Fight Aging!

Every cell contains hundreds of mitochondria, hard at work to produce the chemical energy store molecule adenosine triphosphate (ATP), used to power cellular activities. Mitochondria are complex structures, the evolved descendants of ancient symbiotic bacteria that are now integrated into the cell. At their center is the electron transport chain, a collection of protein complexes that conducts the energetic chemical reactions needed to make ATP. Mitochondria bear copies of a remnant circular genome, DNA distinct from that in the cell nucleus, which encodes some of the mitochondrial proteins necessary for mitochondrial function. The sequences for other mitochondrial proteins have migrated over time into the nuclear DNA.

A great deal of evidence points to a significant role for mitochondrial dysfunction in degenerative aging. This arises in part due to damage to mitochondrial DNA, which is less well protected and maintained than is the case for nuclear DNA. It is also a matter of age-related changes in the expression of mitochondrial genes in the cell nucleus, which appear to affect both function of mitochondria and the clearance of damaged mitochondria via mitophagy, a form of selective autophagy. Mitochondria are dynamic organelles, constantly dividing and fusing together, and imbalances in this behavior can impair mitophagy, as well as lead to smaller numbers of mitochondria than would be optimal.

Today's open access paper takes a look at the proximate outcomes rather than the proximate causes of mitochondrial dysfunction. Firstly a loss of ATP production, and secondly an increase in the production of oxidative molecules as a side-effect of the energetic activities of the electron transport chain. Too much oxidative stress on cells is damaging to their function, and dysfunctional mitochondria are the primary culprit when it comes to producing that oxidative stress.

Aging Triggers Mitochondrial Dysfunction in Mice

The current study sought to investigate the effects of aging on cardiac mitochondrial function by examining various parameters of mitochondrial respiration, ROS production, ATP production, mitochondrial membrane potential, mitochondrial swelling, and proton leakage. The findings of this study suggest that the aging process has a significant impact on cardiac mitochondrial function.

One of the most important findings of this study was that cardiac mitochondrial oxygen consumption was significantly lower in old mice than in young mice. Besides showing a slight reduction in oxygen consumption by complex I under the phosphorylative state (state 3), we observed a strong reduction in oxygen consumption by complex II state 3. This finding suggests that aging reduces mitochondrial respiratory capacity. Furthermore, this dysfunction in the complex II state 3 may indicate a characteristic failure of oxidative phosphorylation during aging. The decreased respiratory capacity in old mice could be attributed to an age-related decline in the expression and activity of electron transport chain complexes or a decrease in the number of functional mitochondria.

Additionally, our study demonstrated that under complex I and complex II state 3 stimulation, the production of mitochondrial reactive oxygen species (ROS) was higher in the hearts of older animals than in younger animals. This finding raises the possibility that the age-related decline in the antioxidant defense system, which lead to results in oxidative stress and cellular damage and may be the cause of the increased ROS production. These results are in agreement with the previously published studies that describe transcriptional changes in pathways related to ROS in the heart. Our study also showed that the mitochondrial ATP production under stimulation of complex I and complex II state 3 was significantly lower in the hearts of old versus young mice. This finding suggests that the production of mitochondrial ATP declines with age. The reduction in the number of functional mitochondria or the age-related decline in the activity of the electron transport chain complexes, which produce the proton gradient for ATP synthesis, may be the cause of this decline in ATP production

Interesting data, in particular, are the significantly depolarized mitochondrial membrane potential in the hearts of old versus young mice. This result explains the increase in mitochondrial ROS production in old mice once a membrane depolarization reduces the rate of electron flow, increasing the degree of electronic reduction in the phosphorylative chain and generating more ROS. Additionally, it explains the reduction in the production of ATP because the membrane depolarization also reduces the proton gradient, reducing the proton driving force through the ATP-synthase and impairing its functioning. The age-related changes in the expression and activity of the electron transport chain complexes or the mitochondrial uncoupling proteins may be the cause of the elevated mitochondrial membrane potential. Finally, the study showed that under complex I and II state 3 stimulation, the mitochondrial proton leakage was significantly higher in old mice compared to young mice hearts. This finding indicates that the mitochondrial proton leakage increases with aging, possibly as a result of the aging-related decline in activity of the electron transport chain complexes or the mitochondrial uncoupling proteins.

A few different approaches have been proposed to clear advanced glycation endproducts (AGEs) from the lens of the eye, where they build up with age to make the lens stiffer. That stiffness results from cross-linking of extracellular matrix molecules by AGEs, restricting their ability to move relative to one another, and thus changing the structural properties of thetissue. That in turn leads to presbyopia as the muscles of the eye can no longer produce the desired changes to the lens needed to focus on near objects. Sadly, the most advanced program of cross-link breaking for the eye, a formulation of lipoic acid choline ester, failed in its phase IIb clinical trial after promising earlier results. We might hope that other, similar approaches to lens cross-linking have a larger effect size, such as the work of Lento Bio, and the project noted here.

Presbyopia is an age-related vision disorder that is a global public health problem. Up to 85% of people aged ≥40 years develop presbyopia. In 2015, 1.8 billion people globally had presbyopia. Of those with significant near vision disabilities due to uncorrected presbyopia, 94% live in developing countries. Presbyopia is undercorrected in many countries, with reading glasses available for only 6-45% of patients living in developing countries. The high prevalence of uncorrected presbyopia in these parts of the world is due to the lack of adequate diagnosis and affordable treatment.

The formation of advanced glycation end products (AGEs) is a non-enzymatic process known as the Maillard reaction. The accumulation of AGEs in the lens contributes to lens aging (leading to presbyopia and cataract formation). Non-enzymatic lens protein glycation induces the gradual accumulation of AGEs in aging lenses. AGE-reducing compounds may be effective at preventing and treating AGE-related processes.

Fructosyl-amino acid oxidase (FAOD) is active on both fructosyl lysine and fructosyl valine. As the crosslinks encountered in presbyopia are mainly non-disulfide bridges, and based on the positive results of deglycating enzymes in cataracts (another disease caused by glycation of lens proteins), we studied the ex vivo effects of topical FAOD treatment on the power of human lenses as a new potential non-invasive treatment for presbyopia.

This study demonstrated that topical FAOD treatment resulted in an increase in lens power, which is approximately equivalent to the correction obtained by most reading glasses. The best results were obtained for the newer lenses. Simultaneously, a decrease in lens opacity was observed, which improved lens quality. We also demonstrated that topical FAOD treatment results in a breakdown of AGEs, as evidenced by gel permeation chromatography and a marked reduction in autofluorescence. This study demonstrated the therapeutic potential of topical FAOD treatment in presbyopia.

Link: https://doi.org/10.3390/ijms24087343

Researchers here report on a large study showing that an increased risk of dementia is correlated with postmenopausal hormone treatment in women. It may well be the case that the people who opt into this form of treatment are doing so because they tend to be more burdened by the processes of aging, and are thus more likely to develop later dementia regardless of the therapy. Under the hood, a range of possibly relevant mechanisms can be used to argue for protective or harmful effects of increased levels of the hormones used in these therapies; the biochemistry is complex and there is a lack of satisfactory answers as to whether long term use is in fact harmful in this way.

Dementia affects more women than men worldwide. Even when controlling for differences in survival rates, the incidence of dementia among women is higher compared with that of men, suggestive of risk factors related to the female sex. Oestrogen is known to have both neuroprotective and neurodamaging properties. Exogenous systemic oestrogen is used in the management of menopausal vasomotor symptoms. The effect of menopausal hormone therapy on the risk of dementia is uncertain.

Recent, large scale observational studies have reported a positive association between use of menopausal hormone therapy and Alzheimer's disease in long term users who initiated treatment before age 60 years. However, the studies were not able to obtain full exposure history of hormone treatment for most of their study population, especially short term use (e.g. up to five years) around the age of menopause. We report a nationwide study on the association between menopausal hormone therapy and development of dementia. 5,589 incident cases of dementia and 55,890 age matched controls were identified between 2000 and 2018 from a population of all Danish women aged 50-60 years in 2000 with no history of dementia or contraindications for use of menopausal hormone therapy.

Compared with people who had never used treatment, people who had received oestrogen-progestin therapy had an increased rate of all cause dementia (hazard ratio 1.24). Increasing durations of use yielded higher hazard ratios, ranging from 1.21 for one year or less of use to 1.74 for more than 12 years of use. Oestrogen-progestin therapy was positively associated with development of dementia for both continuous (hazard ratio 1.31) and cyclic (hazard ratio 1.24) regimens. Associations persisted in women who received treatment at the age 55 years or younger (hazard ratio 1.24). Findings persisted when restricted to late onset dementia (hazard ratio 1.21) and Alzheimer's disease (hazard ratio 1.22).

Link: https://doi.org/10.1136/bmj-2022-072770

The Impetus Grants project has for the past few years aimed to make rapid, low-overhead philanthropic grants to researchers in order to accelerate aging research. While choosing to funding specific proposals, the organizers appear to keep the bigger picture in mind. One might not agree with their chosen directions, but they do try to support work that would otherwise not be supported. The recent call for submissions for the August 2023 $10 million round of grants starts out on a contrarian note, in search of projects that can stress test existing directions and theories in the field, and ends with a thought on accelerating translation of preclinical programs into animal studies.

For my part, I'd say that the best approach to accelerate the field is to fund as many different approaches as possible to the point at which they can leave academia to raise venture funding sufficient to conduct initial clinical trials. Assessing a diverse set of approaches for their ability to produce results in non-human primates and human clinical trials may well be the fastest path to settling arguments about the best way forward for the field, about which mechanisms are most important, about which approaches have the highest priority. Much of the SENS agenda for rejuvenation biotechnology now has at least one company carrying forward an approach, and enough work is going into broadening the pool of venture funding available to the longevity industry for clinical development to give companies with good data a decent chance at raising enough to conduct initial clinical trials. What constitutes "fast" in this context still means waiting a decade, of course.

10 Million Dollars For Aging Science - Round 3 Announcement

Started in 2021, Impetus Grants made its goal to go after ideas in the aging space that would be ignored by traditional funders. Since then, we deployed more than $24 million into science, supporting a number of aging clinical trials, biomarkers, novel tools, and model organisms. In August of 2023, we will launch a new round, together with Hevolution and Rosenkranz foundations, providing $5 Million in matching funding each. Thematically, the upcoming round will be open-ended, with a focus on high-risk high-reward kind of aging science. We are also looking to enable the following kind of research, among other things.

1.Proposals that stress-test popular theories of aging. Example: Recently, there has been published yet another study showing that eliminating senescent cells is detrimental for the organism - this time in the lungs of mice.

2.Proposals that stress-test popular protocols for extending the lifespan. Example: In the last two years reprogramming has become the central topic of many companies and research groups. However, it hasn't been rigorously investigated or reported as to what extent rejuvenating effects of partial reprogramming happen due to the depletion (death) of aged cells in the reprogramming pool.

3.Category-openers or proposals that test novel mechanisms and approaches to reversing aging. Example: In the previous round we funded a project that was deemed to be very risky by our reviewers, as it didn't have any research precedents. That work, "Extending lifespan in C.Elegans by controlling mitochondrial membrane potential with light", pioneered a concept of external energy replacement for treating aging, creating a novel branch of aging research. We are looking forward to funding more proposals that develop absolutely new paradigms and ways of thinking about geroscience, even if it comes at risks.

4. Translation of preclinical findings. We continue looking into creating greater worldwide access to improved model organisms, to make early large-animal studies less prohibitively expensive. We will also continue supporting a great number of proposals that test the context-dependence of known aging modulators.

Applications will open on the main page on August 1st and will stay open until August 31st, 2023. More guidance on writing applications can be found on our website.

A sizable body of evidence indicates that raised blood pressure correlates with increased mortality. There are good reasons for this relationship to exist. Excessive blood pressure damages small vessels and delicate tissues in organs throughout the body, and that damage adds up. It also contributes to harmful remodeling of the heart, making it larger and weaker, and accelerates the growth of atherosclerotic plaque in arterial walls. Excessively low blood pressure in later life is also indicative of conditions that tend to lead to raised mortality, of course. As this study shows, there is a safest range somewhere in the middle.

We aimed to determine survival probabilities to age 90 for various systolic blood pressure (SBP) levels among women aged ≥ 65 years with or without blood pressure (BP) medication. We analyzed blood pressure data from participants in the Women's Health Initiative (n = 16,570) who were aged 65 or older and without history of cardiovascular disease, diabetes, or cancer. Blood pressure was measured at baseline (1993-1998) and then annually through 2005. The outcome was defined as survival to age 90 with follow-up until 2020.

During a follow-up of 18 years, 9,723 (59%) of 16,570 women survived to age 90. The SBP associated with the highest probability of survival was about 120 mmHg regardless of age. Compared to an SBP between 110 and 130 mmHg, women with uncontrolled SBP had a lower survival probability across all age groups and with or without BP medication. A 65-year-old woman on BP medication with an interpolated SBP between 110 and 130 mmHg in 80% of the first 5 years of follow-up had a 31% absolute survival probability. For those with 20% time in range, the probability was 21%.

In conclusion, an SBP level below 130 mmHg was found to be associated with longevity among older women. The longer SBP was controlled at a level between 110 and 130 mmHg, the higher the survival probability to age 90. Preventing age-related rises in SBP and increasing the time with controlled BP levels constitute important measures for achieving longevity.

Link: https://doi.org/10.1101/2023.06.22.23291783

Researchers here report on a demonstration of glial cell competition in the brain, conducted in mice but using human cells. The humanized mice started out with diseased glial cells possessing the mutation characteristic of Huntington's disease. Young human glial progenitor cells without the mutation were transplanted, and subsequently outcompeted the mutated cells, replacing them in the brain. This suggests that a similar strategy could work for a range of neurodegenerative conditions, one treatment to gradually replace problematic supporting cells in the brain. The regenerative medicine community is still struggling to achieve the reliable engraftment and survival of transplanted cells, as well as cost-effective means of generating patient-matched or universal cells, but the road ahead clearly leads to interesting destinations.

Competition among adult brain cells has not been extensively researched. To investigate whether healthy glia can outcompete diseased human glia in the adult forebrain, we engrafted wild-type (WT) human glial progenitor cells (hGPCs) produced from human embryonic stem cells into the striata of adult mice that had been neonatally chimerized with mutant Huntingtin (mHTT)-expressing hGPCs. The WT hGPCs outcompeted and ultimately eliminated their human Huntington's disease (HD) counterparts, repopulating the host striata with healthy glia.

Single-cell RNA sequencing revealed that WT hGPCs acquired a YAP1/MYC/E2F-defined dominant competitor phenotype upon interaction with the host HD glia. WT hGPCs also outcompeted older resident isogenic WT cells that had been transplanted neonatally, suggesting that competitive success depended primarily on the relative ages of competing populations, rather than on the presence of mHTT. These data indicate that aged and diseased human glia may be broadly replaced in adult brain by younger healthy hGPCs, suggesting a therapeutic strategy for the replacement of aged and diseased human glia.

Link: https://doi.org/10.1038/s41587-023-01798-5

I attended the Foresight Institute's 2023 Longevity Frontiers Workshop earlier in the year. This event series provides a chance to make connections with some of the longevity industry figures and academic researchers in the field of aging that are associated with the Bay Area venture and futurist communities. The format this year was rapid-fire seven minute presentations and longer discussions; the presentations are shared online. I presented an informal, abbreviated version of the Repair Biotechnologies viewpoint on the role of cholesterol in aging and disease, trying to cover at least the important points in the time allotted. This viewpoint is informed by our evidence for reversal of atherosclerosis and NASH in animal models following application of a gene therapy to selectively clear only pathological, excess, toxic cholesterol in tissues, which we view as a demonstration of the importance of localized excesses of cholesterol to these conditions.

Reason | Repair Biotechnologies @ Longevity Frontiers Workshop 2023

What are we going to do today? We're going to think differently for seven minutes about cholesterol and aging. I'm not going to mention LDL once. So! What goes wrong in this whole process?

Problem one: this is a problem of cholesterol transport. Localized excesses of cholesterol form when cholesterol transport is disrupted. If you are obese, you are disrupting everything everywhere, your body has nowhere left to put cholesterol, the situation promptly goes south. Otherwise, more subtle effects of aging operate on the cells that are needed to sustain cholesterol transport, leading to less pervasive but locally similar issues.

Problem two: oxidative stress that occurs with aging causes the creation of forms of toxic cholesterol. These are outright disruptive to tissue function, and are a problem that should be gotten rid of.

In both cases this is not really the present dogma in terms of how treatment is targeted or works for conditions related to cholesterol, which is why I'm suggesting that we need to think differently about this. Just focusing for a moment on problem one, the broken cholesterol transport system: as you may or may not know, cholesterol manufacture is expensive, energetically expensive, therefore we evolved not to do it in situ, where the cholesterol is needed. It is manufactured in the liver, largely, with a fifth of it coming from the diet, and then you have a Rube Goldberg system that transports this cholesterol everywhere it needs to be. It is needed everywhere! Every single cell in your body needs cholesterol.

When it works, great! But we can say that about everything in the young body. Aging degrades this system, and particularly the macrophages that are responsible for taking this cholesterol and removing it from where it gets stuck in your blood vessel walls. That is the real problem here, though certainly others exist due to the ability of aging to mess up everything that looks like a complex system.

A localized excess of cholesterol, however it comes about, is toxic. Cells have a limited ability to stash this excess as esterified cholesterol, or refuse to take it up. That capacity can be very easily overwhelmed by physiologically achievable levels of cholesterol - get a little bit fat, and you are causing toxic harm to yourself. Get old, and there is toxic harm taking place due to problems, such as macrophage dysfunction, that reach a tipping point and lead to accumulations of cholesterol in your blood vessel walls.

Excess intracellular cholesterol disrupts cell function and kills cells. Once the excess overwhelms the ability of the cell to esterify it, it becomes free cholesterol, and free cholesterol is explicitly toxic to cell function. This is what happens in the old body, and this is what happens in the obese body. In obesity, you get the very prevalent non-alcoholic steatohepatitis, NASH, which is a silent disease, and very problematic because it is irreversible at present. In the case of your dysfunctional macrophages in your blood vessel walls, you get atherosclerosis, which, coincidentally, is also largely irreversible at the moment. One you have developed a atherosclerotic lesion, that lesion isn't going away, and there is nothing you can do about it using the present standard of care.

These are both very large potential markets, if you can find a way to deal with this problem. But let us look at the other issue for a little bit, our problem two. The other issue is that inflammation and oxidative stress, which go hand in hand in aging, largely due to mitochondrial issues, produce altered, toxic forms of cholesterol. The more oxidative stress you have, when your dysfunctional mitochondrial produce more oxidative molecules than the body can handle, the more that those oxidative molecules are going to oxidize lipids.

That causes problems in many ways, and one of the problems that you are probably all familiar with, because of the work of Cyclarity, is the growing presence of 7-ketocholesterol. This is one of the worst of these oxidized lipids. It is implicated in a whole range of conditions in aging. One of those conditions in atherosclerosis, because 7-ketocholesterol punches above its weight, there are only small amounts of it relative to normal cholesterol, when it comes to the ability to disrupt macrophage function in arterial walls. But again, remember that an excess of normal cholesterol will achieve the same outcome without adding 7-ketocholesterol. 7-ketcholesterol is adding insult to injury on top of that.

How do we address both of these two problems? Cyclarity is addressing the second problem, and hopefully their approach produces a large effect size, something that you can add on top of statins. The way that you address both problems is by selectively clearing cholesterol. But! You can't just go into the body and clear cholesterol. It is in cell membranes. If you put enough cyclodextrins into the body for the small molecules to grab all of the cholesterol out of lesions in the blood vessel walls, the you probably also just turned that patient's blood to mush and killed them along the way, as the treatment will also grab cholesterol from cell membranes.

Thus we need something smarter, and that is what we do at Repair Biotechnologies. We have something smarter, a combination of human enzymes that act to safely break down only the excess free cholesterol inside cells - the non-esterified toxic cholesterol. It also happens to work on modified cholesterols, such as 7-ketocholesterol, when they get taken up into cells. Those molecules are also broken down. We have demonstrated that this produces very profound reversal of both NASH and atherosclerosis in animal models. Localized excess of cholesterol is the major mechanism by which these diseases operate. You have this local excess of cholesterol that produces toxic free cholesterol inside cells.

