Both genders lose muscle mass and strength with age, leading to sarcopenia and frailty. Why do women undergo age-related muscle loss more rapidly following menopause, however? Researchers here suggest that the sex hormone estradiol is necessary to support the activity of muscle stem cells, and thus falling levels of estrogen following menopause is the mechanism driving this outcome. Loss of stem cell function in muscle tissue is also the most credible cause for the onset of sarcopenia without considering gender, so this all fits together quite nicely.

Over the course of an individual's life, skeletal muscle undergoes numerous injurious insults that require repairs in order for function to be maintained. The maintenance and injury repair of skeletal muscle is dependent on its resident stem cell (i.e., the satellite cell). With proliferation, satellite cells undergo asymmetric division through which a subpopulation of the daughter satellite cells do not differentiate, but instead return to quiescence, repopulating the satellite cell pool (i.e., self-renewal). The balance of this asymmetric division process is critical and necessary to ensure the life-long preservation of satellite cells in skeletal muscle.

Aging diminishes the satellite cell pool and, as a result, the regenerative capacity of skeletal muscle in aged males is impaired compared to that of younger males, but such age-induced impairments in females is less studied. Similarly, age-associated changes in the satellite cell environment, in combination with cell-intrinsic alterations, disrupt quiescence and the balance of asymmetric division, ultimately impacting satellite cell maintenance and muscle regenerative potential. Such results support the concept that circulatory factors, including hormones that differ between the young and old systemic environments and the activity of their subsequent signaling pathways, contribute to age-associated decrements in satellite cell maintenance and overall muscle regenerative capacity.

A well-known hormone that changes with age is estradiol, the main circulating sex hormone in adult females. Serum estradiol concentration declines dramatically at the average age of 51 in women, corresponding to the time of menopause. Estradiol deficiency reduces skeletal muscle mass and force generation in women and prevents the recovery of strength following contraction-induced muscle injury and traumatic muscle injury in female mice. However, evidence that this regenerative phenotype involves effects of estradiol directly on satellite cells is lacking.

In this study, we use rigorous and unbiased approaches to demonstrate the in vivo necessity of estradiol to maintain the satellite cell number in females. Further, we use mouse genetics to show that the molecular mechanism of estradiol action is cell-autonomous signaling through estrogen receptor α (ERα). Specifically, we show the functional consequence of estradiol-ERα ablated signaling in satellite cells including impaired self-renewal, engraftment, and muscle regeneration, and the activation of satellite cell mitochondrial caspase-dependent apoptosis. Together, these results demonstrate an important role for estrogen in satellite cell maintenance and muscle regeneration in females.

Link: https://doi.org/10.1016/j.celrep.2019.06.025

Yet another sizable study has shown that common dietary supplements have little to no effect on late life mortality. This finding of course has to compete with the wall to wall marketing deployed by the supplement market. Researchers have been presenting data on the ineffectiveness of near all supplements of years, but it doesn't seem to reduce the enthusiasm for these products. In the past it was fairly easy to dismiss all supplements as nonsense, or at the very least causing only marginal effects that were in no way comparable to the benefits of exercise and calorie restriction, but matters are now becoming more complex. New supplements based on altered mitochondrial biochemistry or senolytic activity, such as nicotinamide riboside, mitoQ, and fisetin, might well have effect sizes that are worth it as an addition to calorie restriction and exercise; we shall see as human studies progress.

In a massive new analysis of findings from 277 clinical trials using 24 different interventions, researchers say they have found that almost all vitamin, mineral, and other nutrient supplements or diets cannot be linked to longer life or protection from heart disease. Although they found that most of the supplements or diets were not associated with any harm, the analysis showed possible health benefits only from a low-salt diet, omega-3 fatty acid supplements and possibly folic acid supplements for some people. Researchers also found that supplements combining calcium and vitamin D may in fact be linked to a slightly increased stroke risk.

Surveys show that 52% of Americans take a least one vitamin or other dietary/nutritional supplement daily. An increasing number of studies have failed to prove health benefits from most of them. "The panacea or magic bullet that people keep searching for in dietary supplements isn't there. People should focus on getting their nutrients from a heart-healthy diet, because the data increasingly show that the majority of healthy adults don't need to take supplements."

The vitamin and other supplements reviewed included: antioxidants, β-carotene, vitamin B-complex, multivitamins, selenium, vitamin A, vitamin B3/niacin, vitamin B6, vitamin C, vitamin E, vitamin D alone, calcium alone, calcium and vitamin D together, folic acid, iron and omega-3 fatty acid (fish oil). The diets reviewed were a Mediterranean diet, a reduced saturated fat (less fats from meat and dairy) diet, modified dietary fat intake (less saturated fat or replacing calories with more unsaturated fats or carbohydrates), a reduced fat diet, a reduced salt diet in healthy people and those with high blood pressure, increased alpha linolenic acid (ALA) diet (nuts, seeds and vegetable oils), and increased omega-6 fatty acid diet (nuts, seeds and vegetable oils). Each intervention was also ranked by the strength of the evidence as high, moderate, low or very low risk impact.

The majority of the supplements including multivitamins, selenium, vitamin A, vitamin B6, vitamin C, vitamin E, vitamin D alone, calcium alone and iron showed no link to increased or decreased risk of death or heart health. "Our analysis carries a simple message that although there may be some evidence that a few interventions have an impact on death and cardiovascular health, the vast majority of multivitamins, minerals and different types of diets had no measurable effect on survival or cardiovascular disease risk reduction."

Link: https://www.hopkinsmedicine.org/news/newsroom/news-releases/save-your-money-vast-majority-of-dietary-supplements-dont-improve-heart-health-or-put-off-death

Accumulation of senescent cells with age is one of the causes of aging. In recent years, the broader scientific community has become convinced of this point, and thus funding is now directed towards many varied investigations of cellular senescence and what to do about it. A young industry has emerged, made up of biotech companies focused on the selective destruction of senescent cells, mostly using small molecule drugs. Since these drugs operate through different mechanisms, tend to be tissue specific, only clear a fraction of senescent cells that varies by tissue, and will thus probably be more effective when combined together, research continues to find ever more senolytic compounds.

