Fight Aging!

The article I'll point out today touches on an important point regarding present efforts to develop therapies capable of slowing or reversing the progression of aging. Some of those therapies manipulate metabolism in ways that are known to modestly slow aging, such as upregulation of autophagy via mTOR inhibition, but the full holistic understanding of how they work is as yet lacking. Others target specific causative mechanisms of aging, such as the accumulation of senescent cells and their disruptive senescence-associated secretory phenotype. There, we lack the full picture of how the well-understood cause contributes in detail to the very complex changes of later stage aging, but we can at least be fairly certain that when we see benefits in older animals and people, we know that the specific targeted mechanism is important in aging.

The development of medicine is heavily regulated. Overly regulated. Laboring under such a vast burden of regulation that it is at times surprising that anything is ever achieved. The costs are vast. In some cases the cost is effectively infinite, such as in the matter of aging. At present there is no regulatory path by which the FDA or equivalent regulatory bodies will approve a therapy for the treatment of aging. There is a great deal of discussion as to what it might take to generate such a path, and some pioneering design and persuasion on the part of those heading up the TAME trial initiative, but no signs that all of this will produce the desired outcome at any point in the near future. That won't stop people continuing to invest time and funding into producing this path, of course.

The principals of every biotech company presently developing therapies that may slow or reverse aspects of aging are ignoring the question of regulatory approval for therapies to treat aging. It is irrelevant to them, because it won't happen soon enough. They instead identify the specific age-related diseases that are most likely to respond favorably to the specific mechanisms of aging targeted by their therapies, and seek approval for the treatment of those diseases. This is the standard approach taken by any biotech, is well understood by conservative biotech investors, and is the way that one succeeds in getting a therapy to market as the principal of a biotech company.

This much is said in the article below. What tends to go unsaid by those who are presently engaged with the FDA is that, following approval, one might expect widespread off-label use to emerge for any therapy with sizable effects on a mechanism of aging. There is where the real battle will be fought over the regulatory path to treat aging. The initial approval via the present regulatory system is the wedge applied to the wood, the shoe in the door. This goes unsaid because the FDA has in the past demonstrated considerable opposition to widespread off-label use, and talking about that may prejudice one's chances of success in regulatory approval. Nonetheless, off-label use is legal and in principle in the hands of physicians, not the FDA. If a medicine is demonstrated safe, and physicians have a reasonable expectation that it will produce patient benefits, they can go ahead. At least until the FDA makes earnest efforts to shut things down and force clinical trials; this is something of a political anarchy, well illustrated in practice by the changing regulatory stance on stem cell treatments over the past few decades. The analogous fight over the treatment of aging will be much larger and much louder.

Another point is that the high costs imposed by the FDA are giving rise to a medical tourism industry outside the US that will grow in size and sophistication as the number of customers grows. Medical tourism to treat disease is a small market in comparison to medical tourism to treat aging. The size of that market will inspire, eventually, an entirely distinct medical ecosystem, in which the option will exist to responsibly run trials and treat people at a fraction of the costs presently required. Small elements of that ecosystem exist today, but only the vastly greater number of potential customers created by viable treatments for aging will create the growth and coordination needed to build a viable alternative. That alternative is needed, as present regulatory regimes are holding back progress to chase an ideal of zero patient risk at any cost.

Getting geroprotective drugs to market for specific disease applications is the first step in eventually making them available for healthier aging

James Peyer, the CEO of the New York-based biotech company Cambrian Bio - which seeks to develop therapeutics to lengthen healthspan - says the first geroprotective drug to gain FDA approval may be something that is already known today - perhaps a drug already approved for another indication - and has only to be validated through clinical trials for longevity. "We have actually 80 interventions, of which about 20 are drugs that extend healthy lifespan in mice," he says, referring to all the known drugs on the market that could potentially be repurposed as well as all the experimental compounds in the pipeline not yet approved to treat any disease that look promising as future geroprotective drugs. Probably a handful of the 80 have sufficient evidence to support running a large clinical trial. But therein lies the problem.