In the case of macrophages it disrupts their function, makes them foam cells, stops them doing their job, advances the tipping point to enable the growth of atherosclerotic lesions that will kill you. In the case of NASH, there is so much cholesterol in a NASH patient that it is just messing everything up: the whole liver is a toxic mess. But specifically, it is a toxic mess because of excess intracellular free cholesterol. If you can get rid of that, then everything else becomes much less of a problem.

That is this short topic in a less-than-seven-minute nutshell, Repair Biotechnologies and why you should think differently about cholesterol and aging. Why you should think differently is because if you clear free cholesterol, you observe profound reversal of conditions that cannot presently be reversed. Anyone who is interested - you know where to find us!

We have made considerable progress since presenting at Foresight last year. We work with lipid nanoparticle (LNP) / mRNA delivery systems at the moment, and we have used them to produce quite extensive reversal of NASH in animal models of the condition. On the strength of this work, we submitted an INTERACT meeting request to the FDA earlier this year, and were told to go straight to a pre-IND meeting. We plan to submit the pre-IND meeting package in, say, Q4 this year.

The density of capillary networks declines with aging, the result of a progressive impairment of the complex process of angiogenesis responsible for growing new vessels. This loss of the smallest components of the circulatory system is likely important in the progression of aging, in that it affects blood pressure and deprives energy-hungry tissues such as muscle and brain of the oxygen and nutrients needed for correct function.

Researchers here view this aspect of vascular aging through the lens of the extracellular matrix, a tissue feature that also changes with age in ways known to be detrimental. Are these changes an important contributing cause of impaired angiogenesis? For any manifestation of aging, it is a challenge to determine which of the potential contributing causes are more or less important, given the inability to intervene in a very selective, pinpoint way. It is most likely faster and better to try to fix every potential issue, finding out along the way that some are not in fact all that important, than to first try to understand which processes should be targeted.

Angiogenesis is the process by which new capillaries form by sprouting from pre-existing ones. Each step in angiogenesis is regulated by the extracellular matrix (ECM). This process involves the migration, proliferation, and differentiation of endothelial cells (ECs) and pericytes and results in elongation of the initial tip, followed by anastomosis with other blood vessels to form perfused vascular branches. Accumulating evidence indicates that angiogenesis is impaired in older adults, contributing to cardiovascular and cerebrovascular disease and delayed wound healing, reducing the quality of life and causing a significant burden for healthcare systems.

Evidence indicates that ageing-related changes in the ECM driven by cellular senescence lead to a reduction in neovascularisation, reduced microvascular density, and an increased risk of tissue ischaemic injury. Elucidating interactions between the ECM and cells during angiogenesis in the context of ageing is necessary to clarify the mechanisms underlying reduced angiogenesis in older adults. In this review, we summarize ageing-related changes in the composition, structure, and function of the ECM and their relevance for angiogenesis. Then, we explore in detail the mechanisms of interaction between the aged ECM and cells during impaired angiogenesis in the older population for the first time, discussing diseases caused by restricted angiogenesis.

We also outline several novel pro-angiogenic therapeutic strategies targeting the ECM that can provide new insights into the choice of appropriate treatments for a variety of age-related diseases. Based on the knowledge gathered from recent reports and journal articles, we provide a better understanding of the mechanisms underlying impaired angiogenesis with age and contribute to the development of effective treatments that will enhance quality of life.

Link: https://doi.org/10.1186/s12967-023-04315-z

Researchers here demonstrate that one can create a signature of replication-based epigenetic change in cells, and that this signature is stronger in old tissues and cancerous tissues. This leads to a view in which increased replication stress on cells in a tissue, meaning a tissue that is made up of cells that have divided more times on average, have shorter telomeres, and are closer to the Hayflick limit, creates an environment that is epigenetically predisposed towards cancer. Looking at this another way, aging is characterized by reduced stem cell function, meaning a lower pace of creation of daughter somatic cells to replace losses in a tissue. It seems inevitable that this must lead to a tissue in which the average somatic cell has replicated a greater number of times, and is thus more at risk of cancerous transformation.

Mutations are not the only, or perhaps even the most important, molecular events that result from cellular proliferation. We and others have shown that DNA methylation (DNAm) is also substantially altered as a direct function of cell division. Further, the epigenome has been shown to undergo dramatic changes with aging and is implicated in establishing, driving, and maintaining many cancers.

Coincidently, the DNAm changes observed in aging, cancer, and proliferation share some notable patterns. In general, they tend to be characterized by gains in methylation at promoters - especially those marked by polycomb group (PcG) factor targets - and loss of methylation in intergenic regions and repetitive elements. Thus, one hypothesis is that as cells replicate in aging tissues, they may also take on epigenetic signatures that are more cancer-like, making the leap to oncogenic transformation progressively more likely with time.

To date, the field has linked (i) age-related epigenetic changes and cancer phenomenon and (ii) replication-related changes to cancer, but little evidence exists linking all three simultaneously. It also remains unclear whether age-related replication-based changes are tumorigenic switches, and can perhaps predate the disease, or whether they are simply outcomes of cancer and uncontrolled proliferation. To test these hypotheses, we quantified a "replication fingerprint" in DNAm data derived from extensively passaged immortalized human cells using a de novo computational training platform.

This signature, termed CellDRIFT, increased with age across multiple tissues, distinguished tumor from normal tissue, was escalated in normal breast tissue from cancer patients, and was transiently reset upon reprogramming. In addition, within-person tissue differences were correlated with predicted lifetime tissue-specific stem cell divisions and tissue-specific cancer risk. Our findings suggest that age-related replication may drive epigenetic changes in cells and could push them toward a more tumorigenic state.

Link: https://doi.org/10.1126/sciadv.adf4163

The established non-surgical forms of cancer treatment, chemotherapy and radiotherapy, induce cellular senescence via stress and damage to cells. The target for these harmful effects is the cancer, but other cells are also inevitably stressed to the point of entering a senescent state. An increased burden of senescent cells in tissues throughout the body is a feature of aging. These cells directly contribute to dysfunction of tissues and organs via secreted signals, the senescence-associated secretory phenotype (SASP). When maintained over the long term, the SASP contributes to the onset and progression of age-related conditions. To the extent that a person suffers an increase in the burden of senescent cells, he or she becomes biologically older.

In this context, it is well known that cancer survivors exhibit a lower life expectancy and increased risk of age-related disease. It is presently thought that senescent cells are likely the primary cause of this outcome. In the near future, we might expect to see that cancer treatments are followed by senolytic therapies to clear the excess of senescent cells produced the therapy. Given sufficiently efficient senolytics, this approach will likely eliminate the lasting consequences of chemotherapy and radiotherapy.

Women treated for breast cancer may age faster than cancer-free women

Women diagnosed and treated for breast cancer have increased biological aging compared to women who remain free of breast cancer, according to a new study. Among women diagnosed with breast cancer, the association with faster biological aging was most pronounced for those who received radiation therapy, while surgery showed no association with biological aging. This finding suggests that developing cancer is not what increases the aging effect.

Biological age reflects a person's cell and tissue health, and it differs from chronological age. To measure biological age, the researchers studied 417 women who had blood samples collected at two time points about eight years apart. About half of the women studied were selected because they had developed breast cancer during that time span. The participants are enrolled in the Sister Study, a research effort that seeks to identify environmental risk factors for breast cancer risk and other health conditions, led by the National Institute of Environmental Health Sciences (NIEHS), part of NIH.

The researchers used three different established "methylation clocks" to determine if there were changes in a women's biological age between the two time points. The clocks measure naturally occurring, chemical modifications to a person's DNA, known as methylation changes. Small variations in methylation patterns can help determine a person's risk of developing an age-related disease. Women diagnosed with breast cancer had faster aging rates by all three clocks, with no significant racial differences, when compared to women who did not develop breast cancer.

Next the scientists examined whether biological age was associated with specific treatment regimens, such as surgery, chemotherapy, radiation therapy, and endocrine therapy. Among women with breast cancer, aging rates varied by treatment type. "Radiation is a valuable treatment option for breast cancer, and we don't yet know why it was most strongly associated with biological age. This finding supports efforts to minimize radiation exposures when possible and to find ways to mitigate adverse health effects among the approximately 4 million breast cancer survivors living in the United States."

Researchers here note an interesting role for one of the common ketone bodies found in mammalian biochemistry, in that it provokes clearance of amyloid-β via its interaction with that molecule. An increase in misfolded amyloid-β is involved in the early stages of Alzheimer's disease, and seems likely to cause some fraction of the pathology of that condition. If comparatively simple approaches could keep amyloid-β levels low in later life, then the incidence of Alzheimer's disease might be reduced. That said, while the mechanism described here is interesting, it doesn't mean that the effect size, relative to other mechanisms involved in Alzheimer's disease, will actually turn out to be large enough to care about. Finding out whether that is the case will require further efforts.

Loss of proteostasis is a hallmark of aging and Alzheimer disease (AD). Here, we identify β-hydroxybutyrate (βHB), a ketone body, as a regulator of protein solubility in the aging brain. βHB is a small molecule metabolite which primarily provides an oxidative substrate for ATP during hypoglycemic conditions, and also regulates other cellular processes through covalent and noncovalent protein interactions.

We demonstrate βHB-induced protein insolubility across in vitro, ex vivo, and in vivo mouse systems. This βHB-induced insolubility leads to misfolded protein turnover in vivo, likely via βHB communication with cellular protein degradation pathways. This activity is shared by select structurally similar metabolites, and is observable in mouse brains in vivo after delivery of a ketone ester. Furthermore, this phenotype is selective for pathological proteins such as amyloid-β, and delivery of exogenous βHB ameliorates pathology in nematode models of amyloid-β aggregation toxicity.

We have generated a comprehensive atlas of the βHB-induced protein insolubility using mass spectrometry proteomics, and have identified common protein domains within βHB target sequences. Finally, we show enrichment of neurodegeneration-related proteins among βHB targets and the clearance of these targets from mouse brain, likely via βHB-induced autophagy. Overall, these data indicate a new metabolically regulated mechanism of proteostasis relevant to aging and AD.

Link: https://doi.org/10.1101/2023.07.03.547547

Prevention of age-related disease is in principle a good deal easier than effecting a cure. This is why it is important to develop methods of early detection of disease, identifying people who are at risk well prior to the onset of symptoms. This is particularly so in the case of neurodegenerative conditions, such as the Lewy body dementia that is the subject of the research noted here, in which the causative biological changes build up over years or decades prior to evident symptoms. Early intervention with even presently available strategies or lifestyle changes might be enough to meaningfully delay the onset of disease.

Lewy body disease is an umbrella term for Parkinson's disease and Lewy body dementia. When movement difficulties are more dominant, the disease is called Parkinson's disease, and when cognitive impairments are dominant, the term Lewy body dementia is used. Lewy body disease is caused by the misfolding of the alpha-synuclein protein in the brain. When this happens, the protein clumps together and forms what are called Lewy bodies, which damage the nerve cells.

Until very recently, it was not possible to determine with certainty whether a person with movement difficulties or cognitive impairments had Lewy bodies in the brain until after their death. But now, with a spinal fluid test, it is possible to see if the person has the misfolded protein. Researches conducted a large study involving over 1,100 individuals, none of whom initially showed any cognitive impairments or motor difficulties. However, it turned out that nearly ten percent had Lewy bodies in their brains according to the spinal fluid test. Therefore, it is possible to detect Lewy body disease even before the first symptoms appear.

"Despite the participants not having any cognitive or neurological problems at the beginning of the study, we observed that those with Lewy bodies in the brain subsequently experienced a decline in their cognitive functions over time. They were also the ones who developed Parkinson's disease or Lewy body dementia in the coming years." An interesting finding was also that Lewy bodies are strongly associated with a reduced sense of smell even before other symptoms have developed. The sense of smell also deteriorates as the disease progresses. The correlation is so clear that it could be justified to screen individuals over 60 years of age with a smell test and then proceed with testing spinal fluid if one wants to detect Lewy body disease early

Link: https://www.lunduniversity.lu.se/article/lewy-body-disease-can-be-detected-symptoms

Mitochondrial copy number is a measure of the average number of mitochondrial genomes found inside each cell in a blood or tissue sample. It is to be expected that cells contain a few hundred or more mitochondria, and a similar number of circular mitochondrial genomes, at least one per mitochondrion. In the case of blood samples, only white blood cells and platelets carry mitochondria. This makes any assessment of mitochondrial function from a blood sample actually an assessment of immune function first and foremost.

A wealth of evidence suggests that mitochondrial copy number is a measure of mitochondrial function, though not necessarily a direct measure. The number of mitochondria in a cell are affected indirectly by various forms of mitochondrial dysfunction because they have consequences on mitochondrial replication, the dynamics of fusion and fission, and clearance of mitochondria by mitophagy. Mitochondrial copy number has also been shown to correlate with self-assessed health and with epigenetic age. Additionally, lower mitochondrial copy number produces what appear to be unfavorable, disease-associated epigenetic changes in a cell.

Today's open access paper adds to these past studies. The authors present interesting results from a sizable epidemiological study of older individuals with a long follow-up. There is a strong correlation between 15-year mortality and mitochondria copy number, but not a straightforward one: both high and low mitochondrial copy number do better than those in the middle tertile of the range, where there is more than a twofold increase in mortality versus the top tertile. High is best, low is worse, but being in the middle is much worse than that. This suggests a complicated relationship between mitochondrial copy number and mitochondrial function is taking place under the hood. Again, this is likely best taken as a measure of immune function first and foremost, and not necessarily indicative of what would be found for mitochondrial health in cells making up the tissues of the body. It is nonetheless food for thought, particularly given the size of the difference in mortality between groups.

The Relationship between All-Cause Natural Mortality and Copy Number of Mitochondrial DNA in a 15-Year Follow-Up Study

The process of ageing is characterized by a progressive decline in organism functions, which leads to multimorbidity and mortality. To respond to the increase in deaths related to population ageing for the leading causes of death, ageing-related health research represents the emergent agenda. There is a battery of molecular markers of "biological age" which are explored as determinants of the rate of ageing, including the copy number of mitochondrial DNA (mtDNA-CN). Mitochondria regulate a number of cellular processes, including ATP production by oxidative phosphorylation (OXPHOS), apoptosis, β-oxidation of fatty acids and the biogenesis of iron-sulfur clusters, and are involved in the production of reactive oxygen species (ROS). Ageing is accompanied by a decay in mitochondria function, alteration in its morphology, mitochondrial content, and OXPHOS capability.

The content of mtDNA in cells and tissues is connected to metabolic activities, but how mtDNA copy number (mtDNA-CN) is adjusted to and maintained at a certain level is poorly understood. Many studies showed a reduction in mtDNA-CN in older subjects, and the estimates of an extent of decline of copies by decade have not been reported. There are facts of the association between low mtDNA-CN and all-cause and cardiovascular (CVD) mortality; however, the studies of mtDNA content in nonagenarians and centenarians have contradictory results. Referring to specific age-related outcomes, the inverse relationship between mtDNA-CN and fatal and non-fatal CVD outcomes was reported in several studies. At the same time, the estimates of potential associations between an alteration in mtDNA-CN and chronic kidney disease or cancer are rather heterogeneous depending on the cancer type and study design.

We examined a random population sample in 2003/2005 (n = 9,360, age 45-69, the HAPIEE project) and followed up for 15 years. Using a nested case-control design, we selected non-external deaths among those free from baseline cardiovascular diseases (CVD) and cancer (n = 371), and a sex- and age-stratified control (n = 785). The odds ratios (ORs) of death were 1.06 per one-decile decrease in mtDNA-CN independent of age, sex, metabolic factors, smoking, alcohol intake, and education.

The age-sex-adjusted ORs of death in the second and first tertiles of mtDNA-CN vs. the top tertile were 2.35 and 1.59; an increased risk was confined to the second tertile after controlling for smoking and metabolic factors. The multivariable-adjusted OR of CVD death was 1.92 in tertile 2 vs. the top tertile of mtDNA-CN, and for cancer-related death the ORs were 3.66 and 2.29 in tertiles 2 and 1 vs. the top tertile. In the Siberian population cohort, the mtDNA-CN was an inverse predictor of the 15-year risk of natural mortality, due to the greatest impact of CVD and cancer-related death. The findings merit attention for exploring further the role of mtDNA in human ageing and the diversity of mortality.

This popular science article surveys the present state of development towards the goal of regenerating teeth and their supporting structures. In animal studies, researchers have managed to grow and implant whole teeth, though much work remains to better control the processes involved. Similarly, proof of concept studies have demonstrated regrowth of enamel to heal cavities. More advanced is regeneration of dental pulp, where the established techniques of regenerative medicine and tissue engineering can be applied to the problem directly.

Teeth can undergo a lot of damage. In particular, when wily bacteria sneak past the protective outer layer of the tooth, they can penetrate the dental pulp that lives at its core. These unwanted residents trigger inflammation - more recognizable to us as searing pain and swelling. The teeth aren't defenseless, though. They can fight off minor infections and repair some damage. This ability to regenerate comes from stem cells buried in the dental pulp. These cells can turn into many of the different cell types required for healthy dental pulp, but they don't always have enough juice on their own to restore tissue damaged by an infection or other injury.

One way that scientists imagine repairing a damaged tooth is by delivering stem cells into the tooth and giving them the right signals to regenerate the damaged cells. The tricky part is knowing exactly which factors will lead to this outcome; after all, growing a glob of fat in a tooth socket would not be helpful. Other groups have developed 3D-printed scaffolds designed to match the shape of the damaged area. A team made scaffolds shaped like human and rat teeth out of biodegradable polymers. The scaffolds had tiny channels to deliver molecules that would steer the stem cells toward bone- and tooth-supporting cell types. After nine weeks implanted in a rat, the desired cells began to form at the base of the scaffold.

The ultimate goal for many regenerative dentists is to grow a whole human tooth for implant. However, that possibility is still far away. Teeth are complex organs, with many different components making up even the smallest incisor: dental pulp, enamel, dentin, and more. During human development, mesenchymal stem cells interact with other types of cells to generate the inner and outer layers of a tooth; this process is still poorly understood, and replicating it artificially is no small task. One challenge that continues to stump the scientists is how to get tissue engineered teeth to grow faster. The teeth still seem to follow their normal biological clocks, so they grow too slowly to make them usable on demand in the clinic.

Link: https://www.drugdiscoverynews.com/stem-cells-take-root-15712

Researchers here report that increased levels of some circular RNAs in leukocytes isolated from blood samples correlate well with age-related frailty. Interventions such as structured exercise programs that known to help with frailty may reduce levels of these circular RNAs, though more exploration than took place in the present study would be needed to confirm that this is the case. As to why this relationship exists between frailty and specific circular RNAs, that is a question for researchers to explore in the years ahead.

Frailty is an intermediate and reversible geriatric syndrome that often precedes dependence. Therefore, its identification is essential to prevent dependence. Several molecules have been proposed as biomarkers of frailty, but none of them have reached clinical practice. Recently, circular RNAs have emerged as new non-coding RNAs. Their regulatory role together with their high stability in biofluids makes them good candidates as biomarkers for various processes, but, to date, no study has characterized the expression of circRNA in frailty.

We studied RNA from leukocytes of 35 frail and 35 robust individuals to determine the best circRNA combination to discriminate frail from robust. In addition, CircRNA candidates were studied in 13 additional elder donors before and after a 3-month physical intervention. We found 89 differentially expressed circRNAs with frailty. Upregulation of hsa_circ_0007817, hsa_circ_0101802 and hsa_circ_0060527 in frail individuals was validated. The combination of hsa_circ_0079284, hsa_circ_0007817 and hsa_circ_0075737 levels showed a great biomarker value with a 95.9% probability of correctly classifying frail and robust individuals. Moreover, hsa_circ_0079284 levels decreased after physical intervention in concordance with an improvement in frailty scores.

This work describes for the first time a different expression pattern of circular RNA (circRNAs) between frail and robust individuals. Moreover, the level of some circRNAs is modulated after a physical intervention. These results suggest that they could be used as minimally invasive biomarkers of frailty.