Senescent cells are created constantly, either in response to damage or a toxic local environment, or more commonly as the result of a somatic cell reaching the Hayflick limit on cell replication. Senescence is an irreversible state in which cell replication shuts down, and a potent mix of inflammatory signals is secreted. This can be useful in the short term, such as during wound healing, or to put a halt to potentially cancerous cells. Near all senescent cells either self-destruct or are destroyed by the immune system quite quickly. It is the tiny minority to linger that contribute to the aging process, such as by generating an environment of chronic inflammation.

The open access paper here is representative of numerous projects presently underway in the research and development communities, performing screening of small molecules from established databases in search of new senolytics. Some of these searches are more informed by prior investigation of plausible mechanisms than others, but at the end of the day the output is compounds that are then evaluated in detail for their ability to selectively destroy senescent cells. The best of the compounds noted here, fenofibrate, is on a par with navitoclax for selectivity, which is about at the lower level of what might be tolerable as a human therapy. The more off-target cells that are destroyed, the worse the side-effects. This is a starting point, however: other compounds in this category will no doubt be better, or might be engineered to be better.

Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy

Increasing evidence about the molecular mechanisms of ageing suggests that many chronic diseases such as osteoarthritis (OA) are associated with the hallmarks of ageing, including cellular senescence and defective autophagy. Accumulation of senescent cells in tissues contributes to age-related diseases. Articular cartilage of patients with OA shows features of senescence. Senescence-associated secretory phenotype (SASP) factors released from chondrocytes, such as pro-inflammatory cytokines and extracellular matrix degrading enzymes, have been identified as major mediators contributing to the development and progression of OA. Similarly, intra-articular injection of senescent cells in mice results in OA-like pathology.

Cartilage ageing can be modified by selective elimination of senescent chondrocytes to prevent the detrimental microenvironment changes occurring in joint dysfunction. A major step into the translation of senolytic treatments for OA was demonstrated by the beneficial effects of selective clearance of senescence chondrocytes using the Bcl-2 family inhibitor Navitoclax in animal models. The broad impact of senolytic treatment is also highlighted by the efficacy of dasatinib and quercetin combination in several models of age-related disease, which results in an extension of healthspan and lifespan in mice.

Cellular senescence and autophagy are not only essential for homeostasis but are potential therapeutic targets for age-related diseases. We aim to test this therapeutic hypothesis in preclinical models of OA, where senescence and autophagy play a relevant role. A novel cell-based dual imaging screening assay was developed to identify both senotherapeutics, able to either suppress markers of senescence (senomorphics) or to induce apoptosis of senescent cells (senolytics), and autophagy modulators.

Senotherapeutic molecules with pro-autophagic activity were identified. Fenofibrate (FN), a PPARα agonist used for dyslipidaemias in humans, reduced the number of senescent cells via apoptosis, increased autophagic flux, and protected against cartilage degradation. FN reduced both senescence and inflammation and increased autophagy in both ageing human and OA chondrocytes whereas PPARα knockdown conferred the opposite effect. Moreover, PPARα expression was reduced through both ageing and OA in mice and also in blood and cartilage from knees of OA patients.

Remarkably, in a retrospective study, fibrate treatment improved OA clinical conditions in human patients from the Osteoarthritis Initiative (OAI) Cohort. Blood from the PROspective Osteoarthritis Cohort of A Coruña (PROCOAC) and human cartilage from non-OA and knee OA patients were employed. Levels of PPARα were lower in OA patients compared to non-OA controls. The potential efficacy of PPARα agonists was also evaluated using the Osteoarthritis Initiative (OAI) Cohort. In this cohort, there were 35 fibrate users and 3322 participants not taking fibrates in the selected sample. Using a genetic matching, 35 fibrate users were matched to 35 participants in the control group. Interestingly, the results indicate that fibrate use by time interaction was associated with a statistically significant improvement of self-reported Western Ontario McMaster Osteoarthritis Index (WOMAC) function and WOMAC total scores. There was also a trend towards a decrease in WOMAC pain score. The results suggest that the fibrate use, when compared with non-use, was associated with a yearly decrease in WOMAC.

Stem cells perform the vital function of supporting surrounding tissue by providing new daughter somatic cells to make up losses and take their place to maintain tissue function. This stem cell activity declines with age, however, due to a combination of intrinsic damage to these cell populations, and increasing inactivity. The latter is an evolved reaction to rising levels of damage, one that serves to reduce cancer risk in earlier old age, but at the cost of a lengthy decline into incapacity. Pick near any dysfunction of aging and it is likely that loss of stem cell activity is to some degree contributing to the outcome.

Successful fracture healing requires the simultaneous regeneration of both the bone and vasculature; mesenchymal stem cells (MSCs) are directed to replace the bone tissue, while endothelial progenitor cells (EPCs) form the new vasculature that supplies blood to the fracture site. In the elderly, the healing process is slowed, partly due to decreased regenerative function of these stem and progenitor cells.

MSCs from older individuals are impaired with regard to cell number, proliferative capacity, ability to migrate, and osteochondrogenic differentiation potential. The proliferation, migration and function of EPCs are also compromised with advanced age. Although the reasons for cellular dysfunction with age are complex and multidimensional, reduced expression of growth factors, accumulation of oxidative damage from reactive oxygen species, and altered signaling of the Sirtuin-1 pathway are contributing factors to aging at the cellular level of both MSCs and EPCs.

Because of these geriatric-specific issues, effective treatment for fracture repair may require new therapeutic techniques to restore cellular function. The causes of cellular aging and the concomitant decline in functionality are wide-ranging, but provide some intriguing indications of potential targets for speeding fracture healing in older individuals. In the future, cell therapies that supplement the inadequate native cellular response with MSCs or endothelial colony forming cells (ECFCs); bone anabolic pharmacological agents, particularly in combination with strategies to localize their delivery to the bone fracture; drugs that reduce oxidative stress, cellular senescence, or activate SIRT1; and/or physical therapeutics may prove effective in promoting fracture healing in the elderly.