Doing clinical trials for longevity is hard. It's expensive. Historically, many have even said it's impossible. "If you took an experimental drug, and I took a placebo, how long would we have to wait to see a real outcome?" Peyer asks me. "Six years. They take six years and they cost $150 million. If you're going to take a drug that has never demonstrated human safety and efficacy before and try to go straight into that six year, $150 million shot on goal, and then maybe afterwards you'll have revenues. It's risky." Six costly years, six risky years - and there's no way around it. That's why people always warned him it couldn't be done.

Instead a preventive medicine is typically tested first for its ability to treat a specific illness. Once it proves safe in humans and effective for that smaller indication, then it moves into the more costly, larger prevention trials. And that's how many companies in the field are moving forward-using what Peyer calls the stepping-stone approach. The idea of targeting treatments for specific age-related diseases is to create value. It avoids the six-year risk of a broader longevity trial and instead tests the drug in well-defined populations, perhaps even people who have a genetic disease and will be highly likely to benefit from the therapy. They may respond more quickly, show results sooner, and allow for shorter, less expensive clinical trials.

The basic idea is simple, says Joe Betts-LaCroix, CEO of the San Francisco-based biotech company Retro Biosciences. "You can start with a disease that has the most acute manifestation in the shortest amount of time with response to some step change in an aging mechanism, produce that as a therapy that gets approved by a health authority, and then slowly expand from there. The idea is that if you can intervene really well in one aging pathway, you can then treat and or prevent multiple downstream diseases at the same time with one therapy."

Researchers here demonstrate that various cell populations found in osteoarthritic joint tissue remain competent and capable of regeneration, but these activities are suppressed by factors found in the local environment. Suspecting an excess of inflammatory signaling as the culprit, the researchers designed an anti-inflammatory cell therapy, employing cell types that act to counter inflammatory signaling. The results were promising in a mouse model of osteoarthritis, and continued to be promising in a small human clinical trial.

It can be hypothesized that functional regeneration of osteochondral defects may occur through the activation of appropriate progenitor cells recruited from the surrounding tissues, such as the synovial membrane, upon the onset of the pro-regenerative phase from the local immune cells. Once these progenitors are activated by trauma, they migrate to the defect site where they attach, proliferate, and undergo chondrogenic differentiation to contribute to tissue regeneration. Subsequently, it can be hypothesized that elements in the synovial environment of osteoarthritis (OA) may interfere with any of these crucial steps, impairing the regenerative potential. These elements would then be a cause, and as a result, a target to treat and potentially cure OA in a clinically effective way.

The synovial fluid (SF) from OA patients was herein identified to be a major inhibitor of the regenerative process in an OA environment. Specifically, the heterogeneous cell population isolated from the SF showed a clear ability to migrate, attach, proliferate, and undergo chondrogenic differentiation, all steps crucial for functional regeneration to occur, under standard assay conditions. However, the presence of autologous SF (aSF) during any of these events drastically impaired these processes. Characterization of the SF cytokine composition linked these results to a specific pro-inflammatory profile, suggesting an imbalance between pro- and anti-inflammatory immune cells in the SF.

On the basis of these findings, an immunomodulatory cell treatment was developed with the goal of restoring joint homeostasis by mimicking crucial events seen during tissue regeneration. The treatment was based on anti-inflammatory cartilage-activated T cells (CATs), which upon coculture with adipose-derived mesenchymal stromal cells (aMSCs), induced chondrogenic priming of the progenitor cells. Intra-articular injection of the final coculture steered articular cartilage regeneration and restored joint homeostasis in a rat OA model. A later clinical evaluation in human patients showed improved quality of life, reduced pain, and articular cartilage regeneration in a compassionate use study.

Link: https://doi.org/10.1126/sciadv.ade4645

Numerous clocks to assess biological age have been constructed based on comparisons of epigenetic, transcriptomic, proteomic, and other data that changes with age. When measured using white blood cells from a blood sample, one might argue that these clocks are overly influenced by the state of the immune system, changing in response to circumstances. With that in mind, researchers here report on the tendency of measured biological age to transiently increase during stressful circumstances. Aging clocks exhibit a range of other quirks, such as the noted insensitivity to physical fitness in early epigenetic clocks, and there is clearly a great deal more work to be accomplished if clocks are to become trusted enough to be used to assess the potential of new approaches to rejuvenation, and thereby guide the direction of research and development.