Link: https://doi.org/10.1186/s12979-023-00356-6

That so many people turn their hand to lobbying government is a sad statement of the character of our era. Those engaged in getting things done start to feel, at some level of funding, that lobbying is a necessary defense on the one hand, against Big Pharma entities who will use regulators to impede and coerce competition, and on the other hand a way to access greater funding and publicity. The trough of public funds is ever an attractive proposition, and never as easy to access without tainting everything involved as people would like to think it is. A world with smaller, less powerful governments would be a world in which one could focus on the important matters, which is to say building the means to treat aging, creating the necessary technological capabilities.

We don't live in that world, unfortunately, and thus a good many people see the first step in advocacy to be petitioning for increases in government funding - as though the National Institute on Aging (NIA) is in any way the place where meaningful progress towards the treatment of aging as a medical condition is taking place. It isn't. The important work presently takes place in some combination of philanthropically funded scientific projects and venture funded biotech companies.

For those who are interested in lobbying as a way forward, today's commentary makes it clear that the present state of efforts is rudimentary, barely underway as assessed in the grand scheme of things. The existence of the opportunity to treat aging as a medical condition is hardly even recognized in those portions of the corridors of power and influence concerned with biotech lobbying. This is somewhat interesting to note, as efforts of one sort or another have been underway for the better part of two decades in the US. Consider the Longevity Dividend attempts to increase NIA funding, or the various non-profit lobbying groups emerging from the early longevity community, such as the Global Healthspan Policy Institute and Alliance for Longevity Initiatives.

Still, today is different from ten years past because a great deal of funding is now involved, and an industry exists. That changes the players and the calculus. Ten years from now, I'd imagine that we'll see a lot more political lobbying and political graft in the longevity field, making it much more like the current status quo between Big Pharma and government, for better or worse.

Cambrian Bio: Launching A Prevention Policy Agenda

Prevention might be worth a pound of cure to the individual, but to the American healthcare innovators, cures are worth much more. It's a well-known axiom that America has a sick-care rather than a health care system. Our ultimate goal at Cambrian Bio is to develop primary preventive medicines, but the sick care system persists. So, we visited the Nation's capital. We talked to elected officials and administration experts, advocates and think tanks about the medicines Cambrian is developing and the challenges inherent in developing preventive medicines.

In policy circles, most people think of longevity science exclusively in terms of behavioral interventions. That's not terribly surprising given the popularity of shows like Limitless and the fact that medicines based on the biology of aging are just starting to make it into human trials. But even the prevention policy experts we spoke with hadn't heard about the possibility that life-extending medicines for mice could be tested in humans. Our Takeaway: We are very early. Those of us in the field need to continue talking about this work, but when we do, we need to assume our audience is starting from scratch. You'll see our policy blog go back to the basics, laying the groundwork to fill this gap.

Shifting demographics may be one of the most important reasons to invest in the prevention of aging-related diseases, but it may not be the most compelling argument in Washington ... yet. We'll keep thinking about this. In today's world, generating the data to prove effectiveness for FDA approval is essential but perhaps not sufficient. The drug development industry may need a new story to tell about how scientists, biotech, and pharma are creating more value for society with their medicines rather than just increasing healthcare costs. Granted, we're biased, but we think inexpensive preventative medicines will be a key lever to drive this point home and unlock support for future innovation. As a field, we believe we have a good story to tell and we think the time is ripe for that pivot.

Rather than popular science, here we have a popular economics article on the present state and future of the longevity industry. It is a superficial survey of the field, but interesting for pulling together some of the available economic statistics and forecasts into one place.

Making human beings live longer in good mental, neurological and physical health would be one of the most important steps humanity has ever taken. Not only because of the suffering experienced by millions of people around the world, but also because of the massive impact it would have on society, the economy and the public policies of any state. Many countries are under the threat of unsustainable spending, due to the high cost of chronic and degenerative disease. In Spain, for example, health spending related to old age will grow by 18% over the coming decade, reaching over $100 billion annually.

We must not forget that the planet rests on a demographic time bomb. The population is aging at an unprecedented rate. It's estimated that, by 2030, there will be 1.4 billion people over the age of 60 worldwide. In 2050, this figure will top 2.1 billion, according to the World Health Organization.

Many have tried to calculate the value of the gigantic anti-aging industry. There are numerous projections, but they vary enormously, depending on the fields that are taken into account. These range from preventive medicine to the reprogramming of cells. Bankers estimate that the value of the global industry will amount to around $610 billion by 2025. Currently, the market is at around $110 billion, while the annual growth rate is at 28%. On the other hand, the projection by the Aging Analytics Agency is more ambitious and broad, even taking into account the financial services markets, such as pension plans and life insurance. It estimates that the longevity economy will reach $33 trillion by 2026.

In Europe and the United States, there are already investment funds focused exclusively on start-ups that are trying to tackle the devastating effects that the passage of time has on cells and molecules. Around $5.2 billion of funds were raised by companies at various stages of their development in the global longevity industry. A decade ago, this sector barely had half-a-billion in capital. Observers believe that investment in anti-aging research will continue to rise: "The market should be able to raise more than $15 billion by 2030 in innovative therapeutic areas such as cell programming, cell membrane restoration, and regenerative medicine."

Link: https://english.elpais.com/economy-and-business/2023-07-17/the-boom-of-the-anti-aging-market-how-to-get-people-to-live-to-be-120-and-in-good-health.html

Several immunotherapies targeting amyloid-β in the brain have now been shown to modestly slow the progression of Alzheimer's disease if applied at an earlier stage of the condition. This is a long way removed from a cure, particularly given the potentially severe side-effects that accompany brain-targeted monoclonal antibody therapies. Alzheimer's is a complicated condition, and it seems clear that removing amyloid-β does too little on its own to reduce pathology in the brain. It is contributing, but it is not the only contribution, or perhaps not even the most important contribution. More will be needed in parallel, such as also targeting inflammatory microglia, or removing pathological tau aggregates, or restoring vascular function that is impaired by aging in many patients with neurodegenerative conditions.

Donanemab is a monoclonal antibody, like the two earlier Alzheimer's drugs, aducanumab (Aduhelm) and lecanemab (Leqembi). These drugs attack plaques in the brain that are made of a protein called amyloid. They disrupt cell function and lead to the rapid spread of another protein called tau. Both amyloid and tau contribute to the development of Alzheimer's disease.

The trial showed donanemab slowed cognitive decline by 35% compared with placebo in patients with low-to-intermediate levels of tau in the brain. These results are similar to those reported with Leqembi, which received FDA approval earlier this month. In the donanemab trial, patients also experienced a 40% lower risk of progressing from mild cognitive impairment to mild dementia, or from mild-to-moderate dementia.

Donanemab was better at removing amyloid plaques compared to Aduhelm and Leqembi. It reduced tau concentrations in the blood, but not in a key area of the brain. While these results are encouraging, an in-depth analysis still is needed to understand how these findings affect patient outcomes. Patients with more advanced disease showed little to no benefit compared to those who received the placebo. Like the two other new Alzheimer's drugs, donanemab was associated with ARIA, amyloid-related imaging abnormalities that may include brain swelling and microbleeds. Serious ARIA occurred in 3.7% of patients, including three deaths. Risks were higher among patients with the APOE4 gene, which is related to an increased risk for Alzheimer's.

Link: https://www.eurekalert.org/news-releases/995699

From the evidence accumulated to date in animal models and studies of human tissue, it seems clear that senescent cells play an important role in the development of fibrosis in a variety of tissues. Fibrosis is a dysfunction of normal tissue maintenance processes, an excessive deposition of collagen extracellular matrix that is disruptive to tissue structure and function. Senescent cells secrete signals that encourage both growth and inflammation, and that sort of signaling sustained for the long term may be necessary for the development of fibrosis. Many age-related fibrotic diseases exist, in lungs, liver, and heart for example, and at present there is little that can be done to even effectively slow the progression of fibrosis once it is identified in a patient.

A number of animal studies of senolytic therapies, those capable of selectively clearing senescent cells from tissues, have resulted in reversal of fibrosis. This gives researchers the hope that targeting cellular senescence will prove fruitful as a treatment for fibrotic conditions, and there is a growing focus on the biochemistry and clearance of senescent cells in this context. As a part of this ongoing research, in today's open access paper the authors show that transplantation of senescent cells into the lung is sufficient to produce pulmonary fibrosis, a fairly compelling demonstration.

One might recall that researchers have similarly demonstrated that transplantation of senescent cells into joint tissue is sufficient to produce osteoarthritis. Interestingly, it has also been shown that in naturally occurring age-related osteoarthritis, locally clearing senescent cells from joint tissue isn't sufficient to improve the condition. It is plausible that the burden of senescent cells elsewhere in the body provides sufficient harmful signaling to make it necessary to remove senescent cells throughout the body rather than targeting only those present in evidently diseased tissue.

Human senescent fibroblasts trigger progressive lung fibrosis in mice

Fibrosing interstitial lung diseases (f-ILDs) constitute a complex and heterogeneous group of diseases characterized by non-resolving pulmonary fibrosis. Idiopathic pulmonary fibrosis (IPF) is the most frequent and representative f-ILD. The pathogenesis of f-ILD is complex and still incompletely understood but cell senescence has recently emerged as a potentially relevant pathogenic player. Cell senescence is an adaptation of cells to circumstances of unrepairable cellular damage. The entry in senescence involves a profound rewiring of cellular biology that is largely irreversible, with a permanent exit from the cell cycle (in the case of proliferating cells), the acquisition of stable epigenetic changes, the expansion of the lysosomal compartment and a vigorous Senescence Associated Secretory Phenotype (SASP). The SASP includes multiple pro-inflammatory and tissue remodelling mediators that can foster a fibrogenic cascade and propagate the senescent phenotype to the surrounding cells.

We hypothesized that senescent human fibroblasts may suffice to trigger a progressive fibrogenic reaction in the lung. To address this, senescent human lung fibroblasts, or their secretome (SASP), were instilled into the lungs of immunodeficient mice. We found that: (1) human senescent fibroblasts engraft in the lungs of immunodeficient mice and trigger progressive lung fibrosis associated to increasing levels of mouse senescent cells, whereas non-senescent fibroblasts do not trigger fibrosis; (2) the SASP of human senescent fibroblasts is pro-senescence and pro-fibrotic both in vitro when added to mouse recipient cells and in vivo when delivered into the lungs of mice, whereas the conditioned medium (CM) from non-senescent fibroblasts lacks these activities; and, (3) navitoclax, nintedanib, and pirfenidone ameliorate lung fibrosis induced by senescent human fibroblasts in mice, albeit only navitoclax displayed senolytic activity.

We conclude that human senescent fibroblasts, through their bioactive secretome, trigger a progressive fibrogenic reaction in the lungs of immunodeficient mice that includes the induction of paracrine senescence in the cells of the host, supporting the concept that senescent cells actively contribute to disease progression in patients with f-ILDs.

Increased klotho expression increases longevity in mice, while reduced klotho expression accelerates aging. The most well studied effects of klotho on organ function involve the kidney and brain, where in both cases it appears protective via a number of different mechanisms. Unfortunately, klotho expression declines with age. Whether treating humans with therapies that increase levels of klotho will produce effects that are as large as those observed in mice remains to be seen. Programs that might lead to treatments remain at a preclinical stage of development, though recently advanced to the point of testing in non-human primates.

The circulating levels of soluble Klotho have been observed to decrease with age, which increases the risk of age-related illnesses. Researchers demonstrated accelerated aging and a shortened lifespan in mice when the Klotho gene was silenced or deficient. In contrast, an extended lifespan was seen when the gene was overexpressed. Likewise, in humans, Klotho has been shown to display many beneficial effects, especially related to anti-aging. Although the membrane-bound Klotho protein was first associated with neurodegenerative diseases, it has been linked to various other age-related disease processes, including cancer biology and cardiovascular, renal, and skin diseases.

Klotho plays a role in cancer biology by serving as both a tumor suppressor and prognostic tumor biomarker, thus preventing and detecting neoplasms. Furthermore, Klotho overexpression (KL-OE) reduces the number of cancer cells that survive. Treatment with soluble Klotho has been shown to reduce tumor volume in preclinical cancer models in organs such as the stomach, pancreas, colon, and breast. Concerning the link between cardiovascular illness and Klotho, researchers discovered that decreased cardiac Klotho expression and increased cardiac fibroblast growth factor (FGF) expression lead to higher cardiovascular risk. Klotho can be used as an early and sensitive biomarker for kidney illnesses, as well as a potential treatment for both acute kidney injury and chronic kidney disease (CKD). It is also protective against ultraviolet B (UVB)-induced damage, and its overexpression can considerably alleviate the UVB-induced damage to cells, an effect which can be seen with aging.

Klotho has positive benefits on the neurological system by causing a higher representation of useful longevity genes, preventing further neuronal damage, and offering neuroprotection. Thus, it has the potential to become a new treatment for many age-related diseases that cause dementia, including multiple sclerosis, Alzheimer's disease, and Parkinson's disease. In this review, we discuss the mechanisms of Klotho's benefits and roles on various organ systems, specifically on nervous system disorders that lead to dementia.

Link: https://doi.org/10.7759/cureus.40043

What distinguishes the brains and biochemistry of people who retain good cognitive function into late life? That question provokes studies such as the one noted here, in which researchers assess structural and biochemical differences between older people with good cognitive function versus those on the more usual declining trajectory. It remains a matter for hypothesis and discussion as to how exactly cognitive function is maintained in only some individuals, in apparent opposition to the mechanisms of aging and their effects on the integrity of the brain. Gathering data remains an important activity at this stage of research.

Some individuals, often designated as superagers, can reach late life with the memory function of individuals 30 years younger. Previous neuroimaging studies have shown that superagers have larger hippocampal volumes, thicker anterior cingulate cortices, and slower cortical atrophy than do typical older adults. Previous studies also explored the association between superager status and some lifestyle factors, such as satisfaction with social relationships. However, most studies had small sample sizes and were cross-sectional in nature, hindering distinction between long-standing structural differences and differential atrophy rates in superageing brains compared with normal ageing brains.

One approach to obtaining larger samples of deeply phenotyped (a cohort of participants with a rich set of different variables, including data for clinical history, lifestyle, neuroimaging data, etc) superagers with longitudinal data is to investigate large longitudinal ageing cohorts. We applied this approach to the Vallecas Project longitudinal study aiming, first, to characterise superagers' cerebral grey matter volume, cross-sectionally and longitudinally, relative to that of age-matched typical older adults; and second, to apply machine learning to identify which demographic, lifestyle, and clinical variables are the greatest differentiating factors between superagers and typical older adults.

We included 64 superagers (mean age 81.9 years) and 55 typical older adults (82.4 years). The median number of follow-up visits was 5.0 for superagers and typical older adults. Superagers exhibited higher grey matter volume cross-sectionally in the medial temporal lobe, cholinergic forebrain, and motor thalamus. Longitudinally, superagers also showed slower total grey matter atrophy, particularly within the medial temporal lobe, than did typical older adults. A machine learning classification including 89 demographic, lifestyle, and clinical predictors showed that faster movement speed (despite no group differences in exercise frequency) and better mental health were the most differentiating factors for superagers. Similar concentrations of dementia blood biomarkers in superager and typical older adult groups suggest that group differences reflect inherent superager resistance to typical age-related memory loss.

Link: https://doi.org/10.1016/S2666-7568(23)00079-X

The primary economic argument presently made for treating aging as a medical condition emerges from the fact that medical spending and medical research is largely entwined with government in much of the world; it is increasingly a public purse, not a collection of private purses. Politicians and bureaucrats care (to some degree) about avoiding the looming financial implosion that will result when present unsustainable spending policies run head-on into the demographic transition to a society in which an ever-larger proportion of people are old, suffering from age-related disease, and many of their expenses paid via entitlement programs. Reducing the burden of old age reduces the costs to public health programs. Sadly, this seems to be a lot more motivating to many people than the goal of reducing the incidence of human suffering and death.

There is a much larger and more important economic argument to be made regarding the costs of age-related death and disease, not just the expenses, but the lost opportunities, the lost progress and knowledge. This cost dwarfs the expenditures of the world's government health services; recent estimates suggested that merely delaying aging by a single year would save $38 trillion per year, just by marginally reducing the present enormous costs of coping with the universal progression to dysfunction and death in later life. Yet this economic argument is met with shrugs, and is much less motivating to those who find themselves in the position to create change for the better, or so it seems. We are not a rational species.

Translational longevity medicine: a Swiss perspective in an ageing country

Breakthroughs in medical research in the last century have led to a significant extension of the human lifespan, resulting in a shift towards an elderly population worldwide. Due to the ongoing progress of global development towards elevated standards of living, this study specifically examines Switzerland as a representative nation to explore the socioeconomic and healthcare ramifications associated with an ageing population, thereby highlighting the tangible impact experienced in this context. Life expectancy in Switzerland has steadily increased over the past few decades. Along with life expectancy, the old age dependency ratio (OADR) has also increased. As ageing is associated with many morbidities, their prevalence is destined to further increase unless further measures are taken. The increased OADR will lead to secular stagnation in the economy and threaten the sustainability of pension systems.

The demographic transition and ageing population, therefore, pose important challenges to Swiss society from several perspectives. Given our findings here, we suggest the following potential strategies to address these challenges. A paradigm shift in medical practice is needed to improve health rather than respond to existing diseases. By researching the molecular mechanisms involved in the biology of ageing and expanding epidemiological and clinical research on ageing, we should aim to bridge the gaps between basic research of geroscience and medical applications. We need to establish protocols for clinical trials on ageing that include functional capacity, frailty, and time to events of onset of age-related diseases. For this, we need to establish clinically relevant biomarkers of healthy ageing and incorporate a more complete interconnected picture of comorbidities. With this, we can hopefully improve the quality of health in the ageing population.

Without changes in the biological and medical fields, the socioeconomic impacts of ageing might become devastating. Hence it is indispensable to invest in the future of ageing research.

Researchers here note that reducing APRT expression affects extends life in short-lived killifish via mechanisms likely related to the calorie restriction response. This regulation of the pace of aging in response to nutrient availability is arguably the most well studied aspect of the biology of aging, but the production of calorie restriction mimetic strategies (such as this one) seems unlikely to result in meaningful therapies for humans. Short-lived species exhibit a much greater extension of life span in response to a low calorie diet than occurs in long-lived species like our own. Mice can live as much as 40% longer when calorie restricted, but humans gain only a few years at most. It seems likely that many of the mechanisms involved in extending life in short-lived species are already turned on all the time in long-lived species.

The AMP-activated protein kinase (AMPK) plays a critical role in cellular energy regulation and organismal metabolism. However, previous attempts to genetically manipulate the AMPK complex in mice yielded unfavorable outcomes. In search of an alternative approach, the research team focused on manipulating the upstream nucleotide pool to modulate energy homeostasis.

Using the turquoise killifish as their model organism, the team targeted and mutated APRT, a key enzyme involved in AMP biosynthesis. Remarkably, this manipulation resulted in a significant extension of lifespan in heterozygous male killifish. The study further employed an integrated omics approach, revealing rejuvenation of metabolic functions in the aged mutant fish. These included the adoption of a fasting-like metabolic profile and enhanced resistance to a high-fat diet. At the cellular level, the heterozygous fish exhibited remarkable traits such as enhanced nutrient sensitivity, reduced ATP levels, and activation of AMPK.

The study also unveiled an intriguing observation. The benefits of extended lifespan and rejuvenated metabolic functions were nullified when lifelong intermittent fasting was applied. Furthermore, the longevity phenotypes were sex-specific. The research sheds new light on the potential of targeting APRT as a promising strategy for promoting metabolic health and extending lifespan in vertebrates. Further investigations in this field hold promise for the development of interventions that enhance healthy aging and combat age-related metabolic diseases.

Link: https://www.eurekalert.org/news-releases/995311

Research groups have been hard at work over the past decade to build better biomarkers for Alzheimer's disease. Several blood-based biomarkers are quite advanced in their development. Here, researchers propose a less convenient cerebrospinal fluid biomarker, but still an improvement over the cost of brain imaging technologies when it comes to tracking the progression of the condition. Better, cheaper assays for Alzheimer's disease are certainly needed, particularly when it comes to the early stages of the condition, in which symptoms are mild or non-existent. Prevention is always easier than coping with a condition in its later stages.