Advanced age is the primary risk factor for a fracture, due to the low bone mass and inferior bone quality associated with aging; a better understanding of the dysfunctional behavior of the aging cell will provide a foundation for new treatments to decrease healing time and reduce the development of complications during the extended recovery from fracture healing in the elderly.

Link: https://doi.org/10.4252/wjsc.v11.i6.281

Cellular senescence is a cause of aging. Cells become senescent in response to a variety of circumstances: damage, a toxic environment, reaching the Hayflick limit on replication, and so forth. In all cell populations, older individuals exhibit increasing numbers of senescent cells, perhaps largely due to the progressive decline of the immune system and its growing failure to clear out unwanted or harmful cells. Lingering senescent cells secrete a potent mix of signals that rouse the immune system into a state of chronic inflammation, and degrade tissue function and structure. The more of them there are, the worse the outcome.

Mesenchymal stem cells (MSCs) are located in specific areas of tissues, called "niches", and are characterized as being in a state of relative quietness, from which they can exit under the proper conditions to obtain the proliferative potential necessary for tissue regeneration. MSCs have sustained interest among researchers by contributing to tissue homeostasis and modulating inflammatory response, all activities accomplished primarily by the secretion of cytokines and growth factors, because their paracrine action is the main mechanism explaining their effects, regardless of source.

Senescence is defined as a mechanism for limiting the regenerative potential of stem cells. It is now evident that senescent cells secrete dozens of molecules, for which the terms "senescence-associated secretory phenotype (SASP)" and "senescence-messaging secretome (SMS) factors" have been proposed. The secreted factors contribute to cellular proliferative arrest through autocrine/paracrine pathways as well as in vivo and in vitro. SMS factors released by senescent cells play a key role in cellular senescence and physiological aging by activation of cytoplasmic signalling circuitry.

The population of mesenchymal stem cells, also known as mesenchymal stromal cells, contributes directly to the homeostatic maintenance of organs; hence, their senescence could be very deleterious for human bodily functions. The milestone in MSC investigation will be discovering senescence markers to determine the quality of the in vitro cells for cell-based therapies. Researchers have proposed TRAIL receptor CD264 as the first cellular senescence mesenchymal marker in bone marrow-derived MSCs, because it has the same expression profile of p21 during culture passage.

Link: https://doi.org/10.4252/wjsc.v11.i6.337

I recently attended the second Ending Age-Related Diseases conference in New York, hosted by the Life Extension Advocacy Foundation (LEAF). The mix of attendees was much the same as last year: an even split between scientists, entrepreneurs, investors, patient advocates, and interested onlookers, all focused on the treatment of aging as a medical condition. The presentations were similarly a mix of scientists talking about their research programs, entrepreneurs presenting on the data produced by their companies, and investors discussing the state of the industry.

For my part, I have already presented several times this year on the work taking place at Repair Biotechnologies, while we were raising our seed round. So rather talk again on a familiar topic, I chose instead to discuss the terrible state of clinical translation in the life science industry - the institutional, widespread, ongoing failure to develop promising research programs into therapies. This is particularly the case for the treatment of aging, given that translational research in gerontology was actively suppressed by leading scientists for much of the last 40 years. This was an overreaction to the "anti-aging" industry of fraud, supplements, and false hope established in the 1970s, and probably set us back decades.

Even now there is a great gulf between academia and industry, into which projects vanish. This gulf is built of many factors: scientists rarely have good connections to the people who could carry forward their projects; academic funding tends to stop once projects get close to the point at which they could be translated; universities do far too little to nurture new companies, and instead focus on being toll collectors; most investors sit around waiting for companies to form and come to them, rather than devoting their resources to helping companies form; and so forth. The result is that the research community is littered with credible projects in a dormant state, just waiting for someone to champion their development.

A number of fellow entrepreneurs in the longevity industry presented their latest data at the conference. Doug Ethell of Leucadia Therapeutics noted the proof of principle of his thesis on the roots of Alzheimer's disease, data obtained in ferrets. Partially occluding the cribriform plate in the skull, to mimic the process of ossification that occurs with age in humans, blocks drainage of cerebrospinal fluid, thus allowing amyloid and other molecular waste to build up in the brain and cause neurodegeneration and cognitive decline.

Greg Fahy of Intervene Immune presented quite a lot of data on what six to twelve months of treatment with growth hormone and DHEA does to the thymus and measures of immune system composition in older individuals. It makes for a compelling story, given their evidence for thymic regrowth and improvement in the immune system, for all that I remain dubious about growth hormone as a mode of treatment for aging. There is a lot of evidence to suggest that it isn't such a great plan. But perhaps undergoing a year of such treatment to have a somewhat larger, somewhat more active thymus going forward is a sensible trade-off, should these results hold up in larger patient groups.

John Lewis of Entos Pharmaceuticals gave a great presentation on the lipid nanoparticle (LNP) platform used by Oisin Biotechnologies to destroy senescent cells and by OncoSenX to destroy cancer cells. This platform is one of the candidate technologies to power all of the next generation of gene therapies, ensuring that most implementations can just work, comparatively simply, and with far less effort than is presently required. The presentation included the final study results from the mouse lifespan study run by Oisin Biotechnologies in which LNPs were set to target cells that expressed p16, p53, or both p16 and p53. That last group lived significantly longer, and had their first death at the point at which half of the control group had died.

Kelsey Moody presented on LysoClear, one of the ever growing number of subsidiary companies generated by the Ichor Therapeutics team. The company is developing an approach to treat macular degeneration by using compounds derived from bacterial enzymes to break down molecular waste that builds up in the lysosome, impairing cell function. His emphasis was on the need to be careful, conservative, and methodical in preclinical development, using LysoClear development as an example of always proving each step before moving on, building on well-proven existing work.

From the scientific community, Maria Blasco discussed at length her work on telomeres and telomerase gene therapy in mouse models. Her group sees loss of telomere length in tissues as a significant contributing cause of aging, with wide-ranging downstream effects, rather than a marker of aging that results from loss of stem cell function. Amutha Boominathan presented on her work at the SENS Research Foundation, moving mitochondrial genes into the cell nucleus in order to prevent the consequences of damage to mitochondrial DNA. In principle this can stop inevitable mitochondrial DNA damage from causing aging. Morgan Levine discussed epigenetic clocks based on DNA methylation, and what lies ahead in getting them to be useful to speed up development of rejuvenation therapies. The clocks and the therapies must develop in parallel, and many different clocks will likely be needed. The biggest task ahead is to understand exactly what it is that these epigenetic clocks are measuring.