Aging is classically conceptualized as an ever-increasing trajectory of damage accumulation and loss of function, leading to increases in morbidity and mortality. However, recent in vitro studies have raised the possibility of age reversal. Here, we report that biological age is fluid and exhibits rapid changes in both directions.

At epigenetic, transcriptomic, and metabolomic levels, we find that the biological age of young mice is increased by heterochronic parabiosis and restored following surgical detachment. We also identify transient changes in biological age during major surgery, pregnancy, and severe COVID-19 in humans and/or mice.

Together, these data show that biological age undergoes a rapid increase in response to diverse forms of stress, which is reversed following recovery from stress. Our study uncovers a new layer of aging dynamics that should be considered in future studies. The elevation of biological age by stress may be a quantifiable and actionable target for future interventions.

Link: https://doi.org/10.1016/j.cmet.2023.03.015

Plasma transfer from young to old individuals has produced mixed results in animals and little to no benefit in humans where assessed rigorously. These studies were driven by the hypothesis that young plasma contains meaningfully beneficial factors missing in old plasma, and mixed to poor results suggest that either this hypothesis is untrue, or that plasma transfer is not delivering enough of those beneficial factors. That said, today's open access preprint paper is an example of a plasma transfer study that did manage to produce benefits in old rats. One might well ask what exactly about the experimental procedure is the important difference when compared with earlier exercises. That the treatment was carried out biweekly for the entire remaining life span of the old rats might be one item of interest.

While the paper plays up the idea that factors present in young plasma may be aiding old animals, compelling evidence generated in parabiosis studies and related efforts conducted over the past decade suggests that this is the less plausible mechanism. Dilution of blood via saline and albumin in old animals has produced more robust evidence for health benefits. That one can produce health benefits via simple dilution of blood demonstrates that there are harmful factors present in the aged bloodstream, and sufficient dilution of these factors improves cell and tissue function.

One might consider that failures to achieve results via plasma transfer are examples of failing to produce enough dilution at any given time to significantly change the signaling environment. That doesn't explain the study noted here, of course! The rats were not given enough plasma in any one treatment to produce the level of dilution achieved with saline and albumin in other studies. So what exactly is the difference between successful and unsuccessful plasma transfer animal studies? Contradictory evidence is everywhere in the literature if one looks hard enough, but there is quite a lot of it related to the topic of plasma transfer.

Young Plasma Rejuvenates Blood DNA Methylation Profile, Prolongs Mean Lifespan and Improves Health in Old Rats

There is converging evidence that young blood conveys cells, vesicles, and molecules able to revitalize function and restore organ integrity in old individuals. Here, we assessed the effects of young rat plasma on the lifespan, epigenetic age, and healthspan of old female rats. Beginning at 25.3 months of age, a group of 9 rats (group T) was intraperitoneally injected with plasma from young rats (2 months) until their natural death. A group of control rats of the same age, received no treatment. Blood samples were collected every other week.

Survival curves showed that from age 26 to 30 months, none of the T animals died, whereas the survival curve of C rats began to decline at age 26 months. The external appearance of the T rats was healthier than that of the C counterparts. Blood DNA methylation (DNAm) age versus chronological age showed that DNAm age in young animals increased faster than chronological age then slowed down progressively, entering a plateau after 27 months. Immediately after the start of the treatment, the DNAm age (i.e., epigenetic age) of the treated rats fell below the DNAm age of controls and remained consistently lower until the end of their lives.

Assessment of each experimental group showed that the blood DNA methylation levels of 1638 CpGs were different between treated and control blood samples. Of these, 1007 CpGs exhibited increased methylation, with age while 631 CpGs showed decreased methylation levels. When rats were grouped according to the similarities in their differential blood DNA methylation profile, samples from the treated and control rats clustered in separate groups. Analysis of promoter differential methylation in genes involved in systemic regulatory activities revealed specific gene ontology (GO) term enrichment related to the insulin-like factors (IGFs) pathways as well as to cytokines and chemokines associated with immune and homeostatic functions. We conclude that young plasma therapy may constitute a natural noninvasive intervention for epigenetic rejuvenation and health enhancement, readily translatable to the clinic.