By studying 667 people at various stages of Alzheimer's disease, the researchers discovered in the cerebrospinal fluid that levels of a specific form of tau - known as microtubule binding region (MTBR)-tau243 - track with the amount of damaging tau tangles in the brain and with the degree of cognitive decline. The average age of participants was 71, and the group included healthy people as well as people at all stages of disease, ranging from those with some amyloid in their brains but no cognitive symptoms, to those with extensive amyloid and tau in their brains and a diagnosis of dementia. The researchers compared cognitive function with levels of various forms of tau in the cerebrospinal fluid and with levels of amyloid and tau in the brain, as measured by amyloid and tau PET scans.

The researchers analyzed data from people who volunteered for Alzheimer's research studies through the Biomarkers For Identifying Neurodegenerative Disorders Early and Reliably (BioFINDER)-2 program. Levels of MTBR-tau243 in the cerebrospinal fluid correlated strongly with brain tau tangle levels and cognitive function. As MTBR-tau243 levels went up, tau levels in the brain also went up, and scores on cognitive tests went down. In contrast, levels of another form of tau in the cerebrospinal fluid, phosphorylated tau, tracked mainly with brain amyloid levels but not with brain tau levels or cognitive function. By combining the two forms of tau in the cerebrospinal fluid - phosphorylated tau and MTBR-tau243 - the researchers were able to predict cognitive function almost as well as by using tau-PET imaging.

Link: https://medicine.wustl.edu/news/tau-based-biomarker-tracks-alzheimers-progression/

Cell reprogramming was first induced by expression of the Yamanaka factors, a way to access the program of rejuvenation and dedifferentiation that takes place in the early embryo. A small fraction of cells in culture exposed to reprogramming factors will change into induced pluripotent stem cells while ohers will undergo an epigenetic reset to adopt a youthful set of behaviors and capabilities. This involves removing age-related changes in gene expression that lead to mitochondrial dysfunction, for example. By virtue of the way in which cellular biochemistry is very interconnected, there should be many ways to access the embryronic program of rejuvenation, and hopefully ways to separate the process of dedifferentiation from the epigenetic reset. It is just a matter of finding those other ways.

An important part of the reprogramming field as it stands today is the expansion from genetic means of provoking reprogramming to the discovery of small molecules that can achieve the same outcome. While gene therapy is the future of medicine, the gene therapy industry of today remains a rounding error next to the size of the small molecule industry. With this in mind, most of the noteworthy organizations involved in the development of reprogramming therapies have a small molecule program. Today's open access paper is a illustrative report from one of the associated research groups in the field, a starting point for a small molecule drug discovery program aimed at producing efficient reprogramming without genetic modification.

Chemically induced reprogramming to reverse cellular aging

Starting in 1962, researchers demonstrated that nuclei contain the necessary information to generate new individuals with normal lifespans. In 2006, researchers demonstrated that the expression of four transcription factors, OCT4, SOX2, KLF4, and c-MYC (collectively known as the Yamanaka factors or OSKM), reprograms the developmental potential of adult cells, enabling them to be converted into various cell types. These findings initiated the field of cell reprogramming, with a string of publications in the 2000s showing that the identity of many different types of adult cells from different species could be erased to become induced pluripotent stem cells, commonly known as "iPSCs".

The ability of the Yamanaka factors to erase cellular identity raised a key question: is it possible to reverse cellular aging in vivo without causing uncontrolled cell growth and tumorigenesis? Initially, it didn't seem so, as mice died within two days of expressing OSKM. But later work confirmed that it is possible to safely improve the function of tissues in vivo by pulsing OSKM expression or by continuously expressing only OSK, leaving out the oncogene c-MYC. In the optic nerve, for example, expression of a three Yamanaka factor combination safely resets DNA methylomes and gene expression patterns, improving vision in old and glaucomatous mice. Numerous tissues, including brain tissue, kidney, and muscle, have now been reprogrammed without causing cancer. In fact, expression of OSK throughout the entire body of mice extends their lifespan. Together, these results are consistent with the existence of a "back-up copy" of a youthful epigenome, one that can be reset via partial reprogramming to regain tissue function, without erasing cellular identity or causing tumorigenesis.

Currently, translational applications that aim to reverse aging, treat injuries, and cure age-related diseases, rely on the delivery of genetic material to target tissues. This is achieved through methods like adeno-associated viral (AAV) delivery of DNA and lipid nanoparticle-mediated delivery of RNA. These approaches face potential barriers to them being used widely, including high costs and safety concerns associated with the introduction of genetic material into the body. Developing a chemical alternative to mimic OSK's rejuvenating effects could lower costs and shorten timelines in regenerative medicine development. This advancement might enable the treatment of various medical conditions and potentially even facilitate whole-body rejuvenation.

In this study, we developed and utilized novel screening methods including a quantitative nucleocytoplasmic compartmentalization assay (NCC) that can readily distinguish between young, old, and senescent cells. We identify a variety of novel chemical cocktails capable of rejuvenating cells and reversing transcriptomic age to a similar extent as OSK overexpression. Thus, it is possible to reverse aspects of aging without erasing cell identity using chemical rather than genetic means.

The most evident symptoms of Parkinson's disease result from the loss of dopamine generating neurons in the brain, a population of cells uniquely vulnerable to the underlying biochemistry of the condition. Researchers have long worked towards therapies based on transplanting new neurons to replace those lost to cell death, and clinical trials have taken place in human patients, but the survival of these cells is a challenge. The process of transplantation, as noted here, has consequences. Suppressing the local immune response to the transplantation procedure may improve matters, however.

The specific loss of midbrain dopamine neurons (mDANs) causes major motor dysfunction in Parkinson's disease, which makes cell replacement a promising therapeutic approach. However, poor survival of grafted mDANs remains an obstacle to successful clinical outcomes. Here we show that the surgical procedure itself (referred to here as 'needle trauma') triggers a profound host response that is characterized by acute neuroinflammation, robust infiltration of peripheral immune cells, and brain cell death.

When midbrain dopamine (mDA) cells derived from human induced pluripotent stem (iPS) cells were transplanted into the rodent striatum, less than 10% of implanted tyrosine hydroxylase (TH)+ mDANs survived at two weeks after transplantation. By contrast, TH- grafted cells mostly survived. Notably, transplantation of autologous regulatory T (Treg) cells greatly modified the response to needle trauma, suppressing acute neuroinflammation and immune cell infiltration. Furthermore, intra-striatal co-transplantation of Treg cells and human-iPS-cell-derived mDA cells significantly protected grafted mDANs from needle-trauma-associated death and improved therapeutic outcomes in rodent models of Parkinson's disease. Co-transplantation with Treg cells also suppressed the undesirable proliferation of TH- grafted cells, resulting in more compact grafts with a higher proportion and higher absolute numbers of TH+ neurons.

Together, this data emphasizes the importance of the initial inflammatory response to surgical injury in the differential survival of cellular components of the graft, and suggest that co-transplanting autologous Treg cells effectively reduces the needle-trauma-induced death of mDANs, providing a potential strategy to achieve better clinical outcomes for cell therapy in Parkinson's disease.

Link: https://doi.org/10.1038/s41586-023-06300-4

It is presently possible to cheaply and reliably determine the bacterial populations making up the gut microbiome via 16S rRNA sequencing. This capability is giving rise to great deal of new knowledge regarding the ways in which changes in the gut microbiome affect health. Populations can provoke inflammation, known to drive the onset and progression of many age-related conditions, or generate harmful or helpful metabolites, about which less is known of the interaction with specific aspects of aging. Adjusting the balance of populations in the gut microbiome, particularly to restore a more youthful gut microbiome in older individuals, may prove to be a useful approach to long-term health once the field moves past tinkering with probiotics in their present form to the use of more powerful techniques such as fecal microbiota transplantation.

Researchers have discovered a link between the levels of certain bacteria living in the gut and coronary atherosclerotic plaques. The new study was based on analyses of gut bacteria and cardiac imaging among 8,973 participants aged 50 to 64 without previously known heart disease. They were all participants in the Swedish CArdioPulmonary bioImage Study (SCAPIS). "We found that oral bacteria, especially species from the Streptococcus genus, are associated with increased occurrence of atherosclerotic plaques in the small arteries of the heart when present in the gut flora. Species from the Streptococcus genus are common causes of pneumonia and infections of the throat, skin, and heart valves."

The research team also found that some of the species linked to the build-up of atherosclerotic plaques in heart arteries were linked to the levels of the same species in the mouth. Furthermore, these bacteria were associated with inflammation markers in the blood, even after accounting for differences in diet and medication between the participants who carried the bacteria and those who did not. "We have just started to understand how the human host and the bacterial community in the different compartments of the body affect each other. Our study shows worse cardiovascular health in carriers of streptococci in their gut. We now need to investigate if these bacteria are important players in atherosclerosis development."

Link: https://www.mynewsdesk.com/uu/pressreleases/gut-bacteria-linked-to-fatty-deposits-in-heart-arteries-3264220

The SENS Research Foundation has released its 2023 annual report. This is one of the few non-profit organizations focused on advancing the state of research and development of rejuvenation therapies. It exists in the same family tree as the Methuselah Foundation and LEV Foundation, and all three now have somewhat different areas of focus within the same broad outline. In comparison to the SENS Research Foundation, the Methuselah Foundation gives more attention to tissue engineering, while LEV Foundation is presently investigating combinations of potential rejuvenation therapies in animal models, a sorely neglected area of research.

The SENS Research Foundation works on a number of interesting projects that might lead to rejuvenation therapies, and the focus remains to unblock promising lines of research that are underfunded, poorly investigated due to a lack of tooling, or otherwise neglected by the research mainstream. The foundation also holds stakes in a range of companies formed to develop programs that SENS Research Foundation was in some way involved in, either conducting, funding, or otherwise assisting in moving that research forward. These include Cyclarity Therapeutics and Repair Biotechnologies, both focused on atherosclerosis, as well as ventures tackling senescent cells, cross-links, and other aspects of aging biology.

Looking at the 2023 report, it is fair to say that the SENS Research Foundation's fundraising has suffered this past year, following the departure of co-founder Aubrey de Grey to form the LEV Foundation. One could argue that this has more to do with the current market downturn, of course. Non-profits tend to do poorly as the market falters. The foundation has a fair-sized war chest, but they can't keep up the present pace on present research programs without increased support from philanthropic donors. This organization does good work; it is a worthy cause that this community has supported well in the past, and should continue to support in the future.

SENS Research Foundation Annual Reports

SRF's ApoptoSENS team are developing ways to target senescent cells that evade existing senolytic strategies while reducing damage to healthy cells. One blind spot in the senolytic story has been the effects of these drugs on "secondary senescent cells." Secondary senescence is a more recently-discovered and understudied form of senescence that occurs when cells are driven into senescence by the signaling molecules released by other cells that had previously become senescent (the "primary" senescent cells). SRF scientists wondered if they might elude many of our existing senolytic drugs, since all such drugs were developed by testing them against primary senescent cells. Sure enough, secondary senescent cells could shrug off several of the best-studied senolytic drugs.

Fortunately, SRF scientists found a novel route of senolytic attack that works well against both types of senescence. These cells intensively engage pathways involved in iron metabolism, and also seem to be primed for ferroptosis, a kind of programmed cell death that depends in part on iron as a trigger. The ApoptoSENS team found that both primary and secondary senescent cells are susceptible to novel attack routes that exploit pain points along this pathway.

Senolytics - senescent cell-destroying drugs - are now one of the most rapidly-advancing rejuvenation biotechnologies. Unfortunately, these drugs do inflict some collateral damage to nonsenescent cells. So how much better might senolytics work if SRF scientists coupled them with strategies to enhance the aging body's flagging regenerative response after treatment? The SenoStem group is preparing to test just such a combination. This team will seek to fortify surviving nonsenescent cells with pro-regenerative signaling factors from mesenchymal stem cells (MSCs).

SRF's MitoSENS team is now working on three ways to deal with mitochondria that bear large deletion mutations. The first approach, which they've been working on since SRF's founding, entails creating "backup copies" of the mitochondrial genes in the nucleus. The team's standout success with the gene ATP8 enabled an engineered backup copy of this gene to express in living mice. Other genes are proving harder to engineer such that their proteins are reliably produced, delivered, and correctly placed in the energy- production machinery. The MitoSENS team is working to overcome the tendency that some mitochondrial proteins have to curl up on themselves.

The MitoSENS team is also in the early stages of working on two alternative strategies. One is a version of a "gene drive," using therapeutic mitochondria engineered with an enzyme that can destroy all the existing mitochondrial genomes in the cell. Once transplanted into an aging patient, these aggressive mitochondria would enter the patient's cells and replicate themselves while buzzsawing through the existing mitochondrial population, replenishing the cell with pristine, functional mitochondria. The other strategy aims to overcome the culling-avoidance superpower of mitochondria that bear large deletions in their genome. The team is testing several different drugs that may be able to force deletion-bearing mitochondria to show their faces and be marked for destruction by the cell maintenance process of mitophagy.

SRF's LysoSENS team is working on an ingenious strategy to clear aging neurons of tau oligomers. Their strategy consists of two major components: a novel cell- penetrating platform to deliver their therapeutic antibody inside the neurons, and the use of catabodies instead of conventional binding antibodies to attack their target. Catabodies, unlike conventional antibodies, cleave their targets into harmless fragments, rather than dragging intact target aggregates one by one out of the brain (and in doing so, damaging the brain's blood vessel barrier). The LysoSENS team is developing both a suite of potential catabodies to test and synthetic tau oligomers against which to test them, to ensure that catabodies that successfully buzz their way through the artificial target will also obliterate the real enemy inside the neuron. When they are satisfied with the oligomers, they will begin testing catabody candidates, and after that move on to studies in cells and in mouse models of tau-driven neurodegenerative aging.

Scientists have been pursuing a way to clear aging cells of lipofuscin for longer than any other LysoSENS target. Past efforts have failed in part because real lipofuscin is hard to isolate from cells, forcing scientists to resort to artificial mixtures of crosslinked materials or a lipofuscin-like material produced by cells under abnormal conditions. With SRF funding, researchers are now attacking the problem using new techniques to isolate true lipofuscin derived from human donor and horse heart tissue. Horse and human heart lipofuscin are very similar, allowing them to work with the larger available quantities of horse material with confidence that the results will also apply to human lipofuscin. The team is now attacking this isolated lipofuscin using the classic LysoSENS strategy of screening environmental bacteria for the ability to survive by breaking it down. Excitingly, their mixed soil bacterial population can degrade lipofuscin and release fluorescent breakdown products. They are now winnowing this population down to determine which species produce the enzymes that do the critical work.

One key change in aging extracellular matrix (ECM) is crosslinking, in which one strand of a structural protein becomes chemically bound to an adjacent strand, limiting both strands' range of motion. Continuous exposure to blood sugar and other essential but highly reactive molecules in the blood can lead to a kind of crosslink termed Advanced Glycation Endproducts (AGE). The evidence currently suggests that the single most common AGE crosslink in the key structural protein collagen is glucosepane. SRF funded research has now shown that each kind of tissue undergoes its own distinct crosslinking pattern, and the crosslinks that form don't simply accumulate over time as was previously believed. Instead, a subset of crosslinks easily breaks during regular tissue stretching, only for new crosslinks of the same type to form afterward.

In fact, while researchers have confirmed that irreversible crosslinks increase in aging tendons with age, this increase is more than counterbalanced by a net loss of the reversible crosslinks, which may contribute to putting us at greater risk of rupturing our tendons as we age. Moreover, while the team has confirmed that the age-related rise in glucosepane seen in human tissues also occurs in mice, there's no sign of some of the other crosslinks previously reported in either species. This careful work is showing that some of these are instead either methodological artifacts or cases of misidentification.

Researchers here discuss a program of drug discovery that led to inhibitors of glycolysis as a potential approach to treatment for neurodegenerative conditions. The researchers note that elevated glycolysis is a characteristic of Alzheimer's disease, for example. There are always many, many mechanisms and altered aspects of cell metabolism one can investigate in aging and age-related disease. The question to ask when looking at any one specific mechanism in isolation is how much of the pathology of the condition lies downstream of this mechanism. It is all to easy to find oneself targeting a side-effect, or a minor mechanism that is not close to the root causes of the condition, which is why it is important to test in animals to observe the degree to which health is improved.

Although it is widely agreed that proteotoxicity drives impairments in Alzheimer's disease (AD) and other neurological diseases, many preclinical and case-report studies indicate that increased microglial production of pro-inflammatory cytokines such as TNF-a mediate proteotoxicity in AD and other neurological conditions. We developed parallel high-throughput phenotypic screens to discover small molecules which inhibit age-related proteotoxicity in a C. elegans model of AD, and microglia inflammation (LPS-induced TNF-a). In the initial screen of 2,560 compounds, the most protective compounds were, in order, phenylbutyrate (HDAC inhibitor), methicillin (beta lactam antibiotic), and quetiapine (tricyclic antipsychotic). These classes of compounds are already robustly implicated as potentially protective in AD and other neurodegenerative diseases.

In addition to quetiapine, other tricyclic antipsychotic drugs also delayed age-related amyloid-beta (Abeta) proteotoxicity and microglial TNF-a. Based on these results we carried out extensive structure-activity relationship studies, leading to the synthesis of a novel congener of quetiapine, #310, which inhibits a wide range of pro-inflammatory cytokines in mouse and human myeloid cells, and delays impairments in animal models of AD, Huntington's, and stroke. #310 is highly concentrated in brain after oral delivery with no apparent toxicity, increases lifespan, and produces molecular responses highly similar to those produced by dietary restriction. Among these molecular responses is inhibition of glycolysis, reversing gene expression profiles and elevated glycolysis associated with AD.

Several lines of investigation strongly supported that the protective effects of #310 are mediated by activating the Sigma-1 receptor, whose protective mechanisms in turn also entail inhibiting glycolysis. Reduced glycolysis has also been implicated in the generally protective effects of dietary restriction, rapamycin, reduced IFG-1 activity, and ketones during aging, suggesting that aging is at least in large part a consequence of glycolysis. In particular, the age-related increase in adiposity, and subsequent pancreatic decompensation leading to diabetes, is plausibly a consequence of age-related increase in beta cell glycolysis. Consistent with these observations, the glycolytic inhibitor 2-DG inhibited microglial TNF-a and other markers of inflammation, delayed Abeta proteotoxicity, and increased lifespan. To our knowledge no other molecule exhibits all these protective effects which makes #310 a uniquely promising candidate to treat AD and other age-related diseases.

Link: https://doi.org/10.1101/2023.06.12.544352

Researchers here report on an improved version of compounds known to reduce the generation of oxidizing molecules by mitochondria. Mitochondrial dysfunction can produce sustained oxidative stress that changes cell behavior for the worse, contributing to aspects of aging. That targeting antioxidants to the mitochondria or upregulating natural antioxidant molecules can produce some benefit to health suggests that the size of the contribution is meaningful. The details matter, however, and as cells use mild mitochondrial oxidative stress to trigger beneficial maintenance activities, with the metabolic response to exercise being one example of this in action, one can't just take a blunt approach to the problem and expect benefits to result. That the approach here works for mitochondrial dysfunction in the context of obesity doesn't necessarily mean it will work well in the context of aging.

Numerous mechanisms and pathways have been suggested to initiate metabolic syndrome and the eventual development of specific diseases. In particular, there is a wealth of literature connecting metabolic syndrome to increased mitochondrial reactive oxygen species (ROS). The most compelling evidence comes from genetic manipulations in mice. Expression or overexpression of enzymes that determine the superoxide and hydrogen peroxide concentrations in the mitochondrial matrix (superoxide dismutase 2, SOD2; peroxiredoxin 3, PRDX3; mitochondria-targeted catalase, mCAT) are all strongly protective. Further support comes from the use of less specific mitochondria-targeted antioxidants (mitoQ, mitoVitE), and of the peptide SS-31. These lines of evidence strongly implicate mitochondria as the source of superoxide/hydrogen peroxide.

Eleven different sites of superoxide/hydrogen peroxide production associated with the mitochondrial electron transport chain have been identified. Of these, site IQ in complex I, site IIIQo in complex III, and site IIF in complex II have the greatest maximum capacities to generate superoxide/hydrogen peroxide in vitro. Compounds have been identified that specifically suppress superoxide/hydrogen peroxide production from site IQ (Suppressors of Site IQ Electron Leak, S1QELs) and site IIIQo (Suppressors of Site IIIQo Electron Leak, S3QELs) without inhibiting the electron transport chain or affecting oxidative phosphorylation. S1QELs and S3QELs have profound protective effects in cell and organ models, demonstrating the biological importance of superoxide/hydrogen peroxide production from sites IQ and IIIQo.