From the investment community, Joe Betts-Lacroix noted that of the 1000 or so biotech startups out there, maybe 70 or so are credibly involved in working on aging and longevity. This industry is in its very earliest stages. One of the worthies in our community is presently assembling a database of those aging-focused startups, which I hope will be made publicly available fairly soon. There is a lot more that our community needs to do in order to help newly arriving entrepreneurs and investors become knowledgeable and productive quickly, and a database of companies is a good idea in this context.

Both James Peyer of the newly founded Kronos BioVentures and Sree Kant of Life Biosciences discussed how to invest in longevity, given the nature of the industry and its present constraints and peculiarities. James Peyer, as always, brought a very interesting set of ideas to the conference, and Life Biosciences is itself a sensible strategic response to the twin challenges of (a) a lack of entrepreneurs and (b) researchers who really don't want to leave academia. Life Biosciences wraps subsidiary companies around research teams, providing an environment that still feels like academia, and in which much of the trouble of running a company is abstracted away into the larger parent organization.

I have of course omitted mention of a number of other presentations and panels, and no offense is intended to the speakers. The above is really just a list of things that caught my attention, or that I happened to be there for rather than being caught up in meetings. All in all it was a good event, as was the case last year. The LEAF volunteers did a great job, and I encourage you to add this conference series to your 2020 agenda.

This popular science article from the AARP is representative of the sort of outsider's view of the longevity industry that is presently dominant. On the one hand, it is good that the media and advocacy organizations such as AARP are finally talking seriously about treating aging as a medical condition. On the other hand, the author looks at two of the most popular areas of development, mTOR inhibitors and senolytics, in a way that makes them seem more or less equivalent, and then further adds diet and exercise as another equivalent strategy. This will be continuing issue, I fear. People, as a rule, don't think about size of effect and quality of therapy when discussing present initiatives.

These strategies are in fact very different, and the differences are important. Clearance of senescent cells via senolytic treatments is a radically different and better class of therapy than mTOR inhibition. Senolytics remove a cause of aging in one treatment, improving all aspects of health in later life in consequence, while mTOR inhibitors must be taken continually and only encourage the aging metabolism into a state that is somewhat more resistant to the underlying damage that causes aging. Tackling underlying causes will always be more effective than trying to cope with those causes without repairing them.

"We've reached the perfect storm in aging science," says physician Nir Barzilai. "Everything is happening. We have the foundation from decades of animal studies. We're ready to move on to people." The ultimate goal: to put the brakes on aging itself - preventing the pileup of chronic health problems, dementia and frailty that slam most of us late in life. "I want 85 to be the new 65," says Joan Mannick, the chief medical officer and cofounder of resTORbio.

The need is enormous. In a decade, nearly 1 in 5 Americans will be 65 or older. Three out of 4 will have two or more serious health conditions. At least 1 in 4 can expect memory lapses and fuzzy thinking, while 1 in 10 will develop dementia. "Right now doctors play whack-a-mole with chronic diseases in older adults. You treat one, another pops up. The goal instead is to tackle aging itself, the major risk factor for almost every major disease. Our society, our drug companies and medical profession aren't addressing all this suffering that happens as people grow old. But the older people in my life are beloved to me. If we can do something about aging, we shouldn't ignore it."

Older people who took the mTOR inhibitor RAD001, a similar drug to resTORbo's RTB101, had a stronger response to a flu vaccine. Their immune systems looked younger, with fewer exhausted T cells - a depressingly common feature of aging called immunosenescence. "This was the first evidence that if you target a pathway in humans, you may actually impact how we age." The results of a trial of RTB101 were particularly strong for people 85 and older; they had 67 percent fewer infections. That's good news, because - in part due to an age-related weakening of the immune system - respiratory infections are the fourth-leading reason older U.S. adults wind up in the hospital and their eighth-leading cause of death.

Alas, there's more going wrong in older cells than on-the-fritz mTOR. Among these issues: inflammation; out-of-whack metabolism; inactive stem cells that can't repair body tissues; damage from stress, environmental toxins and free radicals; reduced "quality control," which can't eliminate rogue cells. These glitches boost the risk for everything from heart disease and stroke to diabetes, osteoarthritis, Alzheimer's disease, Parkinson's and cancer. If these and other cellular issues are the underlying causes of so many diseases, preventing cells from succumbing to them as they age is a key to preventing disease. That's why resTORbio, other biotech start-ups and university aging labs across the U.S. are launching an unprecedented number of human clinical trials with experimental compounds aimed at these mechanisms.

One big target: senescent cells that refuse to die, instead glomming up in joints and other body tissues. They pump out dozens of inflammatory compounds and other chemicals that contribute to age-related diseases. In a raft of mouse studies, clearing out these senescent cells boosted health - easing arthritis pain, improving kidney and lung function, increasing fitness, extending life and even making fur thicker. In January, the first-ever human study of a treatment to kill senescent cells in the lungs was published. Fourteen people with the fatal lung disease idiopathic pulmonary fibrosis took a mix of the drugs dasatinib and quercetin for three weeks. The verdict: The drug combo was safe, triggered just one serious side effect (pneumonia), and seemed to improve study volunteers' basic ability to stand up and walk. There were also hints it may have reduced senescent-cell activity, but the researchers say bigger, longer studies are needed.

Right now, simply staying healthy into our 80s, 90s and beyond is a lot like hitting the lottery jackpot. In a survey of 55,000 Americans age 65-plus, just 48 percent rated their health as very good or excellent. No wonder drugstores, the internet, and human history are littered with unproven rejuvenation come-ons. Meanwhile, as researchers slowly test these more legitimate drugs, what can we do today if we wish to retain good health longer? That answer has been with us all along. Not smoking, eating healthy, getting exercise, managing stress and sleep.