Evolution tends towards reuse of component parts, and as a result no gene has just one function. Telomerase in particular is involved in far more than just extending telomeres, the caps that the ends of chromosomes that are reduced with each cell division. In humans, stem cells express telomerase to maintain long telomeres, while all other cells can replicate only a limited number of times. What are the other functions of telomerase? As first noted some years ago, telomerase may be protective of mitochondrial function, and the paper here lists a few other interesting line items as well: angiogenesis, metabolism, regulation of gene expression, and so forth.

When we see evidence for a large upregulation of telomerase expression achieved via gene therapy to extend life in mice, is this taking place only because increased telomerase expression is extending telomeres, or are other mechanisms also participating to a significant degree? Separately, it is noted that exercise increases telomerase expression, though evidently nowhere near enough to produce the same extension of mouse life span as has been achieved via the use of telomerase gene therapies. Nonetheless, to what degree are the benefits of exercise mediated by telomerase? These are presently questions without firm answers.

Telomerase preserves genomic integrity by maintaining and protecting the telomeres. Seminal findings from 1985 revealed the canonical role of telomerase and motivated investigations into potential therapeutic strategies to combat one of the hallmarks of ageing - telomere attrition. Since then, the field of telomere biology has rapidly expanded, with telomerase serving essential roles in cancer and cell development through its canonical function.

However, telomerase also exerts critical extra-telomeric functions through its protein (telomerase reverse transcriptase, TERT) and RNA components (telomerase RNA component, TERC). Telomerase re-activation or ectopic expression promotes survival and permits unlimited proliferation in tumours and healthy non-malignant cells. TERT gene therapies improve health and lifespan in ageing mice and mouse models of age-related diseases. The extra-telomeric functions of telomerase are critical to ageing. These include protection against oxidative stress, orchestration of chromatin modifications and transcription, and regulation of angiogenesis and metabolism (e.g. mitochondrial function and glucose control).

Given that these biological functions are key adaptations to endurance training and the recent meta-analytical findings that indicate exercise up-regulates TERT and telomerase, a comprehensive discussion on the implications of the canonical and extra-telomeric roles of telomerase is warranted. This review highlights the therapeutic benefits of telomerase-based treatments for idiopathic and chronic diseases that are linked to ageing. Discussion on the canonical and extra-telomeric roles of telomerase are presented, followed by a detailed summary of the evidence on how exercise influences telomerase. Finally, the potential cell signalling underpinning the exercise-induced modulation of telomerase are discussed with directions for future research.

Link: https://doi.org/10.1111/acel.13836

The first epigenetic clocks used to assess biological age were, oddly, insensitive to the state of physical fitness. This is not an intuitive outcome, given that we know lifestyle choices relating to fitness appear have measurable effects on human life expectancy in epidemiological studies. This is one of a number of hints that suggest that most clocks are incomplete, that they only reflect some fraction of the many factors affecting health and mortality. Researchers here instead use a transcriptomic clock to assess the effects of a high intensity exercise program, and do see an effect that looks more reasonable when compared to the results of epidemiological studies of exercise and fitness. This is one small step of many that will need to be taken to calibrate and compare the many different aging clocks in an attempt to find those that can be used in an unbiased way to assess future potential rejuvenation therapies.

While the relationship between exercise and life span is well-documented, little is known about the effects of specific exercise protocols on modern measures of biological age. Transcriptomic age (TA) predictors provide an opportunity to test the effects of high-intensity interval training (HIIT) on biological age utilizing whole-genome expression data.

A single-site, single-blinded, randomized controlled clinical trial design was utilized. Thirty sedentary participants (aged 40-65) were assigned to either a HIIT group or a no-exercise control group. After collecting baseline measures, HIIT participants performed three 10 × 1 HIIT sessions per week for 4 weeks. Each session lasted 23 min, and total exercise duration was 276 min over the course of the 1-month exercise protocol. TA, 10-item perceived stress scale (PSS-10) score, Pittsburgh sleep quality index (PSQI) score, patient health questionnaire 9-item depression module (PHQ-9) score, and various measures of body composition were all measured at baseline and again following the conclusion of exercise/control protocols.