Existing S1QELs and S3QELs are not well suited for systemic in vivo use because of their poor solubility and bioavailability, although they can be added to the diet to affect gut cell function in flies and mice. WHere, we introduce a novel potent, selective and orally bioavailable S1QEL1: S1QEL1.719. S1QEL1.719 was used to test the metabolic effects of suppressing superoxide/hydrogen peroxide production from site IQ in vivo. C57BL/6J male mice fed a high-fat chow for one, two or eight weeks had increased body fat, decreased glucose tolerance, and increased fasting insulin concentrations, classic symptoms of metabolic syndrome. Daily prophylactic or therapeutic oral treatment of high-fat-fed animals with S1QEL1.719 decreased fat accumulation, strongly protected against decreased glucose tolerance and prevented or reversed the increase in fasting insulin level.

Link: https://doi.org/10.1016/j.freeradbiomed.2023.05.022

There is some debate over the degree to which periodontal disease contributes to neurodegenerative conditions. A mechanism to link the two exists: gum disease produces chronic inflammation, allowing bacteria and bacterial products into the bloodstream to provoke the immune system. Chronic inflammation in brain tissue is a feature of neurodegenerative conditions, and inflammation elsewhere in the body tends to generate matching inflammatory behavior in the immune cell populations of the brain. Thus one would expect the brain to fare less well over time given the presence of gum disease. Epidemiology, however, suggests that the effect size here is small, only a few percentage points of greater risk of dementia resulting from gum disease.

In today's research materials, researchers report that oral bacteria associated with periodontal disease can travel to the brain, and there provoke microglia, innate immune cells of the central nervous system, into greater activation. This in turn can accelerate the progression of age-related neurodegeneration leading to Alzheimer's disease and other conditions. Numerous research groups have produced evidence to show that greater inflammatory behavior in microglia is associated with neurodegenerative conditions, and appears to drive the progression of pathology. But is the contribution of periodontal disease to this overactivation of microglia characteristic of later life large or small? The answer to that question remains to be settled.

Gum disease linked to buildup of Alzheimer's plaque formation

In a new paper, researchers demonstrate that gum disease can lead to changes in brain cells called microglial cells, which are responsible for defending the brain from amyloid plaque. This plaque is a type of protein that is associated with cell death, and cognitive decline in people with Alzheimer's. The study provides important insight into how oral bacteria makes its way to the brain, and the role of neuroinflammation in Alzheimer's disease. Using mouse oral bacteria to cause gum disease in lab mice, the scientists were able to track periodontal disease progression in mice and confirm that the bacteria had traveled to the brain. They then isolated the brain microglial cells and exposed them to the oral bacteria. This exposure stimulated the microglial cells, activated neuroinflammation, and changed how microglial cells dealt with amyloid plaques.

Microglial cell response to experimental periodontal disease

Microglial activation is critical for modulating the neuroinflammatory process and the pathological progression of neurodegenerative diseases, such as Alzheimer's disease (AD). Microglia are involved in forming barriers around extracellular neuritic plaques and the phagocytosis of β-amyloid peptide (Aβ). In this study, we tested the hypothesis that periodontal disease (PD) as a source of infection alters inflammatory activation and Aβ phagocytosis by the microglial cells.

Experimental PD was induced using ligatures in C57BL/6 mice for 1, 10, 20, and 30 days to assess the progression of PD. Animals without ligatures were used as controls. Ligature placement caused progressive periodontal disease and bone resorption that was already significant on day 1 post-ligation and continued to increase until day 30. The severity of periodontal disease increased the frequency of activated microglia in the brains on day 30 by 36%. In parallel, heat-inactivated PD-associated total bacteria and Klebsiella variicola increased the expression of TNFα, IL-1β, IL-6, TLR2, and TLR9 in microglial cells in vitro. Incubation of microglia with Klebsiella variicola increased the Aβ-phagocytosis by 394% and the expression of the phagocytic receptor MSR1 by 33-fold compared to the non-activated cells. These results support a direct role of PD-associated pathogens in neuroinflammation.

A great deal of effort goes into preparing for atherosclerotic plaques to rupture, and then coping with the consequences of the resulting stroke or heart attack, and all too little effort into reversal of plaque formation. Researchers here examine plaque rupture in structural detail in a group of patients with sufficiently detailed prior imaging data to determine what happened at the site of rupture. This is less interesting than the associated data showing that raised levels of MMP-9 appear to be predictive of risk of plaque rupture. Whether this means that inhibiting MMP-9 can reduce that risk is an interesting question, but still a poor path forward in comparison to greater work in means to prevent and reverse plaque formation.

In atherosclerosis, fat is accumulated in the artery walls creating atherosclerotic plaques. Plaques that rupture can cause a stroke or myocardial infarction, and a deeper understanding of the mechanisms underlying plaque rupture is needed to prevent serious complications. Researchers now show that atherosclerotic plaques in the carotid arteries often rupture at the beginning of the plaque, at a location closest to the heart. "In our study, we were able to pinpoint exactly where plaques rupture. This is an important step, allowing for a better understanding of why they rupture."

The research is based on studies of atherosclerotic plaques in the carotid arteries from a total of 188 individuals. The researchers used electron microscope and RNA sequencing techniques to get a detailed picture of the location where most plaques rupture. High blood pressure and type 2 diabetes are factors that increase the risk of atherosclerosis and therefore these patient groups were also included in the study.

RNA sequencing showed a strong association between the enzyme MMP-9 and the area where plaques rupture. High levels of MMP-9 could also be associated with an increased risk of future cardiovascular disease in individuals with atherosclerosis. The researchers hope to be able to use MMP-9 as a marker to predict which patients are at risk of having a myocardial infarction or a stroke. They are also investigating if it is possible to develop new treatments that reduce the risk of plaque rupture based on inhibition or blockade of MMP-9.

Link: https://www.eurekalert.org/news-releases/991111

Hearing loss involves either damage or loss of sensory hair cells in the inner ear, or loss of their connections to the brain. It remains somewhat unclear as to whether cell damage, cell death, or connection loss is the primary mechanism of interest in mammals. Researchers here investigate the way in which hair cells repair themselves. Where a mechanism like this exists and is understood, there is the potential to increase its efficiency as a basis for therapy. This may prove to be a useful treatment for some forms of deafness, but only those in which the cells and their connections remain, where hearing loss results from unrepaired structural damage to the hair cells.

The long-term maintenance of sensory hair cells faces a fundamental challenge: to maximize sensitivity, hair cells are built to be delicate and fragile, yet they have to withstand continuous mechanical stress. A potent capacity for repair must therefore be considered indispensable, especially for mammalian auditory hair cells that are not regenerated. In our study, we provide evidence for a novel process that repairs lesions in the stereocilia F-actin core. The damaged sites can be visualized as 'gaps' in phalloidin staining of F-actin, and the enrichment of monomeric actin at these sites, along with an actin nucleator and crosslinker, suggests that localized remodeling occurs to repair the broken filaments.

Herein, we show that gaps in mouse auditory hair cells are largely repaired within 1 week of traumatic noise exposure through the incorporation of newly synthesized actin. We provide evidence that Xin actin binding repeat containing 2 (XIRP2) is required for the repair process and facilitates the enrichment of monomeric γ-actin at gaps. Recruitment of XIRP2 to stereocilia gaps and stress fiber strain sites in fibroblasts is force-dependent, mediated by a novel mechanosensor domain located in the C-terminus of XIRP2. Our study describes a novel process by which hair cells can recover from sublethal hair bundle damage and which may contribute to recovery from temporary hearing threshold shifts and the prevention of age-related hearing loss.

Link: https://doi.org/10.7554/eLife.72681

Inhibitors of mTOR such as rapamycin are increasingly well studied. This class of drug stimulates cellular stress responses, principally autophagy, and thus produces outcomes that are broadly similar to the long-term improvement of health resulting from calorie restriction, exercise, or other demonstrated means of upregulating autophagy. This results in benefits to health, such as those noted in today's open access paper.

It is one thing to demonstrate that a drug improves measures of autophagy known to decline with age, and note that many of the interventions shown to modestly slow aging in laboratory species are characterized by improved autophagy. It is quite another to determine the links between low-level change in cell biochemistry and high level tissue properties. Cellular metabolism is enormously complex, and comparatively little headway has been made towards building broad bridges between (a) specific causative mechanisms of aging, (b) downstream issues with cellular biochemistry such as faltering autophagy, and (c) mechanical, structural, and other properties of tissue and organ function. It remains the case that knowing that a particular intervention works to improve health does not imply knowing how it works to improve health in detail.

Late-life Rapamycin Treatment Enhances Cardiomyocyte Relaxation Kinetics and Reduces Myocardial Stiffness

Diastolic function is controlled by active relaxation of cardiomyocytes and passive stiffness of the myocardium. Cardiomyocyte relaxation is controlled by the interplay of two macromolecular systems: membrane bound Ca2+ handling proteins to send the signal to start and stop contraction, and sarcomeric proteins for force generation and contraction regulation by Ca2+. Passive stiffness of the myocardium is controlled by mechanisms such as extracellular matrix remodeling, titin isoform shift and titin phosphorylation. It has been shown that rapamycin reduces the age-related increase in passive stiffness of the myocardium. The effects of rapamycin on active cardiomyocyte relaxation and the precise molecular mechanisms of rapamycin mediated reduction in passive myocardial stiffness remain unknown. Identifying the mechanisms by which rapamycin improves diastolic function in the aging heart will advance our understanding on its therapeutic potentials in cardiac aging and heart failure with preserved ejection fraction (HFpEF).

To dissect the mechanisms by which rapamycin improves diastolic function in old mice, we examined the effects of rapamycin treatment at the levels of single cardiomyocyte, myofibril, and multicellular cardiac muscle. Compared to young cardiomyocytes, isolated cardiomyocytes from old control mice exhibited prolonged time to 90% relaxation (RT90) and time to 90% Ca2+ transient decay (DT90), indicating slower relaxation kinetics and calcium reuptake with age. Late-life rapamycin treatment for 10 weeks completely normalized RT90 and partially normalized DT90, suggesting improved Ca2+ handling contributes partially to the rapamycin-induced improved cardiomyocyte relaxation.

In addition, rapamycin treatment in old mice enhanced the kinetics of sarcomere shortening and Ca2+ transient increase in old control cardiomyocytes. Myofibrils from old rapamycin-treated mice displayed increased rate of the fast, exponential decay phase of relaxation compared to old controls. The improved myofibrillar kinetics were accompanied by an increase in MyBP-C phosphorylation following rapamycin treatment. We also showed that late-life rapamycin treatment normalized the age-related increase in passive stiffness of demembranated cardiac trabeculae through a mechanism independent of titin isoform shift. In summary, our results showed that rapamycin treatment normalizes the age-related impairments in cardiomyocyte relaxation, which works conjointly with reduced myocardial stiffness to reverse age-related diastolic dysfunction.

The thymus produces the T cells that make up the adaptive immune system, but the organ atrophies with age, contributing to the age-related decline of immune function. A popular science article here comments on a new biotech company seeking to produce thymus tissue for transplantation from decellularized donor tissues. This builds upon work of recent years that improves the understanding of the stem cell and progenitor cell populations that give rise to thymic tissue. Given that understanding, it should be possible to take decellularized thymic tissue and repopulate it with patient-derived cells, or from novel universal cell lines that have been altered so as to allow transplantation into any individual with minimal risk of rejection. While it seems likely that the company will, at the end of the day, remain focused entirely on children born without a thymus rather than on the age-related loss of thymic tissue, there is certainly that potential application waiting in the wings for someone to take up the flag and run with it.

"The thymus had largely been ignored because it's complicated, and historically understanding of the biology had progressed slowly. It's starting to accelerate now and a lot of the work that the Francis Crick Institute has been doing is aimed at understanding the core stem cell niche of the thymus and use this to recreate thymus biology. Until recently, there was uncertainty around the progenitor stem cell that leads to the epithelial cells that gives the thymus function. The Crick researchers discovered novel progenitor cells and Videregen has licensed the resulting patents, which give us the basis of the cell biology. That allows us to build a better functioning thymus from scratch, because we understand the cell biology better than anyone else."

The initial indication for Videregen's immune program is children born without thymus function, which is called complete DiGeorge Syndrome, but this is only the beginning of the company's work in this area. "The thymus is primarily concerned with two things: the first is to provide T cells, which fight infection and circulate our bodies throughout our life, taking out precancerous cells. Over time, our thymus function decreases, which is why in old age, you tend to get more cancers, you respond less well to vaccines, and you get more infections. So addressing thymus atrophy is a big factor in longevity and aging. At the moment, we're focusing on niche, orphan indications, which means we don't need to industrialize to a big scale - we're talking about hundreds or thousands of patients, not millions. But when we get to those kinds of scales of populations, we will need the technology to be able to deliver a mass-produced tissue."

Videregen's approach is built on the company's expertise in decellularization - the process used to isolate the extracellular matrix of a tissue from its inhabiting cells, leaving only a "scaffold" of the original tissue. This scaffold can then be seeded with appropriate cells to enable organ and tissue regeneration. "We've learned that the biology of the extracellular matrix is really important - it isn't just structural. If you preserve the biology well, you get better infiltration of cells, better vascularization, and better repair and function over time. This is achieved by controlling the way the tissue is processed and decellularized - the more natural the better."

Link: https://longevity.technology/news/could-regenerating-the-thymus-boost-human-longevity/

Mitochondria are responsible for producing the chemical energy store molecules, adenosine triphosphate (ATP), used to power cellular processes. Unfortunately, mitochondria become dysfunctional with age, in complex ways and for complex reasons that are not yet fully understood. Mitochondria evolved from symbiotic bacteria, and still act much like bacteria inside the cell. They carry a remnant circular genome, the mitochondrial DNA, they replicate as needed to keep their numbers up, they can fuse together and pass around component parts, they are recycled when worn or damaged by the quality control mechanisms of mitophagy. Within this dynamic system, age-related changes in gene expression and damage to mitochondrial DNA produces a growing loss of function. That in turn impacts the ability of organs in the body to function and maintain themselves.

Aging is an inevitable life process. The ability of aging organs to resist adverse external stimuli decreases, and thus they are more vulnerable to damage. Mitochondrial homeostasis plays an indispensable role in maintaining kidney function, and when mitochondrial function is disturbed, it will accelerate the aging of renal cells. Here, we reviewed the evidence of renal mitochondrial disorders, including abnormal mitochondrial function, abnormal mitophagy, and abnormal activation of oxidative stress and inflammation in renal aging.

Although targeting mitochondria is a potential strategy to slow kidney aging, many questions remain to be addressed, such as what role mitochondrial DNA (mtDNA) plays in renal aging. Although current studies have shown that inhibiting the release of mtDNA can inhibit the activation of inflammation and the occurrence of aging in other tissues and cells, there has been no research on the role of mtDNA in renal aging. Moreover, identifying specific renal mitophagy activators is also needed. Current studies have been conducted on animal and cell models, and there may be significant differences in the aging process and immune system between species that could limit the applicability of these findings to humans. Therefore, the relationship between aging and mitochondrial abnormalities in kidney tissue needs to be clarified in future studies.

When these questions are thoroughly investigated and answered, targeting mitochondria as a strategy to alleviate kidney aging will be viable. In addition, given the importance of mitochondria in biological activity and aging, targeting mitochondria may be a strategy for delaying aging in organs other than the kidney.

Link: https://doi.org/10.3389/fphar.2023.1191517

Researchers continue to search for novel senolytic compounds, those capable of selectively destroying senescent cells while producing a minimal impact on other cells. In youth, senescent cells are rapidly cleared by the immune system, but this clearance falters with age, leading to an accumulating burden of senescence in tissues throughout the body. These lingering senescent cells secrete pro-growth, pro-inflammatory signals that are disruptive to tissue structure and function when sustained over the long term. The lasting presence of senescent cells contributes to the chronic inflammation of aging, as well as to the onset and progression of near all age-related conditions. Animal studies show that clearance of these errant cells can reverse a broad range of age-related conditions, and thus there is considerable interest in the development of senolytic drugs to achieve the same result in humans.

Today's open access paper is illustrative of many similar efforts to discover usefully senolytic compounds that may already exist the vast databases of widely used medicinal products. New discoveries might form the basis for a later clinical development program. Given that every older adult is a potential customer for senolytic drugs, and that these drugs are expected to vary widely in their efficacy from tissue to tissue, there is more than enough room for many different senolytics-focused companies to coexist, and more than enough room for success in many different senolytic clinical programs. We should expect to see a considerable expansion of the set of known senolytic compounds and mechanisms for senolysis in the years ahead.

Identification of resibufogenin, a component of toad venom, as a novel senolytic compound in vitro and for potential skin rejuvenation in male mice

Senescent cells that accumulate with age have been shown to contribute to age-related diseases and organ dysfunction and have attracted attention as a target for anti-aging therapy. In particular, the use of senescent cell-depleting agents, or senolytics, has been shown to improve the aging phenotype in animal models. Since senescence has been implicated in the skin, particularly in fibroblasts, this study used aged human skin fibroblasts to investigate the effects of resibufogenin.

A component of the traditional Chinese medicine toad venom, resibufogenin was investigated for senolytic and/or senomorphic activity. We found that the compound selectively caused senescent cell death without affecting proliferating cells, with a marked effect on the suppression of the senescence-associated secretory phenotype. We also found that resibufogenin causes senescent cell death by inducing a caspase-3-mediated apoptotic program. Administration of resibufogenin to aging mice resulted in an increase in dermal collagen density and subcutaneous fat, improving the phenotype of aging skin. In other words, resibufogenin ameliorates skin aging through selective induction of senescent cell apoptosis without affecting non-aged cells. This traditional compound may have potential therapeutic benefits in skin aging characterized by senescent cell accumulation.

In recent years, increasing attention has been given to the role of microglia in neurodegenerative conditions. Microglia are innate immune cells of the central nervous system, analogous to macrophages elsewhere in the body, but which also participate in the organization of synaptic connections in addition to the other roles one might expect from immune cells. Microglia in the aging brain become more inflammatory and overactive with age. Some become senescent. This contributes to the chronic inflammation of brain tissue observed in older individuals, and which contributes to the onset and progression of neurodegenerative conditions. Interestingly, it is possible to efficiently clear microglia using CSF1R inhibitor drugs, after which the population is recreated over the course of a few weeks, lacking much of the dysfunction. This approach has yet to be earnestly tested as a way to help slow the progression of neurodegeneration, but the research community appears to be slowly moving in that direction.

It is evident that microglia are crucial players in the pathogenesis of Alzheimer's disease (AD), and a deeper understanding of their diverse functions and interactions with other cellular components in the brain will be vital for the development of effective therapeutic strategies. However, despite considerable progress in recent years, there remain significant gaps in our knowledge of microglial biology, particularly concerning their heterogeneity, precise mechanisms of action, and the interplay between various signaling pathways.

Multiple research studies have underscored the significance of specific subsets of microglia, particularly disease-associated microglia (DAM), in the progression of AD. The conjecture underpinning microglial depletion is that certain activated microglia, including DAM, may accentuate AD pathogenesis through a series of actions, such as facilitating the accumulation of Aβ plaques, amplifying neuroinflammation, and potentially influencing tau pathology. DAMs, characterized by a unique transcriptional profile and often found in close proximity to amyloid plaques, are thought to have substantial impacts on neuronal health and function. Consequently, it has been proposed that therapeutic strategies should be more disease-specific and aim at selectively targeting these DAMs.

The implementation of microglial depletion has been achieved through various strategies, most notably using pharmacological and genetic techniques. A common method involves the use of brain-penetrating inhibitors of CSF1R, a crucial cell surface receptor for microglial survival and proliferation. In AD mouse models, these inhibitors have demonstrated improvements in cognition and reductions in both neuroinflammation and neuritic plaque formation. However, the relationship between microglial depletion and amyloid pathology has been inconsistent, highlighting the need for further investigation. The potential of microglial depletion as a therapeutic approach must be carefully evaluated, but more research is warranted to further elucidate the complex roles of microglia, particularly DAM, in AD pathogenesis and treatment.