Link: https://www.aarp.org/health/drugs-supplements/info-2019/pill-drug-aging.html

Researchers here report on the finding that modest impairment of the histones responsible for packaging nuclear DNA into chromatin leads to slowed aging in short-lived laboratory species. This adds to the sizable number of existing forms of stress that can somewhat slow aging via hormetic processes, such as heat, lack of nutrients, and so forth. A little damage induces greater cellular maintenance activities, which on balance leads to more efficient, less damaged cells and tissues over the long term. Unfortunately, effects on life span are very much smaller in long-lived species such as our own, when compared with effects in short-lived species such as flies, worms, and mice.

In the nucleus of cells, DNA wraps itself around histone proteins forming a 'beads-on-a-string' structure called chromatin. Other proteins bind along chromatin and the structure folds further into more complicated configurations. Everything involving DNA would have to deal with this chromatin structure. For example, when a particular gene is expressed, certain enzymes interact with the chromatin structure to negotiate access to the gene and translate it into proteins. When chromatin stress happens, disruption of the chromatin structure can lead to unwanted changes in gene expression, such as expression of genes when they are not supposed to or lack of gene expression when it should occur.

In this study, researchers worked in the lab with the yeast Saccharomyces cerevisiae to investigate how the dosage of histone genes would affect longevity. They expected that yeast genetically engineered to carry fewer copies of certain histone genes than normal or control yeast would have chromatin changes that would result in the yeast living less than controls. "Unexpectedly, we found that yeast with fewer copies of histone genes lived longer than the controls." Yeast with a moderately low dose of histone genes showed a moderate reduction of histone gene expression and significant chromatin stress. Their response to chromatin disruption was changes in the activation of a number of genes that eventually promoted longevity.

"We have identified a previously unrecognized and unexpected form of stress that triggers a response that benefits the organism. The mechanism underlying the chromatin stress response generated by moderate reduction of histone dosage is different from the one triggered by histone overexpression we had previously described, as shown by their different profiles of protein expression responses." The researchers found that chromatin stress also occurs in other organisms such as the laboratory worm C. elegans, the fruit fly, and mouse embryonic stem cells, and in yeast and C. elegans the chromatin stress response promotes longevity. "Our findings suggest that the chromatin stress response may also be present in other organisms. If present in humans, it would offer new possibilities to intervene in the aging process."

Link: https://www.bcm.edu/news/molecular-and-human-genetics/novel-form-of-stress-longevity

Atherosclerosis causes a sizable fraction of all deaths in our species. It is the generation of fatty deposits in blood vessel walls, distorting, narrowing, and weakening the blood vessels. This ultimately leads to the major structural failure of a stroke or heart attack, in which a vital blood vessel ruptures or is blocked. Lipids, such as cholesterols, are carried in the blood stream throughout life, associated with low-density lipoprotein (LDL) particles. The innate immune cells known as macrophages are responsible for removing cholesterol from blood vessel walls via the processes of reverse cholesterol transport: macrophages ingest the cholesterol and pass it on to high-density lipoprotein (HDL) particles, which carry it back to the liver for excretion.

In youth, reverse cholesterol transport keeps blood vessels in good shape. With age, however, an increasing fraction of lipids become oxidized and damaged. This is in part a consequence of mitochondrial dysfunction and increasing chronic inflammation, leading to more oxidizing molecules in the body. Oxidized lipids, even in comparatively small amounts, cause macrophages to become dysfunctional, inflammatory, and sometimes senescent. This degrades the effectiveness of their activities, and leads to macrophage death. The fatty atherosclerotic plaques in blood vessels are in large part the debris of dead macrophages, in addition to lipids and oxidized lipids.

The growth of atherosclerotic plaques is thus a feedback loop, in which macrophages are overwhelmed by oxidized cholesterol, and their struggles attract more macrophages that attempt (and fail) to assist in clearing up the issue. Any signaling or chronic inflammation that induces more macrophages into a pro-inflammatory state rather than a pro-regenerative state will tend to accelerate the progression of atherosclerosis, either by calling in more macrophages, or by making macrophages less effective at reverse cholesterol transport.

That the state of macrophages can influence aging and age-related disease has become a topic of great interest in the research community in recent years, and not just in the context of atherosclerosis. Many age-related conditions have a strong inflammatory component, and it is possible to argue that in all such cases, this inflammation detrimentally affects the activities of macrophages. Researchers divide macrophage populations into the M1, inflammatory and aggressive phenotype and M2, pro-regenerative phenotypes. Both are needed, but with age, the balance shifts too far towards M1, characteristic of the rising chronic inflammation that takes place in later life. A variety of potential therapeutic approaches have been developed in recent years that aim to shift macrophages into the M2 phenotype, to override the signaling that leads them to adopt the M1 phenotype. The example here is one of the more recent ones.

Single systemic transfer of a human gene associated with exceptional longevity halts the progression of atherosclerosis and inflammation in ApoE knockout mice through a CXCR4-mediated mechanism

In recent years, different approaches have been developed to counteract the progression of vascular atherosclerosis, including cholesterol-level lowering and inflammation modulation. Owing to the large numbers of inflammatory molecular and cellular mediators, it is unlikely that blockade of a single cytokine will be therapeutically effective. Long-living individuals (LLIs) delay or escape atherosclerosis-related cardiovascular disease (CVD). We have previously found that LLIs are enriched for a longevity-associated variant (LAV) in BPI fold containing family B, member 4 (BPIFB4).

We report here new exciting results on the pleiotropic activity of LAV-BPIFB4 on different mechanisms of the atherogenic process. These benefits were not associated with changes in the lipid profile. In addition, we provide ex vivo and in vitro evidence that these beneficial actions may extend to human vasculature until to be inversely associated to subclinical index of atherosclerosis in selected patients. Mechanistically, the effects of LAV-BPIFB4 seem to be attributable to a CXCR4-dependent mechanism.

LAV-BPIFB4 gene therapy succeeded in the two primary endpoints, namely improving endothelial dysfunction and reducing adverse vascular effects in ApoE knockout mice fed a high-lipid diet. Interestingly, LAV-BPIFB4 gene therapy did not affect the serum cholesterol profile, but it did contrast the ability of oxidized cholesterol to induce endothelial dysfunction by positively modulating the inflammatory/immune background of atherosclerosis. In line with this, LAV-BPIFB4 redistributed the pool of monocyte subpopulations, redirecting them towards a pro-resolving phenotype.

