled. "In previous work with responsive nanoparticles, we produced speckled fluorescence in the heart attack region, but in this case, we were able to see large continuous hydrogel assemblies throughout the tissue."

Link: https://www.eurekalert.org/pub_releases/2019-04/nu-fab042319.php

The sirtuin gene SIRT6 is involved in DNA repair, among many other processes. Researchers here report that differences in SIRT6 between shorter and longer lived mammals give rise to more efficient DNA repair in the longer-lived species. This might be taken as evidence for nuclear DNA damage to be significant in aging, but the challenge is always in isolating just the one effect. So while altering fly SIRT6 to look more like that of mammals results in extended life spans, proving that this is all due to DNA repair is a challenging project yet to be accomplished.

SIRT6 is often called the "longevity gene" because of its important role in organizing proteins and recruiting enzymes that repair broken DNA; additionally, mice without the gene age prematurely, while mice with extra copies live longer. The researchers hypothesized that if more efficient DNA repair is required for a longer lifespan, organisms with longer lifespans may have evolved more efficient DNA repair regulators. Is SIRT6 activity therefore enhanced in longer-lived species?

To test this theory, the researchers analyzed DNA repair in 18 rodent species with lifespans ranging from 3 years (mice) to 32 years (naked mole rats and beavers). They found that the rodents with longer lifespans also experience more efficient DNA repair because the products of their SIRT6 genes - the SIRT6 proteins - are more potent. That is, SIRT6 is not the same in every species. Instead, the gene has co-evolved with longevity, becoming more efficient so that species with a stronger SIRT6 live longer.

The researchers then analyzed the molecular differences between the weaker SIRT6 protein found in mice versus the stronger SIRT6 found in beavers. They identified five amino acids responsible for making the stronger SIRT6 protein more active in repairing DNA and better at enzyme functions. When the researchers inserted beaver and mouse SIRT6 into human cells, the beaver SIRT6 better reduced stress-induced DNA damage compared to when researchers inserted the mouse SIRT6. The beaver SIRT6 also better increased the lifespan of fruit flies versus fruit flies with mouse SIRT6. Next steps in the research involve analyzing whether species that have longer lifespans than humans - like the bowhead whale, which can live more than 200 years - have evolved even more robust SIRT6 genes.

Link: https://www.rochester.edu/newscenter/longevity-gene-responsible-for-more-efficient-dna-repair-375752/

The immune system declines with age for a range of reasons. The thymus atrophies, reducing the supply of new T cells; persistent infection by cytomegalovirus causes cells to become uselessly specialized rather than ready to tackle new threats; and the hematopoietic stem cells responsible for generating immune cells become damaged, inactive, and dysfunctional. One of these forms of dysfunction is that hematopoietic stem cells begin to generate too many myeloid cells and too few lymphoid cells, the so-called myeloid skew.

The cause of this skewing in cell production is much debated, but researchers have found that chronic inflammation plays a role. Naturally, nowadays whenever inflammation appears to be an important aspect of any age-related dysfunction, attention turns towards senescent cells. Lingering senescent cells accumulate with age in all tissues, and secrete a potent mix of signals that rouses the immune system into an inflammatory state. It seems likely that they are an important part of the problem when it comes to the myloid skew in the hematopoietic stem cell population.

Why do senescent cells accumulate with age? Cells become senescent in great numbers throughout life, but only later do they linger to a significant degree. Near all are destroyed, either by their own programmed cell death processes, or by the immune system, called into action by the inflammatory signaling of the senescent cells. One reason for a greater number of lingering senescent cells in later life is that the immune system declines and falters in destroying errant cells. Thus, like many issues in aging, the relationship between cellular senescence and immune decline is a circular one; these two processes start off very slowly, but feed one other and accelerate as time passes and damage mounts.

Aged marrow macrophages expand platelet-biased hematopoietic stem cells via Interleukin1B

Dysfunction of the human hematopoietic system with age includes diminished immune response, marrow failure, and clonal selection. Aging is also associated with a general increase in tissue inflammation that remains largely unexplained. The mechanisms driving these characteristics of aged hematopoiesis have, to date, primarily been attributed to intrinsic hematopoietic stem cell (HSC) changes. With age, in both humans and mice, the phenotypic long-term HSC (LT-HSC) pool is expanded and globally LT-HSCs differentiate preferentially towards the myeloid lineage.

Multipotent HSCs with platelet bias were recently identified by a number of investigators describing their increased expression of von Willebrand Factor (vWF) and of the Integrin αIIb (CD41). Recent data demonstrate that aged murine HSCs also have increased cell-surface expression of CD41 and vWF. Notably, human aged HSCs display platelet (or megakaryocytic) bias, suggesting that insights in mechanisms determining murine HSC platelet bias will not only improve our understanding of diseases attributed to the aging hematopoietic system, but also provide novel therapeutic approaches to hematopoietic dysfunction associated with advanced age.

Since the bone marrow microenvironment (BMME) critically regulates HSCs, whether it be considered instructive or enabling distinct HSC fates, unique characteristics of the aged BMME could contribute to HSC changes associated with age. In fact, in the Drosophila gonad, extrinsic signals from the niche contribute to stem cell aging, and mathematical models have suggested that non-cell-autonomous changes could drive this process in mammalian HSCs. While data have suggested that aged endothelial and mesenchymal BMME populations are abnormal and may participate in HSC aging, microenvironmental signals governing the megakaryocytic bias of aged HSCs remain unclear. Thus, we hypothesized that defects in critical BMME populations caused by age could lead to the expansion of platelet-biased HSCs.

We found that macrophages (Mφs) within the aged BMME could impose the megakaryocytic bias characteristic of aging in HSCs. Aged human and murine marrow Mφs had distinct transcriptional profiles compared to young Mφs, including an increased inflammatory activation signature. We identified increased interleukin 1B (IL1B) mRNA in aged marrow Mφs and elevated caspase 1 activity in Mφs and neutrophils from aged bone marrow. Moreover, IL1B signaling was necessary and sufficient to induce HSC bias and drive young HSPCs to adopt an aged phenotype.

While investigating the cause of this increase, we made the novel observation that aged marrow Mφs had a defect in efferocytosis - their ability to clear apoptotic cells. Clearance of apoptotic cells is a critical function of Mφs that prevents necrosis of dead cells and associated local inflammation and also triggers anti-inflammatory responses in phagocytes. In young mice, removal of phagocytic cells or genetic loss of the efferocytic receptor Axl increased HSCs with megakaryocytic bias, suggesting that the efferocytic defect in aged marrow Mφs leads to the increase in IL1B activation and signaling. Together these data define a novel mechanism within the aged BMME that enables a specific HSC fate.

Do periods of sedentary behavior, in particular sitting, increase the risk of mortality and age-related disease regardless of whether or not there are periods surrounding exercise? The epidemiological research community can take decades and dozens of studies to chew over questions like this. Most recently, evidence was presented to suggest that sitting for longer periods of time is an independent risk factor for mortality even for those who exercise. The study here presents evidence for a more nuanced conclusion, that exercise does compensate for periods of time spent sitting.

This sort of contradictory data is very much par for the course in this area of study: ignore any single set of results, and look for consensus across as many studies as possible. Meanwhile consider whether or not the arrow of causation might point from health and mortality risk to behavior such as sitting and activity; are less active people exhibiting higher mortality because unhealthy people tend to be less active, for all the obvious reasons, for example?

For less active adults, the amount of time spent sitting may be associated with an increased risk of death; however, increasing physical activity to recommended levels may eliminate this association in some. Recent studies have determined that high levels of sedentary behavior are associated with adverse health outcomes. However, the link between sedentary behavior, mortality, and heart disease are not always well understood.

In this study, researchers aimed to determine the association between sedentary behavior and physical activity on mortality and to estimate the effects of replacing sitting with standing, physical activity and sleep. Participants included 149,077 Australian men and women aged 45 years and older who were asked to complete a questionnaire that determined how many hours per day an individual spent sitting, standing and sleeping. They also were questioned about the total time spent walking or participating in moderate or vigorous physical activity.

After a median follow up time of 8.9 years for all-cause mortality and 7.4 years for cardiovascular disease mortality, higher sitting times (more than six hours) were associated with higher all-cause and cardiovascular disease mortality risks, but mostly in those did not meet physical activity recommendations. Meeting even the lowest requirements for physical activity eliminated the association with all-cause mortality risk, with the exception of those who sat the most (more than 8 hours a day). Compared to those who were highly active and sat for less than four hours per day, the risk remained substantially elevated even among physically inactive participants who sat for 4 hours per day only.

While replacing sitting with standing was associated with risk reduction in low sitters, replacing sitting with physical activity was more consistently associated with risk reduction in high sitters. The researchers found that moderate physical activity only reduced cardiovascular disease death risk among high sitters. The largest replacement effects were seen for vigorous physical activity, but this level of activity may not be possible for all adults.

Link: https://www.eurekalert.org/pub_releases/2019-04/acoc-pam041819.php

Many researchers are exploring the therapeutic utility of microRNAs involved in fundamental cellular processes such as replication. These molecules act to regulate the processes of gene expression, determining how much of specific proteins are produced from their genetic blueprints, and when. Protein amounts are the switches and dials of cellular operation, and delivering microRNAs into cells is one possible way to steer cells into useful behavior - through the sheer complexity of the cell makes identifying the right tools to use quite difficult, and any given microRNA may produce quite sweeping changes, only few of which are helpful in any given context. Nonetheless, as illustrated here, there are some possible paths forward towards near future applications of microRNA delivery in regenerative medicine.

Once the heart is fully formed, the cells that make up heart muscle, known as cardiomyocytes, have very limited ability to reproduce themselves. After a heart attack, cardiomyocytes die off; unable to make new ones, the heart instead forms scar tissue. Over time, this can set people up for heart failure. New work advances the possibility of reviving the heart's regenerative capacities using microRNAs - small molecules that regulate gene function and are abundant in developing hearts. Researchers had earlier identified a family of microRNAs called miR-17-92 that regulates proliferation of cardiomyocytes. In the new work, they show two family members, miR-19a and miR-19b, to be particularly potent and potentially good candidates for treating heart attack.

Researchers tested the microRNAs delivered two different ways. One method gave them to mice directly, coated with lipids to help them slip inside cells. The other method put the microRNAs into a gene therapy vector designed to target the heart. Injected into mice after a heart attack - either directly into the heart or systemically - miR-19a/b provided both immediate and long-term protection. In the early phase, the first 10 days after heart attack, the microRNAs reduced the acute cell death and suppressed the inflammatory immune response that exacerbates cardiac damage. Tests showed that these microRNAs inhibited multiple genes involved in these processes. Longer-term, the treated hearts had more healthy tissue, less dead or scarred tissue and improved contractility, as evidenced by increased left-ventricular fractional shortening on echocardiography. Dilated cardiomyopathy - a stretching and thinning of the heart muscle that ultimately weakens the heart - was also reduced.

Link: https://vector.childrenshospital.org/2019/04/micrornas-heart-attack/

The present consensus on the the development of Alzheimer's disease is that it starts with the accumulation of amyloid-β, though there are many competing theories as to why only some people exhibit this problem to a great enough degree to produce pathology. The biochemistry of oligomers supporting amyloid-β causes sufficient disarray in brain metabolism to set the stage for neuroinflammation, malfunction of immune cells in the brain, and aggregation of altered forms of tau protein into neurofibrillary tangles that cause most of the damage and cell death in the later stages of the condition. The failure to improve outcomes via attempts to remove amyloid-β from the brains of Alzheimer's patients may be a case of too little, too late, but there is still good reason to remove amyloid-β. Doing so early enough and efficiently enough should prevent the later stages of the condition from developing at all.

The most modern approach to drug development, built atop greatly improved capacities in computation and associated modeling of protein structures and interactions, is to find points of intervention through a greater understanding of how proteins interact with one another, in detail, and how those interactions pertain to disease processes. Researchers can then rationally design molecules that (a) interfere at a vulnerable and highly specific point in a desired interaction and (b) due to this specificity are safe enough for clinical use, as they cause only limited disruption elsewhere in the operation of cellular biochemistry. This is the ideal, in any case. The challenge, as ever, is finding a point of intervention that does in fact turn out to be both specific enough and good enough in practice, in patients.

The research noted here today is an example of this approach to development applied to preventing the aggregation of amyloid-β. In principle, sufficient disruption of the process of forming protein aggregates should allow existing systems of clearance to remove excess or damaged protein molecules before they causes issues. In practice, we shall see how it turns out as this work progresses.

Synthetic peptide can inhibit toxicity, aggregation of protein in Alzheimer's disease

Alzheimer's is a disease of aggregation. Neurons in the human brain make a protein called amyloid beta. Such proteins on their own, called monomers of amyloid beta, perform important tasks for neurons. But in the brains of people with Alzheimer's disease, amyloid beta monomers have abandoned their jobs and joined together. First, they form oligomers - small clumps of up to a dozen proteins - then longer strands and finally large deposits called plaques. For years, scientists believed that the plaques triggered the cognitive impairments characteristic of Alzheimer's disease. But newer research implicates the smaller aggregates of amyloid beta as the toxic elements of this disease.

Now, researchers have developed synthetic peptides that target and inhibit those small, toxic aggregates. Their synthetic peptides - which are designed to fold into a structure known as an alpha sheet - can block amyloid beta aggregation at the early and most toxic stage when oligomers form. The team showed that the synthetic alpha sheet's blocking activity reduced amyloid beta-triggered toxicity in human neural cells grown in culture, and inhibited amyloid beta oligomers in two laboratory animal models for Alzheimer's. These findings add evidence to the growing consensus that amyloid beta oligomers - not plaques - are the toxic agents behind Alzheimer's disease. The results also indicate that synthetic alpha sheets could form the basis of therapeutics to clear toxic oligomers in people.

"This is about targeting a specific structure of amyloid beta formed by the toxic oligomers. What we've shown here is that we can design and build synthetic alpha sheets with complementary structures to inhibit aggregation and toxicity of amyloid beta, while leaving the biologically active monomers intact."

α-Sheet secondary structure in amyloid β-peptide drives aggregation and toxicity in Alzheimer's disease

Alzheimer's disease (AD) is characterized by the deposition of β-sheet-rich, insoluble amyloid β-peptide (Aβ) plaques; however, plaque burden is not correlated with cognitive impairment in AD patients; instead, it is correlated with the presence of toxic soluble oligomers. Here, we show, by a variety of different techniques, that these Aβ oligomers adopt a nonstandard secondary structure, termed "α-sheet." These oligomers form in the lag phase of aggregation, when Aβ-associated cytotoxicity peaks, en route to forming nontoxic β-sheet fibrils.

De novo-designed α-sheet peptides specifically and tightly bind the toxic oligomers over monomeric and fibrillar forms of Aβ, leading to inhibition of aggregation in vitro and neurotoxicity in neuroblastoma cells. Based on this specific binding, a soluble oligomer-binding assay (SOBA) was developed as an indirect probe of α-sheet content. Combined SOBA and toxicity experiments demonstrate a strong correlation between α-sheet content and toxicity. The designed α-sheet peptides are also active in vivo where they inhibit Aβ-induced paralysis in a transgenic Aβ Caenorhabditis elegans model and specifically target and clear soluble, toxic oligomers in a transgenic APPsw mouse model. The α-sheet hypothesis has profound implications for further understanding the mechanism behind AD pathogenesis.

Alzheimer's disease begins with the accumulation of amyloid-β in the brain, but this doesn't mean that amyloid-β is purely molecular waste. Yes, it is harmful given the presence of too much of it in the central nervous system, but that is true of most of our biochemistry. There is good evidence for amyloid-β to act as an antimicrobial system, for example, which is the basis for considering persistent infection as a potential contributing cause of Alzheimer's disease, in which infectious agents drive the generation of ever increasing amounts of amyloid-β. Even setting aside that and other evidence, however, it is quite possible to argue that amyloid-β must have some important function, based on evolutionary theory and the fact that the molecule exists at all.

The argument is frequently made that the amyloid-β protein (Aβ) persists in the human genome because Alzheimer's disease (AD) primarily afflicts individuals over reproductive age and, therefore, there is low selective pressure for the peptide's elimination or modification. This argument is an important premise for AD amyloidosis models and therapeutic strategies that characterize Aβ as a functionless and intrinsically pathological protein. Here, we review whether evolutionary theory and data on the genetics and biology of Aβ are consistent with low selective pressure for the peptide's expression in senescence.

Aβ is an ancient neuropeptide expressed across vertebrates. Consistent with unusually high evolutionary selection constraint, the human Aβ sequence is shared by a majority of vertebrate species and has been conserved across at least 400 million years. Unlike humans, the overwhelming majority of vertebrate species do not cease reproduction in senescence and selection pressure is maintained into old age. Hence, low selective pressure in senescence does not explain the persistence of Aβ across the vertebrate genome.

The Grandmother hypothesis (GMH) is the prevailing model explaining the unusual extended postfertile period of humans. In the GMH, high risk associated with birthing in old age has lead to early cessation of reproduction and a shift to intergenerational care of descendants. The rechanneling of resources to grandchildren by postreproductive individuals increases reproductive success of descendants. In the GMH model, selection pressure does not end following menopause. Thus, evolutionary models and phylogenetic data are not consistent with the absence of reproductive selection pressure for Aβ among aged vertebrates, including humans.

Our analysis suggests an alternative evolutionary model for the persistence of Aβ in the vertebrate genome. Aβ has recently been identified as an antimicrobial effector molecule of innate immunity. High conservation across the Chordata phylum is consistent with strong positive selection pressure driving human Aβ's remarkable evolutionary longevity. Ancient origins and widespread conservation suggest the human Aβ sequence is highly optimized for its immune role.

Link: https://doi.org/10.3389/fnagi.2019.00070

The p53 protein sits at the intersection of aging and cancer. Too much p53 activity and cell is activity is shut down, cells are made senescent more aggressively, and this leads to accelerated aging. Too little p53 activity, and precancerous cells might survive to form an ultimately fatal tumor. This is a considerable oversimplification of a very complex set of systems, however. There are plenty of exceptions to the above rule, including examples of conditional upregulation of p53 in mice that both extends life and reduces cancer incidence. The open access paper here discusses some of the complexities and contractions in what is known of the role of p53 - a gene that is well studied, but not yet comprehensively understood.

To accelerate aging, p53 induces apoptosis or cell cycle arrest as a prerequisite to cellular senescence; both can impair the mobilization of stem and progenitor cell populations. To suppress aging, p53 inhibits unregulated proliferation pathways that could lead to cellular senescence and a senescence-associated secretory phenotype (SASP), which creates a pro-inflammatory and degenerative tissue milieu. A review of mouse models supports both possibilities, highlighting the complexity of the p53 influence over organismal aging. These models were originally designed to study cancer but some appear to impact aging and longevity as well. They range from complete p53 null mutations to truncations or point mutations that alter activity. A comparison of these models reveals the complex influence p53 has over organismal aging - which can be independent or a consequence of its tumor suppressor role.

The initial mouse models were simple knockouts that produced no p53 protein. Most p53-/- embryos developed into apparently healthy adults, almost all of which succumb to cancer in about half a year. Heterozygous (p53+/-) mice develop cancer at a later age. Since simple p53-deletion increases cancer, simple overexpression should reduce cancer. Indeed, mice harboring an extra p53 gene contained within a BAC (bacterial artificial chromosome) had a lower incidence of cancer with no obvious effect on aging. Furthermore, increased gene dosage of p53 together with Arf lowered the cancer incidence and improved overall survival. ARF elevates p53 levels by inhibiting MDM2. Similarly, mice with a hypomorphic MDM2 allele, which increased p53 levels, showed a reduced cancer incidence without deleterious side effects. Thus, enhanced p53-mediated cancer suppression was not toxic to adult mice. It is possible that the pro-aging side effects of p53 are manifest only when p53 overwhelms the many regulatory mechanisms that modulate its activity.

The p53-null and p53-elevated mouse models support a simple notion of function; that is, p53 suppresses cancer without toxic side effects. However, other p53-altered mouse models confound this notion. p53 levels influenced aging in mice defective for BRCA1. BRCA1 repairs DNA double strand breaks (DSBs) created during DNA replication as a part of the homologous recombination repair pathway. Deleting one copy of p53 rescued brca1-/- mice from embryonic lethality but these mice displayed an early aging phenotype. Moreover, decreased capacity to repair DSBs caused p53-dependent early cellular senescence in cells and early organismal aging. Another genetic alteration that implicates p53 in aging is REGγ. REGγ-deficient mice display early aging. Elevated p53 might contribute to this phenotype because REGγ is a proteasome activator that regulates p53. Finally, skin-specific MDM2 deficiency resulted in p53-induced senescence in epidermal stem cells and precocious skin aging. These examples are interesting contrasts to the MDM2 hypomorphic allele described above, which reduced cancer without side effects, and suggests that different aspects of p53 regulation, coupled with genetic and environmental variances, can drive distinct biological outcomes.

Further complicating the picture, there are multiple p53 isoforms and family members (p63 and p73) generated from variant promoter usage, alternative splicing, and alternative translation initiation. How these isoforms differ functionally is not fully understood. There is evidence that some of these isoforms could influence aging. For example, expression of the N-terminally truncated p53 isoform in mice lowered cancer risk at the expense of early aging. These mice showed poor tissue regeneration, implicating a defect in stem and progenitor cells. Supporting this possibility, old p53+/- mice exhibited increased levels of hematopoietic stem and progenitor cells, but not if N-terminally truncated p53 was present. The truncated p53 likely forms a tetramer with full-length p53 to improve stability and nuclear localization. Another isoform stabilized p53 in the presence of MDM2. Thus, p53 isoforms have the potential to influence p53 function in a manner that affects aging.

Link: https://doi.org/10.21037/tcr.2016.12.02

Alzheimer's disease is a condition that sits atop a mound of many contributing causes, layered in chains of cause and effect. Given that chronic inflammation and age-related impairment of the cellular housekeeping mechanisms of autophagy both appear to be significant, somewhere in the mix, it is perhaps to be expected that many of the usual healthy lifestyle choices have some modest impact on the progression of the condition. Exercise and calorie restriction both act to upregulate autophagy and it is thought that this accounts for a sizable fraction of the resulting benefits to health and life span. Unfortunately, the sort of stress response upregulation appears to scale down in impact on life span as species life span increases, though the effects on short term health and metabolism appear quite similar. Mice can live up to 40% longer when on a calorie restricted diet, but that is certainly not true for humans; we gain a few years at most.

Autophagy recycles damaged structures and broken proteins inside the cell. Neurodegenerative conditions such as Alzheimer's disease involve the presence of toxic molecules, such as those associated with amyloid-β and tau, but even if not directly involved in clearing away disease-associated damage, increased autophagy is generally protective of cell function. Given that this includes everything from neurons to the microglia responsible for clearing away intracellular debris and protein aggregates, we should expect increased autophagy to modestly improve just about every issue in the aging brain. Sadly, doing better than modest improvement is probably not within the scope of what might be achieved via increased rates of autophagy, even when researchers directly influence regulatory genes such as mTOR.

Physical Activity Alleviates Cognitive Dysfunction of Alzheimer's Disease through Regulating the mTOR Signaling Pathway

Autophagy as an evolutionary-conserved process can maintain normal physiological events or regulate the progression of a series of diseases through sequestering mis-folded/toxic proteins in autophagosomes, thus executing its cytoprotective role. Growing evidence demonstrates that autophagic capacity to degrade harmful proteins in cells declines with increasing age. Moreover, dysfunctional autophagy has also been linked to several aging-related neurodegenerative diseases including Alzheimer's disease (AD). Previous studies have documented the critical role of autophagy in the pathogenesis of AD, including amyloid-β (Aβ) production or deposition, Aβ precursor protein (APP) metabolism, and neuronal death. Furthermore, insufficient or reduced autophagic activity can lead to the formation of harmful protein aggregates, which results in increased reactive oxygen species (ROS), cell death, and neurodegeneration. As a result, autophagy has a crucial role in the regulation of longevity.

Mammalian target of rapamycin (mTOR) regulates a series of physiological processes. On the one hand, mTOR plays an important role in different cellular processes including cell survival, protein synthesis, mitochondrial biogenesis, proliferation, and cell death. On the other hand, the mTOR signaling pathway can execute an important role in memory reconsolidation and maintaining synaptic plasticity for memory formation, due to its regulatory function for protein synthesis in neurons. Moreover, mTOR also can interact with upstream signal components, such as growth factors, insulin, PI3K/Akt, AMPK, and GSK-3. Currently, although the molecular mechanisms responsible for AD remain unclear, more and more studies have confirmed the involvement of dysregulated mTOR signaling in AD. Activated mTOR signaling is a contributor to the progression of AD and is coordinated with both the pathological and clinical manifestations of AD. Furthermore, there is a close relationship between mTOR signaling and the presence of Aβ plaques, neurofibrillary tangles, and cognitive impairment in clinical presentation. Therefore, the development of mTOR inhibitors may be useful for the prevention and treatment of AD.

It has been reported that regular physical activity can improve brain health and provide cognitive and psychological benefits. Mechanically, regular exercise training is related to the inhibition of oxidative stress and apoptotic signaling, thus effectively executing neuroprotection. Previous studies have demonstrated that treadmill or voluntary wheel running is beneficial for the improvement of behavioral capacity, and can promote the dynamic recycling of mitochondria, thereby improving the health status of mitochondria in brain tissues. Moreover, other studies have demonstrated that regular exercise has a beneficial effect on the structure, metabolism, and function of human and rodent brains. Interestingly, our recent study has also documented that the brain aging of d-gal-induced aging rats can be noticeably attenuated by eight-week swimming training, due to the rescuing of impaired autophagy and abnormal mitochondrial dynamics in the presence of miR-34a mediation. Therefore, physical activity is regarded as an effective approach against AD.