Link: https://doi.org/10.3389/fnagi.2023.1201982

That the brain has a lymphatic system is a comparatively recent realization. It coincides with another recent realization that perhaps drainage of fluid from the brain is important in maintaining brain health, carrying away molecular waste that would otherwise accumulate to cause pathology. Common age-related neurodegenerative diseases are characterized by rising inflammation and increasing presence of protein aggregates and other molecular waste in the brain, and it is now known that drainage pathways from the brain to the body are impaired with age. It remains to be seen how well restored drainage performs as a basis for therapy, though Leucadia Therapeutics nears human clinical trials of their implant to restore cerebrospinal fluid drainage through the cribriform plate, a different pathway from the glymphatic system that is more relevant to the onset of Alzheimer's disease.

It was traditionally believed that the lymphatic system didn't exist in the central nervous system. Thus, cell debris, potential neurotoxic proteins, and other metabolites with large molecular weight were considered to be removed in a different clearance pathway than brain vasculature. In 2012, the researchers found that cerebrospinal fluid (CSF) can enter brain parenchyma and exchange with brain interstitial fluid (ISF) in the presence of aquaporin-4 (AQP4) on astrocytes. Likewise, when the mixed fluid was drained from the brain, Amyloid-β (Aβ) was transported along with the outflow. Since the function of this "drainage" pathway is similar to that of the lymphatic system and supported by astrocytes, it was named the glymphatic system after the role of glia cells.

Since last decade, many researchers in the field of neurology, neurodegenerative diseases and physiology have aimed to study and develop the glymphatic system, providing a brand-new perspective for us to understand brain diseases: the overall fluid flow of the brain rather than a specific lesion or structure. Herein, we summarized the components of the glymphatic system, the fluid circulation mode within this system, how pathogenic solutes are transported in certain diseases, affecting factors of its function, and by what means we can study the glymphatic system. It may provide direction and reference for brain diseases and medical researchers.

Link: https://doi.org/10.3389/fnagi.2023.1179988

Klotho is one of the few genuinely longevity-associated genes, in that greater than normal expression increases life span in mice, while lower than normal expression shortens life span in mice. In humans, greater levels of circulating soluble klotho correlate with greater longevity. Klotho is thought to operate in the kidneys, in some way that is protective against the mechanisms of age-related decline, but there is a great deal of evidence for greater circulating klotho to improve cognitive function. At the same time, it seems unclear as to whether klotho is actually doing anything in the brain; it may be that the benefit is derived from preventing loss of kidney function, as kidney function is quite important to brain health. Still, this is subject to further discovery, and far from being a settled answer.

Various groups are working towards the use of the recombinant klotho protein as a therapy, or some form of gene therapy as a way to increase circulating levels in humans. This seems as likely to be initially developed as a treatment for cognitive impairment as for kidney conditions, given the evidence on the table. Certainly, that is the intent at UNITY Biotechnology, a company that licensed academic work from recent years on the effects of soluble klotho on cognitive function in mice. That same line of work now leads to today's study, in which soluble klotho is tested as a protein therapy in aged non-human primates. It appears to work as a way to improve cognitive function, but interestingly only at lower doses, suggesting that the path forward is probably going to be more complex than desired.

Longevity factor klotho enhances cognition in aged nonhuman primates

Klotho (KL) is a longevity factor that declines in aging. Elevating KL boosts cognitive functions in mice through transgenic overexpression and acute peripheral administration. KL (secreted α-klotho) circulates as a hormone following cleavage from its transmembrane form and impacts insulin and fibroblastic growth factor (FGF) signaling, Wnt and N-methyl-d-aspartate receptor (NMDAR) functions. Systemic elevation of KL in mice increases synaptic plasticity, cognition, and neural resilience to aging, Alzheimer's, and Parkinson's disease-related toxicities. Notably, systemic administration of KL does not cross the blood-brain barrier. Human relevance for KL in brain health is supported by studies showing that individuals with elevated KL, due to genetic Klotho variation or other reasons, demonstrate better cognition, attenuated neuropathological measures, or decreased dementia risk in aging and Alzheimer's disease.

We sought to test whether a low-dose, subcutaneous administration of KL could, in parallel to mice, boost cognition in aged rhesus macaques, a type of non-human primate (NHP). Like humans, rhesus macaques undergo age-induced cognitive decline with synaptic changes, without significant neuronal loss, impairing brain regions, including the hippocampus and prefrontal cortex (PFC). Targeted earlier by aging, the PFC subserves executive functions such as working memory and, in rhesus macaques, shows age-induced deficits in neuronal firing, regulated protein kinase C (PKC) activity, neurotransmitter balance and structural decline.

Our primary goal was to test whether a KL dose in rhesus macaques that increases serum levels to a range present during the human lifespan, and is comparable to therapeutically effective increases in mice, can enhance cognition. Our secondary goal was to explore higher KL doses in rhesus macaques to test whether KL-mediated benefits on cognition could be dose-dependent. Our data show that KL (10 μg/kg) enhanced cognition in aging rhesus macaques, an effect that persisted for at least 2 weeks in measures of memory. KL-mediated cognitive enhancement similarly persisted in mice for at least 2 weeks, suggesting organizational, longer-lasting and beneficial effects on the synapse and brain. In both species, the cognitive effect outlasted the putative half-life of the hormone, 7 minutes in rodents and estimated at 29.5 hours in aging rhesus macaques.

Higher doses of KL (20 and 30 μg/kg) did not enhance cognition in monkeys. Of note, the higher doses tested did not impair cognition as the 2-5% changes were not significantly increased or decreased statistically; however, it remains to be determined whether doses even higher than those tested could impair cognition. Together, these data indicate that KL-mediated cognitive enhancement extends to NHPs in a complex genetic, anatomical, and functional brain similar to humans. These data also suggest that lower, more 'physiological' levels of the hormone in the body may be required for a therapeutic window of cognitive enhancement in humans.

At this point in the development of senolytic therapies to clear harmful, lingering senescent cells from aged tissues, it is more interesting to find an aspect of aging that isn't improved by removal of senescent cells than to continue adding to the long list of age-related conditions and dysfunctions that are meaningfully reversed by senescent cell clearance. Here, researchers show that measures of the immune response to influenza infection in mice are not improved followed treatment with the senolytic combination of dasatinib and quercetin. This is a perhaps surprising result, given the expectation based on evidence to date that senolytics should improve immune function in later life.

Age is the greatest risk factor for adverse outcomes following influenza infection. The increased burden of senescent cells with age has been identified as a root cause in many diseases of aging and targeting these cells with drugs termed senolytics has shown promise in alleviating many age-related declines across organ systems. However, there is little known whether targeting these cells will improve age-related deficits in the immune system.

Here, we utilized a well characterized senolytic treatment with a combination of dasatinib and quercetin (D + Q) to clear aged (18-20 months) mice of senescent cells prior to influenza infection. We comprehensively profiled immune responses during the primary infection as well as development of immune memory and protection following pathogen reencounter. Senolytic treatment did not improve any aspects of the immune response that were assayed for including: weight loss, viral load, CD8 T-cell infiltration, antibody production, memory T cell development, or recall ability. These results indicate that D + Q may not be an appropriate senolytic to improve aged immune responses to flu infection.

Link: https://doi.org/10.3389/fragi.2023.1212750

The heart is one of the least regenerative tissues in the body. Damage resulting from loss of blood flow during a heart attack leads to scarring and loss of function, rather than any meaningful degree of regeneration. While preventing the atherosclerosis that causes occlusion of blood vessels is the most desirable goal, finding ways to repair a damaged heart is also a high priority for the research community. Many groups have worked towards regenerative therapies based on delivery of cells and scaffolding material, even layers of artificial tissue made by combining the two, but progress has been frustratingly slow.

Cardiovascular diseases (CVD) are the leading cause of hospitalization and death globally. CVD includes disturbances of the heart rhythm, cardiac valve pathologies, genetically driven malformations and, ultimately, peripheral artery disease (PAD) or coronary artery disease (CAD), which may culminate, respectively, in critical limb ischemia (CLI) and heart failure (HF). The use of cells with stem/progenitor characteristics in PAD and CLI has shown a success in clinical translation to a certain extent, given the ability of the chosen cells (e.g., derived from bone marrow, peripheral blood, or cord blood) to promote de novo vasculogenesis by a robust "paracrine effect". By contrast, the use of a similar setting to regenerate the contractile mass of the heart to compensate the loss of myocytes due to acute/chronic ischemia and/or inflammation has been largely unsuccessful and controversial, due to the absence of resident stem cells that could be activated in situ and/or expanded in vitro prior to being reinjected into the failing hearts.

Alternatives to this deficiency have been sought in the use of induced pluripotent stem cells (iPSCs), whose derived cardiomyocytes (CMs) have been employed in preclinical models in small and large animals, and even in pioneering studies in humans. Although scaled-up systems to produce therapeutic quantities of these cells with enhanced purity have been set, anticipating industrial production, several caveats have been expressed due to risks of arrhythmogenicity, incomplete maturation, potential tumor formation, and (at least for allogenic use) immune reactions.

Given the lack of endogenous regenerative capacity of the myocardium, the consequence of acute/chronic cardiac ischemia is still considered an irreparable damage leading to progressive replacement of the contractile cells with a stiff, fibrotic scar. Under these conditions, the heart undergoes a series of morphological transformations (e.g., rearrangement of the contractile apparatus and modification of the geometry), changes in mechanical characteristics and reduction of the pumping efficiency, representing signs of HF. With the advent of tissue engineering, the introduction of biological fabrication methods combined with refined systems for cellular genetic manipulation and decryption of mechanosensitive cues has enabled new strategies to enhance the efficacy of cardiac cell therapy and the elaboration of disease modeling systems using scaffolds, tissue printing, and tissue engineering approaches. This renews the hope that after the disappointment arising from the failure of the "classical" cell therapy approaches, it will be possible to reach a condition to regenerate the human heart, which still represents the "holy grail" of cardiology.

Link: https://doi.org/10.3390/jcm12103398

Chronic inflammation is a feature of aging, a continual activation of the immune response without any triggering injury or infection. Many different mechanisms contribute to this state of unresolved inflammatory signaling: the accumulation of senescent cells and the senescence-associated secretory phenotype (SASP); mitochondrial dysfunction leading to mislocalized mitochondrial DNA that triggers an innate immune reaction; signaling from visceral fat cells in those who are overweight; changes in the gut microbiome and intestinal barrier that allow microbes and microbial metabolites to provoke the immune system; and so on and so forth.

Inflammatory signaling is vital in the short term, necessary for the immune response to function correctly in the context of regeneration from injury, destruction of pathogens, and destruction of malfunctioning cells. When sustained for the long term, however, inflammatory signaling becomes increasingly disruptive to cell and tissue function. A meaningful fraction of degenerative aging results from chronic inflammation; research suggests that all of the common fatal age-related conditions have a strong inflammatory component to their pathologies.

Chronic inflammation and the hallmarks of aging

Recently, the hallmarks of aging were updated to include dysbiosis, disabled macroautophagy, and chronic inflammation. In particular, the low-grade chronic inflammation during aging, without overt infection, is defined as "inflammaging," which is associated with increased morbidity and mortality in the aging population. Emerging evidence suggests a bidirectional and cyclical relationship between chronic inflammation and the development of age-related conditions, such as cardiovascular diseases, neurodegeneration, cancer, and frailty. How the crosstalk between chronic inflammation and other hallmarks of aging underlies biological mechanisms of aging and age-related disease is thus of particular interest to the current geroscience research.

This review integrates the cellular and molecular mechanisms of age-associated chronic inflammation with the other eleven hallmarks of aging. Extra discussion is dedicated to the hallmark of "altered nutrient sensing". The deregulation of hallmark processes during aging disrupts the delicate balance between pro-inflammatory and anti-inflammatory signaling, leading to a persistent inflammatory state. The resultant chronic inflammation, in turn, further aggravates the dysfunction of each hallmark, thereby driving the progression of aging and age-related diseases.

The crosstalk between chronic inflammation and other hallmarks of aging results in a vicious cycle that exacerbates the decline in cellular functions and promotes aging. Understanding this complex interplay will provide new insights into the mechanisms of aging and the development of potential anti-aging interventions. Given their interconnectedness and ability to accentuate the primary elements of aging, drivers of chronic inflammation may be an ideal target with high translational potential to address the pathological conditions associated with aging.

Will senolytic drugs to destroy senescent cells and senomorphic drugs to reduce the harmful senescence-associated secretory phenotype (SASP) turn out to improve on present poor approaches to treat skin aging in humans? Few groups appear motivated to find out. Those developing senotherapeutics as drugs focus on more serious concerns than skin aging, and are arguably right to do so, while those developing senotherapeutics as cosmetics have little incentive to conduct expensive, robust clinical trials of their products. Success in selling cosmetic products has little connection with whether or not the products actually work. Nonetheless, we might hope that at some point someone will robustly quantify the effects of clearing senescent cells on the aging of human skin.

In recent years, researchers have attempted to counteract aging using senotherapeutics that selectively target senescent cells. Senotherapeutics are categorized into two groups. Senolytic drugs selectively eliminate senescent cells, and senomorphic drugs inhibit the negative effects of their SASP. Since the combination of dasatinib and quercetin was proposed as the first senolytic drug to suppress genes that are increased in senescent cells, many studies have shown that various substances such as ABT-737, ABT-263, A1155463, and fisetin have anti-aging properties.

In particular, ABT-263 and ABT-737, which are Bcl-2 inhibitors, have been found to selectively eliminate SA β-gal-positive senescent cells in skin both in vitro and ex vivo. Researchers demonstrated that either ABT-263 or ABT-737 treatment selectively eliminated dermal fibroblasts in an intrinsic skin aging mouse model. They also showed that the treatment increased the collagen density, epidermal thickness, and keratinocyte proliferation while reducing SASPs including MMP-1 and IL-6. Further, the team revealed that treatment with ABT-263 and ABT-737 also attenuated the induction of MMPs and decreased collagen density in the photoaging mouse model. In addition, ABT-263 showed potential in reducing pigmentation caused by photoaging in human skin inducing apoptosis of p16INK4A-positive fibroblasts with its senolytic activity, resulting in decreased levels of melanin and tyrosinase activity.

One of the most notable targets of senomorphic agents is the mechanistic target of rapamycin (mTOR) pathway, which regulates cellular metabolism and is linked to cellular growth, proliferation, and autophagy. The mTOR pathway is also involved in the synthesis of SASP. Rapamycin, an mTOR inhibitor, exhibited significant reduction in senescence markers and SASP as well as oxidative stress in UV-induced photoaged human dermal fibroblasts. Moreover, researchers revealed the potential anti-aging effect of topical application of rapamycin (an mTOR inhibitor). A total of 17 subjects over the age of 40 years with age-related photoaging of the skin applied a rapamycin-containing hand cream to the dorsum of one hand and a placebo hand cream to the other hand daily for 8 months and found that the rapamycin-treated hand had a decrease in p16 and an increase in collagen VII protein.

Taken together, these promising results suggest that senotherapeutics may be a novel therapeutic option for skin aging; however, the limitations of these drugs, such as their specificity, selectivity, and efficiency, still need to be addressed, and their mechanisms of action and side effects must be better understood.

Link: https://doi.org/10.3389/fphys.2023.1195272

With the caveat that mouse models of Alzheimer's disease are quite artificial, as aged wild-type mice do not suffer from any condition resembling Alzheimer's, and the models are thus built upon assumptions about which processes are important to the progression of the condition, researchers here show that resistance exercise slows the pathology and loss of cognitive function in one such model. Resistance exercise is well demonstrated to improve metabolism, immune function, and reduce mortality in both older animals and humans. It would not be too surprising to find that sedentary individuals are performing more poorly in the onset of dementia in addition to other aspects of degenerative aging.

Physical exercise has beneficial effects by providing neuroprotective and anti-inflammatory responses to Alzheimer's disease (AD). Most studies, however, have been conducted with aerobic exercise, and few have investigated the effects of other modalities that also show positive effects on AD, such as resistance exercise (RE). In addition to its benefits in developing muscle strength, balance and muscular endurance favoring improvements in the quality of life of the elderly, RE reduces amyloid load and local inflammation, promotes memory and cognitive improvements, and protects the cortex and hippocampus from the degeneration that occurs in AD.

Therefore, the aim of this study was to investigate the effects of 4 weeks of RE intermittent training on the prevention and recovery from these AD-related neuropathological conditions in APP/PS1 mice. For this purpose, 6-7-month-old male APP/PS1 transgenic mice and their littermates, negative for the mutations (Control), were distributed into three groups: Control, APP/PS1, APP/PS1+RE. RE training lasted four weeks and, at the end of the program, the animals were tested in the open field test for locomotor activity and in the object recognition test for recognition memory evaluation. The brains were collected for immunohistochemical analysis of Aβ plaques and microglia, and blood was collected for plasma corticosterone by ELISA assay.

APP/PS1 transgenic sedentary mice showed increased hippocampal Aβ plaques and higher plasma corticosterone levels, as well as hyperlocomotion and reduced central crossings in the open field test, compared to APP/PS1 exercised and control animals. The intermittent program of RE was able to recover the behavioral, corticosterone and Aβ alterations to the Control levels. In addition, the RE protocol increased the number of microglial cells in the hippocampus of APP/PS1 mice. Altogether, the present results suggest that RE plays a role in alleviating AD symptoms, and highlight the beneficial effects of RE training as a complementary treatment for AD.

Link: https://doi.org/10.3389/fnins.2023.1132825

A number of organizations organize yearly conferences relevant to both participants in the longevity industry and its surrounding community, and those who want to participate, whether as investors, researchers, advocates, entrepreneurs, or employees of biotech startups. Here I'll point out a few events that may be of interest to those who want to become more involved in this field. Come out to attend some of the better conferences! That is is the advice I give to most people who want to work in a longevity biotech company, start a longevity biotech company, make connections with self-experimenters and those who know more about the current state of research, or simply learn more about who is who. For another list of industry conferences, one might look to the Aging Biotech Info conference page.

August 10th, 2023: Ending Age-Related Diseases, New York City

Lifespan.io has organized a yearly conference series in NYC for some time now. This year they are trying something new, and mixing the longevity community with the blockchain community. A good number of high net worth blockchain industry folk have a strong interest in the longevity industry, and have both invested in biotech companies and funded research programs. There are also initiatives like VitaDAO that emerged from an intersection of the interest in longevity and blockchain applications, this being one of the more interesting attempts of the past twenty years to try to create a sustainable financial incentive to fund early stage research.

August 17th, 2023: Longevity Summit Dublin 2023, Dublin

The LEV Foundation, the present vehicle for the work of Aubrey de Grey since his separation from the SENS Research Foundation, hosts a yearly event in Dublin, Ireland. Like the conferences hosted by the SENS Research Foundation and Forever Healthy Foundation in past years, the summit aims to be a good mix of pushing forward on the fundamental science of rejuvenation, as well as bringing that science into the clinic.

August 28th, 2023: the 10th Aging Research and Drug Discovery Meeting, Copenhagen

ARDD is a primarily scientific conference focused on research that might lead to treatments for aging, but the event also attracts a significant number of of longevity industry entrepreneurs and investors. For industry participants, this is the mixture to seek out, as it offers the greatest chance of fortunate connections. Perhaps by virtue of continuing largely undaunted while other conferences were slow to return following COVID-19, ARDD has become one of largest and best events for that part of the longevity community that lies at the intersection of industry and academia.

September 7th, 2023: RAAD Festival, Anaheim

RAADfest remains, as in past years, a fascinating mix of scientists and alchemists, legitimate companies working on means of rejuvenation next to the frauds of the "anti-aging" industry. Go, by all means, should you feel equipped to tell the difference! At some point, working medicine that is capable of achieving a specific goal in control over the human body drives out the charms and potions. It hasn't happened yet in the matter of aging, but it will as the longevity industry advances.

September 27th, 2023: Longevity Investors Conference, Gstaad

As the title might suggest, this is a fully investor-focused conference intended to directly educate and expand the investor community focused on the longevity industry. While that investor community has certainly expanded by leaps and bounds in recent years, many more participants are needed as increasing numbers of longevity industry companies move beyond the preclinical stage of development into the very much more expensive clinical stage. The sizable funding for clinical trials of therapies capable of slowing or reversing the mechanisms of aging must come from somewhere, and educating the community of conservative investors that manage very large funds is a project in and of itself.