This was reflected by the increased abundance of CXCR4+Ly6C-high monocytes in bone marrow and spleen, the two major tissue reservoirs of monocytes available to mobilize towards injured tissues. In the margination process, CXCR4 is considered the retention force in the vasculature. Therefore, we speculate that the higher level of CXCR4 in blood Ly6C-high monocytes after LAV-BPIFB4 treatment in mice may finely tune the transit time into the circulation, completing a protective intravascular differentiation process. Consistent with their functionally distinct immunological roles, newly recruited Ly6C-high but not Ly6C-low monocytes uniquely differentiate into pro-resolving M2 macrophages, driving murine atherosclerotic regression at the early stages of the disease. Accordingly, we documented an enrichment of M2 splenic macrophages, which can contribute to dampen T cell activation and proliferation in a CXCR4-dependent manner. This latter result is in keeping with the reported ability of CXCR4 to promote the acquisition of the M2 phenotype in healthy monocyte-derived macrophages.

It is reasonable to hypothesize that the mechanisms of hunger might mediate some fraction of the short-term and long-term benefits to health and life span noted to occur as a result of calorie restriction. Which in turn suggests that strategies for the practice of calorie restriction that suppress hunger might be counterproductive. The hormone ghrelin is involved in the response to hunger, and like most proteins it is involved in a range of processes in metabolism. Evolution tends to result in reuse of protein machinery in many mechanisms. Researchers here report on the connection between ghrelin and memory function, which, like many of the interactions between body and brain, is quite indirect.

Ghrelin is produced in the stomach and secreted in anticipation of eating, and is known for its role to increase hunger. For example, ghrelin levels would be high if you were at a restaurant, looking forward to a delicious dinner that was going to be served shortly. Once it is secreted, ghrelin binds to specialized receptors on the vagus nerve - a nerve that communicates a variety of signals from the gut to the brain. Researchers recently discovered that in addition to influencing the amount of food consumed during a meal, the vagus nerve also influences memory function. The team hypothesized that ghrelin is a key molecule that helps the vagus nerve promote memory.

Using an approach called RNA interference to reduce the amount of ghrelin receptor, the researchers blocked ghrelin signaling in the vagus nerve of laboratory rats. When given a series of memory tasks, animals with reduced vagal ghrelin signaling were impaired in a test of episodic memory, a type of memory that involves remembering what, when, and where something occurred, such as recalling your first day of school. For the rats, this required remembering a specific object in a specific location.

The team also investigated whether vagal ghrelin signaling influences feeding behavior. They found that when the vagus nerve could not receive the ghrelin signal, the animals ate more frequently, yet consumed smaller amounts at each meal. Researchers think that these results may be related to the episodic memory problems. "Deciding to eat or not to eat is influenced by the memory of the previous meal. Ghrelin signaling to the vagus nerve may be a shared molecular link between remembering a past meal and the hunger signals that are generated in anticipation of the next meal."

Link: https://www.eurekalert.org/pub_releases/2019-07/sfts-he070519.php

Stem cells are responsible for maintaining surrounding tissue function via generation of daughter cells to make up losses. Stem cell activity declines with age, and research of the past twenty years suggests that a sizable fraction of this decline is a reaction to rising levels of cell and tissue damage, rather than being due to intrinsic damage to the stem cells themselves. Thus researchers are searching for the signals that influence stem cell activity, with the intent of interfering in order to boost stem cell activity in old tissues. This seems a worse strategy than repairing the underlying damage that causes stem cell decline, but it is nonetheless a popular field of research, and there is plenty of evidence for it to be possible to produce some degree of benefits via this approach.

Researchers have discovered how regenerative capacity of intestinal epithelium declines when we age. Targeting of an enzyme that inhibits stem cell maintaining signaling rejuvenates the regenerative potential of an aged intestine. This finding may open ways to alleviate age-related gastrointestinal problems, reduce side-effects of cancer treatments, and reduce healthcare costs in the ageing society by promoting recovery.

The age-induced reduction in tissue renewal makes dosing of many common drugs challenging. Targeting of an inhibitor called Notum may provide a new way to increase the therapeutic window and to promote recovery in societies with the aging population. Researchers believe that in addition to direct targeting of Notum, lifestyle factors such as diet may also provide means to reduce Notum, and thus improve tissue renewal and repair.

Using organoid culture methods, researchers understood that poor function of tissue repairing stem cells in old intestine was due to aberrant signals from the neighboring cells, known as Paneth cells. "Modern techniques allowed us to examine tissue maintenance at a single cell level, and revealed which cell types contribute to the decline in tissue function. We were surprised to find that even young stem cells lost their capacity to renew tissue when placed next to old neighbors."

Normally intestinal epithelium is renewed by stem cells that rely on activity of Wnt-signaling pathway. Surrounding cells produce molecules that activate this pathway. The study shows that during ageing, Paneth cells begin to express a secreted Wnt-inhibitor called Notum. Notum enzymatically inactivates Wnt-ligands in the stem cell niche, decreasing regenerative potential of intestinal stem cells. However, pharmacologic inhibition of Notum rejuvenated stem cell activity and promoted the recovery of old animals after treatment with a commonly used chemotherapeutic drug with severe side-effects in the gut.

Link: https://www.helsinki.fi/en/news/life-science-news/repair-of-aged-tissue-can-be-enhanced-by-inhibiting-signals-from-neighbouring-cells

Mitochondria are the power plants of the cell, hundreds of bacteria-like organelles that divide like bacteria and are selectively destroyed when damaged by cellular quality control mechanisms. They carry out the energetic chemical reactions needed to package the chemical energy store molecule ATP that is used to power cellular processes. Some of the protein machinery vital to this function is encoded in mitochondrial DNA, a circular genome that resides in mitochondria themselves rather than in the cell nucleus with the majority of a cell's DNA. It is this DNA that is the Achilles' heel of mitochondria, as it is less well protected and repaired than is the case for nuclear DNA. It becomes damaged over time, and this damage leads to dysfunction in mitochondria and the cells that host them, particularly as cellular quality control mechanisms decline in efficiency with advancing age.