The blood-brain barrier is a specialized layer of cells that wrap blood vessels passing through the central nervous system, ensuring that only certain molecules can pass in either direction. Thus the biochemistry of the central nervous system is kept distinct from that of the rest of the body. This separation is necessary for correct function, as illustrated by the point that the blood-brain barrier begins to break down with advancing age. This produces damage and dysfunction in the brain, as unwanted cells and molecules leak through the faulty blood-brain barrier. As noted here, however, the relative scope and size of this contribution to neurodegeneration, in comparison to other contributing factors, is far from fully determined.

Changes in the immune system have long been recognized to occur with aging, and it is now appreciated that neuroinflammation likely contributes to age-associated neurological diseases. However, it is less well understood how specific changes in the immune system with aging may affect central nervous system (CNS) functions and contribute to neurological disease. We posit that brain barriers, especially the blood-brain barrier (BBB) and blood-CSF barrier (BCSFB), are important interfaces between CNS and peripheral tissues that are affected by age-associated changes in the immune system. The BBB/BCSFB may, in turn, affect homeostatic functions of the CNS, and/or exhibit more detrimental responses to pathological stimuli.

One of the most-studied (and yet, poorly understood) aspects of BBB dysfunction is disruption, which is typically defined by the apparent leakage of normally BBB impenetrant molecules. Recent imaging results argue that BBB disruption does occur in healthy aging, and is worse in individuals with mild cognitive impairment, which is considered a prodrome of Alzheimer's disease (AD). One common approach to proxy BBB disruption in living humans is to measure the ratio of abundant, BBB-impermeant proteins such as albumin or immunoglobulin G (IgG) in cerebrospinal fluid (CSF) versus serum. However, these measures may be confounded by other known CNS deficits with aging, such as altered production and reabsorption of CSF, and inflammatory changes in the serum and CSF levels of these proteins. Further, there may be leakage of the BCSFB and altered protein synthesis at this site with age. Recent studies have implemented advanced imaging technologies that can visualize leakage of intravenously injected tracers via dynamic contrast MRI, and these have indicated that vascular BBB disruption does occur in the aging human brain, albeit at low levels.

In healthy aged mice, leakage of IgG into the parenchymal space of the cerebral cortex and hippocampus occurs when compared with young mice, suggesting that there is BBB disruption in this model. Increased IgG leakage in aged mice was associated with astrogliosis, endoplasmic reticulum (ER) stress, and increased endothelial cell levels of TNF-α; the latter measure significantly correlated with circulating levels of IL-6. In the same study, a significant reduction in occludin expression per brain endothelial cell was also observed in aged mice. Other studies have corroborated findings of BBB disruption in aging mice. Molecular mechanisms of BBB disruption in aging have been identified, and include reduced expression of sirtuin-1, a de-acetylase enzyme which has been implicated in the regulation of lifespan, senescence, and inflammatory responses to environmental stress.

BBB disruption in the context of aging or disease could result in disease exacerbation through leakage of potentially harmful proteins into the brain. However, it is not entirely clear that BBB disruption under any circumstance will always lead to brain damage. For example, certain therapeutic strategies for delivery of chemotherapeutics to the brain have relied on transiently disrupting the BBB, and are generally well-tolerated when brain cancers are the target. Recent work has also indicated that repeated transient BBB disruption in humans with AD using focused ultrasound did not cause any serious clinical or radiological adverse events. In contrast, healthy rodents with no prior brain abnormalities showed symptoms of reactive gliosis and neurodegeneration when transiently perfused with mannitol to cause widespread disruption of the BBB, and also had increased deposition of harmful serum proteins like fibrinogen in the CNS. The apparent paradox in efforts to disrupt the BBB as a therapeutic strategy versus BBB disruption having known adverse consequences on the CNS and associations with many CNS diseases highlights the complexities of BEC barrier functions that are likely nuanced and context-specific. Why BBB disruption in and of itself is apparently innocuous under some conditions, but clearly detrimental in others remains to be understood in greater molecular detail.

Link: https://doi.org/10.3390/ijms20071632

In recent years, with the enthusiastic adoption of accelerometers by the designers of epidemiological studies, it has become clear that even quite modest levels of physical activity correlate strongly with improved health and a slower pace of age-related degeneration. In most human data there is no way to establish which of these is cause and which of these is consequence, but animal studies are quite definitive on the point that exercise produces improvements in health, even if it doesn't appear to extend life span. Physical activity, like all interventions, has a dose-response curve, and there is a sizable difference between being sedentary and being even modestly active. It is still a better idea to be more than just modestly active, of course; research suggests that the recommended levels of exercise, 150 minutes per week, may well be too low.

Considerable evidence suggests that engaging in regular physical activity (PA) may prevent cognitive decline and dementia. Active individuals have lower metabolic and vascular risk factors, and these risk factors may explain these individuals' propensity for healthy brain aging. Even short-term exercise interventions have been shown to prevent hippocampal atrophy in older adults11 and may also improve brain connectivity. Furthermore, cross-sectional epidemiologic studies have established an association of physical inactivity with brain aging. However, further work is needed to pinpoint the optimal dosage of PA needed to promote healthy brain aging.

A growing body of literature has established light-intensity PA as an important factor for improving health outcomes, but in our review of the literature, light-intensity PA has not often been considered separately from total PA for its association with brain structure. Previous studies have identified positive associations of self-reported PA with brain volume, but accelerometry studies often have smaller sample sizes and have focused on examining the association of total PA with brain volume. However, PA variables are associated with one another, so in our analyses, we went a step further and modeled them together to determine what type of PA intensity (low or high) is driving the association of PA with brain volume.

The simplification of PA as a predictor variable has potentially masked more nuanced associations of components of PA with brain health. Compared with previous research, our study provides multiple PA levels and intensities and uses accelerometry-determined intensity thresholds (ie, light-intensity PA and moderate to vigorous PA) in the same statistical models to provide a more sensitive measure of PA doses and examine what type of PA is driving the associations we observe.

The study sample of 2354 participants had a mean age of 53 years, 1276 were women, and 1099 met the PA guidelines. Incremental light-intensity PA was associated with higher total brain volume; each additional hour of light-intensity PA was associated with approximately 1.1 years less brain aging. Among individuals not meeting the PA guidelines, each hour of light-intensity PA and achieving 7500 steps or more per day were associated with higher total brain volume, equivalent to approximately 1.4 to 2.2 years less brain aging. After adjusting for light-intensity PA, neither increasing moderate to vigorous PA levels nor meeting the threshold moderate to vigorous PA level recommended by the PA guidelines were significantly associated with total brain volume.

Link: https://doi.org/10.1001/jamanetworkopen.2019.2745

Artificial structures capable of replicating at least some of the functions of natural organs and tissues may turn out to be quite different in shape, structure, and content when compared to their natural counterparts. This is particularly true for chemical factory tissues, such as the liver, or tissues in which cells migrate and collaborate, such as lymph nodes. In today's research, scientists demonstrate that a comparatively simple structure can perform some of the same useful functions of a lymph node, at least those related to training and replicating T cells to attack a particular pathogen or cancer cell population.

Natural lymph nodes act as a point of coordination for the immune system, allowing cells to recognize threats and marshal in numbers to fight it. Unfortunately lymph nodes deteriorate and become fibrotic with age, and this degrades the immune response by preventing the necessary coordination between cells. It is a major concern for the many groups attempting to produce rejuvenation of the aged immune system in one way or another. It is interesting to consider that there may be shortcuts towards useful implanted structures in the near future, artificial constructs that are far removed from an actual tissue engineered replacement lymph node, but that nonetheless alleviate a part of this problem. The work here is a very early proof of concept carried out with the goal of replicating T cells more efficiently outside the body, but it could nonetheless be carried forward to potential use in implants.

Scientists Advance Creation of 'Artificial Lymph Node' to Fight Cancer, Other Diseases

n the past few years, a wave of discoveries has advanced new techniques to use T-cells - a type of white blood cell - in cancer treatment. To be successful, the cells must be primed, or taught, to spot and react to molecular flags that dot the surfaces of cancer cells. The job of educating T-cells this way typically happens in lymph nodes, small, bean-shaped glands found all over the body that house T-cells. But in patients with cancer and immune system disorders, that learning process is faulty, or doesn't happen.

CAR-T therapy generally takes about six to eight weeks to culture engineered T-cells in laboratories. To make the engineered T-cells' environment more biologically realistic, researchers tried using a jelly-like polymer, or hydrogel, as a platform for the T-cells. On the hydrogel, the scientists added two types of signals that stimulate and "teach" T-cells to hone in on foreign targets to destroy. In their experiments, T-cells activated on hydrogels produced 50 percent more molecules called cytokines, a marker of activation, than T-cells kept on plastic culture dishes.

Because hydrogels can be made to order, scientists created and tested a range of hydrogels, from the very soft feel of a single cell to the more rigid quality of a cell-packed lymph node. One of the surprising findings was that T-cells prefer a very soft environment, similar to interactions with individual cells, as opposed to a densely packed tissue. More than 80 percent of T-cells on the soft surface multiplied themselves, compared with none of the T-cells on the most firm type of hydrogel. "As we perfect the hydrogel and replicate the essential feature of the natural environment, including chemical growth factors that attract cancer-fighting T-cells and other signals, we will ultimately be able to design artificial lymph nodes for regenerative immunology-based therapy."

Engineering an Artificial T-Cell Stimulating Matrix for Immunotherapy

T cell therapies require the removal and culture of T cells ex vivo to expand several thousand-fold. However, these cells often lose the phenotype and cytotoxic functionality for mediating effective therapeutic responses. The extracellular matrix (ECM) has been used to preserve and augment cell phenotype; however, it has not been applied to cellular immunotherapies. Here, a hyaluronic acid (HA)-based hydrogel is engineered to present the two stimulatory signals required for T-cell activation - termed an artificial T-cell stimulating matrix (aTM).

It is found that biophysical properties of the aTM - stimulatory ligand density, stiffness, and ECM proteins - potentiate T cell signaling and skew phenotype of both murine and human T cells. Importantly, the combination of the ECM environment and mechanically sensitive TCR signaling from the aTM results in a rapid and robust expansion of rare, antigen-specific CD8+ T cells. Adoptive transfer of these tumor-specific cells significantly suppresses tumor growth and improves animal survival compared with T cells stimulated by traditional methods. Beyond immediate immunotherapeutic applications, demonstrating the environment influences the cellular therapeutic product delineates the importance of the ECM and provides a case study of how to engineer ECM-mimetic materials for therapeutic immune stimulation in the future.

Researchers here report on discovering that an existing farnesyltransferase inhibitor drug reverses the accumulation of altered tau protein aggregates in a mouse model. The death and dysfunction of nerve cells in the neurodegenerative conditions known as tauopathies is driven by the formation of neurofibrillary tangles, made of tau protein. That in turn has deeper causes, such as the chronic inflammation produced by senescent cells and disruption of immune cell activity in the central nervous system, one of which is no doubt being adjusted in some way by the action of the drug in this case. As in all such quite indirect mechanisms, there is the question as to whether results in mice will translate to humans in any useful way. In the case of an existing drug, there is at least a shorter path to an answer.

Tau, a protein found primarily in neurons, is typically a somewhat innocuous, very soluble protein that stabilizes microtubules in the axon. However, when soluble, stable tau misfolds the resulting protein becomes insoluble and tangled, gumming up the works inside the neuron as a neurofibrillary tangle. In one of several neurodegenerative diseases caused by tau, frontotemporal dementia, the frontal and temporal lobes of the brain are impaired, resulting in problems with emotion, behavior and decision-making.

By taking skin cell samples from a few individuals who harbor tau mutations and converting them in vitro into stem cells, and then into neurons, researchers found that three genes were consistently disregulated in those with tau mutations, one of which was of particular interest: RASD2 - a gene expressed primarily in the brain that belongs in a family that catalyzes energy-producing molecules (GTPases) and which has been studied extensively. A GTPase called Rhes is encoded by the gene RASD2. Like its cousins in the Ras superfamily, Rhes is a signaling protein that does its work on the cell surface, where it is attached to the inner membrane by a small carbon chain - a farnesyl group - through a process called farnesylation.

This attachment has been the target of a couple decades and millions of dollars of cancer research under the assumption that if the Ras protein connection to the cell membrane could be interrupted, so would the signals that cause unregulated growth of tumor cells and other cancer behaviors. The drugs in this category, called farnesyltransferase inhibitors, have been tested in humans. But, they did not work in cancer.

In mice models with frontotemporal dementia, however, it seems they do. And the results are dramatic. Using the drug Lonafarnib, the researchers treated mice who at 10 weeks were erratic - running around in circles or completely apathetic - and by 20 weeks they were sniffing around their cage or nest building and doing other normal mouse behaviors. Scans revealed the arrest of brain tissue deterioration and inflammation. Most dramatic: The once-insoluble neurofibrillary tangles were greatly reduced, and in some areas including the hippocampus - the memory part of the brain - were nearly completely gone. To prove the drug was targeting the farnsylated Rhes protein, the scientists introduced into the brains of other mouse models an inhibitory RNA gene that specifically suppresses the production of Rhes. And the results completely replicated the effects of the drug.

Link: https://www.news.ucsb.edu/2019/019394/dissolving-gordian-knot

While clearing out amyloid-β from the brain has so far proven to be a matter of too little, too late in late stage Alzheimer's disease patients, there is still a strong basis of evidence for the merits of removing amyloid-β. It is reasonable to say that it causes meaningful pathology; if people did not accumulate amyloid-β deposits, then there would be no consequent disarray in the function of neurons and immune cells in the brain. This particular foundation of the development of dementia would be removed. Even if the mechanisms of the later stages of Alzheimer's, the chronic inflammation and tau protein aggregation, for example, were blocked, then amyloid-β accumulation would still cause at least mild cognitive impairment on its own. Thus despite the continued failure of clinical trials, even those in which amyloid-β was in fact cleared to a fair degree from the brains of Alzheimer's patients, we should still be encouraged by new approaches and other signs of progress in this area of the field.

Present therapies for Alzheimer's disease (AD) have either no or minimal disease-modifying effect, and thus, there is an urgent need for new effective treatments. Numerous therapeutic strategies are under investigation to delay the onset or slow progression of the disease. Active and passive immunotherapeutic approaches have been suggested to improve clinical progression and cognitive impairment through different mechanisms: (i) inhibition of amyloid-β (Aβ) production; (ii) interference with the formation of toxic aggregation intermediates; and (iii) accelerated clearance of Aβ from the central nervous system into the periphery.

Several anti-Aβ antibodies have demonstrated effective clearance of Aβ together with cognitive improvements in transgenic animal models and consequently progressed to clinical trials. However, translation to safe and efficacious therapies for humans has been challenging as AD clinical trials have failed to show sufficient clinical benefits. Recently, the monoclonal antibody (mAb) Solanezumab, that binds monomeric Aβ, was extensively evaluated in a phase III prevention trial in patients with mild AD. The study was however terminated due to failure in showing cognitive improvements.

It has been proposed that challenges related to the failure in showing overall clinical improvement or clear disease-modifying results of these mAbs could be addressed to some of the inherent properties of antibodies. Thus, new approaches based on engineered antibody domains or alternative scaffold-proteins that generally lack immunoglobulin-related effector functions are now investigated and moving into clinical development, as they might provide safer and more effective treatments. Antibody derivatives and non-immunoglobulin affinity proteins are in general smaller than full-length antibodies. Their smaller size could potentially result in a different in vivo biodistribution profile as well as simplified administration routes, which could be important in the treatment of e.g., AD.

Affibody molecules represent a class of promising alternative scaffold proteins that have been investigated for various applications. We have previously reported on the generation of an affibody molecule (denoted ZAb3) that binds to monomeric Aβ. This Aβ-sequestering affibody molecule has demonstrated efficient inhibition of formation of Aβ aggregates in an in vivo Drosophila AD model, and abolished the neurotoxic effects as well as restored the life span of the flies. The affibody molecule was further engineered into a truncated genetic dimer, ZSYM73-ABD.

Encouraged by these positive results, we here investigate the efficacy of ZSYM73-ABD as a therapeutic candidate to prevent the development of AD-related pathology in transgenic AD mice. The animals received three weekly injections of 100 μg therapeutic protein or negative control protein during 13 weeks, starting at the expected onset of pathology development. Extensive behavioral assessment together with histological evaluation demonstrated a significantly lower amyloid burden in both cortex and hippocampus, as well as rescued cognitive functions of the ZSYM73-ABD treated mice relative to controls.

Link: https://doi.org/10.3389/fnagi.2019.00064

In today's open access paper and publicity materials, researchers report on an assessment of induced mesenchymal stem cells (iMSCs) derived from induced pluripotent stem cells (iPSCs). The iPSCs were produced via the usual approach of reprogramming from tissue samples taken from old adults. The researchers then compared the gene expression profiles of these iMSCs with similar MSCs taken from fetal and adult tissues. They declare the the profile to be rejuvenated in comparison to that of the adult MSCs, but I think one has to be careful when using that word. We might better call the profile reflective of reprogramming, in that while it has commonalities with the fetal MSCs, it also has has commonalities with the iPSCs, expression of proteins usually not found in adult cells.

The reason for attempting this experiment is that there are concerns regarding the safety and efficacy of MSCs derived from the tissues of old individuals, such as in the case of autologous stem cell therapies. These cells are damaged and in some ways notably dysfunctional, such as in the decline of mitochondrial function. If those cells could be derived instead from a skin sample and then via iPSCs, with many of their age-related defects corrected along the way, acquiring a more beneficial phenotype, then perhaps this would be a better option. The question is always whether or not this is just unsafe in a different direction, such as risk of cancer. A great deal of work is going into answer that question.

Reprogramming somatic cells into iPSCs clearly repairs a range of age-related phenotypes exhibited by cells in old tissues, most notably mitochondrial dysfunction. Moreover, these cells begin to secrete signals that on balance beneficial for regeneration, inflammation, and other aspects of cellular metabolism that become problematic in aging. Most stem cell transplants provided in clinics today work in this way, producing benefits due to the signals issues by the transplanted cells, which soon die rather than integrating into tissues. This signaling and damage repair are the basis for experimental work in inducing pluripotency in the tissues of living animals, and for advances on that work such as the epigenetic not-quite-reprogramming of Turn.bio.

Human iPSC-derived MSCs from aged individuals acquire a rejuvenation signature

The use of primary mesenchymal stem cells (MSCs) is fraught with ageing-related shortfalls such as limited expansion and early senescence. Human induced pluripotent stem cells (iPSCs) -derived MSCs (iMSCs) have been shown to be a useful clinically relevant source of MSCs that circumvent these ageing-associated drawbacks. A collaborative study analysed the acquisition of rejuvenation-associated hallmarks in iMSCs. In their study, the team compared cellular features, transcriptomes and secretomes of iMSCs differentiated from embryonic stem cells (ESCs-H1) and iPSCs, emanating from MSCs isolated young and elderly individuals. The generated iMSCs (irrespective of source) met the criteria set out for MSCs and dendrogram analyses confirmed that the transcriptomes of all iMSCs clustered together with the parental MSCs and distinct from pluripotent stem cells.

Irrespective of donor age and initial cell type, iMSCs acquired a rejuvenation-associated 50-gene comprising signature which is also expressed in pluripotent stem cells but not in the parental MSCs. Significantly, in terms of regenerative medicine, iMSCs acquired a secretome similar to that of primary MSCs, thus highlighting their ability to act via paracrine signalling. The iMSC concept has enabled circumventing the drawbacks associated with the use of adult MSCs and thus provide a promising tool for use in various clinical settings in the future.

Human iPSC-derived MSCs (iMSCs) from aged individuals acquire a rejuvenation signature

Primary human bone marrow-derived stem cells (MSCs) contain a sub-population of multipotent stem cells. Due to highly proliferative, immune-modulatory properties, and paracrine orchestration, MSCs offer significant therapeutic potential for an increasing aging demographic. Although the bone marrow can be collected routinely to isolate MSCs, there are several drawbacks associated with the use of MSCs from aged individuals. The expansion possibilities and application potential of primary MSCs are limited, in part, by changes in the differentiation/response potential and function of MSCs isolated from aged donors. However, to date, it remains unclear whether there are any age-related differences in transcriptome and secretome signatures between human fetal MSCs and MSCs from elderly donors.

Recent studies have shown that the shortfalls associated with primary MSCs can be circumvented by reprogramming them to induced pluripotent stem cells (iPSCs). An iPSC-derived cell type that is of prime interest for circumventing shortfalls associated with primary MSCs are MSCs differentiated from iPSCs and ESCs (iMSCs). The similarity of iMSCs to primary MSCs and their regenerative potential in vivo has already been demonstrated. Moreover, the reflection of donor age in iMSCs was shown to be reverted into a younger state and at the same time reflected in iMSCs from patients with early onset aging syndromes. Although the paracrine effects of iMSCs have been indicated, relatively little is known about the potential to rejuvenate the paracrine features of MSCs from elderly patients via iMSC generation.

In view of this, there is a dire need to clarify in more detail whether age-related features inherent to primary MSCs isolated from elderly patients are retained in the corresponding iMSCs at the transcriptional, secretome, and functional level. In this study, we report the age-associated differences between fetal MSC (fMSC) populations and MSCs isolated from elderly donors with respect to their transcriptomes. We successfully reprogrammed fMSCs (55 days post conception) and adult MSC (aMSC; 60-74 years) to iPSCs and, subsequently, generated the corresponding iMSCs. In addition, iMSCs were also derived from ESCs. The iMSCs were similar although not identical to primary MSCs. We unraveled a putative rejuvenation and aging gene expression signature. We show that iMSCs irrespective of donor age and cell type re-acquired a similar secretome to that of their parental MSCs, thus re-enforcing their capabilities of context-dependent paracrine signaling relevant for tissue regeneration.

It isn't long now until the Life Extension Advocacy Foundation will be hosting their second Ending Age-Related Diseases conference in New York City. The event takes place on July 11th and 12th this year, and features a mix of noted researchers, investors, and entrepreneurs involved in the present development of means to treat aging as a medical condition. Last year's conference was a great event for networking with new members of our growing longevity science and advocacy community, and video of the presentations can be found online.

Aging research is on the cusp of some major breakthroughs in the battle against age-related diseases, and we invite you to join us for an action-packed event filled with exciting talks and discussion panels featuring some of the leaders of aging research and the biotech business. We are still announcing more speakers for this exciting event and think that today is a great time to update everyone about what has been happening. We are delighted that Dr. Maria Blasco will be speaking at the conference this year. Dr. Blasco is a true pioneer in aging research, and her work with cancer and telomeres is well known.

Dr. João Pedro de Magalhães from Liverpool University has also just confirmed that he is going to be speaking at the event this year. Dr. Magalhães believes that the complexity and multi-dimensional nature of aging require that this biological problem be tackled using a combination of disciplines and approaches. He and his team have been conducting studies of the genetics, physiology, and cell biology of long-lived animals. He is perhaps best known for his genetic studies on long-lived species, such as the bowhead whale and the naked mole rat.

We will also be joined by Dr. Michael Lustgarten from Tufts University. Dr. Lustgarten is no stranger to us, as he has appeared in an episode of the Journal Club, a special microbiome webinar, and an interview with us. Dr. Lustgarten is a researcher at the Nutrition, Exercise Physiology, and Sarcopenia Laboratory (NEPS) at the Human Nutrition Research Center on Aging at Tufts. His research is focused on how the gut microbiome and serum metabolome affect muscle mass and function in older people. Dr. Lustgarten is an expert on the gut microbiome, exercise, biomarkers, and nutrition.

Link: https://www.leafscience.org/ending-age-related-diseases-conference-april-update/

Expression of the STAT3 gene influences a number of vital cellular processes, such as mitochondrial activity, cellular differentiation, and cellular proliferation. Researchers have investigated its activity in the context of spurring greater regenerative activity in heart muscles, for example. Arguably this is a good example of a regulatory gene that is involved in too many processes to make it a good target for therapeutics, however. More specific, lower-level mechanisms for specific desired goals would be helpful. That requires slow and costly investigative work, however, picking apart the relationships between proteins and their roles.

Researchers have uncovered a molecular signaling pathway involving Stat3 and Fam3a proteins that regulates how muscle stem cells decide whether to self-renew or differentiate - an insight that could lead to muscle-boosting therapeutics for muscular dystrophies or age-related muscle decline. "Muscle stem cells can 'burn out' trying to regenerate tissue during the natural aging process or due to chronic muscle disease. We believe we have found promising drug targets that direct muscle stem cells to 'make the right decision' and stimulate muscle repair, potentially helping muscle tissue regeneration and maintaining tissue function in chronic conditions such as muscular dystrophy and aging."

Muscle wasting occurs as part of the natural aging process, called sarcopenia, or due to genetic diseases such as muscular dystrophy. Sarcopenia affects nearly 10 percent of adults over the age of 50 and nearly half of individuals in their 80s. Muscle stem cells select between two fates over a person's lifetime: Either differentiate to become adult muscle cells or self-renew to replenish the stem cell population. Accumulating evidence shows that mitochondrial respiration is a key switch that drives muscle stem cells to differentiate, an energy-intensive process, instead of self-renew.