December 1st, 2023: Foresight Vision Weekend, Paris and San Francisco

The Foresight Institute puts on a number of events relevant to the longevity community, firstly a longevity-focused workshop earlier in the year and then a yearly gathering that covers all of the organization's areas of interest in developing technologies, including the treatment of aging as a medical condition. The crowd is typically made up of the Bay Area investment and entrepreneurial community, but it draws visitors from many parts of the longevity industry and research community. It is an excellent opportunity to make connections with people who have been at the core of the longevity industry since its inception.

December 5th, 2023: Longevity Summit, San Francisco

The Longevity Summit is a new conference series, held at the Buck Institute just north of the Bay Area. Like the other conferences I'd consider to be at the better end of the spectrum, the organizers make an effort to gather together a good mix of scientists, entrepreneurs, and investors. I didn't attend last year, but those who did spoke highly of it.

December 7th, 2023: 23rd Bay Area Aging Meeting, San Francisco

While ostensibly a meeting for the scientific community, plenty of the participating labs have given rise to longevity industry biotech companies in recent years. Still, this is probably the most wholly academic/scientific of the events in this list. If you are a scientist at an academic institution in the US, starting here might be a good plan.

The FLT1 gene encodes the vascular endothelial growth factor receptor 1 (VEGFR1) protein, relevant to the process of angiogenesis, among others. Researchers here note that a longevity-associated variant of FLT1 appears to be protective in hypertensive individuals. It is tempting to speculate as how this variant beneficially alters blood vessel maintenance and creation, but finding out would require much more than just the epidemiological data presented here.

Longevity is written into the genes. While many so-called "longevity genes" have been identified, the reason why particular genetic variants are associated with longer lifespan has proven to be elusive. The aim of the present study was to test the hypothesis that the strongest of 3 adjacent longevity-associated single nucleotide polymorphisms - rs3794396 - of the vascular endothelial growth factor receptor 1 gene, FLT1, may confer greater lifespan by protecting against mortality risk from one or more adverse medical conditions of aging - namely, hypertension, coronary heart disease (CHD), stroke, and diabetes.

In a prospective population-based longitudinal study we followed 3,471 American men of Japanese ancestry living on Oahu, Hawaii, from 1965 until death or to the end of December 2019 by which time 99% had died. Cox proportional hazards models were used to assess the association of FLT1 genotype with longevity for 4 genetic models and the medical conditions. We found that, in major allele recessive and heterozygote disadvantage models, genotype GG ameliorated the risk of mortality posed by hypertension, but not that posed by having CHD, stroke, or diabetes. Normotensive subjects lived longest and there was no significant effect of FLT1 genotype on their lifespan.

In conclusion, the longevity-associated genotype of FLT1 may confer increased lifespan by protecting against mortality risk posed by hypertension. We suggest that FLT1 expression in individuals with longevity genotype boosts vascular endothelial resilience mechanisms to counteract hypertension-related stress in vital organs and tissues.

Link: https://doi.org/10.18632/aging.204722

In past years, researchers have attempted various forms of cell therapy for Parkinson's disease, with the goal of replacing the population of dopamine generating neurons that are lost to disease processes. Fetal sources of neurons have been used, but since the discovery of cellular reprogramming, the trajectory has been towards the production of neurons from induced pluripotent stem cells. As noted here, this has reached the stage of human clinical trials.

Bayer AG and BlueRock Therapeutics LP, a clinical stage cell therapy company and wholly owned independently operated subsidiary of Bayer AG, today announced positive top-line results from a Phase I clinical trial of investigational drug, bemdaneprocel (BRT-DA01), a potential first-in-class cell therapy for Parkinson's disease. The trial showed that bemdaneprocel was well-tolerated in all 12 patients in the study to date, with no major safety events. In addition, an assessment of the study's secondary endpoints demonstrated feasibility of transplantation and evidence of cell survival and engraftment in the brain through one year. Based on these results, planning is underway for a Phase II study that is expected to begin enrolling patients in H1 (first half) 2024.

Bemdaneprocel (BRT-DA01), an investigational therapy comprised of dopamine producing neurons derived from pluripotent stem cells, is surgically implanted into the brain of a person with Parkinson's disease. When transplanted, these cells have the potential to reform neural networks that have been destroyed by Parkinson's disease in the hope of restoring motor and non-motor function to patients. The primary objective of the Phase I trial is to assess the safety and tolerability of bemdaneprocel (BRT-DA01) transplantation at one-year post-transplant. The secondary objectives of the trial are to assess the evidence of transplanted cell survival and motor effects at one- and two-years post-transplant, to evaluate continued safety and tolerability at two years, and to assess feasibility of transplantation.

Link: https://www.bluerocktx.com/bluerocks-neuronal-stem-cell-therapy-for-parkinsons-disease-is-first-to-show-positive-results-in-phase-i-clinical-study/

As the longevity industry grows, the need for investment grows with it. A big leap in funding is needed to move from preclinical to clinical development, and ever more companies are arriving at the point of making that transition. Raising the few million dollars in seed funding needed for a small lab team to produce proof of principle studies to demonstrate that a novel therapy works in mice is a very different prospect in comparison to raising tens of millions of dollars to conduct GMP manufacturing and phase II clinical trials in humans, never mind the even larger sums needed for later phase III trials. The types of investors to participate at early and later stages are very different, with very different ideas of risk. It is typically the case that larger the check, the more institutional and conservative the investor.

Institutional, conservative biotech investors care greatly about the way in which they are perceived, since their ability to raise funds from limited partners is very much affected by that perception. When it comes to investing in the longevity industry, conservative investors are attracted by the potential for profit, but bothered by the long-standing existence of a fraudulent "anti-aging" marketplace, alongside numerous groups claiming membership of the longevity industry while selling supplements or treatments via medical tourism with claims that are in no way backed by rigorous evidence. These investors have carefully cultivated reputations, and fear the loss of reputation that results from investing sizable funding into ventures that fail. And some fraction of ventures always fail. When those ventures were by-the-book, nothing-new-here, conservative endeavors that checked all of the proper boxes, that can be forgiven. But venturing out into the unknown? That is less forgivable.

Thus as the longevity industry matures, elements within it are creating industry associations and paving the way to a perception of the longevity industry as a by-the-book, rigorous, nothing-new-here endeavor, just like the rest of the medical biotechnology space. They draw a circle that excludes everyone who sidesteps the existing regulatory system for drug development: the supplement companies; the cosmetic companies; the companies focusing on medical tourism rather than the FDA; and so forth. Today's position statement is authored by the founders, investors, and leadership of a number of the longevity industry companies closest to clinical trials. This is a part of the process of laying the groundwork to make it easier to find the much greater funding needed for the phase II and phase III trials that lie ahead.

Defining a longevity biotechnology company

The Longevity Biotechnology Association (LBA) is a non-profit organization created to foster collaboration, propose guidelines for industry, educate stakeholders, and translate geroscience to prevent the diseases associated with aging and extend healthspan. Billions of dollars are being allocated to basic and translational research in aging biology, but parameters and guide rails for the longevity biotechnology industry remain undefined. The efficacy of a new intervention can only be rigorously demonstrated by a sufficiently powered clinical trial. Today, there are products on the market that claim to boost longevity but lack robust scientific evidence in humans to support these claims. Academic scientists, drug developers, and entrepreneurs developing new drugs arising from aging research need to direct their efforts toward elucidating the mechanisms of action of potential interventions and conducting human trials. Similarly, investors, regulators, members of the media and others require a framework to evaluate the claims made by translational longevity biotechnology projects and their potential to demonstrate effectiveness of an intervention in humans.

The LBA proposed framework for a longevity biotechnology company includes four pillars: (1) mission, (2) drug discovery approach, (3) initial clinical development and regulatory approval, and (4) targeting multi-morbidity and healthspan. By creating a framework that defines best practices in longevity biotechnology, we hope to facilitate communication with audiences that include drug developers, investors, regulators, policymakers, journalists and the general public. Clarification of the field's goals and approaches will help to direct resources to efforts with the greatest potential for trial success and regulatory approval, move innovations from the bench into clinical practice, and ultimately improve the lives of older adults.

Interest and investment into the longevity drug development space continue to grow, with the number of players in the sector expected to increase. Following the proposed framework by having a specific mission, generating a drug that targets known hallmark mechanisms, and going through the processes of early- and late-stage clinical trials will demonstrate to any scientist, investor, company, journalist or member of the public that a specific organization is positioned to contribute positively to the field of longevity biotechnology.

When a novel field of research captures the interest of academics, investors and the public, it is common for various approaches to proliferate. Some of these approaches will leverage novel science to yield patient benefit. However, as noted, less rigorous actors might exploit the public interest to sell products to consumers and patients. The onus rests with the experts within the new research field to help non-experts distinguish between the two. In the early 2000's this was done expertly for the stem cell field by the International Society for Stem Cell Research (ISSCR), which has helped maintain and update those standards in recent decades. We helped create the LBA as a non-profit entity to achieve a similar goal. Although the organization is still young, we have put forward this framework to identify those efforts that have a high likelihood of contributing to the goal of not just creating new interventions based on aging research, but also demonstrating that the interventions increase human healthspan in clinical trials.

Researchers here consider dysregulation of lipid metabolism at the cellular level as an aspect of aging that causes downstream issues. Like many manifestations of aging observed in cells in aged tissues, why this happens is a matter for debate, setting aside situations such as the environment of a fatty liver or atherosclerotic plaque in which there is a localized excess of lipids to explain the overload inside cells. In a number of neurodegenerative conditions, the presence of cells loaded with lipid droplets is a prominent feature. It remains to be seen as to whether new classes of therapy under development, capable of clearing lipids in a selective manner, will prove to be useful in that context.

It is widely accepted that nine hallmarks - including mitochondrial dysfunction, epigenetic alterations, and loss of proteostasis - exist that describe the cellular aging process. Adding to this, a well-described cell organelle in the metabolic context, namely, lipid droplets, also accumulates with increasing age, which can be regarded as a further aging-associated process. Independently of their essential role as fat stores, lipid droplets are also able to control cell integrity by mitigating lipotoxic and proteotoxic insults.

As we will show in this review, numerous longevity interventions (such as mTOR inhibition) also lead to strong accumulation of lipid droplets in Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster, and mammalian cells, just to name a few examples. In mammals, due to the variety of different cell types and tissues, the role of lipid droplets during the aging process is much more complex. Using selected diseases associated with aging, such as Alzheimer's disease, Parkinson's disease, type II diabetes, and cardiovascular disease, we show that lipid droplets are "Janus"-faced. In an early phase of the disease, lipid droplets mitigate the toxicity of lipid peroxidation and protein aggregates, but in a later phase of the disease, a strong accumulation of lipid droplets can cause problems for cells and tissues.

Link: https://doi.org/10.3390/biom13060912

Researchers here show that increased expression of the autophagy regulator gene ATG4B improves health and extends life in flies, most likely via improved autophagy - though other mechanisms are involved, as is usually the case. Expression of the human version of ATG4B declines with age, and in humans long-lived individuals tend towards higher levels of expression. Autophagy is a maintenance process that clears out damaged proteins and structures.

A great deal of evidence points to the value of autophagy to long-term health, and to cellular stress responses in general, though the effect on life span in long-lived species seems to be much less impressive than is the case in short-lived species. In principle, more efficient clearance of damage leads to better cell and tissue function, but it is possible that cell maintance in long-lived species has already evolved to be much more efficient than is the case in short-lived species, leaving less room for benefits to be achieved via this sort of intervention.

Autophagy plays important but complex roles in aging, affecting health and longevity. We found that, in the general population, the levels of ATG4B and ATG4D decreased during aging, yet they are upregulated in centenarians, suggesting that overexpression of ATG4 members could be positive for healthspan and lifespan. We therefore analyzed the effect of overexpressing Atg4b (a homolog of human ATG4D) in Drosophila, and found that, indeed, Atg4b overexpression increased resistance to oxidative stress, desiccation stress and fitness as measured by climbing ability. The overexpression induced since mid-life increased lifespan.

Transcriptome analysis of Drosophila subjected to desiccation stress revealed that Atg4b overexpression increased stress response pathways. In addition, overexpression of ATG4B delayed cellular senescence, and improved cell proliferation. These results suggest that ATG4B have contributed to a slowdown in cellular senescence, and in Drosophila, Atg4b overexpression may have led to improved healthspan and lifespan by promoting a stronger stress response. Overall, our study suggests that ATG4D and ATG4B have the potential to become targets for health and lifespan interventions.

Link: https://doi.org/10.3390/ijms24129893

Cells become senescent constantly, throughout life and throughout the body. Most such cells have reached the Hayflick limit on replication, but cells can also become senescent in response to damage, stress, or the signaling of other senescent cells. In youth, senescent cells are efficiently cleared by the immune system, but this clearance falters with age for reasons that are incompletely understood at the present time. The consequence of a mismatch between pace of creation and pace of clearance is a growing burden of lingering senescent cells. These cells secrete a mix of signals, the senescence-associated secretory phenotype (SASP), that is disruptive to tissue structure and function, and provokes continual, unresolved inflammation. This directly contributes to the onset and progression of many age-related conditions.

In today's open access paper, researchers discuss the presence of senescent cells and SASP in the context of bone tissue specifically. Bone loses density with age, leading to osteoporosis. This results from an imbalance between the activities of osteoblasts, creating bone, and osteoclasts, removing bone. Many contributing factors lead to a growing gap that favors the breakdown of bone tissue by osteoclasts, and the signaling produced by senescent cells is one such factor. Further, bone is a tissue of significant size, and the SASP produced by senescent cells spreads throughout the body. The larger the organ, the greater the impact as some proportion of cells becomes senescent. Cellular senescence in larger tissues such as skin, muscle, and bone may well have meaningful harmful effects elsewhere in the body.

"Bone-SASP" in Skeletal Aging

Substantial evidence supports the causal role of cellular senescence in bone tissue during natural aging, premature aging syndromes, and many age-associated skeletal disorders, such as osteoporosis and osteoathritis. A central mechanism by which senescent cells expand the senescence program and impair the bone and bone marrow microenvironment is via senescent bone cell-associated SASP, namely "bone-SASP." It is now well recognized that the SASP is highly heterogeneous, varies depending on cell type and the senescence-inducing stimulus, and is very dynamic, changing over time after the stimulus. Thus, it is important to use a proteomic, unbiased approach to gain insights into highly complex SASP profiles.

However, in most studies of the detection of bone-SASP in pathological conditions such as the progeria-associated bone disorders, osteoarthritis, and osteoporosis, unbiased profiling of the SASP factors was not conducted. Only chosen panels of inflammatory factors and cytokines were detected. Given that the newly generated SenMayo dataset identifies bone-SASP across tissues and species with high fidelity, further detailed characterization and comprehensive identification of the bone-SASP in different age-associated skeletal conditions are warranted.

Recent studies suggest that the SASP, as a feature of cellular senescence, not only exerts a detrimental effect locally but may also cause systemic adverse effects. Although the SASP has an endocrine effect on regulating the activities of tissues and organs at remote sites, the endocrine role of the bone-SASP remains largely unexplored. Recent evidence revealed that PDGF-BB produced by senescent preosteoclasts serve as a systemic pro-aging factor that contributes to age-associated increase in arterial stiffness and cerebrovascular impairment. Further assessment is needed of the involvement of bone-derived PDGF-BB in the aging process of other organ systems to validate its endocrine function.

In summary, research into the endocrine role of senescent cells is still in the early stage. Given that some bone-SASP factors identified to date are important inflammatory factors and pro-aging factors, there is no doubt that the systemic effect of bone-SASP factors will become one of the main topics in the field of skeletal research.

How much of the characteristic loss of muscle mass and strength that takes place with aging is the result of mitochondrial dysfunction? Mitochondria produce the chemical energy store molecules needed to power cellular processes, but in addition to the loss of this capacity, dysfunction in mitochondria can also generate oxidative stress that further impairs cell function. Some degree of mitochondrial dysfunction emerges from damage to mitochondrial DNA, but it is also the case that age-related changes in gene expression reduce the efficiency of mitochondrial quality control, the process of mitophagy responsible for removing damaged mitochondria. These processes are well investigated, and researchers are presently establishing ways to transplant mitochondria in large enough numbers to restore function throughout the body, but how great a benefit this systemic rejuvenation will produce has yet to be assessed in animal studies.

A hallmark of muscle aging is the buildup of dysfunctional and damaged mitochondria. However, the mechanisms leading to the accumulation of unhealthy mitochondria and whether this drives some of the aging-induced alterations are not fully understood yet. The process responsible for the selective degradation of damaged mitochondria, also known as mitophagy, is key in the maintenance of mitochondrial quality. Besides, mitophagy is tightly tuned with mitochondrial dynamics, and this coordination is essential during mitochondrial quality control. Indeed, alterations in these processes have been found to contribute to the accumulation of dysfunctional mitochondria in aged muscles.

In particular, we have shown that a reduction in the mitochondrial fusion protein Mitofusin 2 (Mfn2) during aging drives metabolic deterioration, muscle atrophy, and sarcopenia by a deregulation of mitochondrial dynamics and mitophagy. Interestingly, as a consequence of the accumulation of damaged and ROS-generating mitochondria, an adaptive mitophagy pathway involving ROS-induced expression of the mitophagy protein BNIP3 is activated in order to minimize mitochondrial damage. Pharmacological inhibition of this adaptive mitophagy pathway or genetic downregulation of muscle BNIP3 worsens mitochondrial quality and potentiates muscle atrophy. In contrast, re-expression of Mfn2 to levels comparable to those of young mice prevents muscle atrophy in old mice. Altogether, these data demonstrate a tight connection between mitochondrial health and the development of muscle atrophy and sarcopenia.

Link: https://doi.org/10.18632/aging.204857

There are a number of functionally immortal lower species, such as hydra, jellyfish, and planarians. Individual animals do not exhibit aging, in that mortality rate does not rise over time. An interesting question is the degree to which these species employ much the same strategy of cellular reprogramming as occurs in the early embryo of mammals, in order to maintain a youthful epigenome. Some of these species only maintain immortality under certain circumstances, and researchers have made use of that in order to examine what happens to cellular biochemistry when individuals switch from a state of aging to a state of rejuvenation and functional immortality.

An ability to delay aging or to reverse the negative effects of aging could prevent age-related disease and greatly enhance quality of life in old age. However, whether it is possible to globally reverse the physiological effects of aging in order to extend healthspan is unknown. The freshwater planarian Schmidtea mediterranea has been considered immortal due to its exceptional tissue regeneration capabilities. Here, we report that a sexually reproducing lineage of S. mediterranea exhibits age-associated physiological decline 12 months after birth. Age-associated changes include alterations in sensory organs, loss of neurons and muscle, loss of fertility, and impaired motility, but no reduction in stem cells at the age of 3 years.

Differential gene expression analysis, comparing young and old planarian cells, furthermore revealed cell-type-specific changes in transcription as well as changes in classical aging pathways (e.g., insulin signaling). Remarkably, amputation followed by regeneration of lost tissues led to a global reversal of these age-associated changes. Older individuals that underwent regeneration showed restored youthful patterns of gene expression, stem cell states, tissue composition and rejuvenation of whole-animal physiology. Our work reveals a naturally evolved solution to age reversal in planaria that may provide insights into anti-aging strategies in humans.

Link: https://doi.org/10.1101/2023.06.24.546358

In today's open access paper, researchers report on a study of age-related changes in metabolite profiles in blood, muscle, and urine, with samples taken from healthy members of age groups spanning the 20s to 80s. As might be expected, the results point to many of the usual suspects in aging, such as senescent cell burden and mitochondrial dysfunction.

It is certainly possible to use metabolomic data to construct aging clocks in much the same way as for epigenetic data, and some researchers have done just that in recent years. There are indeed characteristic changes in a range of metabolite levels that appear to reflect biological age, the burden of damage and dysfunction, rather than chronological age.