This mitochondrial dysfunction that manifests with age is an important component of age-related disease and disruption of normal tissue function. It is better studied in energy hungry tissues such as muscles and the brain, but it is a global phenomenon throughout the body. Evidence strongly implicates loss of mitochondrial function in sarcopenia, the loss of muscle mass and strength that occurs with age, and in all of the common age-related neurodegenerative conditions.

What can be done about this? The SENS approach is to create backups of mitochondrial genes in the cell nucleus, a process known as allotopic expression, with the challenge being that the resultant proteins have to be altered in ways that allow them to be delivered to mitochondria where they are needed. In principle this can eliminate the consequences of damage to mitochondrial DNA. This has been carried out as proof of principle at least for several mitochondrial genes. Other researchers have proposed the use of tools that can selectively destroy mutated mitochondrial DNA. Still others have suggested delivering new mitochondria into cells by exploiting one of a number of mechanisms by which this can happen naturally.

Of these approaches, only allotopic expression has made much progress towards realization, and even that line of work is arguably only at an advanced stage for one mitochondrial gene, via the work at Gensight Biologics. The open access paper here is illustrative of the present state of work on convincing cells to take up new mitochondria: the specific process used only works in cell cultures, and is thus only of potential near term use in rescuing the deteriorated function of cells from an aged patient prior to use in cell therapy. Even that might not be as useful a technique as induced pluripotency, which appears to clear out damaged mitochondria fairly effectively.

There is also the question of whether delivering new mitochondria without clearing out the old, damaged mitochondria will actually help in the long term. Damaged mitochondria can take over cells because their damage grants them either resistance to quality control mechanisms or the ability to replicate more readily than their undamaged peers. In that circumstance, new mitochondria will be quickly outcompeted by the existing damaged population, and whatever benefit is obtained will be short-lived.

Primary allogeneic mitochondrial mix (PAMM) transfer/transplant by MitoCeption to address damage in PBMCs caused by ultraviolet radiation

A substantial number of in vitro and in vivo assays have demonstrated the natural ability of cells to transfer mitochondria amongst each other. This phenomenon is most commonly observed in mitochondrial transfer from healthy mesenchymal stem/stromal cells (MSCs) to damaged cells. The transfer replaces or repairs damaged mitochondria and thereby reduces the percentage of dead cells and restores normal functions. In 1982, researchers introduced a type of artificial mitochondrial transfer or transplant (AMT/T) model using a co-incubation step between the recipient cell and exogenous mitochondria. Their pioneering study demonstrated for the first time that the mitochondrial DNA (mtDNA) of donor cells could be integrated into recipient cells and subsequently transmit hereditary traits and induce functional changes. AMT/T mimics the natural process of mitochondrial transfer, reprograms cellular metabolism, and induces proliferation. The introduction of this model elucidated the possible use of mitochondria as an active therapeutic agent.

Our study tests a modification of the original MitoCeption protocol which reduces the time and complexity of the protocol. We sought to determine if primary allogenic mitochondrial mix (PAMM) MitoCeption could be used to repair peripheral blood mononuclear cells (PBMCs) damaged by ultraviolet radiation (UVR). PAMM is composed of the PBMCs of at least three donors. Our results showed that when PBMCs are exposed to UVR, there is a decrease in metabolic activity, mitochondrial mass, and mtDNA sequence stability as well as an increase in p53 expression and the percentage of dead cells. When PAMM MitoCeption was used on UVR-damaged cells, it successfully transferred mitochondria from different donors to distinct PBMCs populations and repaired the observed UVR damage.

To our knowledge, this study is the first to demonstrate in-vitro that MitoCeption can be used to re-establish mitochondrial function loss caused by UVR exposure. Additionally, we successfully transferred a mix of different PBMC donors to one PAMM that was used to repair damaged cells. Other research groups have successfully transferred mitochondria from one cell donor type to others; however, none of them have mixed mitochondria isolated from different donors for the transfer/transplant. This study elucidates the potential to use mitochondria from different donors (PAMM) to treat UVR stress and possibly other types of damage or metabolic malfunctions in cells, resulting in not only in-vitro but also ex-vivo applications.

Cancer cells depend on lengthening their telomeres, usually via telomerase activity. Telomeres are the caps of repeated DNA sequences at the ends of chromosomes. A little length is lost with each cell division, and when short a cell either self-destructs or becomes senescent and ceases replication. Cancer cells can only replicate continually if telomeres are extended continually. Thus some research groups are looking into sabotage of telomerase or the alternative lengthening of telomeres (ALT) processes as the basis for a truly universal cancer therapy. Others, as here, are investigating ways to interfere in mechanisms that protect telomeres from degradation, hopefully obtaining much the same result in the end.

In the context of tumorigenesis, telomere shortening is associated with apparent antagonistic outcomes: on one side, it favors cancer initiation through mechanisms involving genome instability, while on the other side, it prevents cancer progression, due to the activation of the DNA damage response (DDR) checkpoint behaving as a cell-intrinsic proliferation barrier. Consequently, telomerase, which can compensate for replicative erosion by adding telomeric DNA repeats at the chromosomal DNA extremities, is crucial for cancer progression and is upregulated in nearly 90% of human cancers.

In human cells, telomeric chromatin is organized into a terminal loop (t-loop), nucleosomes, the non-coding RNA TERRA, the protein complex shelterin, and a network of nuclear factors. The shelterin complex is essential for telomere protection and comprises six subunits: Three subunits bind telomeric DNA (TRF1, TRF2, and POT1), while the three others establish protein-protein contacts: RAP1 with TRF2, TIN2 with TRF1, TRF2, and TPP1 with TIN2 and POT1. Each shelterin subunit has a specific role in telomere protection, i.e., TRF1 prevents replication stress, TRF2 blocks ataxia telangiectasia-mutated (ATM) signaling and non-homologous end joining (NHEJ), while POT1 blocks ataxia telangiectasia and Rad3-related (ATR) signaling.