In the study, the scientists used mouse models to demonstrate that Stat3 promotes mitochondrial respiration. Because Stat3 regulates many cellular processes, the scientists combed through genes expressed during muscle growth to find additional proteins regulated by Stat3 that might serve as more specific targets. These efforts uncovered the protein Fam3a. Further work conducted, including generating a mouse model and cell lines that lack Fam3a, demonstrated that the protein is required for muscle stem cell differentiation and muscle growth. The researchers also showed that Fam3a is secreted by muscle cells during muscle repair, and treatment with the protein restored mitochondrial respiration and stem cell differentiation in muscle stem cells that lacked Stat3 - all demonstrating the integral role of Fam3a in determining muscle stem cells' fate.

Link: https://www.eurekalert.org/pub_releases/2019-04/sbpm-bms041519.php

The thymus is vital to the function of the adaptive immune system. It is where T cells mature after their creation as thymocytes in the bone marrow, acquiring the necessary tolerance and function to venture forth into the body and defend it against pathogens, cancerous cells, and senescent cells. Unfortunately the thymus declines in size with age, its active tissue replaced with fat, in a process known as thymic involution. The consequence of this is an ever smaller supply of new T cells, ready to tackle threats. The adaptive immune system becomes ever less functional as a result, its limited set of cells uselessly specialized to threats such as cytomegalovirus, and otherwise ever more damaged and dysfunctional, lacking replacements.

A broad spectrum of efforts in the research community are focused on reversing the loss of thymus tissue with age. Even just considering companies actively involved in development: Lygenesis is building thymus organoids to insert into patient lymph nodes; Intervene Immune is trying human trials with a mix of hormones that have had some effect in animal studies; and Repair Biotechnologies, founded by Bill Cherman and I, is working on FOXN1 upregulation via gene therapy. Looking back into the research community, there have been past efforts with recombinant KGF, which unfortunately doesn't seem to work in humans, interest in upregulation of BMP4, and more.

Which mechanisms are most important in the age-related portion of thymic involution? This appears quite different in cause and trajectory from the rapid, regulated loss of thymus tissue that occurs in the transition from child to adult. In today's open access paper, the authors suggest that the chronic inflammation of aging causes a quite specific disruption in processes essential to tissue maintenance in the thymus. In fact the thymus, by virtue of its comparative simplicity in structure, might be a good starting point for understanding in general how inflammation disrupts tissue maintenance throughout the body, accelerating the onset of degenerative aging and loss of function.

Cell-type-specific role of lamin-B1 in thymus development and its inflammation-driven reduction in thymus aging

Elevated proinflammatory cytokines in aging animals, including humans, have been shown to contribute to various organ dysfunctions and human diseases. Indeed, extensive studies in vitro have shown that proinflammatory cytokines can induce senescence of a number of tissue culture cells. For example, either overexpression of CXCR2 in human primary fibroblasts or treatment of these cells with IL-1α or TNF-α induces cellular senescence. These proinflammatory cytokines can also reinforce cellular senescence in other primary tissue culture cells triggered by forced oncogene expression. Despite these studies, however, the cell/tissue source of age-associated inflammation and whether such inflammation disrupts structural proteins and thus contributes to organ aging remain unclear in any organism.

Considering the varied environments different tissues/organs reside in and the different functions they perform, it is highly likely that the inflammatory causes and consequences are different in different tissues and organisms. Cellular senescence triggered by inflammation has been implicated in aging and organ degeneration in mammals. The multitudes of senescence-associated cellular changes have, however, made it difficult to pinpoint which of these changes makes a key contribution toward age-associated organ dysfunction. Additionally, vertebrate organs often contain complex cell types, which makes it challenging to identify the cell sources and targets of inflammation that contribute to organ aging. Among many organs, the vertebrate thymus has a relatively simple stromal cell population called thymic epithelial cells (TECs) that are essential for thymic development, organization, and function. The TECs can thus serve as a relatively simple model to understand how inflammation and cellular senescence could influence structural proteins and in turn contribute to organ aging.

As a primary lymphoid organ, the thymus produces naïve T cells essential for adaptive immunity. Differentiated from the Foxn1-positive progenitors, the TECs consist of cortical TECs (cTECs) and medullary TECs (mTECs) that make up the cortical and medullary compartments of the thymus, respectively. The age-associated thymic involution or size reduction is known to contribute to the dysfunction of the immune system. Studies in mice have shown that thymic involution can be separated into two phases. The first phase occurs within ~6 weeks after birth and is characterized by a rapid reduction of thymic size. This phase is referred to as the developmentally related involution and it does not negatively affect the immune system. The second phase of thymic involution occurs during the process of organism aging and is manifested as a gradual reduction of thymic size and naïve T-cell production. Foxn1 reduction in TECs soon after birth appears to contribute to the first developmental phase of thymic involution, but the cause of the second age-associated phase of involution is unknown.

Among the structural proteins, lamins, the major component of the nuclear lamina that forms a filamentous meshwork in the nucleus has been implicated in proper organogenesis. Interestingly, reduction of lamin-B1 is found in the aging human skins, Alzheimer's disease patient brains, and various Drosophila organs, but the cause of such reduction and its impact on organ function, especially in mammals, remain poorly understood. We show that of the three lamins, only lamin-B1 is required in TECs for the development and maintenance of the spatially segregated cortical and medulla compartments critical for proper thymic function. We identify several proinflammatory cytokines in the aging thymus that trigger TEC senescence and TEC lamin-B1 reduction. Importantly, we report the identification of 17 adult TEC subsets and show that lamin-B1 reduction in postnatal TECs contributes to the age-associated TEC composition change, thymic involution, reduced naïve T-cell production, and lymphopenia.

Epigenetic clocks are weighted combinations of the DNA methylation status of various locations on the genome, shown to reflect chronological or biological age. DNA methylation is an epigenetic marker involved in regulating the production of proteins from their blueprint genes, and these markers constantly shift in response to circumstances, a part of the feedback loop of cellular metabolism. Definitive references to the epigenetic clock, singular, usually mean the original clock established by Steve Horvath's team and called DNA methylation age. A fair amount of work has gone into characterizing the behavior of this clock, particularly the association of higher measured ages with age-related disease: as a general rule, at a given chronological age, people who manifest age-related disease tend to have a DNA methylation age that is higher than their chronological age. This is thought to reflect a faster pace of aging.

The challenge here is that no-one has a good idea as to what exactly these characteristic DNA methylation changes actually reflect, which underlying processes of aging cause them. Since the most important goal of any reliable metric of aging is to use it to assess potential rejuvenation therapies, and thereby greatly speed up the processes of development, this lack of knowledge is a problem. Researchers cannot be assured that any specific approach to rejuvenation will actually exhibit the desired lower DNA methylation age - there is no necessary reason for any specific cause of aging to be reflected in the chosen sites for DNA methylation. They could very well turn out to reflect just a few of the full spectrum of contributing processes of damage that lie at the root of aging.

There is considerable between-person variation in the rate of ageing, and individual differences in their susceptibility to disease and death. The identification of individuals at greatest risk of age-related diseases and death would provide important opportunities for targeting prevention and intervention. There is thus great interest in molecular targets as clinical biomarkers which accurately predict the risk of age-related diseases and mortality. These biomarkers, which include cellular senescence, genomic instability, telomere attrition, and mitochondrial dysfunction, appear to capture pivotal aspects of biological age and have been associated with a number of age-related diseases and mortality.

It is well established that as individuals age, there is a raft of molecular changes that occur within the cells and tissues. Changes in DNA methylation patterns have been shown to occur with ageing, and thus may be a fundamental mechanism that drives human ageing. Epigenetic biomarkers of ageing, otherwise known as the epigenetic clock, have been developed using DNA methylation measurements. Referred to specifically as 'DNA methylation age' (DNAmAge), they provide an accurate estimate of age across a range of tissues, and at different stages of life, and are some of the most promising biomarkers of ageing. DNAmAge has also permitted the identification of individuals who show substantial deviations from their actual chronological age, and this 'accelerated biological aging' has been associated with unhealthy behaviours, frailty, cancer, diabetes, cardiovascular diseases, dementia, and mortality risk.

An increasing number of studies have investigated the association between DNAmAge, longevity, age-related disease, and mortality, with a total of 23 studies included in this systematic review and all published from 2015 onwards. Our primary finding is that there is sufficient evidence to support an association between accelerated DNAmAge and an increased risk of all-cause mortality. However, it remains unclear whether these methylation changes at specific CpGs are driving ageing or are consequences of the ageing process (cellular ageing, underlying disease processes.

Link: https://doi.org/10.1186/s13148-019-0656-7

3-D bioprinting is a form of rapid prototyping adapted to the tissue engineering industry. Printers assemble tissues from ink containing cells and supporting materials of various types. Given a suitable recipe, the result is a functional tissue quite close to the real thing in structure and function. The interesting part of this open access paper is not that the team bioprinted small-scale model hearts as their proof of concept, given that these are not fully functional heart tissues capable of the electrical coordination required to exhibit a heart beat, and nor is it that they used materials personalized to a specific patient. Rather, it is that they demonstrate the ability to bioprint networks of small blood vessels sufficient to support the interior cells of a thick tissue.

This is an important advance, even given that it is not the full microvascular networks of capillaries found in natural tissue. This matter of blood vessels is a major challenge in the tissue engineering community. Cells need a supply of blood in order to survive, and that supply must be carried by blood vessels for any distance much over a millimeter. Finding a reliable way to incorporate blood vessel networks into tissues is the primary roadblock holding back construction of replacement organs, and it is why so much work today is focused on the production of tiny, thin organoid tissue sections.

Generation of thick vascularized tissues that fully match the patient still remains an unmet challenge in cardiac tissue engineering. Here, a simple approach to 3D-print thick, vascularized, and perfusable cardiac patches that completely match the immunological, cellular, biochemical, and anatomical properties of the patient is reported. To this end, a biopsy of an omental tissue is taken from patients. While the cells are reprogrammed to become pluripotent stem cells, and differentiated to cardiomyocytes and endothelial cells, the extracellular matrix is processed into a personalized hydrogel. Following, the two cell types are separately combined with hydrogels to form bioinks for the parenchymal cardiac tissue and blood vessels.

In recent years, the strategy of 3D tissue printing evolved, allowing the creation of vasculature within hydrogels. However, in most of the studies, the endothelial cells (ECs) that form the blood vessels were printed without the parenchymal tissue, which was later on casted on top of the vessels. In other pioneering works, the researchers were able to print ECs together with thin surrounding tissues. However, the obtained tissues were not thick, the ECs did not form open blood vessels and perfusion through them was not demonstrated. Different strategies include printing of the parenchymal tissue with open, a-cellular channels in between, followed by external perfusion of ECs to form the blood vessels. Finally, decellularized hydrogels were also used for printing nonvascularized tissues. Therefore, to the best of our knowledge, the aforementioned studies did not demonstrate printing of a full, thick vascularized patch in one step.

Here, we report on the development and application of advanced 3D printing techniques using the personalized hydrogel as a bioink. In this strategy, when combined with the patient's own cells, the hydrogel may be used to print thick, vascularized, and perfusable cardiac patches that fully match the immunological, biochemical and anatomical properties of the patient. Furthermore, we demonstrate that the personalized hydrogel can be used to print volumetric, freestanding, cellular structures, including whole hearts with their major blood vessels

Link: https://doi.org/10.1002/advs.201900344

It is undeniably the case that both diet and exercise influence the course of aging, though the size of the beneficial effect, even in the case of optimal lifestyle choices, is nowhere near as large as we'd all like it to be. Animal studies show calorie restriction extending maximum life span in mice by up to 40%, as well as lesser effects from various other forms of dietary strategy. Exercise meanwhile doesn't extend life span in mice, but does postpone age-related dysfunction and disease. Unfortunately, the effects on life span due to any of the strategies that are based on the metabolic effects of exercise and reduced calorie intake scale down as species life span scales up. These lifestyle choices upregulate stress response mechanisms, such as the cellular housekeeping systems of autophagy, resulting in more functional, less damaged cells. Yet calorie restriction, while extending mouse life span significantly, adds no more than a few years at most to human life spans.

That said, the beneficial effects of a good diet and regular moderate exercise are highly reliable, and they cost nothing beyond the time and willpower needed to introduce them into one's lifestyle. Modest, reliable, and free effects can be worth the effort. Just recognize that, at the end of the day, much more will be needed to avoid the same fate as every other human who has ever lived, aged, and died. We need the development of new biotechnologies capable of addressing the root causes of aging in order to live longer and in better health than can be provided via a good lifestyle. Only technology can purchase us additional decades of healthy life, or extend the human life span by more than a few years beyond its present limits.

Move more to live longer

The largest study to date of cardiorespiratory fitness in healthy people found that moving more is linked to living longer, regardless of age, sex, and starting fitness level. "People think they have to start going to the gym and exercising hard to get fitter. But it doesn't have to be that complicated. For most people, just being more active in daily life - taking the stairs, exiting the metro a station early, cycling to work - is enough to benefit health since levels are so low to start with. The more you do, the better."

The study included 316,137 adults aged 18-74 years who had their first occupational health screening between 1995 and 2015 in Sweden. Cardiorespiratory fitness was measured using a submaximal cycle test and expressed as maximal oxygen uptake (VO2 max) in ml/minute/kg body weight. This is the maximum amount of oxygen the heart and lungs can provide the muscles during exercise. You can estimate your VO2 max using either submaximal cycle tests, treadmill tests, or walking tests. Swedish national registries were used to obtain data on all-cause mortality and first-time cardiovascular events (fatal and non-fatal myocardial infarction, angina pectoris, or ischaemic stroke) during 1995-2015. The risk of all-cause mortality and cardiovascular events fell by 2.8% and 3.2%, respectively, with each millilitre increase in VO2 max.

Ability to lift weights quickly can mean a longer life

Power depends on the ability to generate force and velocity, and to coordinate movement. In other words, it is the measure of the work performed per unit time (force times distance); more power is produced when the same amount of work is completed in a shorter period or when more work is performed during the same period. Climbing stairs requires power - the faster you climb, the more power you need. Muscle power gradually decreases after 40 years of age. "We now show that power is strongly related to all-cause mortality. But the good news is that you only need to be above the median for your sex to have the best survival, with no further benefit in becoming even more powerful."

The study enrolled 3,878 non-athletes aged 41-85 years who underwent a maximal muscle power test using the upright row exercise between 2001 and 2016. The average age of participants was 59 years, 5% were over 80, and 68% were men. During a median 6.5-year follow-up, 247 men (10%) and 75 women (6%) died. Median power values were 2.5 watts/kg for men and 1.4 watts/kg for women. Participants with a maximal muscle power above the median for their sex (i.e. in quartiles three and four) had the best survival. Those in quartiles two and one had, respectively, a 4-5 and 10-13 times higher risk of dying as compared to those above the median in maximal muscle power.

Healthy diet helps older men maintain physical function

Researchers examined data from a total of 12,658 men from the Health Professionals Follow-Up Study, tracking them from 2008 to 2012. The team used criteria from the Alternate Healthy Eating Index-2010 to assess the quality of each of the men's diets and assign an individual score. These criteria included six food categories for which higher intake is better (vegetables, fruit, whole grains, nuts and legumes, long-chain omega-3 fatty acids and polyunsaturated fatty acids); one food category for which moderate intake is better (alcohol), and four categories for which lower intake is better (sugar-sweetened beverages and fruit juice, red and processed meats, trans fatty acids and sodium).

Researchers found that higher diet scores (meaning better diet quality) were strongly associated with decreased odds of physical impairment, including a 25 percent lower likelihood of developing impairment in physical function with aging. An overall healthy diet pattern was more strongly associated with better physical function than an individual component or food. But the team did see that greater intake of vegetables, nuts, and lower intake of red or processed meats and sugar-sweetened beverages each modestly lowered risk of impairment.

Regular physical exercise acts to slow the characteristic loss of muscle mass and strength that occurs with aging, a condition known as sarcopenia once it reaches the point of frailty. In this, strength training appears to work more effectively than aerobic exercise, but both have their place in the overall picture. In the paper here, researchers report on their assessment of proteomic changes with both aging and exercise. They find that, much as expected, the changes in protein levels that occur with age are largely opposed by the changes in protein levels caused by physical activity.

The decline in muscle strength is one of the most striking phenotypes of aging, which is only partially accounted for by a reduction in muscle mass, suggesting a loss of cellular and molecular integrity of muscle tissue, and/or impairment of neuromuscular control with aging. Low muscle strength is a powerful, independent predictor of slow gait, mobility disability, and early mortality. No interventions are currently available that can prevent or attenuate the decline in muscle strength with aging except exercise, especially resistance training. In spite of this evidence, the percentage of people who regularly exercise is still low and this percentage declines with aging.

It has been suggested that people who have an active lifestyle in daily life have a slower decline of muscle mass and strength with aging. Understanding how physical activity in daily life affects muscle physiology in older persons might help in developing new interventions that, by targeting the same mechanisms triggered by physical activity, could prevent the development of muscle impairment with aging. Numerous studies have investigated the impact of a sedentary lifestyle and low physical activity on health outcomes in both younger and older individuals. Physical inactivity, either long or short-term, negatively affects muscle performance and is associated with diminished aerobic capacity, as well as reduced insulin sensitivity and basal metabolic rate. Furthermore, physical activity alone has been shown to improve and regulate metabolic homeostasis and metabolic efficiency.

Overall, an active lifestyle could be conceptualized as a mixture of aerobic and resistance exercise, but the intermittent, and variable mixture of these activities make it difficult to study. Endurance and resistance training elicit both common and specific metabolic/morphologic adaptations in muscle, some of which are common between tissues. In general, the stress that is induced by exercise challenges energy homeostasis in myocytes, shifting the cellular environment towards an oxidative state. This induces microdamage that stimulates both transcriptional and posttranscriptional responses, which then promotes synthesis of specific proteins that seek to reestablish a different homeostatic equilibrium. Endurance training maximally stimulates mitochondrial biogenesis, enhances aerobic metabolism and fatty acid utilization, and produces change in muscle fiber composition. In contrast, heavy resistance training stimulates the synthesis of contractile proteins, leading to muscle hypertrophy, and increases in maximal contractile force speed and output. Whether an active lifestyle is sufficient to activate the same biological mechanisms triggered by endurance and resistance training is unknown.

In recent years, a handful of studies have examined the protein composition of human muscle cell types and tissues including proteomic differences between old and young muscle, athletes and non-athletes, exercise in extreme conditions, and physical activity and metabolic disorders. These studies have helped to characterize the physiological adaptations of healthy human muscle to different types of exercise. Most of these studies focused on the acute and immediate effects of short bouts of high intensity exercise in either human or mice/rat models, as well as long-term effects of exercise. However, very little research has focused on assessing the association of daily physical activity with the muscle proteome in healthy community-dwelling individuals.

To verify whether an active lifestyle is associated with detectable changes in skeletal muscle and to start to characterize these changes, we performed a quantitative, mass spectrometry-based proteome analysis of muscle specimens from a group of well-characterized healthy individuals with a wide age-range (20-87 years) and who self-reported different levels of physical activity. Independent of age and technical covariates, we found that high levels of physical activity (versus low levels) were associated with an overrepresentation of mitochondrial proteins, tricarboxylic acid (TCA) cycle enzymes, chaperone proteins, and proteins associated with genome maintenance. In contrast, proteins related to the spliceosome and transcription regulation, immune proteins, apoptosis proteins, DNA damage proteins, and senescent proteins were underrepresented in muscle of participants who reported higher physical activity. Differences observed were mostly opposite to those observed with skeletal muscle aging.

Link: https://doi.org/10.3389/fphys.2019.00312

There is no shortage of theorizing on the nature of aging: its biochemical causes; its evolutionary origins; how it progresses; how to measure it. In any era in which thinking is cheap and life science research is expensive, there will be a lot more theorizing than data. While the tools of biotechnology cost less than ever, and the price continues to fall even as capabilities increase radically, I think it arguably the case that we are still in the era of relatively cheap thought and relatively expensive research.

One area in which theory and modeling has over the years found its way to practical use in clinical medicine is in the construction of measures of aging based on a straightforward combination of measures, such as grip strength, markers of inflammation, and so forth. Geriatric medicine has and continues to make widespread use of these assessments of frailty. A great deal of work on measures of aging still takes place, as illustrated by the growth of epigenetic clocks on the one hand and more complex algorithmic combinations of simple health metrics on the other. The work here is an example of the latter, with the choice of metrics and their combination driven by a systems biology view of aging.

Even to the untrained eye it has always been apparent that different people age differently. Subjective evaluation of age rather accurately assesses the ravages of time and coincides quite adequately to more objective metrics. Nevertheless, we would like to be able to reference such objective measures to examine in greater detail the dimensions of aging. The dimensions of aging encompass at least three different aspects. The first incorporates prediction of survival or mortality. In other words, we want to be able to relate a process, aging, to an outcome, longevity. This has long been a domain of aging research, and it continues to engage biodemographers. The second attempts to relate an aging process to the ability to function. So-called healthy aging derives from this approach. Finally, the need to evaluate potential therapies or interventions to extend this healthspan is yet another dimension.

Deficit indices, also known as frailty indices, constitute an uncomplicated way in which to describe the behavior of a complex aging system. Deficit indices have a long history in human aging research and in geriatrics. A deficit index is constructed from a number of signs, symptoms, marks, and manifestations. The number can be relatively small, about twenty, or much larger, as long as it is statistically sufficient. These deficits should encompass many different body or physiological systems. The deficit index arises by summing the deficits counted and dividing by the total number of deficits assessed. Increasing the number of deficits scored improves deficit index performance.

Recently, the deficit index has acquired a strong theoretical underpinning. The deficits are represented by the components of a network, in which they can be damaged or undamaged (deficits per se). By definition, the components are connected by edges. Some of them have more edges than others, performing a more critical role in the network. Damage in this network, whether partial or complete, is propagated across the network or system because of the edges. This rational, systems biology-based nature of the deficit index distinguishes it from other quantitative measures of biological age. In addition, the deficit index is uncomplicated mathematically, as opposed to most of the other measures, and it predicts mortality without the incorporation of chronological age as one of its items.

We have constructed a deficit index we call frailty index-34 (FI34), consisting of 34 health and function variables. The reference to frailty in the name stresses the relevance of the index as a measure of relative health. FI34 is a good predictor of mortality, so it is a measure of biological age. It increases exponentially with calendar age, as we would expect of a predictor of mortality. Moreover, it distinguishes different patterns of aging, and it is heritable. FI34 also captures the individual variability or heterogeneity of aging among individuals. Although constantly increasing with chronological age across a population, it shows variation among individuals in cross-section and longitudinally.

Link: https://doi.org/10.3389/fgene.2019.00263

The Life Extension Advocacy Foundation (LEAF) volunteers were at the recent Undoing Aging conference in Berlin, and spent much of their time interviewing a selection of the attending scientists and entrepreneurs. The interviews are being published at the LEAF blog as they are made ready, and here I'll point out the latest. The research and development communities focused on treating aging are becoming very diverse. A wide range of activities are underway, driven by an equally wide range of views on the nature of aging and where best to intervene. Most work at the present time, well represented in these interviews, involves upregulation of stress responses, attempts to encourage greater stem cell activity, reduction in chronic inflammation, greater mitochondrial function, and other forms of overriding the regulation of aged metabolism, forcing it into a modestly better state.

As regular readers well know, I am strongly in favor of an alternative strategy, meaning a focus on the damage that causes aging. Striking as close to the root of aging as possible is the best path forward. That damage must either be repaired or made irrelevant, whichever of those two options turns out to be easier and faster in each specific case. If damage is removed, then the operation of metabolism will largely take care of itself. This should also be less challenging than any other approach: there are comparatively few root causes of aging and comparatively many downstream issues. Further, the causes are largely less complex than the forms of dysfunction and disease that result. Nonetheless, most present medical development initiatives attempt to compensate for the downstream issues of aging, and are thus both expensive and largely ineffective in the grand scheme of things. We need to do better than this if we are to live to see meaningful extension of healthy human life spans.

An Interview with Drs. Kelsey Moody and Huda Suliman of Ichor Therapeutics

Can you tell us what kind of things Ichor Therapeutics is going to be doing?

One of the challenges in the aging space is that the kind of underlying discovery work that usually drives translational pipelines is really lacking, because the space is just so new. If you're looking at molecular targets of cardiovascular disease, cancer, or things like that, a lot of these targets have been thoroughly vetted by academic institutions in the peer-reviewed literature, and you have some level of confidence that the thing that you're going after is actually an appropriate target. But, because the aging space is so new, there's lots of new targets that are being discovered, but there hasn't really been enough time for academia to properly vet those targets. Some of them are very good real targets that we should be going after, and others are artifacts and might not actually be real or as impactful as we think.

So, at Ichor, we started doing, a while ago, a lot of contract work to try to help other companies that need to bring industrial-grade rigor to basic science and to early discovery and then move from that early-stage discovery work into full-on development programs, which are more akin to a traditional pharmaceutical pipeline. That contract work has grown; we've helped a lot of companies and worked with a lot of clients, and we've run into a need to have dedicated teams for project management and really making sure that all of the client projects get plugged into the pipeline to get our best efforts and everything else, and that's where Huda's coming in and spinning out all of our contract research into Icaria Life Sciences.

An Interview with Dr. Steven Braithwaite of Alkahest

Why is Alkahest focusing on plasma proteins as a promising area for rejuvenation therapies?

Our founding science demonstrated that there are certain proteins present in plasma that can confer effects on biological function in aging. Their relation to the processes of aging is supported by the observation that many of these functional proteins increase or decrease with age - we have termed these functional plasma proteins chronokines. There are beneficial chronokines known to decline with age that we can increase and thus delay the onset of aging-related disorders, and there are detrimental chronokines which increase with age that we can inhibit for this purpose. We have therefore focused on deeply understanding the plasma proteome as a source of therapies, both plasma-based and traditional pharmaceutical modalities like small molecule inhibition.