Cross-sectional analysis of healthy individuals across decades: Aging signatures across multiple physiological compartments

Human studies make use of biomarker changes in fluids and tissues, such as blood, skeletal muscle, and urine, that occur during the aging process to infer biological changes due to aging per se. These studies are made even more complex by the difficulty in distinguishing between changes compensatory to the emergence of pathology and those that simply reflect aging itself. In addition, findings from studies that investigated age-related changes in the metabolome that occurred in just one compartment, such as plasma or serum, may not necessarily translate to other biological fluids or tissues.

We hypothesized that simultaneously investigating age-related differences in various fluid and tissue compartments may shed more light on the underlying mechanisms that drive changes in the metabolome with age and that ultimately contribute to the phenotypic manifestations of aging. Here, we report the results of a comprehensive profiling of age-related metabolomic changes across three compartments simultaneously: the circulatory system (plasma), the excretory system (urine), and a solid organ (skeletal muscle). To minimize the interference of changes in metabolites reactive to pathology, we enrolled in this study individuals that were healthy based on a comprehensive clinical evaluation performed by trained health professionals. To reduce variability that can result from different quantification methods, the same targeted metabolomic platform was used for all compartments. Herein, we carry out a cross-sectional analysis of 'healthy' individuals who were free from disease to formulate hypotheses based on the metabolic exchanges that occur between different compartments with aging.

Here, we summarize the metabolic pathways that emerged from our analysis of metabolites in plasma, muscle, and urine. These pathways include inflammation and cellular senescence, microbial metabolism, mitochondrial health, sphingolipid metabolism, lysosomal membrane permeabilization, vascular aging, and kidney function. It is important to underline that while these biological mechanisms are far from being a comprehensive list of the biological processes at play over human life spans, they provide insight into some of the basic metabolomic age signatures of cross compartmental, interconnected changes.

It is becoming clear that characteristic age-related changes in the composition of the gut microbiome accompany specific age-related diseases, and may well be contributing meaningfully to the development of those conditions. At the very least, the aged gut microbiome creates chronic inflammation, and that unresolved inflammatory signaling is disruptive to cell and tissue function throughout the body. There may be many other meaningfully involved mechanisms, however, such as changes in metabolite production. Many microbial metabolites have a beneficial effect on cell function, such as butyrate, and are known to decline with age.

The gut microbiota is critical for host protection against pathogens, immune development, and metabolism of dietary nutrients and drugs. In healthy individuals, the gut microbial composition is established early in life and remains relatively stable over time. Nevertheless, this ecosystem may become destabilized as a result of aging, environmental factors, and lifestyle habits such as diet. Shifts in gut microbial composition and diversity (i.e., gut dysbiosis) have been reported to influence neuroimmune and neuroendocrine functions through a bottom-up fashion resulting in neuroinflammation, microglial dysregulation, and aberrant protein aggregation in the Alzheimer's disease (AD) brain. Accordingly, this dysbiotic condition may set the stage for a toxic brain environment that stimulates AD neuropathophysiology, including the deposition of amyloid-beta (Aβ) plaques and neurofibrillary tangles.

The relationship between disruptions in the microbiota-gut-brain axis and AD can be explained by the Seed and Soil Model of Neurocognitive Disorders. Based on this model, the "seed" represents a predisposition to a neurocognitive disorder (e.g., genetic profile) and the "soil" refers to factors that moderate the expression of that seed. Together, the seed and the soil ultimately determine whether a person will develop the disorder. This model was created to explain why some people who are predisposed to develop neurocognitive disorders do not develop them. Although this model did not originally apply to the microbiota-gut-brain axis, the concept is general enough that it can be applied to many new contexts as ideas evolve.

In the case of AD and the microbiota-gut-brain axis, the seed could represent a polygenic risk score or family history of AD, whereas the soil could be represented by certain dysbiotic taxa. Dysbiotic taxa can contribute to many consequences including altered intestinal permeability that leads to a leaky gut and fosters the activation of local and distant immune cells. Given that the metabolites of gut leakiness are linked to increased permeability of the blood-brain barrier, these dysfunctions promote the translocation of bacterial endotoxins from the gut to the brain and increase inflammation within the system. According to the Seed and Soil Model of Neurocognitive Disorders, this translocation would create a toxic microenvironment in the brain vulnerable to pathogenesis, especially for those with a genetic predisposition to AD.

Consistent with this notion, a recent systematic meta-analysis showed that individuals with AD exhibited less gut microbial diversity than those with mild cognitive impairment (MCI) or healthy controls. Likewise, the gradient changes of abundance from normal cognition to MCI and AD stage were observed in several strains of gut microbiota (i.e., phylum Proteobacteria, family Clostridiaceae, and genus Phascolarctobacterium). Prior evidence also has revealed that gut-derived lipopolysaccharide (endotoxin) acts as an Aβ fibrillogenesis promoter, potentially leading to neuroinflammation and neurodegeneration.

Link: https://doi.org/10.18632/aging.204840

In animal studies, reduced intake of the essential amino acid methionine mimics many of the beneficial effects of calorie restriction on long-term health and life span, even when calorie intake is maintained at the same level as the control groups. One of the triggers for the calorie restriction response to increase cell maintenance activities is based on nutrient sensing that is specific to methionine. Low methionine diets are perhaps more challenging to organize than the practice of calorie restriction, however. Researchers here offer an interesting alternative, which is to use an enzyme to break down methionine in the diet before it has the chance to enter the body. That enzyme can be delivered directly in the diet or, intriguingly, manufactured by bacteria that are introduced to the gut microbiome.

Obesity increases with aging. Methionine restriction affects lipid metabolism and can prevent obesity in mice. In the present study we observed C57BL/6 mice to double their body weight from 4 to 48 weeks of age and become obese. We evaluated the efficacy of oral administration of recombinant-methioninase (rMETase)-producing E. coli (E. coli JM109-rMETase) or a methionine-deficient diet to reverse old-age-induced obesity in C57BL/6 mice.

Fifteen C57BL/6 male mice aged 12-18 months with old-age-induced obesity were divided into three groups. Group 1 was given a normal diet supplemented with non-recombinant E. coli JM109 cells orally by gavage twice daily; Group 2 was given a normal diet supplemented with recombinant E. coli JM109-rMETase cells by gavage twice daily; and Group 3 was given a methionine-deficient diet without treatment.

The administration of E. coli JM109-rMETase or a methionine-deficient diet reduced the blood methionine level and reversed old-age-induced obesity with significant weight loss by 14 days. There was a negative correlation between methionine levels and negative body weight change. Although the degree of efficacy was higher in the methionine-deficient diet group than in the E. coli JM109-rMETase group, the present findings suggested that oral administration of E. coli JM109-rMETase, as well as a methionine-deficient diet, are effective in reversing old-age-induced obesity. In conclusion, the present study provides evidence that restricting methionine by either a low-methionine diet or E. coli JM109-rMETase has clinical potential to treat old-age-induced obesity.

Link: https://doi.org/10.18632/aging.204783

It is not hard to argue that there is too little investment in progress towards the treatment of aging as a medical condition. Collectively, the underlying mechanisms of degenerative aging are the cause of two-thirds of human mortality, and likely a somewhat greater fraction of loss of function, suffering, and pain. The cost of that mortality is vast, no matter how one likes to model the value of a human life, or a year spent alive in good health. This is much the same argument that can be made for greater investment in medical research in general. Medical research funding as a whole is a very, very tiny fraction of the costs that coping with currently incurable, unmanageable conditions impose upon us. But our species isn't really all that rational when it comes to collective action, whether or not the topic is saving our lives.

It seems inevitable that the urge for scientific progress will at some point lead to the development of impressive rejuvenation therapies. Rejuvenation is just a special case of medicine, which is just a special case of control over complex molecular systems. The ideal of achieving meaningful progress towards that broader goal is entrenched into the scientific and technological culture of the past century; it seems likely to continue. Today's cutting edge technology demonstrations in exerting fine control over aspects of our cellular biochemistry will be commonplace building blocks in the toolkit in three decades, and ancient history in six decades. But inevitability over the longer term certainly doesn't translate to inevitability on useful timescales, such as sometime before you or I become too old or too dead to benefit from novel approaches to controlling the processes that drive aging.

In the short term, there are always challenges inherent in selling investors on a plan of action, in the obstacles and costs imposed by regulators, in the perverse incentives operating in the pharma industry, in persuading people to support the cause, in the right entrepreneurs having the right ideas and connecting with the right scientists. One can throw as much funding as one likes at a problem, but many component parts of the intricate dance involving many different humans trying to make progress on a given problem simply can't be compressed to much below a few years. In the present regulatory system, and culture of science, it is always going to take more than a decade to move from lab to widespread availability for most ultimately successful programs, even given many well-funded, competing factions working on their versions of a solution.

Curing aging is a question of investment, not time

"When you think about treating aging, what we're really talking about is treating this whole range of different diseases - cancer, heart disease, stroke, dementia - all of these things are caused by the aging process. So, there's a huge opportunity to make a big difference in the world. If these drugs can potentially slow down or reverse the aging process, then they ultimately have a market of every living human,. You can imagine a situation where everyone over the age of 50 or 60, once they've accumulated enough of whatever age-related change your drug is targeting, will want to start using that medication. It's going to be a completely new paradigm for medical treatment, and it's a huge opportunity for investors."

Of course, investing in longevity isn't as simple as it sounds - the field is vast and diverse, with hundreds of companies targeting different hallmarks, mechanisms, and drivers of aging. Andrew Steele's hope is that investment will also extend into the basic science needed to advance some of these areas to the point where potential treatments are ready to turn into biotech or pharma endeavors. "I believe these treatments will often turn out to be complementary to other areas of longevity development. I often talk about a cure for aging, but that doesn't mean I think it's going to be a single pill - we're probably going to have dozens of different approaches to tackle lots of different age-related changes. So, I'd really encourage investors to go out and try and find some of these other age-related changes that aren't getting aren't getting quite so much limelight."

Longevity science is a field where predictions about timeframes to achieving certain milestones are often bandied around. It's a practice that Andrew Steele feels is unhelpful. "I think the way people often try and give their predictions as a certain number of years away is a bit wrongheaded. I think we should really think about developments in science as being a certain investment away from fruition." Essentially there are a certain number of "nerd hours" between where we are now and getting to the point of being able to treat the aging process sufficiently well to bring it under medical control. And those nerd hours cost money. "I don't know how much money that's necessarily going to involve - it's hard to look at current levels of investment and multiply that up. But what I do know is, the more we invest, the faster a lot of this science can progress."

Researchers here demonstrate accelerated healing of bone loss in rats, using a novel implanted scaffolding material that provides a nanostructure to encourage cell growth and repair activities. As described in this paper, bone is made up of both harder and softer small-scale structures, and suitable choices of material and structure that better mimic these features can provoke osteogenic cells into greater activity than would otherwise be the case.

Several studies have shown that nanosilicate-reinforced scaffolds are suitable for bone regeneration. However, hydrogels are inherently too soft for load-bearing bone defects of critical sizes, and hard scaffolds typically do not provide a suitable three-dimensional (3D) microenvironment for cells to thrive, grow, and differentiate naturally. In this study, we bypass these long-standing challenges by fabricating a cell-free multi-level implant consisting of a porous and hard bone-like framework capable of providing load-bearing support and a softer native-like phase that has been reinforced with nanosilicates.

The system was tested with rat bone marrow mesenchymal stem cells in vitro and as a cell-free system in a critical-sized rat bone defect. Overall, our combinatorial and multi-level implant design displayed remarkable osteoconductivity in vitro without differentiation factors, expressing significant levels of osteogenic markers compared to unmodified groups. Moreover, after 8 weeks of implantation, histological and immunohistochemical assays indicated that the cell-free scaffolds enhanced bone repair up to approximately 84% following a near-complete defect healing. Overall, our results suggest that the proposed nanosilicate bioceramic implant could herald a new age in the field of orthopedics.

Link: https://doi.org/10.1021/acsami.3c01717

Age-associated B cells are one of a number of dysfunctional or maladaptive immune cell subpopulations that appear in increasing numbers in later late, and which likely impair the many functions of the immune system by their presence. Clearing all B cells rather than trying to selectively clear age-associated B cells is a viable proposition, as the B cell population regenerates quite rapidly following clearance, and the new cells lack the age-associated B cell phenotype. This has been demonstrated in animal models, but has yet to make it to the clinic as a treatment to improve the aged immune system.

Age-associated B cells (ABC) accumulate with age and in individuals with different immunological disorders, including cancer patients treated with immune checkpoint blockade and those with inborn errors of immunity. Here, we investigate whether ABCs from different conditions are similar and how they impact the longitudinal level of the COVID-19 vaccine response.

Single-cell RNA sequencing indicates that ABCs with distinct aetiologies have common transcriptional profiles and can be categorised according to their expression of immune genes, such as the autoimmune regulator (AIRE). Furthermore, higher baseline ABC frequency correlates with decreased levels of antigen-specific memory B cells and reduced neutralising capacity against SARS-CoV-2.

ABCs express high levels of the inhibitory FcγRIIB receptor and are distinctive in their ability to bind immune complexes, which could contribute to diminish vaccine responses either directly, or indirectly via enhanced clearance of immune complexed-antigen. Expansion of ABCs may, therefore, serve as a biomarker identifying individuals at risk of suboptimal responses to vaccination.

Link: https://doi.org/10.1038/s41467-023-38810-0

Today's open access papers report on studies of the gut microbiome in older individuals exhibiting cognitive impairment. They add to a growing body of evidence for specific changes in the gut microbiome to contribute to age-related neurodegenerative conditions. The most obvious way in which this might happen is via a greater number of microbes capable of provoking a state of constant inflammation, either directly by engaging with the immune system, or more indirectly by contributing to dysfunction of the intestinal barrier, and thus allowing leakage of unwanted microbes and microbial metabolites into tissue. But it is also possible that loss of beneficial metabolites is a meaningful issue in later life.

The relative sizes of microbial populations making up the gut microbiome change with age, for reasons still under exploration, but in which the aging of the immune system may play a sizable role. The gut microbiome becomes more uniquely dysfunctional from individual to individual, but it is nonetheless the case that studies of cognitive decline and dementia are finding features of the gut microbiome that can be used to distinguish between healthy and cognitively impaired individuals.

It is not all that challenging to reset an aged gut microbiome via fecal microbiota transplantation from a young individual, at least not on an individual basis, without considering all of the overhead of regulatory approval. Fecal microbiota transplantation improves health and extends life in animal studies. There comes a point at which investigation must give way to clinical trials as a means to test whether restoration of a more youthful gut microbiome can meaningfully postpone neurodegenerative conditions; it seems a reasonable wager, given what is known.

Altered gut microbiota in older adults with mild cognitive impairment: a case-control study

Gut microbiota alterations in mild cognitive impairment (MCI) are inconsistent and remain to be understood. This study aims to investigate the gut microbial composition associated with MCI, cognitive functions, and structural brain differences. A nested case-control study was conducted in a community-based prospective cohort where detailed cognitive functions and structural brain images were collected. Thirty-one individuals with MCI were matched to sixty-five cognitively normal controls by age strata, gender, and urban/rural area. Fecal samples were examined using 16S ribosomal RNA (rRNA) sequencing. Compositional differences between the two groups were identified and correlated with the cognitive functions and volumes/thickness of brain structures.

There was no significant difference in alpha diversity and beta diversity between MCIs and cognitively normal older adults. However, the abundance of the genus Ruminococcus, Butyricimonas, and Oxalobacter decreased in MCI patients, while an increased abundance of nine other genera, such as Flavonifractor, were found in MCIs. Altered genera discriminated MCI patients well from controls and were associated with attention and executive function.

Gut microbiota and intestinal barrier function in subjects with cognitive impairments: a cross-sectional study

To investigate the differences in gut microbial composition, intestinal barrier function, and systemic inflammation in patients with Alzheimer's disease (AD) or mild cognitive impairment (MCI), and normal control (NC) cases, a total of 118 subjects (45 AD, 38 MCI, and 35 NC) were recruited. Cognitive function was assessed using Mini-Mental State Examination (MMSE), and Montreal Cognitive Assessment Scale (MoCA). Functional ability was assessed using Activity of Daily Living Scale (ADL). The composition of gut microbiome was examined by 16S rRNA high-throughput sequencing. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) was used to predict functional transfer of gut microbiota. Gut barrier dysfunction was evaluated by measuring the levels of diamine oxidase (DAO), D-lactic acid (DA), and endotoxin. The serum high-sensitivity C-reactive protein (hs-CRP) level was used to indicate systemic inflammation.

Compared with normal controls, patients with cognitive impairments (AD and MCI) had lower abundance of Dorea and higher levels of DAO, DA, and endotoxin. Kyoto Encyclopedia of Genes and Genomes (KEGG) results showed that the pathways related to glycan biosynthesis and metabolism increased in MCI patients, while the ones related to membrane transport decreased. The abundance of Bacteroides and Faecalibacterium was negatively correlated with the content of endotoxin, and positively correlated with the scores of MMSE and MoCA. The hs-CRP levels were similar among the three groups. A significant negative correlation was observed between the severity of gut barrier dysfunction and cognitive function.

The enteric nervous system is the nervous system of the intestines, and likely an important part of the relationship between the gut microbiome and the brain. One of the more interesting parts of this review paper is the discussion regarding relationships between the gut microbiome and enteric nervous system. All too little is known in detail, even while it is possible to find reports of specific associations and points of communication between gut microbiome and nervous system. Given the attention to measuring and altering the balance of populations in the gut microbiome, one might hope that the advent of ways to sizeably and favorably adjust the gut microbiome will meaningfully improve late life health.

The gut and the brain communicate via the nervous system, hormones, microbiota-mediated substances, and the immune system. These intricate interactions have led to the term "gut-brain axis". Unlike the brain-which is somewhat protected-the gut is exposed to a variety of factors throughout life and, consequently, might be either more vulnerable or better adapted to respond to these challenges. Alterations in gut function are common in the elder population and associated with many human pathologies, including neurodegenerative diseases. Different studies suggest that changes in the nervous system of the gut, the enteric nervous system (ENS), during aging may result in gastrointestinal dysfunction and initiate human pathologies of the brain via its interconnection with the gut.

This review aims at summarizing the contribution of normal cellular aging to the age-associated physiological changes of the ENS. Morphological alterations and degeneration of the aging ENS are observed in different animal models and humans, albeit with considerable variability. The aging phenotypes and pathophysiological mechanisms of the aging ENS have highlighted the involvement of enteric neurons in age-related diseases of the central nervous system such as Alzheimer's or Parkinson's disease. To further elucidate such mechanisms, the ENS constitutes a promising source of material for diagnosis and therapeutic predictions, as it is more accessible than the brain.

Link: https://doi.org/10.3390/ijms24119471

The various microbial populations making up the gut microbiome shift in relative size with age, favoring harmful microbes capable of provoking chronic inflammation over helpful microbes that manufacture beneficial metabolites. That this aging of the gut microbiome can contribute to the chronic inflammation of old age implicates it in the development of many age-related conditions. Unresolved inflammatory signaling is known to be disruptive to cell and tissue function throughout the body, and neurodegenerative conditions in particular exhibit a strong inflammatory component to pathology. Restoring a more youthful gut microbiome may prove to be a useful class of therapy.

A progressive degradation of the brain's structure and function, which results in a reduction in cognitive and motor skills, characterizes neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). The gut-brain axis (GBA) is now known to have a crucial role in the emergence of NDs. The gut microbiota is a conduit for the GBA, a two-way communication system between the gut and the brain. The myriad microorganisms that make up the gut microbiota can affect brain physiology by transmitting numerous microbial chemicals from the gut to the brain via the GBA or neurological system.

The synthesis of neurotransmitters, the immunological response, and the metabolism of lipids and glucose have all been demonstrated to be impacted by alterations in the gut microbiota, such as an imbalance of helpful and harmful bacteria. In order to develop innovative interventions and clinical therapies for NDs, it is crucial to comprehend the participation of the gut microbiota in these conditions. In addition to using antibiotics and other drugs to target particular bacterial species that may be a factor in NDs, this also includes using probiotics and other fecal microbiota transplantation to maintain a healthy gut microbiota.

In conclusion, the examination of the GBA can aid in understanding the etiology and development of NDs, which may benefit the improvement of clinical treatments for these disorders and ND interventions. This review indicates existing knowledge about the involvement of microbiota present in the gut in NDs and potential treatment options.

Link: https://doi.org/10.3389/fnagi.2023.1145241