A wealth of recent findings points toward shelterin as a valuable alternative to telomerase to fight cancer. Researchers have identified small molecule compounds targeting TRF1 using an FDA-approved library to screen for TRF1 expression and localization. Several of the drugs downregulating TRF1 expression interfere with common cancer signaling pathways. Treatment of lung cancer and glioblastoma cells with these compounds triggered DDR activation at telomeres and telomere replication defects. In patient-derived glioblastoma stem cells (GSC), these TRF1 inhibitors reduced stemness in vitro.

Link: https://doi.org/10.15252/emmm.201910845

Exercise is known to improve cognitive function, and researchers here delve into one of the mechanisms that may be responsible for this effect. Specifically, this work relates to synaptic plasticity in the brain, the ability of neurons to restructure their connections. This is important for learning and memory function. The work here is not the only project to have picked out specific genes and proteins relating to the regulation of brain function. It remains to be seen whether this can lead to some form of enhancement therapy at the end of the day, as may be the case for klotho and its effects on cognitive function.

The beneficial cognitive effects of physical exercise cross the lifespan as well as disease boundaries. Exercise alters neural activity in local hippocampal circuits, presumably by enhancing learning and memory through short and long-term changes in synaptic plasticity. The dentate gyrus is uniquely important in learning and memory, acting as an input stage for encoding contextual and spatial information from multiple brain regions. This circuit is well suited to its biological function because of its sparse coding design, with only a few dentate granule cells active at any one time. These properties also provide an ideal network to investigate how exercise-induced changes in activity-dependent gene expression affect hippocampal structural and synaptic plasticity in vivo.

While exercise is a potent enhancer of learning and memory, we know little of the underlying mechanisms that likely include alterations in synaptic efficacy in the hippocampus. To address this issue, we exposed mice to a single episode of voluntary exercise, and permanently marked activated mature hippocampal dentate granule cells using conditional Fos-TRAP mice. Exercise-activated neurons (Fos-TRAPed) showed an input-selective increase in dendritic spines and excitatory postsynaptic currents at 3 days post-exercise, indicative of exercise-induced structural plasticity.

Laser-capture microdissection and RNASeq of activated neurons revealed that the most highly induced transcript was Mtss1L, a little-studied I-BAR domain-containing gene, which we hypothesized could be involved in membrane curvature and dendritic spine formation. shRNA-mediated Mtss1L knockdown in vivo prevented the exercise-induced increases in spines and excitatory postsynaptic currents. Our results link short-term effects of exercise to activity-dependent expression of Mtss1L, which we propose as a novel effector of activity-dependent rearrangement of synapses.

Link: https://doi.org/10.7554/eLife.45920

There has been much discussion in the aging research community these past few years on the topic of whether or not there is a limit to human life span, and how one might even go about defining such a thing. While life spans are in a slow upward trend due to general improvements in medical technology, can this trend continue without end, or will it run into a roadblock? In essence this is a debate over what can be extracted from poor data, and which data is in fact poor. Since there are few extremely old people, and since verifying age becomes ever harder the further back one has to go to search for records, the data for human mortality at advanced ages is very open to interpretation and reinterpretation, highly dependent on statistical methodologies used, and opinions on reliability of various sources of data.

In a more practical sense, this is all a storm in a teacup. Obviously there are mechanisms at work that ensure that even the statistical outliers don't make it much past 120. Autopsies carried out on supercentenarians revealed transthyretin amyloidosis, and consequent heart failure, as the dominant cause of death. It is reasonable to hypothesize that this form of age-related damage ensures the effective upper limit on human life span - in the sense that there is no hard limit, but if critical organ dysfunction ensures that mortality rates are 50% yearly or higher, then the odds catch up pretty quickly.

Equally obviously, all of this is absolutely dependent on the present state of medical technology. If transthyretin amyloid can be broken down, such as via the theraputic approach developed by Covalent Bioscience, then the result will be that everyone who periodically undergoes the treatment will live longer. The same goes for clearance of senescent cells, and all the rest of the SENS program of ways to repair the causes of aging. If medical technology addresses the damage of aging, then the length of life changes.

A related topic is the question of whether or not mortality rates stop increasing in very late life. Studies show that extremely old flies stop aging, in the sense that aging is defined as an increase in mortality rate per unit time. The flies have very high mortality rates, as is fitting for being in very poor shape, burdened by the damage of aging, but those very high rates appear to plateau. Over the past fifteen years, various analyses have suggested and then refuted that such a plateau exists in humans. Again we come back to the point that the data for very advanced ages isn't all that great, and so there tends to be a great deal of debate. At present, the balance of evidence and argument suggests that, for our species at least, mortality rates do keep increasing past the age of 110.

Are We Approaching a Biological Limit to Human Longevity?

Until recently human longevity records continued to grow in history, with no indication of approaching a hypothetical longevity limit. Also, earlier studies found that age-specific death rates cease to increase at advanced ages (mortality plateau) suggesting the absence of fixed limit to longevity too. In this study we re-examine both claims with more recent and reliable data on supercentenarians (persons aged 110 years and over).

We found that despite a dramatic historical increase in the number of supercentenarians, further growth of human longevity records in subsequent birth cohorts slowed down significantly and almost stopped for those born after 1879. We also found an exponential acceleration of age-specific death rates for persons older than 113 years in more recent data. Slowing down the historical progress in maximum reported age at death and accelerated growth of age-specific death rates after age 113 years in recent birth cohorts may indicate the need for more conservative estimates for future longevity records unless a scientific breakthrough in delaying aging would happen.

Many gerontologists are now more conservative regarding the future growth of longevity, citing results confirm that further growth of maximum lifespan for humans becomes an increasingly difficult task. Still there are reasons for cautious optimism here. Systematic analysis of human mortality throughout the 20th century revealed that, once a particular cause of death is accounted for, there is a proportional increase in both median age of death and maximum life span. So the authors of this study believe that application of aging-focused interventions could result in a continued increase not only in the median, but in maximal life span in humans as well.

Further research is needed to overcome obvious limitations of our study by addressing remaining concerns about data quality and representativeness, as well as increasing sample sizes. Still the data used in our study are the best available data so far, and their analysis suggests that there may be a provisional limit to human life in our current state of biomedical knowledge.