An Interview with Dr. Joan Mannick of resTORbio

Why use rapalogs rather than just rapamycin? Is there actually good data showing that rapamycin in moderate doses is harmful to humans?

Our lead program is determining if TORC1 inhibition improves the function of the aging immune system and thereby decreases the incidence of respiratory tract infections (RTIs) in elderly humans. In a Phase 2a clinical trial, we found that RTB101, a catalytic site mTOR inhibitor (not a rapalog), led to a greater reduction in infection rates than the rapalog everolimus. We used very low doses of both RTB101 and everolimus in this trial, and both drugs were safe and well tolerated at these low doses.

When do you anticipate finishing clinical trials and being able to offer commercially available therapies for RTIs and other diseases that resTORbio is targeting?

We anticipate finishing two Phase 3 clinical trials, which will determine if RTB101 decreases the incidence of respiratory illness in people age 65 and older, in 2020. If the Phase 3 trials are successful, we anticipate submitting a New Drug Application.

An Interview with Prof. Jerry Shay of UT Southwestern

What do you think is the best method of measuring telomeres?

We call the most sensitive assay TeSLA, for telomere shortest length assay. Most scientists use a qPCR assay that is not very reliable but easy to use. It is well established that it is the shortest telomeres that leads to replicative senescence. There are thousands of published papers using the qPCR making extraordinary claims based on very small differences in average telomere length. Other methods include TRF and Q-FISH, and these are intermediate in their ability to see some but not all the shortest telomeres.

What are your thoughts on restoring telomere length using transient telomerase induction as a therapeutic approach to aging?

It is a reasonable idea, and we are currently doing such experiments. Initially, it will be done ex vivo, e.g. in the cell culture lab, to prove it works and does no harm. We can then give individuals back their own cells, potentially with slightly elongated telomeres.

Researchers here report on a demonstration in which they used electrostimulation to improve the working memory of old people to put it on a par with young people. It will be interesting to watch the investigation into the underlying mechanisms in the years ahead, though I expect it will be quite difficult to work backwards from such a non-invasive stimulus focused on brain waves, and into the underlying biochemistry of the brain.

Researchers have demonstrated that electrostimulation can improve the working memory of people in their 70s so that their performance on memory tasks is indistinguishable from that of 20-year-olds. The research targets working memory - the part of the mind where consciousness lives, the part that is active whenever we make decisions, reason, recall our grocery lists, and (hopefully) remember where we left our keys. Working memory starts to decline in our late 20s and early 30s, as certain areas of the brain gradually become disconnected and uncoordinated. By the time we reach our 60s and 70s, these neural circuits have deteriorated enough that many of us experience noticeable cognitive difficulties, even in the absence of dementias like Alzheimer's disease.

Researchers asked a group of people in their 20s and a group in their 60s and 70s to perform a series of memory tasks that required them to view an image, and then, after a brief pause, to identify whether a second image was slightly different from the original. At baseline, the young adults were much more accurate at this, significantly outperforming the older group. However, when the older adults received 25 minutes of mild stimulation delivered through scalp electrodes and personalized to their individual brain circuits, the difference between the two groups vanished. Even more encouraging? That memory boost lasted at least to the end of the 50-minute time window after stimulation - the point at which the experiment ended.

Coupling occurs when different types of brain rhythms coordinate with one another, and it helps us process and store working memories. Slow, low-frequency rhythms - theta rhythms - dance in the front of your brain, acting like the conductors of an orchestra. They reach back to faster, high-frequency rhythms called gamma rhythms, which are generated in the region of the brain that processes the world around us. But when the theta rhythms lose the ability to connect with those gamma rhythms to monitor them, maintain them, and instruct them, then the melodies within the brain begin to disintegrate and our memories lose their sharpness. Meanwhile, synchronization, when theta rhythms from different areas of the brain synchronize with one another, allows separate brain areas to communicate with one another. This process serves as the glue for a memory, combining individual sensory details to create one coherent recollection. As we age, our theta rhythms become less synchronized and the fabric of our memories starts to fray.

The present work suggests that by using electrical stimulation, we can reestablish these pathways that tend to go awry as we age, improving our ability to recall our experiences by restoring the flow of information within the brain. And it's not just older adults that stand to benefit from this technique: it shows promise for younger people as well. In the study, 14 of the young-adult participants performed poorly on the memory tasks despite their age - so the researchers called them back to stimulate their brains too. "We showed that the poor performers who were much younger, in their 20s, could also benefit from the same exact kind of stimulation. We could boost their working memory even though they weren't in their 60s or 70s. Coupling and synchronization exist on a continuum. On one end of the spectrum, someone with an incredible memory may be excellent at both synchronizing and coupling, whereas somebody with Alzheimer's disease would probably struggle significantly with both. Others lie between these two extremes-for instance, you might be a weak coupler but a strong synchronizer, or vice versa."

Link: https://www.bu.edu/research/articles/electrostimulation-can-improve-working-memory/

Disability adjusted life years (DALYs) are a statistical construct used in epidemiology to assess the harms caused by disease, particularly the chronic diseases of aging, as these are by far the greatest burden of disease that is inflicted upon the population as a whole. The costs of aging are huge, however they are measured. It is the greatest single cause of human suffering and death, and the economic effects of this constant destruction of human lives and capabilities are sized to match. The greatest good any of us can do in the world as it stands today is to work towards bringing aging under medical control.

Disability-adjusted life years (DALYs) are used globally to quantify the number of healthy years of life lost from the presence of a disease, disability, or injury. The burden of chronic, non-fatal health loss and early mortality is evaluated separately and compared across populations. More studies are needed for understanding how aging is linked with disease. Calculating the years lived with a disease (YLDs) and years of life lost (YLLs) from premature mortality will provide insights into the burden of common health conditions for the growing aging adult population. This information can help to identify which health conditions contribute most to the number of healthy years of life lost for aging adults, thereby informing how healthcare providers and interventions prioritize treatment and prevention efforts. The purpose of this study was to determine the burden of 10 common health conditions for a nationally-representative sample of middle-aged and older adults in the United States.

The principal findings of this investigation revealed that over 1-million years of healthy life were lost for middle-aged and older Americans from the 10 health conditions evaluated over the 16 year study period. Although aging adults were impacted by each health condition, hypertension accounted for the greatest burden; whereas, hip fractures had the lowest number of DALYs. There were 30,101 participants included. Sex stratified DALY estimates ranged from 4092 (fractured hip) to 178,055 (hypertension) for men and 13,621 (fractured hip) to 200,794 (hypertension) for women. The weighted overall DALYs were: 17,660 for hip fractures, 62,630 for congestive heart failure, 64,710 for myocardial infarction, 90,337 for COPD, 93,996 for stroke, 142,012 for cancer, 117,534 for diabetes, 186,586 for back pain, 333,420 for arthritis, and 378,849 for hypertension. In total, there were an estimated 1,487,734 years of healthy life lost from the 10 health conditions examined over the study period.

Link: https://doi.org/10.1186/s12877-019-1110-6

The institutions of the world are slowly waking to the potential of treating aging as a medical condition, thereby postponing, reversing, and ultimately entirely preventing age-related disease. The side-effect will be greatly extended lives, lived in good health, in youthful vigor. Aging is the accumulation of cell and tissue damage, and rejuvenation is the periodic repair of this damage. The research and development communities are only just starting on the road of damage repair in medicine. The first rejuvenation therapies, in the form of senolytic treatments to selectively destroy senescent cells, are only now emerging. They will make a sizable difference, far more than has been achieved by any other approach to medicine for age-related disease, but this is just the first step on a long road.

Alongside progress towards rejuvenation therapies and methods of modestly slowing aging, advocates for the treatment of aging have been working energetically at the task of steering the agendas at large research and medical institutions. This has been going on for something like two decades now. It is a slow process, but is finally starting to bear fruit, as illustrated by today's news regarding the recently established Healthy Longevity Global Grand Challenge organized by the National Academy of Medicine. That very conservative organizations are now willing to talk in public about treating aging, and the ability to significantly alter the trajectory of human aging, is a sizable advance over the state of affairs even as recently as a decade ago.

Yet there is more to accomplish: the representatives of these organizations are still unwilling to talk about extending human life spans, in good health, for as long as possible. They talk about healthspan and prevention of age-related disease, and skip over the point that, for so long as health is maintained, people will live for longer. Aging is damage, health is the absence of that damage. Extended life span and extended health are bound together; you can't have one without the other.

When radical life extension is not on the table as a goal, the inevitable result is that significant funding and attention goes towards projects that are capable of only small degrees of influence over aging. Take mTOR inhibitors, or metformin, or any of the other approaches to calorie restriction mimetics that upregulate stress responses, for example. These are an improvement over most older approaches to age-related disease, but that is a very low bar to pass. They are an exceptionally poor choice when compared with repairing the underlying damage that causes aging, such as by destroying senescent cells. But there is enormous enthusiasm for objectively worse strategies in the treatment of aging at the present time. I have to think that the mainstream rejection of the goal of adding decades or more of healthy life, extending the human life span far beyond its present limits, has something to do with this poor strategic prioritization.

National Academy of Medicine: Healthy Longevity Global Grand Challenge

Dramatic breakthroughs in medicine, public health, and social and economic development have resulted in unprecedented extensions of the human lifespan across the world over the past century. This triumph for humanity provides new opportunities as well as new challenges. Globally, we are facing a major demographic shift. Today, 8.5% of people worldwide (617 million) are aged 65 and over. By 2050, this percentage is projected to more than double, reaching 1.6 billion. The global population of the "oldest old" - people aged 80 and older - is expected to more than triple between 2015 and 2050, growing from 126 million to 447 million.

At the current pace, population aging is poised to impose a significant strain on economies, health systems, and social structures worldwide. But it doesn't have to. We can envision, just on the horizon, an explosion of potential new medicines, treatments, technologies, and preventive and social strategies that could help transform the way we age and ensure better health, function, and productivity during a period of extended longevity. Multidisciplinary solutions are urgently needed to maximize the number of years lived in good health and a state of well-being. Now is the time to support the next breakthroughs in healthy longevity, so that all of us can benefit from the tremendous opportunities it has to offer.

The National Academy of Medicine is launching a Global Grand Challenge for Healthy Longevity - a worldwide movement to increase physical, mental, and social well-being for people as they age. The initiative will have two components: a prize competition to catalyze breakthrough innovations from any field, and an evidence-based report authored by an international commission.

Johnson & Johnson Innovation Announces Collaboration with National Academy of Medicine to Help People Live Longer, Healthier Lives

Johnson & Johnson Innovation today announced the signing of a sponsorship agreement with the National Academy of Medicine (NAM) to be the principal corporate partner of the Healthy Longevity Catalyst Awards in the United States. Part of the Healthy Longevity Global Grand Challenge1 founded by the NAM, the Catalyst Awards are a global prize competition to launch later this year, designed to stimulate innovation to transform the field of healthy longevity. The program will culminate in one or more Healthy Longevity Grand Prizes for major breakthroughs in increasing human healthspan.

The NAM Grand Challenge will roll out over three distinct phases and employ a tiered model of awards and prizes to stimulate new research and solutions around healthy longevity. Under the agreement, Johnson & Johnson Innovation will provide funding for the foundational Healthy Longevity Catalyst Awards in the U.S., to identify innovative, entrepreneurial proposals that have the greatest chance of being translatable into solutions to prevent, intercept and/or cure disease or deficits related to aging. "We envision a world in which widespread disease is a historical artifact and people enjoy longer, healthier lives, promoted by technological and medical advances. To achieve this, we need to shift the paradigm from today's widespread focus on 'disease care' - where we wait for people to get sick, to only then do something about it - towards true health care, by keeping people well in the first place, eliminating disease and restoring people to full health."

The link between age-related kidney dysfunction and cognitive impairment is an interesting one, particularly in the context of research into klotho, which has functions in both the kidney and the brain, and has been shown to extend life and improve cognitive function in animal studies. It isn't completely clear as to which of these areas of the body is most important to the noted benefits to cognitive function in animal models, produced via various strategies for klotho overexpression. The most recent research on this topic tends to suggest that the mechanisms are indirect, involving many organ systems, rather than being a direct effect in the brain. Klotho in the brain might not be as important as initially thought.

The link between brain dysfunction and chronic kidney disease (CKD) was first noted in 1930, so it is not a new finding. Experts spoke of "dialysis dementia" or "uremic encephalopathy". What is new, however, is the finding that mild cognitive impairment (MCI) may already be present in earlier stages of CKD, affecting approximately one in two CKD patients (prevalence varies in studies between 30% and 60%). In contrast to "normal" dementia, CKD-related MCI is not age-related, meaning the cognitive impairment exceeds that expected of the normal aging process. It usually worsens with declining glomerular filtration rate (GFR) of patients - the lower the GFR, the higher the risk of being affected by cognitive impairments.

The pathogenesis appears complex, involving a variety of factors besides vascular disease - the most frequent trigger for "standard" dementia in elderly people. Dialysis does not help or stop the process of cognitive decline, thus experts believe that factors which are not corrected completely by dialysis, for example the clearance of middle molecules, uncontrolled secondary hyperparathyroidism and anemia, may further the process of cognitive impairment. One interesting finding, though, is that kidney transplantation appears to slow cognitive decline.

The paucity of intervention strategies is the reason why there is no routine screening for MCI in CKD patients. Cognitive decline is one of many manifestations of brain damage that clearly accompany the decline of kidney function. Other manifestations include sleep disorders and depression, both of which are also common in CKD patients. "Chronic kidney disease is an illness that obviously affects the body and the brain. The latter has been neglected by research, but new tools in neuroscience, such as tractography or two-photon microscopy hold out the promise of gaining further insights in the pathogenesis of MCI so that we might identify therapy targets and be able to treat it one day. Until then, we have to be aware that CKD is a severe disease which affects not only the kidneys, but also other organs systems and the brain - even in early stages. This is why we should strengthen CKD prevention strategies and raise awareness for this illness that is much more severe than most people think."

Link: https://www.eurekalert.org/pub_releases/2019-04/e-kdt041019.php

Researchers here use organoid models of tissue to recapitulate some of the epigenetic changes that occur in the bodies of old individuals, as a way to investigate how those changes alter the risk of cancer. There are of course numerous factors involved in the fact that cancer risk is age-related: rising levels of mutational damage; the above mentioned epigenetic changes that diminish protective anti-cancer mechanisms inside cells; inflammatory tissue environments that support the very early growth of precancerous cells; the declining ability of the immune system to find and destroy cancerous cells. Evidence suggests that the latter item, the aging of the immune system, is the most important factor over the course of the present human life span, but until the research community can repair or reverse that process, it will be hard to say in certainty.

Most cancers contain epigenetic and genetic alterations, but how they work together to cause cancer was not well understood. Researchers have found that epigenetic alterations characterized by changes in DNA methylation - a process by which cells add a tiny methyl group to a beginning region of a gene's DNA sequence, often silencing the gene's activation - are a key component of cancer initiation. In their laboratory model, known cancer-driving gene mutations did not cause colon cancers to form unless epigenetic methylation changes to the DNA were also present.

Cancer is primarily a disease of aging, with the majority of cancers occurring in people over age 60. To study colon cancer in the setting of aging, researchers used a mouse colon organoids derived from six- to eight-week old mice. Organoids are lab-grown cells that clump together and resemble specific normal organs, such as the colon in this case, and can grow indefinitely. The researchers compared colon organoids with and without mutations in the BRAFV600E, a known cancer-driving gene mutation common particularly to human right sided colon cancer. As the organoids aged, they remained genetically stable but became epigenetically unstable, even without the BRAF mutation being introduced. The scientists found that acquired DNA methylation during "aging" of the organoids, silenced cancer protective genes in a pattern similar to human aging that associates with risk for colon cancer by decade.

The team engineered the colon organoids to contain a transgenic BRAF mutation they could activate on demand. In all of the BRAF-activated organoids, DNA methylation was necessary for the mutation to initiate tumor development. Without this epigenetic change, the mutation did not initiate cancer in mice. "Essentially, we 'aged' young cells to become old, methylation-wise. In general, the risk of cancer increases with age, but if we can shift the epigenetic landscape through lifestyle changes to limit the impact of methylation fluctuations, we might be able to prevent cancer from developing. Although these studies were done to examine BRAFV600E-mediated tumorigenesis, we believe our findings apply to the cancer driver roles of other oncogenic mutations."

Link: https://www.hopkinsmedicine.org/news/newsroom/news-releases/johns-hopkins-researchers-create-novel-cell-model-of-aging-related-colon-cancer-risk

The practice of calorie restriction, a reduction of up to 40% below the usual ad libitum calorie intake, while still obtaining optimal levels of dietary micronutrients, is well known to slow aging and extend life in near all species and lineages tested to date. Calorie restriction produces sweeping changes in the operation of cellular metabolism, such as upregulation of a range of cellular stress responses, including the maintenance processes of autophagy. It also, however, has the obvious outcome of greatly reducing body fat, particularly the visceral fat that clusters around the organs of the abdomen.

Visceral fat tissue is metabolically active and quite harmful over the long term, so there is always the question of the degree to which the benefits of calorie restriction derive from loss of fat tissue versus upregulated autophagy and the like, and how that balance is different between species. Visceral fat tissue creates chronic inflammation via a variety of mechanisms: cell signaling that is similar to the results of infection; the immune response to debris from dead fat cells; increased numbers of senescent cells in fat tissue. Chronic inflammation then accelerates the development and progression of all common age-related disease. We can see this in the epidemiology of the obese and overweight, as these individuals suffer a shorter life expectancy, a greater risk of age-related disease, and higher lifetime medical costs, with these disadvantages scaling in size with ever greater excess fat tissue.

Yet, on the other hand, if autophagy is disabled through genetic manipulation, calorie restriction no longer functions to extend life span in mice. This data strongly argues for the primacy of upregulated cellular housekeeping over loss of visceral fat tissue as the primary driver of slowed aging via calorie restriction. Yet again, consider that researchers have also shown that surgical removal of visceral fat from mice has a significant effect on life span, though not as great as calorie restriction, which argues an opposite conclusion. It is a challenging phenomenon to investigate.

The open access paper noted here discusses another fat-related aspect of the calorie restriction response, which is to enhance the plasticity of fat deposits, their ability to transform from harmful to beneficial forms of fat tissue. Taken at the high level, white fat is harmful, while brown fat is beneficial - the real picture is somewhat more complex, but this will do as a starting point. As we age the browning of white fat is diminished, but calorie restriction helps to maintain this function, with consequent benefits to health over the long term, distinct from those related to the amount of fat present in the body.

Long-term caloric restriction ameliorates deleterious effects of aging on white and brown adipose tissue plasticity

Aging is associated with an increased risk of metabolic disorders such as obesity, insulin resistance (IR), and other manifestations of metabolic syndrome in both humans and rodents. In parallel with these alterations, a low grade of inflammation has also been described in several tissues associated with aging. Aging is typically associated with increased adiposity and redistribution of adipose tissue (AT), characterized by a loss of subcutaneous adipose depot mass and a gain of fat in the abdominal visceral compartment.

Caloric restriction (CR) is the most efficient intervention to delay the deleterious effects of age-related metabolic diseases. Previous studies in several animal models have shown that CR has physiological effects on lifespan, and reduces body weight and glucose and insulin serum levels. Whether CR interventions in humans slow aging is not yet known. Accumulating data indicate that moderate CR with adequate nutrition has numerous beneficial effects against obesity, diabetes, inflammation, and cardiovascular diseases. However, the mechanisms involved in the amelioration of aging effects by CR are not well understood. Accretion of AT has been related to the development of age-associated metabolic alterations such as IR. Moreover, reduction of adiposity by CR or fat removal have demonstrated to ameliorate age-associated IR. The improvement of the metabolic status achieved by CR may well be due, at least in part, to the decreased adiposity.

Furthermore, increased adiposity by hypertrophy and/or hyperplasia has been demonstrated to increase macrophage infiltration. This circumstance, together with changes in adipocyte physiology that includes hypoxia, reticulum, and oxidative stress, leads to an inflammatory state which is a key factor in the AT expandability capacity. Nevertheless, AT is a complex organ with different localizations and functions beyond its traditional role as a fat storage unit.

A complete understanding of CR effects on AT biology requires the elucidation of whether these effects are preferentially mediated by white AT (WAT) and/or brown AT (BAT), the contribution of specific WAT depots, and the relevance of differentiation/trans-differentiation to beige AT. WAT also has an important endocrine role by secreting different peptide hormones (adipokines) including adiponectin, which regulates insulin sensitivity, as well as glucose and energy homeostasis. In contrast to WAT, BAT plays a central role in energy expenditure via expression of uncoupling protein 1 (UCP-1). BAT is the major site for both cold- and diet-induced thermogenesis, and its atrophy has been observed in obese and older individuals in association with increased visceral fat and hyperglycemia. Consequently, defective WAT and BAT function may exacerbate the development of metabolic complications of obesity/aging.

Here, we aimed to investigate whether the plasticity of the WAT and BAT depots (hypertrophy and/or hyperplasia, extracellular matrix remodeling, inflammation, and browning or whitening capacity) is differentially affected at middle age, and whether moderate CR results in beneficial metabolic effects regulating the functionality of these AT depots. We show that several metabolic alterations of old animals are already being developed in middle-aged animals. These alterations include development of IR, altered WAT and BAT plasticity, as well as alteration of thyroid axis status, which can be mitigated, at least to some extent, by moderate and long-term CR.

As a companion piece to recent research on immune dysfunction in the central nervous system as the bridge between early amyloid-β and later tau pathology in Alzheimer's disease, here is a another recent discussion of work demonstrating cellular senescence to arise from amyloid-β aggregation in the brain. In this view of Alzheimer's disease, the primary reason why amyloid-β plaques set the stage for the later, much more harmful phase of the condition, is that the plaques cause cells to become senescent. These cells secrete a mix of inflammatory signals, and the consequent neuroinflammation and dysfunction of immune cells spurs aggregation of tau into neurofibrillary tangles. That in turn causes cell death, synaptic destruction, dementia, and death.

Fortunately, these new discoveries strongly suggest that senolytic therapies that can bypass the blood-brain barrier should be effective in treating Alzheimer's disease. Quite effective in comparison to any existing therapy, at least, which is admittedly a low bar to pass at this point in time. Nonetheless, given the robust results produced by senolytics for all of the other most common inflammatory conditions of aging in animal studies, we might be optimistic. Recent demonstrations in mice have shown reversal of neuroinflammation and tau pathology via the use of senolytic drugs, reinforcing this hope. We shall see how this progresses in humans in the years ahead.

A new study adds evidence that Alzheimer's disease (AD) pathology makes nearby cells senescent. Scientists now report that in both people and animals, oligodendrocyte precursor cells (OPCs) surrounding amyloid-β (Aβ) plaques stop differentiating into myelin-repairing oligodendrocytes. Instead, they release inflammatory molecules into their environment and leave damaged axons bare of myelin. Drugs that clear senescent cells - known as senolytics - eliminated senescent OPCs and reduced neuroinflammation, microgliosis, and Aβ load in transgenic mouse models of AD, all the while improving their learning and memory. The results tap senolytic drugs as a potential therapy for Alzheimer's disease.

Senescent cells are proliferative cells that have stopped dividing with age, usually after a certain number of divisions. They remain metabolically active, however, releasing proinflammatory cytokines. Senescent cells have been found to contribute to peripheral disorders, including diabetes, cancer, and atherosclerosis. Scientists have started asking whether senescent cells accumulate in the brain. Researchers found that neurons containing tangles had entered a senescent state in both postmortem AD brain tissue and rTg4510 mice. They reported that tau pathology caused senescence of astrocytes and microglia in PS19 mice. Both sets of researchers found that clearing away the aged cells prevented or slowed neurodegeneration and cognitive deficits in mice.

Do Aβ plaques bring about senescence in the brain? In the current study, researchers examined human postmortem tissue. In samples of the inferior parietal cortices of eight AD patients, eight with mild cognitive impairment, and eight age-matched controls, they used antibodies to label Aβ plaques, microglia, astrocytes, and OPCs. OPCs occur throughout the brain - even in gray matter where there are fewer myelinated axons than in white matter - and they migrate to sites of neurodegeneration to repair myelin there. In AD patients, OPCs co-localized with markers of senescence, namely tumor-suppressor proteins p16 and p21, in 80 percent of the plaques. Astrocytes and microglia did not appear to be senescent.

What if the researchers cleared senescent OPCs from mouse brains? Zhang treated APPPS1 mice with two FDA-approved senolytic compounds. Dasatinib and quercetin (D+Q) eliminate senescent cells from tissues by transiently inhibiting tyrosine kinases that suppress apoptosis, thus killing only senescent cells. Because it takes time for healthy, dividing OPCs to become senescent, the drugs can be given intermittently. In this way, treating 5-month-old APPPS1 mice for nine days halved OPC senescence. Once-weekly treatments for 11 weeks beginning at 3.5 months old almost eliminated senescent OPCs in the hippocampi of APPPS1 mice. These animals better remembered which arm they had previously explored in a Y maze and where the hidden platform was in a water maze. D+Q treated mice accumulated about one-third the Aβ plaque load and half the level of inflammatory cytokines in the hippocampus and entorhinal cortex, as untreated controls.

Link: https://www.alzforum.org/news/research-news/plaques-age-glial-precursors-stoking-inflammation

In most European countries, unlike the US, forming a single issue political party is an entirely viable approach to advocacy for a cause. It can work at any scale, even when starting with a few volunteers and a few hundred supporters. Examples of success and growth to the large scale include the various Green parties of the environmentalist movement, and the more recently established Pirate Party. The German Party for Health Research is a single issue party focused on raising awareness of work on the treatment of aging, and delivering greater support to that cause so as to speed up the clinical availability of therapies capable of slowing or reversing aging. These advocates have been active for a few years now, and continue their efforts even now.

What is the founding story and motivation behind the Party for Health Research?

In 2012 I learned that we have a chance to develop effective medicine against all diseases of old age in the near future. Because I think that this is so very important, I decided to make it to my life´s purpose to help with this development. The question I asked myself was, how I could most effectively do that. There are already non-profit organisations in this area, to which people can donate money to help this research directly and they do advocacy. I decided to also do advocacy, because in my opinion much more advocacy is needed. The more people know about this, the more support the movement will get. I decided to found a single-issue party with others, the German Party for Health Research (German name: Partei für Gesundheitsforschung).

The party is not only a very good way to do advocacy, but it also gives people an additional easy option, to support this cause by voting for the party in elections, by giving a support signature for the party's participation in the elections and by joining the party. One goal of our party is, that the big parties will also include our issue more into their program and they will probably only do that, if they would get votes for that. So the more votes we get the more likely it is. Unfortunately, our issue is ignored by most people, both by politicians and by the general public. Almost nobody actively demands more government investments in this field, e.g. there are no big demonstrations for more research against age-related diseases. By doing advocacy, we try to change that.

Why did you choose single-issue politics as the political action to follow in terms of battling aging-related diseases?

In my opinion, we need to educate much more scientists and have much more people doing research in this field to hasten the development of effective medicine against the diseases of old age significantly. All other political optimizations will not have the desired effect without this one. Our party only covers this one issue and no other issues. If a small party, who covers all issues, gets 2% and a big party gets 20%, the big party will have no reason to include the demands of the small party more into their program, because they would probably lose more votes than they would win. But if we manage to get 2% with our single issue, the big parties would have a very good reason to include our demand into their program, because almost nobody opposes more research against the diseases of old age, so they wouldn't lose any votes with that, only potentially win over some of our voters. With a single issue, everyone knows exactly, why people voted for us, and how extremely important our demand is for them.

What are the main points of your programme for the EU election?

We only have one point: We demand, that an additional 30 billion per year of the EU budget are invested into the development of effective medicine against the diseases of old age. To my knowledge at the moment only about 1 billion per year of the EU-budget are invested in the whole area of health research with no aim of the big parties yet to increase this amount significantly.

Link: http://longevitypolitics.global/interview-felix-werth/

The Life Extension Advocacy Foundation (LEAF) volunteers were out in force at the recent Undoing Aging conference in Berlin, networking and conducting interviews. The event was a who's who of the rejuvenation research and broader longevity science communities. These are in fact two different things: despite the growing focus on senolytics to clear senescent cells from aged tissues, work on methods of rejuvenation after the Strategies for Engineered Negligible Senescence (SENS) model of damage repair is still something of a minority concern embedded within a broader field that is much more concerned with stress response upregulation via calorie restriction mimetics and similar approaches. If the goal is an end to aging as soon as possible, then want to see more rejuvenation capable in principle of large, reliable gains in health and life expectancy, and less tinkering with metabolism that is only capable in principle of small, unreliable gains in health and life expectancy. In this context, it doesn't hurt that central, important events like Undoing Aging are organized by people with a strong rejuvenation focus.

LEAF will be publishing any number of interviews in the weeks ahead, and today's example is an interview with one of the hosts of Undoing Aging, Aubrey de Grey of the SENS Research Foundation. I feel that by now de Grey should require little introduction. For the past fifteen years or more, he has been one of the most vocal proponents of tackling aging as a medical condition, in particularly by developing therapies to repair, reverse, or work around the root causes of aging. Quite early on, de Grey assessed the literature and proposed a set of research programs that would tackle all of the forms of molecular damage and cell dysfunction that cause aging. This was an extensive work of synthesis, drawing together strands of research from throughout the life science community that had, up until that point, been given all too little attention. It has been a long road from the stage of a few voices in the wilderness to today's realization of the first actual, real, working rejuvenation therapies, in the form of senolytics. Nonethless, here we are, finally.

An Interview with Dr. Aubrey de Grey

How has SENS been progressing over the years, and what's going on right now?

The idea of comprehensive damage repair as a way to really bring aging under proper medical control and keep people useful much later in life has now become completely mainstream. It's been kind of reinvented by various groups over the past few years so that now it's kind of become the orthodox way of thinking. Moreover, the progress that's been made in the laboratory by, of course, us with our various projects, and also by other people, has got to the point where these projects have become investable. They've got to the point where people, perhaps not every investor, but at least the more visionary investors who are comfortable with high-risk, high-reward activities, are getting in there. They're seeing how to join the dots as a value proposition. The result is that we've, so far, over the past few years, been able to spin out half a dozen of our projects into startup companies and align in parallel with us. There's dozens and dozens more companies coming along literally once a week, now, it's ridiculous how rapidly, that are doing stuff that is very much rejuvenation, very much damage repair.

In terms of the seven deadly things that SENS plans to tackle, could you give us some examples of where we are specifically for each of them or some of them?

The best news at the level of SENS Research Foundation is that the most challenging, the most difficult components of SENS are now beginning to yield. We're really now seeing very significant, dramatic progress, albeit still early stage, but going much faster than it was even a couple of years ago. The ones that are slightly less hard, for example, the removal of molecular waste products inside cells, those things have gone far enough that they have become spin-off companies. We've got two companies created that way: we've got a company that's looking at the extracellular stiffening problem of restoring elasticity, and we've got a company looking at death-resistant cells, cells that are getting into a senescent state. This is all going amazingly well.

For the most difficult things, in which I will especially include mitochondrial mutations, we're now undisputedly the world leaders in these areas. These are lines of research that everyone had totally given up on to the point of being really certain that they were completely impossible and would never make progress. We just had the persistence to do enough to get there. It really is a great example of how the short term-ism that is imposed upon scientists by the system of science funding that exists worldwide has had an enormously damaging effect in stopping people from working on the most valuable work and forcing them to work on low-hanging fruit that doesn't scale.

As a final question, how do you like how the conference is going?

The main thing that I've got to say about this particular conference that blows my mind is the sheer number of people that are here. We have run conferences starting with my own conferences back in 2003. We've run lots and lots of them over the years, and they never grow; my first conference back in '03, had maybe 200, 250 people, and all the other ones that I ran, that series in Cambridge, were about the same, fluctuating by 20 or so. We were not seeing any increase in enthusiasm, and so on, resulting from the work that was being done. That was the same with the conferences that we ran in California in the period like 2014 through '17. It was also true for conferences that other people have run, they started but they're not grown.

Now, we may be just hitting that point where it's take-off time. Last year, the first time that the Berlin Conference happened, the first one in Europe in five years since my last conference in 2013 in Cambridge, and it was big. It was 300 people; that's on the high side. I thought, well, that's great, but it's probably just because I haven't done one in Europe for five years. I was thinking this year, they'll do really well to keep it at 300 people, and we sold out, which is 500 people; we literally were not allowed to bring any more people in because of the size of the venue and the fire regulations and so on.

Glial cells in the brain are a class of immune cell responsible for a wide range of supporting activities necessary to brain function, a great deal more than merely tackling pathogens and cleaning up metabolic waste. It is the ingestion and breaking down of metabolic waste in the brain, a process called phagocytosis, that is the focus of this open access paper, however. Neurodegenerative conditions, such as Parkinson's disease in this case, are largely characterized by the presence of solid deposits of misfolded or otherwise altered proteins. The capacity of glial cells to carry out phagocytosis of these protein aggregates is disrupted with advancing age, particularly by rising levels of chronic inflammation. It is suspected that this loss of function is a significant contribution to the progression of neurodegeneration. Recent studies showing that clearance of senescent glial cells produces significant benefits in animal models of neurodegeneration supports this line of thinking, but there is still much work to be accomplished in this area of study.

The clinical symptoms of Parkinson's disease (PD) reflect the underlying systemic neurodegeneration and protein deposition. A common denominator of both inherited and sporadic forms of PD is the loss of dopaminergic (DA) neurons of the substantia nigra pars compacta projecting to the putamen that control voluntary movements. Additionally, proteinaceous inclusions mainly composed by the protein α-synuclein (α-syn) are located in the perikarya (Lewy Bodies, LBs) and within the cell processes (Lewy neurites, LNs) of the surviving nerve cells.

Although less often discussed than neuronal pathology, α-syn-containing inclusions in astrocytes have been repeatedly detected in the substantia nigra, cerebral cortex and other brain regions in idiopathic PD samples. The density of α-syn immunoreactive astrocytes parallels the occurrence of LNs and LBs in neurons. Neuronal loss and the presence of cytoplasmic inclusions in neuronal and non-neuronal cells are also accompanied by reactive changes of astrocytes and microglia referred to as gliosis. Microglia as well as astrocytes are inflammatory cells that express immune-associated molecules including the major histocompatibility complex (MHC) class II, pro-inflammatory cytokines, and inducible oxide synthase (iNOS). Moreover, astrocytes become hypertrophic and accumulate the intermediate filament protein, glial fibrillary acidic protein (GFAP).

Although reactive glial cells and the upregulation of cytokines was found in the brains and cerebrospinal fluid of patients with PD, the role of neuroinflammation in the pathogenesis of PD is still undetermined. Neuroinflammation in PD has long been considered a downstream response to neuronal damage. However, alteration of glial physiological functions are emerging as causally linked to brain diseases. In the healthy brain, astrocytes maintain ion homeostasis of the microenvironment, provide structural and metabolic support, regulate synaptic transmission, water transport, and blood flow. Additionally, microglia continuously extend and retract their process to interact with neurons and other types of glial cells, including astrocytes.

Microglial phagocytosis (alongside other mechanisms, such as synaptic stripping and "trogocytosis") plays an important role in the engulfment of synaptic elements. Recent studies also revealed that astrocytes contribute to phagocytic clearance in a similar manner during normal physiological conditions and there is abundant evidence that microglia and astrocytes communicate with each other. It was further proposed that astrocytes can ingest aggregated proteins from the extracellular environment, suggesting that astrocytes keep, in coordination with microglia, the brain clean. Since the elimination of unwanted and potentially harmful matter is crucial for central nervous system (CNS) function, dysregulation of glial phagocytosis and degradation might have a key role in PD pathogenesis.

Link: https://doi.org/10.1186/s13024-019-0314-8

Alzheimer's disease progresses from the slow accumulation of amyloid-β plaques, that appear to cause comparatively mild dysfunction, to the accumulation of neurofibrillary tangles composed of altered tau protein, which cause major dysfunction and cell death in the later stages of the condition. Along the way chronic inflammation in brain tissue arises, along with dysfunctional behavior on the part of immune cells in the brain. As is the case in the open access review paper here, one can take these facts and suggest that amyloid-β deposition causes immune cell dysfunction, which in turn causes tau deposition. There is certainly evidence to support this view, such as the recent studies showing that clearance of senescent microglia turns back tau pathology and inflammation in animal models of Alzheimer's disease. This is probably just one of several lines of cause and consequence, however: Alzheimer's is a very complex condition.

Neuroinflammation is considered one of the cardinal features of Alzheimer's disease (AD). Neuritic plaques composed of amyloid β and neurofibrillary tangle-laden neurons are surrounded by reactive astrocytes and microglia. Exposure of microglia, the resident myeloid cell of the central nervous system (CNS), to amyloid β causes these cells to acquire an inflammatory phenotype. While these reactive microglia are important to contain and phagocytose amyloid plaques, their activated phenotype impacts CNS homeostasis.

In rodent models, increased neuroinflammation promoted by overexpression of proinflammatory cytokines can cause an increase in hyperphosphorylated tau and a decrease in hippocampal function. The peripheral immune system can also play a detrimental or beneficial role in CNS inflammation. Systemic inflammation can increase the risk of developing AD dementia, and chemokines released directly by microglia or indirectly by endothelial cells can attract monocytes and T lymphocytes to the CNS. These peripheral immune cells can aid in amyloid β clearance or modulate microglia responses, depending on the cell type.

The contribution of specific pro-inflammatory and anti-inflammatory factors in AD is not straightforward, especially since the evaluation of cognition, amyloid β pathology, and neurofibrillary tangles yields conflicting results in mouse models. Furthermore, translating rodent studies that have modulated expression of specific cytokines in the CNS is challenging. In addition, studies that have shown promise, such as the beneficial effects of pioglitazone in mouse models of AD, do not always prove effective in humans.

Nonetheless, the immune response is deeply tied to the development of pathology, and with advancing technologies, we are able to more fully dissect the complexity of this response and the effector cells that carry it out. Our knowledge of how microglia and peripheral immune cells interact has proved invaluable in understanding how this delicate balance goes awry in disease. Immunomodulation in AD offers multiple, promising pathways of investigation that might lead to therapeutics that can prevent or halt the development of amyloid and tau pathology and cognitive decline.

Link: https://doi.org/10.1186/s12974-019-1453-0

It is fair to say that the extended chemotherapy treatment that is provided to cancer patients has the side-effect of accelerating aging. On the one hand, we can look at the epidemiological data to see the reduction in life expectancy and increased risk of age-related disease suffered by cancer survivors who underwent chemotherapy. It is also possible to look at various aging-associated biomarkers and see that they indicate an older biological age in these former patients. With the modern acceptance of senescent cell accumulation as an important cause of aging, it has become clear that the generation of excess senescent cells by chemotherapeutics is most likely the primary cause of accelerated aging in chemotherapy patients.

Lingering senescent cells build up in tissues with age, and secrete a potent mix of inflammatory signals and other harmful molecules that rouse the immune system into chronic inflammation, disrupt tissue structure and function, and cause nearby cells to change their behavior for the worse as well. When treating cancer, forcing cancer cells into senescence is beneficial: they stop replicating, and most self-destruct. Chemotherapy is fairly indiscriminate, however, and adds to the burden of senescence throughout the body. These cells then go on to speed up the development of all of the common age-related diseases via chronic inflammation, fibrosis and other disruptions of tissue regeneration, and other mechanisms. This is better than dying of cancer, but certainly worse than having fewer senescent cells.

Today's open access study is just about the opposite of senolytic therapies to clear senescent glial cells in the brain could reverse neuroinflammation and tau protein aggregation in a mouse model of Alzheimer's disease. The late stages of this condition are marked by neurofibrillary tangles of hyperphosphorylated tau protein, and it seems likely that chronic inflammation, senescence, and dysfunction of other sorts in glial cells are an important mechanism bridging the gap between early accumulation of amyloid-β and later accumulation of tau protein in the progression of Alzheimer's. In the work reported here, researchers used a chemotherapeutic to general more senescent cells in mice, and showed that this accelerated aggregation of tau protein in the brain.

Chemotherapy accelerates age-related development of tauopathy and results in loss of synaptic integrity and cognitive impairment

More than 74% of the 15.5 million cancer survivors in the United States are 60 years old or older. Various reports suggest that 35%-85% of patients treated for cancer suffer from long term reductions in cognitive function, which include attention deficits, decreased executive functioning and multitasking, and decreased memory function. Neuroimaging data obtained in patients treated for cancer indicate that cognitive deficits in these patients are associated with changes in the functional connectome and in structure of the white matter. In at least a subset of cancer survivors, there is evidence for accelerated biological aging.

Aging increases neuronal vulnerability and is associated with buildup of damaged proteins that perturb neuronal circuits. During aging, conformational changes and post-translational modifications of tau protein, such as phosphorylation, result in dissociation of tau from axonal microtubules. These changes in tau lead to missorting and clustering of the protein, a process known as age-related tauopathy. Tauopathy is associated with the synapse loss and neuroinflammation that occur during aging, and is exaggerated in human Alzheimer's disease patients and in animal models of the disease.

Most studies on chemotherapy-induced cognitive impairment have been done in patients undergoing treatment for breast cancer. However, there is accumulating evidence that patients treated with platinum-based compounds for solid tumors including testicular, lung, bladder, and head and neck cancer also frequently develop cognitive deficiencies and structural abnormalities in the brain. Preclinical studies have shown that administration of chemotherapeutic agents, including cisplatin and doxorubicin to mice increases expression of cellular senescence markers. We and others showed that treatment of young adult rats or mice with these chemotherapeutics reduces their performance in cognitive function tasks and induces structural changes in the brain.

We hypothesized that chemotherapy-induced cognitive impairment is associated with accelerated development of tau clustering in the brain as a sign of accelerated aging. We show for the first time that treatment of adult (7-8 month-old) male C57BL/6 mice with cisplatin results in reduced cognitive function and a marked increase in the number of large endogenous tau clusters in the hippocampus when assessed 4 months later. In contrast, we detected only few small tau clusters in the hippocampus of age-matched 11-12 month-old control mice. Our current findings indicate that the chemotherapeutic cisplatin accelerates development of age-related tauopathy, identifying chemotherapy as one of the possible causes for the accelerated aging in cancer patients. Further studies should include additional chemotherapeutics and also investigate ways to prevent the development of tauopathy after chemotherapy in order to mitigate accelerated brain aging in patients treated for cancer.

The metabolic response to calorie restriction, a sustained reduction in calorie intake while maintaining optimal micronutrient intake, is sweeping and complex. It also extends life span quite dramatically in short-lived species. Near everything changes, which makes it a challenge to characterize the few important mechanisms early in the chain of cause and effect. It also makes it a very fruitful area of study from the pure science perspective, as there is always something new to be discovered, as illustrated by the research results reported here.

While calorie restriction itself is widely studied, and a good lifestyle choice in this modern world of cheap calories and their consequences, I remain unconvinced that the biochemistry of calorie restriction is the road to therapies capable of meaningful extension of the healthy human life span. The gain might be a few years, and better health along the way. This is not to be rejected if that were the outer limits of what is possible, but it is not. It is a poor strategy in a world in which we could plausibly gain decades of additional time in good health by focusing on repair of the damage that causes aging, rather than trying to pick apart the evolved responses to diet.

Calorie restriction (CR) is among the most robust ways to extend lifespan and delay age-related diseases in mammals. Considerable evidence indicates that cell nonautonomous factors, often driven by neuroendocrine signaling, play an essential role in mediating the life- and health-span enhancing effects of CR. Less is known about the specific hormone targets of these neuroendocrine factors that ultimately promote the health-enhancing CR state. CR lowers plasma concentrations of numerous anabolic hormones, including growth hormone (GH), insulin, and insulin-like growth factor 1 (IGF1), which may be contributors.

By contrast, glucocorticoids, which play a major role in responding to stressors, are elevated in CR animals, although again their roles have not be delineated. Glucocorticoids are anti-inflammatory, and attenuated inflammation is widely observed in CR animals. These observations have led to the hypothesis that the hyperadrenocorticism of CR contributes to the attenuation of inflammation in CR animals. Here, we tested this hypothesis directly using a corticotropin-releasing hormone knockout (CRHKO) mouse, which is glucocorticoid deficient and has increased inflammation following allergen exposure.

There were four control groups: CRHKO mice and wild-type (WT) littermates fed either ad libitum (AL) or CR (60% of AL food intake), and three experimental groups: (a) AL-fed CRHKO mice given corticosterone (CORT) in their drinking water titrated to match the integrated 24-hr plasma CORT levels of AL-fed WT mice, (b) CR-fed CRHKO mice given CORT to match the 24-hr CORT levels of AL-fed WT mice, and (c) CR-fed CHRKO mice given CORT to match the 24-hr CORT levels of CR-fed WT mice. Inflammation was measured volumetrically as footpad edema induced by carrageenan injection. As previously observed, CR attenuated footpad edema in WT mice. This attenuation was significantly blocked in CORT-deficient CR-fed CRHKO mice. Replacement of CORT in CR-fed CRHKO mice to the elevated levels observed in CR-fed WT mice, but not to the levels observed in AL-fed WT mice, restored the anti-inflammatory effect of CR. These results indicate that the hyperadrenocorticism of CR contributes to the anti-inflammatory action of CR, which may in turn contribute to its life-extending actions.

Paradoxically, hyperadrenocorticism is well known to be detrimental to health and lifespan. In humans, chronically elevated glucocorticoids are associated with insulin resistance and are the cause of Cushing's syndrome, a life-threatening disorder of glucocorticoid overproduction. Chronic elevation of CORT levels increases the risk of hypertension, hyperkalemia, diabetes, atherosclerosis, osteoporosis, glaucoma, and impairment of the immune and reproductive systems. Elevation of CORT damages hippocampal cells in rats, which in turn is associated with neurodegeneration and cognitive impairment in rodents.

However, all evidence for deleterious effects of hyperadrenocorticism occurs under conditions of ad libitum food intake. There is no evidence that the hyperadrenocorticism associated with CR is deleterious. The results of this study suggest that it may be beneficial - to the extent that resilience against inflammatory stressors is advantageous for the organism. These results not only suggest glucocorticoids are necessary for the anti-inflammatory actions of CR in mice but also buttress previous results that hyperadrenocorticism of CR may be involved in the retardation of aging by CR.

Link: https://doi.org/10.1111/acel.12944

Researchers here note that the bacteria associated with gum disease are found more frequently in the brains of Alzheimer's disease patients. While looking over this research, it is worth bearing in mind that a recent large study found only a 6% increased risk of dementia in patients with periodontitis. So rather than thinking that there is a very large contribution to the disease process here, we might consider an alternative model: that people with Alzheimer's disease may be more likely to have a leaky blood-brain barrier, allowing greater traffic of normally forbidden molecules, cells, and pathogens into the brain. Vascular dysfunction is common in Alzheimer's patients, many of whom also exhibit vascular dementia in addition to the signs and symptoms of Alzheimer's disease. Thus the infiltration of bacteria into the brain may be a consequence of underlying damage rather than a cause of it, and this bacterial infiltration, while being clearly associated with disease-related mechanisms, may cause only modest additional harm over and above the more direct consequences of that damage.

The bacterium, Porphyromonas gingivalis, is the bad actor involved in periodontitis, the most serious form of gum disease. While previous researchers have noted the presence of P. gingivalis in brain samples from Alzheimer's patients, new results offer the strongest evidence to date that the bacterium may actually contribute to the development of Alzheimer's disease. The researchers compared brain samples from deceased people with and without Alzheimer's disease who were roughly the same age when they died. They found P. gingivalis was more common in samples from Alzheimer's patients, evidenced by the bacterium's DNA fingerprint and the presence of its key toxins, known as gingipains.

In studies using mice, they showed P. gingivalis can move from the mouth to the brain and that this migration can be blocked by chemicals that interact with gingipains. An experimental drug from Cortexyme that blocks gingipains, known as COR388, is currently in phase 1 clinical trials for Alzheimer's disease. Researchers are working on other compounds that block enzymes important to P. gingivalis and other gum bacteria in hopes of interrupting their role in advancing Alzheimer's and other diseases.

The researchers also report evidence on the bacterium's role in the autoimmune disease rheumatoid arthritis, as well as aspiration pneumonia, a lung infection caused by inhaling food or saliva. "P. gingivalis's main toxins, the enzymes the bacterium need to exert its devilish tasks, are good targets for potential new medical interventions to counteract a variety of diseases. The beauty of such approaches in comparison to antibiotics is that such interventions are aimed only at key pathogens, leaving alone good, commensal bacteria, which we need."

Link: https://www.eurekalert.org/pub_releases/2019-04/eb-gbi032819.php

In today's research materials, the authors report on the use of follistatin-like molecules to enhance bone density and increase muscle mass in mice. Myostatin and follistatin are well known to control muscle growth, and are consequently among the most promising targets for near future gene therapies. Either inhibition of myostatin, which can be achieved via antibody therapies in addition to gene therapies, or upregulation of follistatin can be used to deliver increased muscle growth in mammals. There are natural myostatin loss of function mutants in many species, including a few humans, and a range of heavily muscled engineered lineages in mice, dogs, and the like. There is robust evidence for this alteration to be essentially beneficial, and it does in fact modestly increase life span in mice in addition to the direct benefits relating to muscle mass.

While additional muscle growth at any age sounds quite desirable, the main reason for considering this sort of therapy is to slow or perhaps turn back to some degree the characteristic loss of muscle mass and strength that occurs with advancing age. This happens to everyone, and is given the name sarcopenia. While targeting myostatin or follistatin seems likely to be effective to some degree, and reliably effective if the animal data is any guide, it doesn't address the underlying causes. It is a compensatory approach only, and even the highly effective compensatory approaches eventually run into the wall of ever-increasing molecular damage that overflows the mechanisms of compensation.

The interesting aspect of the line of work supporting the research noted here, which apparently dates back quite a few years, is that follistatin is just one point in a spectrum of potential molecules that can influence bone density in addition to muscle mass. The myostatin / follistatin gene therapies of the near future may turn out to deliver follisatin-like molecules into tissues rather than follistatin itself, these molecules tailored to specific outcomes in their bone or muscle development.

New medication gives mice bigger muscles

Researchers have studied a new group of medication which could prove beneficial for the elderly and the chronically ill who suffer a loss of bone- and muscle mass. They have named the group of medicinal products IASPs, Inhibitors of the Activin-receptor Signaling Pathway. IASPs inhibit a signal pathway which is found in virtually all cells. The difference between the various medications in the group is that they inhibit different routes into the pathway. The researchers have shown that it is possible to achieve an effect on different tissues such as muscle tissue, bone tissue, or blood cells depending on the IASP they used.

"We found an increased muscle mass of 19 per cent in mice after just one week. At the same time as an effect on the muscle mass, we saw that the drugs also counteracted osteoporosis." However, there is an Achilles heel. The effect on the blood cells has presented the researchers with a challenge. Thus far the drugs in the group of medicinal products have stimulated the formation of red blood cells. "This isn't bad if we're dealing with someone suffering from anaemia, low muscle mass, and osteoporosis all at once, as is the case for some. But for the majority of patients with a normal blood per cent, this increases the risk of blood clots." The researchers have therefore been working on a solution. They have succeeded in creating a molecule in the IASP group which for the first time works on bones and muscles but does not affect the blood.

A follistatin-based molecule increases muscle and bone mass without affecting the red blood cell count in mice

Inhibitors of the activin receptor signaling pathway (IASPs) have become candidate therapeutics for sarcopenia and bone remodeling disorders because of their ability to increase muscle and bone mass. However, IASPs utilizing activin type IIA and IIB receptors are also potent stimulators of erythropoiesis, a feature that may restrict their usage to anemic patients because of increased risk of venous thromboembolism. Based on the endogenous TGF-β superfamily antagonist follistatin (FST), a molecule in the IASP class, FSTΔHBS-mFc, was generated and tested in both ovariectomized and naive mice.

In ovariectomized mice, FSTΔHBS-mFc therapy dose-dependently increased cancellous bone mass up to 42% and improved bone microstructural indices. For the highest dosage of FSTΔHBS-mFc, the increase in cancellous bone mass was similar to that observed with parathyroid hormone therapy. The quadriceps femoris muscle mass dose-dependently increased up to 21% in ovariectomized mice. In both ovariectomized and naive mice, FSTΔHBS-mFc therapy did not influence red blood cell count or hematocrit or hemoglobin levels. If the results are reproduced, a human FSTΔHBS-mFc version could be applicable in patients with musculoskeletal conditions irrespective of hematocrit status.

An interesting discovery in the field of calorie restriction research is noted here: in a short-lived species, the offspring of older mothers benefit more from a restricted calorie intake. Now, these animals also have shorter life spans and impaired reproductive fitness. This suggests that they bear a greater load of molecular damage when born, which one might expect given what is known of both aging and the health effects observed with advanced maternal age observed in many species. Since calorie restriction upregulates cellular stress responses, leading to greater maintenance and repair activities, it may well work more effectively in those animals with more damage and dysfunction to stave off. There may well be no practical outcome in human medicine that results from this finding, but it is intriguing.

There has been evidence for well over a century, from experiments done in a wide variety of animal species and from data in humans, that offspring from older mothers have shorter lifespans and lower rates of reproduction, but it wasn't well understood how a mother's age might affect other aspects of her offspring's health or response to interventions. Using rotifers, researchers studied the effects of maternal age on offspring aging and their response to dietary changes. In their experiments, they fed mother rotifers a regular diet. They then studied the offspring from young (about three days old), middle-aged, and advanced-aged (about nine days old) mothers. The offspring were fed one of three different diets: constant high food, constant low food, or alternating between high food and fasting every other day.

"These calorie-restricted and intermittent-fasting diets are known to significantly increase lifespan in rotifers and many other species, "Our study confirmed that offspring from older mothers have shorter lifespans and lower reproductive rates than offspring of younger mothers. However, offspring of older mothers, we found, have a greater increase in lifespan in response to caloric restriction than do young-mother offspring." In the offspring born from older mothers, the decreased lifespan seemed to be due to an earlier onset of aging. This early onset was delayed when those offspring were subject to caloric restriction. Even though offspring from older mothers responded more positively to caloric restriction, it did not improve their overall fitness. In evolutionary terms, "fitness" takes into consideration both lifespan and rates of reproduction. For old-mother offspring on caloric restriction or full food diets, the window for reproduction was shortened and they had half as many offspring - only 14-15, instead of the average of 25 to 30 for young-mother offspring. Caloric restriction did not rescue reproduction.

Link: https://www.mbl.edu/blog/offspring-of-older-mothers-are-more-responsive-to-aging-interventions-study-finds/

The NIA Interventions Testing Program (ITP) is a very conservative organization. The organizers take compounds that cannot possibly do more than slightly slow aging, largely those that upregulate stress response mechanisms in a similar way to calorie restriction, and rigorously test them in large mouse studies. The results are of the best quality, and tend to demonstrate that most earlier, less rigorous studies overestimated the effects of compounds on life span. This is an expensive business, but I would say one of dubious practical value.

The practice of calorie restriction shows us the likely bounds of the possible when it comes to upregulating stress responses in humans. It is not the road to large increases in human life span; calorie restriction, while improving health noticeable, doesn't add more than a few years to life span in our species. This is despite extending mouse life span by up to 40%. Upregulation of stress responses has evolved to have a much larger effect on life span in short-lived species. So when we see results in mice on the order of 5% extension of life span in the ITP study noted here, one can expect it to have absolutely no detectable result at all in humans.

The NIA Interventions Testing Program (ITP) has to date reported on four drugs with consistent major effects on mouse lifespan in one or both sexes and found evidence for significant but less dramatic effect of four other drugs. Rapamycin, started at 9 months of age, was found to increase median lifespan by as much as 26% in females and 23% in males. Acarbose can lead to an increase of 22% in median lifespan in male mice, and to a significant, but smaller, 5% increase in female mice. A third drug, 17-α-estradiol (17aE2), a nonfeminizing congener of the well-known estrogen 17-β-estradiol, increases lifespan of male mice by 19%. Lastly, NDGA (nordihydroguaiaretic acid) has been shown to increase lifespan of male mice only, with an increase of 12% in median lifespan. Of the other agents tested so far by the ITP, four (methylene blue, aspirin, Protandim, and green tea extract [GTE]) provided some evidence for possible health benefits.

Diets low in the amino acid methionine have been shown to extend median and maximum lifespan in rats. Glycine plays a special role in methionine metabolism, serving as the only acceptor for methyl groups, through action of glycine-N-methyl transferase (GNMT), the key enzyme in the only pathway for methionine clearance in mammals. Methionine toxicity can be blocked by dietary glycine, consistent with the notion that GNMT is the principal effector of methionine clearance, at least at toxic levels. These data suggest that excess dietary glycine might depress methionine levels and thus mimic some of the benefits of a low methionine diet.

We therefore evaluated the effects of an 8% glycine diet on lifespan and pathology of genetically heterogeneous mice in the context of the Interventions Testing Program. Elevated glycine led to a small (4%-6%) but statistically significant lifespan increase, as well as an increase in maximum lifespan, in both males and females. Pooling across sex, glycine increased lifespan at each of the three independent test sites. Glycine-supplemented females were lighter than controls, but there was no effect on weight in males.

Link: https://doi.org/10.1111/acel.12953

The accumulation of senescent cells in all tissues throughout the body is one of the causes of aging. These errant cells are never present in enormous numbers relative to non-senescent cells that make up the overwhelming majority of tissues even in very old people. Yet they cause significant harm. Senescent cells secrete a mix of inflammatory signals that disrupts tissue structure and function, and provokes a state of chronic inflammation that further contributes to the progression of age-related disease. Much of this signaling, as for any cell type, is carried via extracellular vesicles, membrane-bound packages of molecules that pass between cells.

In recent years, a great deal of attention has been given to the secretion of vesicles and their effects on recipient cells. One strong motivation for this work is that vesicles they are comparatively easy to harvest and use in comparison to the cells that create them. Many first generation stem cell therapies, those that produce therapeutic effects via signals delivered by the transplanted cells in the short time before they die, might be replaced with delivery of vesicles, which is logistically a much easier form of treatment.

In the case of senescent cells, researchers are investigating secreted vesicles and their contents to better understand exactly how these cells contribute to age-related disease, at the very detailed level of molecular interactions. This work is largely disconnected from efforts to destroy senescent cells via senolytic treatments, however: the development community doesn't need to understand how senescent cells cause harm in order to prevent them from causing harm. This is an important aspect of much of the present development of rejuvenation therapies, in that the mode of treatment effectively bypasses the lack of scientific knowledge regarding exactly how specific mechanisms of aging progress in detail.

Senescence cell-associated extracellular vesicles serve as osteoarthritis disease and therapeutic markers

Osteoarthritis (OA) is an age-related and posttraumatic degenerative joint disease that is accompanied by cartilage degradation, persistent pain, and impairment of mobility. Senescent cells (SnCs) are a newly implicated factor in the development of OA. Cellular senescence is characterized by a proliferation arrest, which protects against cancer, as well as other changes that can also contribute to aging phenotypes and pathologies. SnCs accumulate with age in many tissues, including articular cartilage, where they promote pathological age-related deterioration.

These and other tissue pathologies are presumably mediated by the secretion of extracellular proteases, proinflammatory cytokines, chemokines, and growth factors, termed the senescence-associated secretory phenotype (SASP), by SnCs. The local elimination of SnCs in a murine model of posttraumatic OA (PTOA) reduced pain and increased cartilage development. Bridging these results to human cells, the selective removal of senescent chondrocytes improved the cartilage-forming ability of chondrocytes isolated from human arthritic tissue. Recent findings suggest that SnCs can transmit limited senescent phenotypes to nearby cells, termed secondary or paracrine senescence. Understanding the mechanisms of this SnC transmission may inform mechanisms of OA disease causation.

Extracellular vesicles (EVs), including exosomes and microvesicles, are small membrane-limited particles that can participate in intercellular communication. EVs mediate local tissue development and homeostasis through the transfer of cargoes, such as proteins and microRNAs (miRs). For example, the EVs present in articular cartilage and synovial fluid can contribute to mineralization of the cartilage extracellular matrix (ECM) and formation of an inflammatory joint environment. Recently, it was reported that SnCs secrete more EVs compared with their nonsenescent counterparts. These senescent-associated EVs may also induce senescence in neighboring cells. In the case of arthritis, SnCs can modulate the environment of the articular joint, increasing inflammation and ECM degradation. It is not known whether EVs secreted by SnCs in the articular joint are responsible for the progression of OA or whether they can be use as indicators of disease progression and treatment efficacy.

In this study, we found that senescent chondrocytes isolated from OA patients secrete more EVs compared with nonsenescent chondrocytes. These EVs inhibit cartilage ECM deposition by healthy chondrocytes and can induce a senescent state in nearby cells. We profiled the miR and protein content of EVs isolated from the synovial fluid of OA joints from mice with SnCs. After treatment with a molecule to remove SnCs, termed a senolytic, the composition of EV-associated miR and protein was markedly altered. The senolytic reduced OA development and enhanced chondrogenesis, and these were attributable to several specific differentially expressed miRs (miR-30c, miR-92a, miR-34a, miR-24, miR-125a, miR-150, miR-186, and miR-223) and proteins (Serpina and aggrecan). In aged animals, treatment with senolytic modulated the inflammatory response by decreasing recruitment and activation of myeloid and phagocytic cells. Collectively, these findings suggest that altered levels of synovial EV miRs and proteins are a potential mechanism by which SnCs can transfer senescence, inhibit tissue formation, and promote OA development. When isolated from synovial fluid, EVs may also be used to predict therapeutic response to senolytic therapies in the articular joint.

In this interview, Aubrey de Grey of the SENS Research Foundation discusses the present state of rejuvenation biotechnology. The first rejuvenation therapies now exist, these being the various methods of selectively removing senescent cells that de Grey and others called for back in 2002. The world is finally catching up to the vision of rejuvenation therapies that our community has advocated for more than fifteen years. Now that we are finally here, there is, if anything, even more work to be accomplished than was the case in past years. The funding for clinical development exists, but it is still true that many lines of work relevant to rejuvenation are moving too slowly in the laboratory, or in the transition to for-profit development. There is much left to do if we are to build the means of radical life extension in our lifetimes.

Can you compare 2018 to 2017 or early years? What is changing?

2018 was a fantastic year for rejuvenation biotechnology. The main thing that made it special was the explosive growth of the private-sector side of the field - the number of startup companies, the number of investors, and the scale of investment. Two companies, AgeX Therapeutics and Unity Biotechnology, went public with nine-digit valuations, and a bunch of others are not far behind. Of course this has only been possible because of all the great progress that has been made in the actual science, but one can never predict when that slow, steady progress will reach "critical mass".

In 2017 SENS RF have received about $7 million. What has been accomplished in 2018?

We received almost all of that money right around the end of 2017, in the form of four cryptocurrency donations of $1 million or more, totalling about $6.5 million. We of course realised that this was a one-off windfall, so we didn't spend it all at once! The main things we have done are to start a major new project at Albert Einstein College of Medicine, focused on stem cell therapy for Alzheimer's, and to broaden our education initiative to include more senior people.

What breakthroughs of 2018 can you name as the most important by your choice?

On the science side, well, regarding our funded work I guess I would choose our progress in getting mitochondrial genes to work when relocated to the nucleus. We published a groundbreaking progress report at the end of 2016, but to be honest I was not at all sure that we would be able to build quickly on it. I'm delighted to say that my caution was misplaced, and that we've continued to make great advances. The details will be submitted for publication very soon.

You say that many rejuvenating therapies will work in clinical trials within five years. Do you mean first - maybe incomplete - rejuvenation panel, when you speak on early 2020?

Yes, basically. SENS is a divide-and-conquer approach, so we can view it in three overlapping phases. The first phase is to get the basic concept accepted and moving. The second phase is to get the most challenging components moving. And the third phase is to combine the components. Phase 1 is pretty much done. Phase 2 is beginning, but it's at an early stage. Phase 3 will probably not even properly begin for a few more years. That's why I still think we only have about a 50% chance of getting to longevity escape velocity by 2035 or so.

Is any progress in the OncoSENS program? Have you found any alternative lengthening of telomeres (ALT) genes? Is there any ongoing research in WILT?

No - in the end that program was not successful enough to continue with, so we stopped it. There is now more interest in ALT in other labs than there was, though, so I'm hopeful that progress will be made. But also, one reason why I felt that it was OK to stop was that cancer immunotherapy is doing so well now. I think there is a significant chance that we won't need WILT after all, because we will really truly defeat cancer using the immune system.

Link: https://medium.com/@arielf/finally-rejuvenation-is-a-thing-910d48aa6c6e

Senescent cells are now a prominent target for the development of therapies to treat aging and age-related diseases. Senescent cells accumulate with age, and are responsible for a sizable amount of the chronic inflammation that accompanies old age - as well as fibrosis, compromised regeneration, and a laundry list of other issues. While the dominant approach is selective destruction of these cells, which appears to produce rejuvenation robustly and effectively in mice, a fair number of research groups are interested in finding ways to prevent cells from becoming senescent in the first place. The investigation here into cellular senescence and osteoarthritis is an example of the type.

I'm not convinced that this is as useful a path forward. Firstly it means constantly taking the treatment over decades, rather than once every so often, as needed. Secondly, cells become senescent for a reason, usually some form of DNA damage or environmental stress. Preventing senescence may result in a higher risk of cancer or other problems in tissue due to cells that should in fact be removed from the picture. That may still be better than the alternative of more rather than fewer senescent cells, as was the case in the short term for the mice in this study, but it doesn't compare favorably with destroying these errant cells.

Mesenchymal stem cells (MSCs) are widely distributed in adult tissues and are involved in tissue repair and homeostatic maintenance. Over time, MSCs exhibit an age-associated decline in their number and function, namely, MSC senescence, which may be implicated in the loss of tissue homeostatic maintenance and leads to organ failure and degenerative diseases. Therefore, an understanding of the mechanisms underlying MSC senescence will likely reveal novel therapeutic targets for ameliorating degenerative diseases.

Osteoarthritis is a prevalent aging-associated disorder that is characterized by the progressive deterioration of articular cartilage. Previous reports have demonstrated that cells isolated from mouse and human articular cartilage express MSC markers and characteristics. Cell death induced by oxidative stress or wound occurs primarily at the surface zone of cartilage. When such cell death is inhibited by chemicals, cartilage disorganization and matrix loss are greatly reduced. Therefore, MSCs or chondrocyte progenitor cells residing in cartilage may be a critical target for the prevention of osteoarthritis. Although the transplantation of ex vivo cultures of MSCs into the osteoarthritic joint has been shown to improve the symptoms, the rejuvenation of endogenous senescent MSCs may also be a therapeutic option for osteoarthritis.

Senescent mesenchymal stem cells (MSCs) residing in the joint cartilage may be a critical target for the prevention of osteoarthritis; however, the key regulators of MSC senescence are little known, and targeting aging regulatory genes for the treatment of osteoarthritis has not yet been reported. Here, we show that Yes-associated protein (YAP), a major effector of Hippo signaling, represses human mesenchymal stem cell senescence through transcriptional up-regulation of forkhead box D1 (FOXD1). Lentiviral gene transfer of YAP or FOXD1 can rejuvenate aged hMSCs and ameliorate osteoarthritis symptoms in mouse models. We propose that the YAP-FOXD1 axis is a novel target for combating aging-associated diseases.

Link: https://doi.org/10.1371/journal.pbio.3000201

The angiogenesis hypothesis of aging suggests that loss of capillaries throughout the body is an important driver of age-related decline. This loss must be a downstream consequence of other forms of damage and dysfunction, issues that lead to a disruption of the balance of signals and cell capabilities needed to maintain the network of capillary blood vessels. Hundred of capillaries pass through every square millimeter of tissue, allowing the bloodstream to nourish the resident cells. If the density of that network declines, then ever lesser amounts of oxygen and nutrients are delivered to the cells that need them. This is particularly important in tissues requiring a great deal of energy, such as muscles and the brain. As for all aspects of aging, of course, there is good evidence for this process of capillary loss to be relevant, but the relative size of the effect is unknown, when comparing against other processes of aging. Only when specific aspects of age-related decline can be repaired in isolation is it possible to see the size of their contribution.

The retina is considered a part of the central nervous system, and thus the eyes can act as a window into the state of aging in the brain and major nerves. In today's open access paper, researchers report on the use of scanning technologies to visualize the decline in capillary density in the retina. This is a mark of aging, related to just how much deterioration and damage has taken place in tissues. This is why it correlates well to incidence of Alzheimer's disease, I would expect. Alzheimer's disease has many causes and disease processes, of which at least some, such as chronic inflammation in the central nervous system, can be credibly argued to disrupt the regenerative processes responsible for maintaining tissues and blood vessel networks.

Eyes reveal early Alzheimer's disease

It's known that patients with Alzheimer's have decreased retinal blood flow and vessel density but it had not been known if these changes are also present in individuals with early Alzheimer's or forgetful mild cognitive impairment who have a higher risk for progressing to dementia. Multicenter trials could be implemented using this simple technology in Alzheimer's clinics. Larger datasets will be important to validate the marker as well as find the best algorithm and combination of tests that will detect high-risk subjects. The back of the eye is optically accessible to a new type of technology (OCT angiography) that can quantify capillary changes in great detail and with unparalleled resolution, making the eye an ideal mirror for what is going on in the brain.

Researchers recruited 32 participants who had cognitive testing consistent with the forgetful type of cognitive impairment, and age-, gender- and race- matched them to subjects who tested as cognitively normal for their age. All individuals underwent the eye imaging with OCT angiography. The data were analyzed to identify whether the vascular capillaries in the back of the eye were different between the two groups of individuals. Now the team hopes to correlate these findings with other more standard (but also more invasive) types of Alzheimer's biomarkers as well as explore the longitudinal changes in the eye parameters in these subjects.

Parafoveal vessel loss and correlation between peripapillary vessel density and cognitive performance in amnestic mild cognitive impairment and early Alzheimer's Disease on optical coherence tomography angiography

Optical coherence tomography angiography (OCTA) is a non-invasive clinical tool that can capture the retinal capillary microcirculation at the micrometer resolution. Previous retinal vascular studies using retinal functional imager and laser flowmetry have shown decreased flow in the temporal retinal vein and major parafoveal arterioles and venules in Alzheimer's disease (AD) and mild cognitive impairment (MCI) individuals. However, OCTA provides a unique opportunity to investigate the microvasculature in a specific retinal vascular plexus of interest. OCTA has demonstrated that retinal neural sub-layers are supplied by distinct capillary plexuses, each reflecting the metabolic demand of a particular neuronal layer. Importantly, we know that the inner retina layer in both the macula and optic disc bears the brunt of AD pathology including the loss of ganglion cells, thinning of the retinal nerve fiber layer (RNFL), and deposition of amyloid-β plaques according to histological and OCT structural imaging studies.

Our study shows that compared to matched cognitively normal controls, participants with early cognitive impairment demonstrated significantly decreased superficial parafoveal vessel density and blood flow. In addition, we found that parafoveal and peripapillary densities were positively correlated with the Montreal Cognitive Assessment (MoCA), a measure of overall cognitive impairment. Most importantly, we demonstrated the role of OCTA in detecting early capillary changes, which may represent potentially early, non-invasive biomarkers of AD. Future directions include a larger cohort as well as longitudinal studies that examine the temporal relationship between vascular damage and pathological loss of ganglion cells, their nerve fibers, and cognitive decline.

One of the many jobs undertaken by microglia in the central nervous system is to clean up pathogens, cell debris, and other molecular waste, ingesting it and breaking it down. Microglia become less capable with age, which is at least in part attributed to the more inflammatory environment characteristic of older individuals, but there are probably other significant causes. These cells do not replicate, and so are most likely more vulnerable to the accumulation of molecular damage than most cell populations.

In particular, this and other forms of stress can lead to cellular senescence, and senescent microglia have now been implicated in the progression of Parkinson's disease and Alzheimer's disease. The advent of senolytic therapies to selectively destroy senescent cells may turn out to produce significant benefits to patients with these and other neurodegenerative conditions. Of note, cellular senescence causes issues in part because these errant cells produce inflammatory signaling that rouses and disrupts the immune system, including other microglia. Cause and effect in the brain can be quite circular and confusing.

The ingest-then-digest procedure employed by microglia and other immune cell types in the body is called phagocytosis. A new study used laboratory techniques to identify mouse genes whose activity either impairs or enhances microglial phagocytosis and whose activity levels either increase or decrease substantially with age. The investigators picked about 3,000 genes encoding proteins that they judged could be targeted by drugs or that had already been the focus of drug development. The goal was to learn how each blockade affected the ability of cultured mouse microglia to ingest small particles of latex. One at a time, they blocked each gene's ability to encode a protein. In a parallel experiment, the investigators determined which of those approximately 3,000 genes are more or less active in microglia from the hippocampi of young mice versus old mice.

Surprisingly, when the scientists compared the results of both experiments, they found just one gene that affected microglial phagocytosis and whose activity in microglia substantially changed with advancing age. Older microglia produced far more copies of this gene - a proxy for upregulated production of the protein for which the gene is a blueprint - than younger ones did, and knocking out its function greatly improved microglial phagocytosis. So they zeroed in on this gene, called CD22, which is found in both mice and humans. In a follow-on experiment, the CD22 protein turned up three times as often on the surface of older mice's microglia as on those of younger mice's microglia, confirming the gene-activity finding. These proteins could be blocked by antibodies, molecules that bind to a specific protein and can be generated in the lab. Antibodies are bulky and don't easily penetrate cells, but they're excellent for targeting cell-surface proteins.

The team injected antibodies to the CD22 protein into the hippocampus on one side of mice's brains. Along with the antibodies, the scientists administered bits of myelin. This substance coats numerous nerve cells, for which it provides insulation. But myelin debris accumulates in aging brains and has been shown to overwhelm microglia's ability to clear it away. The researchers found that, 48 hours later, the myelin bits they'd injected into the mice's hippocampi were far less prevalent on the side where they had administered CD22-blocking antibodies. The investigators conducted analogous experiments, substituting a protein called beta-amyloid, whose buildup in the brain is a hallmark of Alzheimer's disease, and alpha-synuclein, another protein similarly associated with Parkinson's disease. In both cases, microglia exposed to CD22-blocking antibodies outperformed their peers in ingesting the neurodegeneration-linked substances.

The team observed that old mice receiving these infusions outperformed control mice of the same age on two different tests of learning and memory that are commonly used to assess mice's cognitive ability. "The mice became smarter. Blocking CD22 on their microglia restored their cognitive function to the level of younger mice. CD22 is a new target we think can be exploited for treatment of neurodegenerative diseases."

Link: http://med.stanford.edu/news/all-news/2019/04/blocking-proteins-activity-restores-cognition-in-old-mice.html

Turn.bio is working on an interesting approach to induction of pluripotency in the tissues of living animals. They use a form of temporary reprogramming to take cells only some of the way to a pluripotent state, far enough that they issue the sort of beneficial signaling expected of induced pluripotent stem cells, and potentially also repair some of their internal damage, such as via the clearance of dysfunctional mitochondria, but not so far they they actually become induced pluripotent stem cells. The cells revert back to their original state, but with the benefit of some damage repair, and a changed signaling environment. As the company progresses, we shall see whether or not this more careful, partial approach is enough to avoid the risk of cancer that is suspected to result from inducing pluripotency in vivo.

We've already seen successful partial cellular reprogramming in living animals through OSKM induction. How does your approach differ?

Well, I think that work is absolutely the first proof of principle that some kind of cellular rejuvenation is triggered by the expression of reprogramming factors. The only caveat is that our work is significantly different from their work, in the sense that our work really demonstrates for the first time that in the naturally aged context, that's what we can also do. We looked at human samples all the way from 50 to 95 years old. We have shown this across multiple cell types; we have looked holistically and comprehensively at all the hallmarks of aging, including transcriptomic, methylation clock, physiology of aging, and stem cell homeostasis. Another fundamental difference is the fact that we're using mRNAs. Now, mRNAs are non-integrative, they are clinically translatable, and so they huge potential to bring this to the clinic.

In your experiment, you reach a four day transient expression period, using these factors. How did you reach that four-day figure?

It's not four days for all cell types; it depends on the cell type. If we differentiate cells like fibroblasts and endothelial cells, we use four days, for chondrocytes, three days, and for muscle stem cells, we use two days. This is actually part of the secret of finding the sweet spot, the empirical moment in time just before the point of no return where the cell is becoming partially reprogrammed but has not yet lost its identity. We know that during the process, it takes 12-15 days for cells to go all the way back to iPSCs. We know from previous studies that already, by day five, we can see early signs of the activation of genes that are pluripotency-associated. For fibroblasts or endothelial cells, that's the time when we see these early events, so we want to stop before that because that would potentially trigger or instigate a potential loss of cell identity.

How would we systemically treat a human in this manner if different cells need different reprogramming times?

Well, the short answer to that is that we don't know that yet, and we need to figure that out. I can tell you the way we're approaching this, particularly on the company side: there is a short-term application, which is most likely going to be the ex vivo approach. The stem cells are going to be isolated from the tissue, rejuvenated in vitro, and then transplanted back. In that type of scenario, we have a uniform population of cells for which we have found this sweet spot so that we can utilize them. Also, because it is done ex vivo, we can make sure the target cells have not changed their identity and are safe. That's one approach.

Do you think your technology has the potential to make systemic rejuvenation in humans a plausible and available prospect in, say, the next 10 to 20 years?

Yes, I strongly believe so, even though at first glance it may seem really difficult, and maybe to some extent impossible, because we naively think about getting everywhere in the body. There is another possibility: what if we could, for example, as we said before for the muscle, what if we can actually target a tissue or an organ that actually has a very dramatic systemic effect on its own? In other words, what if we could, for example, target the hypothalamus? The hypothalamus is one of the main systemic regulators of endocrine functions, and it is shown that inflammation in the hypothalamus affects the entire body. So, what if we started with the hypothalamus, or what if we started at the endothelium in the body, which is pretty much everywhere in every single vessel? The endothelial cells secrete a lot of pro-inflammatory or anti-inflammatory cytokines, so just on its own, this one tissue could actually have a dramatic, systemic effect.

Link: https://www.leafscience.org/an-interview-with-prof-vittorio-sebastiano-of-turn-bio/

Mitochondria are the power plants of the cell, generating the chemical energy store molecule adenosine triphosphate (ATP) that powers cellular processes. Every cell possesses a herd of mitochondria, replicating like bacteria, and monitored by quality control mechanisms. Damaged, potentially harmful mitochondria are removed and dismantled for raw materials through a variant of autophagy called mitophagy. A mountain of evidence links mitochondrial function to aging, just as a mountain of evidence links the cellular recycling mechanisms of autophagy to aging. Both mitochondrial function and autophagic activity decline with age, producing downstream consequences that contribute to age-related diseases. There is the strong suspicion, with evidence to back it up, that it is the quality control of mitochondria, and thus maintenance of mitochondrial function without harmful side-effects resulting from damaged mitochondria, that is the common factor here.

Enhanced autophagy is a feature common to many of the methods by which aging can be slowed and life span extended in short-lived laboratory species. Most of these work via upregulation of cellular stress responses - to heat, lack of nutrients, oxidative damage, and so forth - and autophagy is an important stress response mechanism, making cells more resilient. Minor or short stresses lead to a longer upregulation of the response to stress, and thus the overall result is an improvement in health and longevity. This is called hormesis, and is a major part of the way in which intermittent fasting or calorie restriction work. Researchers have in the past demonstrated that calorie restriction actually fails to extend life in animals in which autophagy is disabled.

The topic for today is specifically the permeability of the mitochondrial membrane and its role in the relationship between mitochondrial function and autophagy. A fair amount of attention has been directed in recent years towards the mitochondrial permeability transition pore structures in the mitochondrial membrane, and their role in mitochondrial dysfunction. Clearly greater pore activity and thus greater permeability are a feature of aging, alongside mitochondrial dysfunction, but joining the dots on what is cause and what is consequence in our biochemistry is far from simple. It is known that mitophagy falters in later life, and it is known that this appears to be at least partly a consequence of reduced levels of mitochondrial fission - but consider how long it took to join just those two items. Why do mitochondrial fission rates fall? How does that relate to permeability and the membrane structures that support it? The complexity is overwhelming, which is perhaps why the path forward towards near term therapies is usually to cut the Gordian knot in some way, bypass the system that is poorly understood. Many of the SENS-style proposed rejuvenation therapies based on repair of underlying damage are of this form.

Mitochondrial permeability plays a key role in aging, recovery from ischemic injury

The ability of molecules to pass through the membrane of mitochondria - the cellular structures that convert nutrients into energy - may determine whether or not autophagy, a cellular process that removes damaged and dysfunctional molecules and cellular components, is beneficial or detrimental to the health of an organism. As the accumulation of damaged molecules and defective proteins is considered a hallmark of aging, autophagy has been associated with increased longevity. In fact, model organisms in which gene mutations or measures such as calorie restriction lead to lifespan extension depend on autophagy for their beneficial effects. However, autophagy can also play a role in cancer, diabetes, neurodegeneration and in the ischemia/reperfusion injury caused by restricted blood flow.

Previous studies have suggested that inhibition of the mTORC2 molecular pathway, which controls several critical metabolic functions, shortens lifespan. Organisms in which mutations in mTORC2 or in the gene encoding its downstream effector protein SGK-1 have reduced lifespan also show increased autophagy. Experiments revealed that inhibition of autophagy can restore a normal lifespan in mTORC2/SGK1 mutant C. elegans roundworms. The researchers also found that SGK-1 can regulate the opening of the mitochondrial permeability transition pore (mPTP), which allows very small molecules to pass through the mitochondrial membrane. Excessive opening of the mPTP, either by inhibition of the mTORC2/SGK-1 pathway or by direct genetic stimulation, transforms autophagy from a beneficial to a detrimental function, resulting in a shortened lifespan. Overall, the results indicate that the beneficial effects of autophagy depend on low levels of mitochondrial permeability.

Since autophagy is believed to contribute to ischemic injury, the investigators looked at its potential role in ischemia/reperfusion (I/R) injury - the exacerbation of tissue damage that occurs when blood flow is restored to tissue to which it had been restricted. They found that mice in which expression of the gene for SGK-1 was knocked out in the liver were more susceptible to I/R injury of the liver than were unmutated animals. While both current and previous research has indicated that elevated autophagy and mitochondrial permeability are harmful in the early phases of reperfusion injury, autophagy may help reduce the severity of tissue damage at later stages when damaged cellular components must be cleared from the cell.

Mitochondrial Permeability Uncouples Elevated Autophagy and Lifespan Extension

Autophagy is required in diverse paradigms of lifespan extension, leading to the prevailing notion that autophagy is beneficial for longevity. However, why autophagy is harmful in certain contexts remains unexplained. Here, we show that mitochondrial permeability defines the impact of autophagy on aging. Elevated autophagy unexpectedly shortens lifespan in C. elegans lacking serum/glucocorticoid regulated kinase-1 (sgk-1) because of increased mitochondrial permeability. In sgk-1 mutants, reducing levels of autophagy or mitochondrial permeability transition pore (mPTP) opening restores normal lifespan.

Remarkably, low mitochondrial permeability is required across all paradigms examined of autophagy-dependent lifespan extension. Genetically induced mPTP opening blocks autophagy-dependent lifespan extension resulting from caloric restriction or loss of germline stem cells. Mitochondrial permeability similarly transforms autophagy into a destructive force in mammals, as liver-specific Sgk knockout mice demonstrate marked enhancement of hepatocyte autophagy, mPTP opening, and death with ischemia/reperfusion injury. Targeting mitochondrial permeability may maximize benefits of autophagy in aging.

The data presented in this open access paper provides a good example of the complexity of the metabolic processes that influence life span. The researchers overexpress the UPD1 gene in various different tissues in flies. While the UPD1 protein acts via the JAK/STAT pathway in each case, the results on fly life span are wildly different. This sort of thing is exactly why it is very challenging, very slow, and very expensive to try to even modestly slow aging by tinkering with the operation of metabolism, to make an organism more resilient to the damage of aging. There are far better ways forward than this, notably those that involve periodic repair of the damage of aging.

The JAK/STAT signaling pathway is involved in many aging-related cellular functions. However, effects of overexpression of genes controlling JAK/STAT signal transduction on longevity of model organisms have not been studied. Here we evaluate the effect of overexpression of the unpaired 1 (upd1) gene, which encodes an activating ligand for JAK/STAT pathway, on the lifespan of Drosophila melanogaster.

Overexpression of upd1 in the intestine caused a pronounced shortening of the median lifespan by 54.1% in males and 18.9% in females, and the age of 90% mortality by 40.9% in males and 19.1% in females. In fat body and in nervous system of male flies, an induction of upd1 overexpression increased the age of 90% mortality and median lifespan, respectively. An increase in upd1 expression enhanced mRNA levels of the JAK/STAT target genes domeless and Socs36E.

Conditional overexpression of upd1 in different tissues of Drosophila induces pro-aging or pro-longevity effects in tissue-dependent manner. The effects of upd1 overexpression on lifespan are accompanied by the transcription activation of genes for the components of JAK/STAT pathway. As the JAK/STAT pathway is evolutionarily conserved it may be possible to discover compounds that fit the criteria of geroprotector. In our future work we plan to test the compounds from DrugAge and geroprotectors.org and other libraries potentially modulating upd, domeless and Socs36E on the lifespan of Drosophila and other organisms.

Link: https://doi.org/10.1186/s12918-019-0687-x

In a world in which nothing can be done about aging and inevitable death, acceptance is necessary. To remain sane and productive, to work towards a golden future that we will not live to see, requires a stoic viewpoint. One must accept the aspects of the world that are beyond control, and understand that we can control our own reactions to those aspects, so as to lead the best possible life under the circumstances. Aging has long been an aspect of the world beyond our control; one could endeavor to be more healthy rather than less healthy, but in the end there was still the inevitable decrepitude, suffering, and death.

Yet now biotechnology offers the near future possibility of the medical control of aging - and even today, the first rejuvenation therapies, those that selectively destroy senescent cells, are already available to anyone adventurous enough to try. In this environment, where funding, support, and the will to progress are all required to build out the full portfolio of means of human rejuvenation, acceptance of aging has become harmful and poisonous. It holds us back, and tens of millions of lives are the cost of every significant delay.

When you are repeatedly subjected to an unpleasant or painful situation over which you seem to have no control, there comes a point past which you simply give up on the very idea that you could possibly escape your predicament. Once you learn that you're helpless in the face of circumstances beyond your control, you could end up simply accepting what is happening to you, even when the circumstances have changed enough to offer a way out.

We find this relevant because this learned helplessness could play a role in the pro-aging trance - or, at least, what happens in people's minds because of the pro-aging trance is very much reminiscent of learned helplessness. If you're new around here and have no idea what the pro-aging trance is, it's basically one of the main drivers of irrational opposition to rejuvenation therapies; it's the groundless conviction that aging is a blessing in disguise and that the fact that people age to death is actually good, despite the overwhelming, blatant evidence that this is not the case.

Even though you don't spend your entire life with worsening eyesight, diabetes, cancer, or heart disease (to name but a few), you - like everyone else on the planet - were brought up with the notions that aging is inevitable and that one day it will kill you if nothing else does it first. You're accustomed to the thought that, as you age, you will lose your health to at least some extent, and you have an idea of what you might be like in old age - weak, hunched over, easily fatigued, and with feeble senses and, if you're unlucky, even more serious health problems. This idea is woven into every fiber of our society, arts, and institutions; even if you're not exposed directly to the ailments of aging for most of your life, you are exposed to the unpleasant thought that your clock is ticking - a clock that measures not just the time you have left but also your remaining health - and that there's no way that you could ever stop the clock.

In other words, you spend your entire life with the knowledge that your health is slowly declining, a decidedly unpleasant thing that, ultimately, you have no power to prevent. Therefore, you learn to accept it and make your peace with it, perhaps whimpering about it every now and again, but doing nothing else about it. Once the effects of aging manifest themselves in your old age, the feeling of helplessness gets even more real, as your health problems are no longer hypothetical and your doctor can essentially only help you manage your symptoms. This overall situation has much in common with the definition of learned helplessness.

Link: https://www.leafscience.org/learned-helplessness-and-the-acceptance-of-aging/

Senescent cells are a cause of aging. They accumulate with the passage of years and decades, a process that is in part just a matter of numbers and averages over time, in which a minuscule fraction of the vast number of newly senescent cells arising every day manage to evade destruction. Importantly, it is also due to the progressive failure of the immune system in its surveillance of errant cells. Senescent cells, like cancer cells, are attacked and destroyed by immune cells, and thus their numbers rise as immune cells become less competent. The harm done by senescent cells is mediated by the wide range of inflammatory, harmful factors that they secrete. The presence of even a small number of senescent cells disrupts tissue function, structure, and regenerative capacity.

As noted in today's open access paper, the presence of senescence cells is important in the aging of the heart and the rest of the cardiovascular system. Cellular senescence contributes to ventricular hypertrophy, the process by which heart muscle becomes larger and weaker. Senescent cells are also implicated in the fibrosis found to disrupt structure and function of heart tissue; removing senescent cells via senolytic treatment reserves this fibrosis. Further, the chronic inflammation produced by senescent cells is generally harmful to the cardiovascular system, contributing to the progression of arterial stiffening via smooth muscle cell dysfunction, and atherosclerosis via macrophage dysfunction.

Senescent cells actively enforce their contribution to the state of aging via their secretions. Remove the cells, and that contribution vanishes, leaving behind downstream damage that can be repaired by cell populations to a sizable degree. Senolytic therapies to clear senescent cells have been demonstrated to extend life in mice, and turn back the progression of many aspects of aging and age-related diseases. Targeted destruction of senescent cells is a rejuvenation therapy, albeit a narrowly focused form of rejuvenation, targeting only one of many forms of damage that cause aging. The work here is one of many papers to demonstrate this point.

Pharmacological clearance of senescent cells improves survival and recovery in aged mice following acute myocardial infarction

Cellular senescence is classically defined as the irreversible cell cycle arrest of somatic cells. While senescence can act as a potent antitumour mechanism, recent studies have shown that senescent cells accumulate in several tissues with age where they contribute to age-dependent tissue dysfunction and several age-related diseases. Senescent cells are thought to contribute to aging via a pro-oxidant phenotype and the secretion of a senescence-associated secretory phenotype (SASP), which is pro-inflammatory, profibrotic, and can also promote senescence in surrounding cells.

Senescence has been shown to occur in the heart during aging and contributes to the pathophysiology of a number of cardiovascular diseases, as clearance of senescent cells in aged and atherosclerotic mice using both genetic and pharmacological approaches improves vascular and myocardial function and attenuates age-dependent remodelling. However, the impact of senescent cells in myocardial infarction (MI) has not been investigated thus far. In this study, we hypothesise that senescent cells contribute to the poor prognosis and survival of aged individuals following MI. Previously we found that in addition to clearing senescent cells, navitoclax treatment reduced fibrosis and cardiomyocyte (CM) hypertrophy in aged mice and considered that these beneficial effects may help to improve outcomes in aged mice following MI. We therefore performed a more detailed longitudinal study to examine this possibility and to explore potential mechanisms.

Histological analysis was performed on a cohort of noninfarcted mice, to assess the baseline effects of navitoclax treatment. In addition to decreasing CM hypertrophy, treatment reduced markers of CM senescence, indicating clearance of senescent cells from the hearts of treated aged mice. Furthermore, we found a significant reduction in expression of profibrotic TGFβ2, which we previously identified as a key component of CM SASP. Functionally, navitoclax treatment significantly reduced the age-dependent increase in left ventricular (LV) mass but did not impact on ejection fraction (EF). Aged mice also exhibited a decrease in the percentage change in diastole versus end systole LV wall thickness, indicating an increased LV rigidity compared with young animals, which was also partly rescued by navitoclax treatment. Clinically, increased ventricle stiffness is related to fibrosis and hypertrophy during aging, is symptomatic of diastolic dysfunction and is observed in heart failure with preserved ejection fraction patients.

We observed that aged mice had significantly higher mortality rates following MI (60% over 5 weeks) compared with young mice and that this outcome was rescued by prior navitoclax treatment. In contrast to young mice, old mice show a significant reduction in EF between 1 and 4 weeks post-MI. Importantly, navitoclax was able to rescue this functional decline which may help to explain the improved survival of this group. Furthermore, expression of senescence markers p16 and p21 at 4 weeks following MI was reduced in the hearts of navitoclax-treated mice, consistent with reduction of the senescence burden.

Collectively, this study shows that pharmacological clearance of senescent cells in aging mice alleviates age-dependent myocardial remodelling and attenuates expression of profibrotic mediators. Navitoclax improved the maintenance of cardiac function following MI, ultimately increasing survival. An important limitation of this study is that our experimental strategy was not able to distinguish which senescent cell types are responsible for this effect, and it is possible that clearance of senescent cells in noncardiac organs impact on survival following MI. We have focussed our attention on CMs in this study as our earlier findings showed that, in the heart, markers of senescence accumulate primarily in CMs during aging. However, further studies using animal models where senescent cells can be cleared in a cell-type specific manner are required to formally show the contribution of senescent CMs to cardiac recovery post-MI.

Mitochondria are the power plants of the cell, present by the hundred in near every cell type in the body. They are important in many fundamental cellular processes, but their primary task is to package chemical energy stores in the form of adenosine triphosphate (ATP). Mitochondrial function declines with age in all tissues, and this is particularly problematic in energy-hungry tissues such as the brain and muscles. The cause of this decline may be failure of the quality control mechanisms of mitophagy, responsible for dismantling damaged mitochondria, or it may have deeper roots, such as loss of capacity for mitochondrial fission. Until some of those possible roots can be fixed reliably, it will be hard to assign relative importance to their contributions.

Given that mitochondrial function declines across the board, it will not be surprising to find that any given mechanism exhibits problems in older individuals. Mitochondria are wrapped in membranes, and those membranes use ion channels to pass various ions essential to their operation, such as calcium, back and forth. The open access paper here examines age-related mitochondrial dysfunction through the lens of ion channels and disruption of their activity. This seems likely a downstream issue, but as ever it is quite hard to determine cause and consequence in the mechanisms associated with aging without the ability to reliably intervene to fix just one thing in isolation.

Mitochondria are often referred to as the powerhouse of the cell, however, their physiological role goes well beyond that Mitochondria are highly dynamic organelles regulating their structure in line with metabolism, redox signaling, mitochondrial DNA maintenance, and apoptosis. Besides from generating adenosine triphosphate (ATP) for cellular energy, mitochondria are also deeply involved in providing intermediates for cellular signaling and proliferation. Mitochondria can alter their size and organization as a result of mitochondrial fission and fusion in response to various intracellular and extracellular signals. Fission and fusion events occur to meet metabolic demands and for the removal of damaged/dysfunction mitochondria. The role of mitochondrial fission and fusion in facilitating metabolism has been researched extensively. Fused mitochondrial networks typically engage more oxidative pathways of metabolism, whilst fragmentation as a result of stress impairs the oxidative pathway and increases cellular demand on glycolysis.

Ion channels are intimately involved in regulating mitochondrial function. The essential role of cationic hydrogen (H+) ion transfer in ATP production was noted as early as 1961. H+ ions are pumped from the mitochondrial matrix into the intermembrane space by the flow of electrons through the electron transport chain. These ions are then utilized to drive the ATPase machinery and phosphorylate ATP, thus creating energy for the cell. The movement of ions across the mitochondrial membrane is also essential in establishing membrane potential and maintaining proton (H+) flux. Ions transported across the inner membrane include potassium (K+), sodium (Na+) and calcium (Ca2+), alongside H+. The most well-studied ion channel within the mitochondrion is the voltage-dependent anion channel, VDAC, which is the primary route of metabolite and ion exchange across the outer mitochondrial membrane.

Mitochondrial channelopathies have been found in aging, affecting the K+, Ca2+, VDAC and permeability transition pore (Ca2+; PTP) channels. Mitochondrial Ca2+ cycling is impaired with aging in neurons, resulting from reduced Ca2+ channel activity and reduced recovery after synaptosomal stimulation. This reduced calcium recovery rate results in reduced mitochondrial membrane potential and delayed repolarization, causing mitochondrial dysfunction with aging. This effect has been found in the heart of 2 year old senescent rats. In terms of potassium channels, it has been shown that their density on the surface of mitochondria significantly declines with age and with metabolic syndromes in the heart sarcolemma. This has been shown to reduce tolerance to ischemia-reperfusion and increased injury in aged guinea pig and rat hearts, and also humans.

These effects have repercussions in increasing susceptibility to myocardial infarction and reducing neuronal activity in the elderly as mitochondrial K+ channels have been shown to play a neuroprotective role in neurological reperfusion injury in postnatal mouse pups. Amyloid-β plaques in Alzheimer's disease have been shown to increase intracellular calcium levels. This increase in intracellular calcium, and uptake into the mitochondria through the VDAC and calcium uniporter, has been shown to increase mitochondrial stress responses and initiate apoptosis in rat cortical neurons in vitro and hippocampal slices ex vivo. Recent studies in Parkinson's disease, have revealed that α-synuclein acts via the VDAC to promote mitochondrial toxicity of respiratory chain components in a yeast model of Parkinson's.

Link: https://doi.org/10.3389/fphys.2019.00158

Nicotinamide riboside supplementation is one of the ways to increase levels of NAD+ in mitochondria, thus improving mitochondrial function. This probably does little for young people, particularly young and physically fit people, but in old age NAD+ levels decline along with mitochondrial function. Mitochondria are the power plants of the cell, and with aging they suffer a general malaise that is detrimental to tissue function, especially in energy-hungry tissues such as muscles and the brain. The causes are still poorly understood, though a faltering of the quality control mechanism of mitophagy due to loss of mitochondrial fission appears to be involved. Increased NAD+ appears to override this decline to some degree, albeit without addressing any of the underlying and still problematic root causes.

In early human trials, NAD+ upregulation has been shown to modestly improve vascular function in older individuals, most likely by reversing some of the dysfunction in smooth muscle cell behavior. In mice a broader range of benefits has been demonstrated, though it remains to be seen how many of those also appear in humans to a significant degree. The work here is more along the same lines, in which researchers show that nicotinamide riboside supplementation can restore intestinal stem cell function in older mice. This should improve tissue function, but again it is worth bearing in mind that this is only overriding a reaction to the underlying damage of aging - it doesn't fix that damage, which still carries on to produce all of its other downstream issues.

Researchers have long studied the link between aging and sirtuins, a class of proteins found in nearly all animals. Sirtuins, which have been shown to protect against the effects of aging, can also be stimulated by calorie restriction. In 2016 it was found that, in mice, low-calorie diets activate sirtuins in intestinal stem cells, helping the cells to proliferate. In a new study, researchers set out to investigate whether aging contributes to a decline in stem cell populations, and whether that decline could be reversed.

By comparing young (aged 3 to 5 months) and older (aged 2 years) mice, the researchers found that intestinal stem cell populations do decline with age. Furthermore, when these stem cells are removed from the mice and grown in a culture dish, they are less able to generate intestinal organoids, which mimic the structure of the intestinal lining, compared to stem cells from younger mice. The researchers also found reduced sirtuin levels in stem cells from the older mice.

Once the effects of aging were established, the researchers wanted to see if they could reverse the effects using a compound called nicotinamide riboside (NR). This compound is a precursor to NAD, a coenzyme that activates the sirtuin SIRT1. They found that after six weeks of drinking water spiked with NR, the older mice had normal levels of intestinal stem cells, and these cells were able to generate organoids as well as stem cells from younger mice could.

To determine if this stem cell boost actually has any health benefits, the researchers gave the older, NR-treated mice a compound that normally induces colitis. They found that NR protected the mice from the inflammation and tissue damage usually produced by this compound in older animals. "That has real implications for health. Just having more stem cells is all well and good, but it might not equate to anything in the real world. Knowing that the guts are actually more stress-resistant if they're NR-supplemented is pretty interesting."

Link: http://news.mit.edu/2019/reverse-aging-intestinal-stem-cell-0328

Today's open access paper illustrates one of the many issues inherent in the study of the biochemistry and genetics of exceptionally long-lived people, which is that the data from various different initiatives rarely agrees. The effects of individual or even groups of gene variants are small and hard to pin down. Past studies have suggested that exceptional longevity is correlated with a lack of cardiovascular risk factors, whether genetic or measured aspects of biochemistry such as lipid levels in blood. That seems a sensible hypothesis: cardiovascular disease removes people from the population, therefore older cohorts should exhibit fewer signs of risk for cardiovascular disease. Yet that is not the case in the work presented here: there is no good association between longevity and lesser presence of risk factors.

What this sort of distribution of results should tell us is that the biochemistry of exceptional human longevity is a poor area of study if the goal is to produce reliable therapies with large effects on human aging. Old people who survive to very late life do so largely because they are either lucky (in exposure to pathogens, in the way in which the damage of aging progressed in a stochastic manner in their case) or because they made good lifestyle choices for much of their span of years. Or both. Beneficial genetic variants and consequent differences in cellular metabolism appear to confer only very modest increases in the odds of living for a long time, and even for those people who do live longer, the impact of degenerative aging is very significant. An environment of small, unreliable effects should be skipped in favor of research strategies with larger potential gains at the end of the day.

Exceptional Longevity and Polygenic Risk for Cardiovascular Health

Exceptional longevity, defined as exceeding the average life expectancy, is multifaceted with genetic, environmental, and epigenetic factors all playing a role. Exceptionally long-lived (ELL) individuals are examples of successful ageing with a proportion demonstrating compression of morbidity. It is important to study these models of successful ageing, as these rare individuals may reveal novel longevity-associated pathways, which may ultimately translate into strategies to promote health in our ageing population.

There is evidence linking healthier cardiovascular risk profiles and lower incidence of cardiovascular disease with longevity. Analysis of lipid metabolism in longevous families identified changes in lipid concentration in the offspring of nonagenarians. Levels of apolipoproteins, important lipid transporters in the circulatory system, have been observed to decline with age. However, higher apolipoprotein levels in the exceptionally long lived have been reported, suggesting a younger apolipoprotein profile that may promote longevity.

Polygenic risk scores (PRS) for cardiovascular-related phenotypes can now be calculated due to the availability of summary data from genome-wide association studies (GWAS) examining a broad range of traits from lipids to coronary artery disease. This facilitates the evaluation of the contribution of polygenic risk for cardiovascular risk factors and disease to exceptional longevity and successful ageing. Thus, the purpose of this study was to explore the genetic profiles of ELL individuals aged (≥95 years) by assessing their polygenic risk for cardiovascular related risk and disease phenotypes relative to middle-aged controls.

This study did not confirm the hypothesis that ELL individuals have lower polygenic risk scores for cardiovascular-related phenotypes. Only the HDL cholesterol and triglyceride PRS were nominally significantly associated with ELL participants. In contrast and as expected, ELL individuals had higher polygenic risk scores for exceptional longevity (EL). In regards to the associations of the various cardiovascular PRS with EL, no findings survived correction for multiple testing. This is despite validating the utility of the lipid PRS by confirming positive associations with measured lipid levels in our sample. Interestingly, the different lipid PRS were based on GWAS that found a large number of genome-wide significant loci. ELL individuals had lower LDL and total cholesterol levels than controls in this study, but they did not differ on their respective PRS. This may suggest that environmental factors, perhaps lifestyle-related, influenced these lipid levels, which possibly promote longevity.

In contrast, the UK Biobank study observed that extreme parental longevity (defined as at least one parent who survived to the top 1% of age at death) had lower polygenic risk for several cardiovascular health measures. Namely coronary artery disease, systolic blood pressure, body mass index, high-density lipoproteins, low-density lipoproteins, and triglycerides. A similar result for HDL cholesterol and extreme parental longevity (EPL) by the UK Biobank to the current study was reported. Again, similar results were reported by the UK Biobank for LDL. However, the observed discrepancies between our analysis and the UK Biobank were most likely due to methodological differences, including the use of PRS that were based on different GWAS.

Exercise, like all interventions that improve health, has a dose-response curve. As in most such curves, the initial difference between no treatment (a sedentary or near-sedentary lifestyle) and some treatment (moderate physical activity every day) is quite large. Further increments in activity can add increasing benefits, but ever less as activity time increases further. There is an optimal point at which one can be fairly certain of capturing most of the benefits, even given the usual uncertainties in measurement and variation in the response of individuals. For aerobic exercise, and the average human being, the optimal point is probably a greater amount of time than the 30 minutes daily presently recommended.

Regular moderate- to vigorous-intensity physical activity (MVPA) is associated with a lower risk of cardiovascular disease; certain cancers; and premature death. In addition, the amount of time spent sedentary - distinct from physical inactivity - is associated with a higher risk of death and disease. That may be a result, at least in part, from sedentary behavior displacing physical activity.

Most previous studies have explored the potential effect of sedentary time without considering the physical activity it displaces, leaving a gap in the understanding of the issue. To explore further, investigators analyzed self-reported sitting time, light physical activity, and moderate/vigorous physical activity among 92,541 participants in the ACS's Cancer Prevention Study II Nutrition Cohort.

The analysis reviewed sedentary time and activity levels over 14 years. It found among those who were the least active at baseline (less than 17 minutes/day moderate to vigorous physical activity), replacing 30 minutes/day of sitting with light physical activity was associated with a 14% reduced risk of death, while replacement with moderate to vigorous physical activity was associated with a 45% reduced risk of death.

The investigators found similar but smaller associations among moderately active participants: replacing a half hour of sedentary time with light physical activity was associated with a 6% reduction in mortality among those who were moderately active; replacing 30 minutes of sitting time with moderate to vigorous physical activity was associated with a 17% mortality reduction in this group. However, for the most active (more than 38 minutes/day of MVPA), substitution of sitting time with light physical activity or MVPA was not associated with a reduction in mortality risk.

Link: https://www.eurekalert.org/pub_releases/2019-03/acs-rst032519.php

Cellular senescence is one of the causes of aging; the inflammatory signals generated by growing numbers of senescent cells disrupt tissue maintenance and cell function, and play an important role in many age-related conditions, including osteoarthritis. The best approach to senescent cells appears to be the simple one: destroy them. They accumulate slowly, and therapies that selectively remove senescent cells have been shown in animal studies to produce significant reversal of numerous aspects of aging. Nonetheless, many research groups are more interested in preventing or modulating senescence, with the open access paper here an example of the former. To my eyes, therapies that have to be taken over decades to slow the accumulation of senescent cells are a very poor second best to methods of immediate clearance of these cells.

Stem cell senescence contributes to stem cell exhaustion, a major cause of physiological and pathological aging. Mesenchymal stem cells (MSCs) are adult multipotent cells in various mesodermal tissues that are capable of differentiating into mature cells such as osteoblasts, chondrocytes, and adipocytes. Both physiologically aged individuals and patients with premature aging syndromes exhibit functional degeneration in mesodermal tissues, along with exhaustion of MSC populations, thus characterized by atherosclerosis, osteoporosis, osteoarthritis, etc.

CBX4, a component of polycomb repressive complex 1 (PRC1), plays important roles in the maintenance of cell identity and organ development through gene silencing. However, whether CBX4 regulates human stem cell homeostasis remains unclear. In this study, we reported that CBX4 was downregulated during human MSC (hMSC) senescence and accordingly investigated the role of CBX4 in maintaining cellular homeostasis in hMSCs. Targeted CBX4 depletion in hMSCs resulted in loss of nucleolar heterochromatin, enhanced ribosome biogenesis, increased protein synthesis, and accelerated cellular aging. CBX4 overexpression alleviated senescent phenotypes in both physiologically and pathologically aged hMSCs.

More importantly, lentiviral vector-mediated CBX4 overexpression attenuated the development of osteoarthritis in mice. We demonstrate that CBX4 safeguards hMSCs against cellular senescence through the regulation of nucleolar architecture and function, suggesting a target for therapeutic interventions against aging-associated disorders.

Link: https://doi.org/10.1016/j.celrep.2019.02.088

A very large fraction of the research aimed at the production of interventions to slow aging involves some form of screening small molecule compounds for potential effects. There are huge stock libraries of these things, and many well established approaches to carrying out such screening processes. While new ventures are using machine learning to try to make this process far more efficient than is presently the case, after the fashion of In Silico Medicine, I'd say that the future will be a matter of gene therapy making small molecules obsolete. Gene therapy offers the possibility of precise alteration of the gene expression of a rationally chosen target, rather than the uncertainty, serendipity, and off-target effects inherent in small molecule development.

Still, much of the community, particularly the business community, will remain firmly tied to small molecule development programs for the foreseeable future. Researchers will continue to innovate when it comes to novel ways to run such programs. The example here makes use of nematode worms as the screening system: pick a set of compounds, see what they do to worm longevity, then investigate the biochemistry of the successes to understand whether or not they work in the expected fashion, and whether or not the mechanism might be applicable to mammals.

It is worth noting that most such discoveries work via alterations of stress response systems or other aspects of metabolism that do not produce large gains in life span in long-lived species. A doubling or more of nematode life span has been achieved in a variety of ways, but none of those are based on underlying mechanisms that have anywhere near the same effects when triggered in mammals. We need to look elsewhere to achieve that outcome, meaning work on deliberative repair of the underlying causes of aging, rather than adjustment of metabolism to modestly slow aging.

Discovery of life-extension pathway in worms demonstrates new way to study aging

Lifespan studies using C. elegans worms typically involve the deletion or silencing of a particular gene in the embryonic stage of life to see if that extends the average lifespan of affected animals. Researchers took a different approach, using small-molecule compounds to disrupt enzyme-related pathways in adult worms, in the hope that this would uncover pathways that regulate lifespan. The team used a library of about 100 such compounds, all known to inhibit enzymes called serine hydrolases in mammals. "Metabolic processes are very important in determining the rate of aging and lifespan, and serine hydrolases are major metabolic enzymes, so we thought there was a good chance we'd find an important aging-related enzyme this way."

After finding ways to get the compounds through the tough outer skin of the worms, the researchers tested them on worms that were 1 day into adulthood, and found that some of the compounds extended average worm lifespan by at least 15 percent. One, a carbamate compound called JZL184, extended worm lifespan by 45 percent at the optimal dose. More than half the worms treated with JZL184 were still alive and apparently healthy at 30 days, a time when virtually all untreated worms were dead of old age. JZL184 was originally developed as an inhibitor of the mammalian enzyme monoacylglycerol lipase (MAGL), whose normal job includes the breakdown of a molecule called 2-AG. The latter is an important neurotransmitter and is known as an endocannabinoid because it activates one of the receptors hit by the main psychoactive component in cannabis.

Curiously however, a corresponding MAGL enzyme does not exist in C. elegans worms, so JZL184's target in these animals was a mystery. Researchers found, though, that one of the main target enzymes for JZL184 in worms was fatty acid amide hydrolase 4 (FAAH-4). Although FAAH-4 and MAGL are not related in terms of their amino-acid sequences or 3-D folds, further experiments revealed, surprisingly, that FAAH-4 in worms does what MAGL does in humans and other mammals: it breaks down 2-AG. 2-AG has been linked to aging in mammals; one recent study found evidence that its levels fall in the brains of aging mice, likely due to greater MAGL activity. The results suggest, then, that studying the FAAH-4/2-AG pathway in worms could one day yield lifespan-extending strategies for humans.

Pharmacological convergence reveals a lipid pathway that regulates C. elegans lifespan

Phenotypic screening has identified small-molecule modulators of aging, but the mechanism of compound action often remains opaque due to the complexities of mapping protein targets in whole organisms. Here, we combine a library of covalent inhibitors with activity-based protein profiling to coordinately discover bioactive compounds and protein targets that extend lifespan in Caenorhabditis elegans. We identify JZL184 - an inhibitor of the mammalian endocannabinoid (eCB) hydrolase monoacylglycerol lipase (MAGL or MGLL) - as a potent inducer of longevity, a result that was initially perplexing as C. elegans does not possess an MAGL ortholog.

We instead identify FAAH-4 as a principal target of JZL184 and show that this enzyme, despite lacking homology with MAGL, performs the equivalent metabolic function of degrading eCB-related monoacylglycerides in C. elegans. Small-molecule phenotypic screening thus illuminates pure pharmacological connections marking convergent metabolic functions in distantly related organisms, implicating the FAAH-4/monoacylglyceride pathway as a regulator of lifespan in C. elegans.

The Life Extension Advocacy Foundation (LEAF) volunteers were all at the Undoing Aging conference in Berlin this last week. Given that they, like most of the insiders, were spending much of their time interviewing and networking, they are little better a source than I am when it comes to reporting on the actual content of the presentations and announcements. Clearly we need to assign someone with a notepad to a seat next year, and make sure he or she stays there. The LEAF folk carried out a great many interviews, and we'll no doubt see those posted in the weeks ahead.

The atmosphere of the event was very much friendly and informal, with plenty of opportunities to join conversations with researchers and advocates during the breaks while having a bite or a drink. The lineup of speakers included many big names, including Mike West, Judith Campisi, Vadim Gladyshev, Jerry Shay, Nir Barzilai, Kelsey Moody, Julie Andersen, and Ruby Yanru Chen-Tsai. Everyone I asked said that the presentations were all top notch, but I can't really say anything about them, given that I spent nearly every moment of my stay running after researchers who were being pulled left and right by people who needed to meet them for whatever reason.

Even though I'd gotten used to asking people for interviews fairly quickly, it still felt funny to have breakfast every morning while Nir Barzilai was sitting with other researchers a few tables away, hearing the unmistakable voice of Aubrey de Grey as he entered the room, or knowing that I could easily bump into, say, MitoSENS lead Matthew O'Connor, as I walked around the hotel. Speaking of MitoSENS, at the end of her talk, Dr. Amutha Boominathan mentioned the upcoming MitoSENS 2 campaign on Lifespan.io, which will be aimed at testing allotopic expression in mice, providing proof of concept that the technique can work in mammals; in other SENS news, during the conference, Aubrey de Grey announced the tenth anniversary of the SENS Research Foundation, and a shiny new website was recently launched in celebration.

Personally, I think the best part of Undoing Aging 2019 was the feeling of being together with so many like-minded people who all agree that aging can and should be defeated; they may all have different reasons to want to see the end of aging, and they may even have different opinions on how and when this will be accomplished, but they're all working together, each in his or her own way, to achieve this common goal. It was heartening to see that they all agree that aging can be brought to its knees, even if they might disagree on methodologies and timeframes; their optimism is what we need to convince the public that a life without aging isn't a pipe dream anymore.

Link: https://www.leafscience.org/my-experiences-at-undoing-aging-2019/

Metabolism in heart tissue is disrupted in a number of ways in patients with heart failure. Researchers here followed up on the suspicion that fat metabolism is important in this context. They attempt a genetic modification in mice that compensates for just one of the observed changes in how heart tissue manages (or perhaps mismanages) the adaptation to increased stress, namely the much reduced levels of acyl-CoA. They find that this helps. This may or may not lead to a compensatory therapy that strives to make the end stage disease state less terrible, something that I've always thought is a less desirable development strategy, comparing unfavorably to attempts to repair the underlying causes of the condition. It may, however, have more significance as an assessment of the degree to which metabolic disruption of this nature is important in the progression of heart failure.

Before any physical signs or symptoms of heart failure are present, the first maladaptive changes occur in cardiac cell metabolism - how the heart fuels itself to pump blood through the body constantly. Our hearts burn fuel, much like combustion engines in cars. Instead of gasoline, our heart cells burn fats and a small amount of glucose. When our hearts become chronically stressed, they try to adapt, but some of those changes make things worse.

Researchers examined both mouse models of heart failure and human heart tissue obtained from heart failure patients before and after heart assist devices were surgically implanted. They found that the amount of a reactive fat compound, called acyl-CoA, is nearly 60 percent lower in failing hearts compared to normal hearts. This disruption in the heart's normal metabolism creates toxic fats that impair the heart's ability to function and pump properly. Then the team tested mice that overexpressed a gene for a protein called ACSL1, that's known to make acyl-CoA. When exposed to conditions that cause heart failure, the mice kept making normal amounts of acyl-CoA and the extent of heart failure was reduced and delayed.

By maintaining this fat compound, acyl-CoA, the hearts retained their ability to burn fat and generate energy. Importantly, overexpression of ACSL1 also reduced toxic fats, normalized cell function, and reduced the progressive loss of function in the enlarged mouse hearts. When the team examined failing human hearts that had the help of a left ventricular assist device (LVAD), they found similar effects - the levels of acyl-CoA had restored to normal when the sick hearts didn't have to work beyond their capacity. "This tells us there's an important relationship between fat metabolism in the heart and the inability to pump well, and we need to learn more. We believe targeting the normalization of acyl-CoA is a new approach to explore." Next, the team wants to explore how normalizing acyl-CoA helps reduce toxic fats and increase protective fats inside the heart. Soon, they hope to use advanced imaging to track fat metabolism and function in patients' hearts.

Link: https://wexnermedical.osu.edu/mediaroom/pressreleaselisting/new-metabolic-target-for-heart-failure

I recently attended the second Undoing Aging conference in Berlin, the big central conference for our long-standing - and recently greatly expanded - community of researchers, entrepreneurs, investors, and numerous supporters, all engaged in some way in the great project of building the technologies needed for human rejuvenation. This year the event was significantly bigger than last year. The conference was hosted by the Forever Healthy Foundation and the SENS Research Foundation, and is in many ways a platform for spreading and building upon the views of Aubrey de Grey and Michael Greve on aging and how it should be tackled by the medical research and development community. That means addressing the fundamental causes of aging, those outlined in the SENS rejuvenation research programs.

Interestingly, there was a strong Russian contingent present, researchers, venture capitalists, and advocates. They don't make it out to the US quite so often. I finally met Mikhail Batin, one of the figures behind the Science for Life Extension Foundation and Open Longevity initiatives, whose writing I have noted over the years. I made a $50 bet with him that senolytics either will or won't be shown to finally work this year. You can probably guess which side of that wager I took. Like many in the Russian longevity community, he perhaps feels that removal of senescent cells is too simple a strategy in the face of the metabolic complexity of aging. It is a little too trite to say that Russians tend towards a programmed aging viewpoint, but it isn't entirely incorrect. Targeting points of comparative simplicity, the causes of aging, is of course the SENS rejuvenation research strategy - but as this exchange illustrates, we advocates have yet to convince everyone, even in the community, and even given the stunning technical successes in senolytic studies of recent years.

Among the Russian investors, Andrey Fomenko of IVAO made an appearance to chat to some of the entrepreneurs present, such as Doug Ethell of Leucadia Therapeutics and the Oisin Biotechnologies team. Fomenko is worthy of note here, distinct from several other Russian venture capital folk, for setting up the Eternal Youth Fund, somewhat analogous to some of the funds in the English language world, such as the Longevity Fund or Juvenescence. Jim Mellon of Juvenescence was also present at the conference, of course, with rarely a spare moment to say hello between being pitched on one project for another. Given that he has funded a good fraction of the companies in the rejuvenation biotechnology space at this point in time, this will probably be a good summary of his daily experience for the next decade or so. This is a vigorous growth market.

You'll have to forgive me for providing few details as to what was actually presented at Undoing Aging, either in posters or the presentations. The science progresses, but these days I am an entrepreneur with my own biotech company working on methods of rejuvenation, and so when I go to conferences it is now the case that I am no longer able to listen to all that many of the presentations. Instead I must pitch investors and network relentlessly. Fortunately, the presentations were recorded, including my outline of how things are going at Repair Biotechnologies with our preclinical work on thymic rejuvenation and reversal of atherosclerosis, and they will be uploaded to YouTube once the technical folk are done with them.

Taken as a whole, a great deal of interesting research and development was announced at the conference, both by startup companies and research groups. Undoing Aging is very much the event to be presenting at if one wants to gain attention for one's work. Like the upcoming July Ending Age-Related Diseases conference organized by LEAF in New York City, this is a meeting of people with funds and the people who can deploy those funds to make progress towards the goal of the medical control of aging. Transactions take place, and a great deal of new funding is entering this space. Numerous organizations and high net worth individuals are setting up funds devoted to the longevity industry, following Juvenescence, Life Biosciences, and the like, or changing their focus to include this novel area of biotechnology as it expands rapidly. A tipping point has passed, and there is now more than enough seed stage funding out there for anyone with a credible project and team.

One of the topics of discussion that came up several times, with a number of different people, quite independently of one another, is that given the amount of time we advocates spend trying to educate entrepreneurs and investors new to the field, we should produce a bible on how to enter the longevity space, either to start a company, or to fund a company. A good dozen people in our core community, those who have been involved for a decade or more, have had that experience over the past few years, so the memories are still fresh. We don't have enough entrepreneurs in the present community to tackle even a tiny fraction of all the rejuvenation biotechnology projects that could proceed to preclinical development in a startup, and thus these entrepreneurs must arrive from somewhere, comparatively ignorant. We want them to take up effective projects based on the SENS view of aging, and not be sidetracked into marginal work.

Equally, on the investment side of the house, investors in any field have traditionally had the challenge of identifying high expectation value projects, when the differences between great, merely good, and useless are extremely technical. When it comes to treating aging as a medical condition, there is an enormous chasm between the benefits that might be realized through traditional small molecule tinkering with metabolism (e.g. calorie restriction mimetics) and new approaches that actually reverse the causes of aging (e.g. senolytics). The latter are reliable, have large effects, and progress is comparatively easy. The former are unreliable, have marginal effects, and progress is challenging and expensive. It can take some time to learn enough to be able to determine which of these categories any given therapy falls into.

Thus we, the advocates, definitely need to step up and become more organized. We can't reach out one by one with a personal connection to every investor and entrepreneur, and carry out an intervention to prevent more marginal initiatives from launching. That doesn't scale. What we can do is establish a baseline of education and common sense regarding the field, and spread that understanding far and wide. We can thus help newcomers enter the community with enough knowledge to further educate themselves, and to make more sensible choices along the way regarding the projects they undertake.

Of the interesting news from the conference, the SENS Research Foundation is (finally) directly spinning out a for-profit company, rather than only being more indirectly involved in the process of commercializing SENS-related biotechnology. The initiative involves an interesting take on how to get rid of the 7-ketocholesterol that is an important cause of atherosclerosis, spurring the condition by turning macrophages into inflammatory foam cells. The SENS Research Foundation researchers have found a class of molecule that seems fairly innocuous in terms of side-effects and is willing to bind to 7-ketocholesterol and remove it from cells. We will no doubt be hearing more on this later, as the project progresses beyond the setup phase and into properly running as a business and raising venture funding.

It also seems that the Forever Healthy Foundation crowd have the ambition to establish an aging research institution for Berlin after the model of the Buck Institute in California, to work towards making the city a center for aging research as well as all the other items it is famed for. This is a constructive ambition, and the people involved have the connections and the resources to make it happen, given enough time. I look forward to seeing this project make progress. Per a discussion with the Forever Health Foundation principles at the end of the conference, the third Undoing Aging conference next year should prove to be yet bigger than this year's. The event has outgrown the present venue quite handily, and was forced to turn people away in the final days of registration. These are all signs of success, I hope. Still, it is now up to all of those working on therapies and the foundations of therapies to take the new opportunities for funding, and use that funding make the biotechnologies of repair and rejuvenation a reality. Convincing the investors and philanthropists of the world to fund these goals is just step one in the process.

Many sorts of cell therapy work because of the signals secreted by the transplanted cells. In most cases, near all such cells die quite quickly, failing to integrate into the recipient tissue. Methods of reliably improving cell survival could be used to make these first generation therapies more effective, but more importantly enable a whole range of second generation therapies that are presently impractical. One approach that seems to be gaining traction is to generate a tissue-like structure in which cells are better supported, and transplant that: heart patches are an example of the type. Another approach is outlined here, in which transplanted cells are encapsulated in alginate, an approach that protects and supports them sufficiently well to allow regenerative therapies, such as the example here involving the use of macrophages to spur regeneration, to become a practical concern.

Researchers have made small capsules from brown algae which hold macrophages, a type of white blood cell. Tests in mice have shown that these algae capsules may be able to increase blood flow in the limbs where tissue has been damaged. The researchers now hope to move this research into human clinical trials to help the people visiting hospital with critical limb ischaemia (CLI). Scientists have been experimenting with cells as a treatment to grow arteries in the leg for years, however, these treatments have not been effective in humans. A big challenge is that many of the cells injected into the injured area die, move away to surrounding areas, or are detected as 'foreign' by the immune system and rejected.

In this study, scientists delivered the new algae-based capsules containing macrophages to areas of injured muscle tissue in the back legs of mice. Alginate from the cell walls of brown algae, which is mainly found in cold waters in the Northern Hemisphere, was used to form the capsules. They found that these macrophages successfully remained in the injured area, new blood vessels formed, and as a result more blood reached the damaged area. Currently, to treat CLI and restore blood flow in the limbs, the blocked section of the artery has to be either bypassed during surgery or widened using a small piece of expandable mesh called a stent. However, in up to a third of patients, these methods will eventually fail or are not possible to begin with and amputation is the only option. The researchers therefore hope that this new way of delivering cells could be the key to creating an effective treatment for people suffering with CLI.

Link: https://www.bhf.org.uk/what-we-do/news-from-the-bhf/news-archive/2019/march/algae-could-prevent-limb-amputation

Following on from recent confirmation of adult neurogenesis in humans, researchers here report on the identification of the stem cell population responsible for supplying neurons to the hippocampus in mice. The process by which new neurons are created and integrated into neural networks is considered an important target for future regenerative therapies. If the pace can be increased in older individuals, it may go some way towards reversing aspects of age-related cognitive decline, or enhance recovery after brain injury. Characterizing the stem cells responsible for creation of new neurons is an important step on the road towards targeted, selective upregulation of neurogenesis.

It was once believed that mammals were born with the entire supply of neurons they would have for a lifetime. However, over the past few decades, neuroscientists have found that at least two brain regions - the centers of the sense of smell and the hippocampus, the seat of learning and memory - grow new neurons throughout life. Researchers have now shown, in mice, that one type of stem cell that makes adult neurons is the source of this lifetime stock of new cells in the hippocampus. These findings may help neuroscientists figure out how to maintain youthful conditions for learning and memory, and repair and regenerate parts of the brain after injury and aging.

The researchers showed that the neural stem cells they found had a common molecular signature across the lifespan of the mice. They did this by labeling neural stem cells in embryos when the brain was still developing and following the cells from birth into adulthood. This approach revealed that new neural stem cells with their precursor's label were continuously making neurons throughout an animal's lifetime. This capacity is called plasticity, which is the brain's ability to form new connections throughout life to compensate for injury and disease and to adjust in response to new input from the environment. The next step for the researchers is to look for the same neural stem cells in other mammals, most importantly in humans, starting the search in post-mortem brain tissue, and to investigate how this population of neural stem cells are regulated.

Link: https://www.pennmedicine.org/news/news-releases/2019/march/penn-researchers-discover-the-source-of-new-neurons-in-brain-hippocampus