Transcriptomic age reduction of 3.59 years was observed in the exercise group while a 3.29-years increase was observed in the control group. Also, PHQ-9, PSQI, BMI, body fat mass, and visceral fat measures were all improved in the exercise group. A hypothesis-generation gene expression analysis suggested exercise may modify autophagy, mTOR, AMPK, PI3K, neurotrophin signaling, insulin signaling, and other age-related pathways. A low dose of HIIT can reduce an mRNA-based measure of biological age in sedentary adults between the ages of 40 and 65 years old. Other changes in gene expression were relatively modest, which may indicate a focal effect of exercise on age-related biological processes.

Link: https://doi.org/10.1111/acel.13841

The many varied types of age-related condition emerge from the effects of a much smaller set of underlying processes of aging. People age at different rates, largely the result of differences in lifestyle choices and environmental factors such as exposure to persistent pathogens. If an individual manifests a greater number of age-related conditions, forms of degeneration that have grown to the degree that a clinical diagnosis of loss of function can be made, then this greater number of conditions is a reflection of a faster progression of the underlying processes of aging. One should expect that this individual to exhibit a raised risk of the emergence of other age-related conditions.

This point is demonstrated in today's open access paper, reporting on the correlation between the presence of age-related conditions and the risk of frailty. Many older individuals suffer comorbidity, the presence of multiple age-related conditions. More conditions implies a greater risk of later frailty because both the conditions and frailty emerge from the underlying burden of cell and tissue damage that causes aging and age-related disease. Frailty is characterized by chronic inflammation and immunosenescence, and it is certainly the case that those issues play a sizable role in many age-related conditions.

The impact of long-term conditions on the progression of frailty

Population ageing leads to increased demand for health and social care and associated cost pressures. By 2028, 25% of England's population will be aged 65 and over, with 8% classified as frail. Frailty increases with age and is associated with higher healthcare utilization, and its determinants are key for effective healthcare services provision. Studies have identified protective (e.g. higher wealth, increased social support) and harmful (e.g. lower wealth, educational achievement, presence of long-term conditions, being female) factors associated with frailty progression. However, there is a lack of evidence on the impact of multiple long-term conditions (LTCs) longitudinally as a separate determinant of frailty progression. LTCs are defined as "A long term condition is one that cannot currently be cured but can be controlled with the use of medication and/or other therapies."

This study aimed to explore longitudinally the impact of multiple LTCs on frailty progression separately for males and females due to behavioural, social, and biological differences. A functional frailty measure (FFM) was used to examine putative determinants of frailty progression among participants aged 65 to 90 in the English Longitudinal Study of Ageing (ELSA), across nine waves (18 years) of data collection. A multilevel growth model was fitted to measure the FFM progression over 18 years, grouped by LTC categories (zero, one, two and more).

There were 2,396 male participants at wave 1, of whom 742 (31.0%) had 1 LTC and 1147 (47.9%) had ≥2 LTCs. There were 2,965 females at wave 1 of whom 881 (29.7%) had one LTC and 1,584 (53.4%) had ≥2 LTCs. The FFM increased 4% each 10 years for the male participants with no LTCs, while it increased 6% per decade in females. The FFM increased with the number of LTCs, for males and females. The acceleration of FMM increases for males with one long-term health condition or more; however in females the acceleration of FMM increases when they have two LTCs or more. In conclusion, frailty progression accelerates in males with one LTCs and females with two LTCs or more. Health providers should be aware of planning a suitable intervention once the elderly have two or more health conditions.

Use of electromagnetic fields to influence cell behavior is understudied in comparison to the use of small molecules. Researchers here offer an example of a potential use for this class of approach to therapy in wound healing, working in models of skin tissue. Tissue models are not tissue, but nonetheless, it is interesting to look at this work in the context of the few other studies suggesting that regeneration can be accelerated by the suitable application of electric currents and electromagnetic fields.

The researchers worked from an old hypothesis that electric stimulation of damaged skin can be used to heal wounds. The idea is that skin cells are electrotactic, which means that they directionally 'migrate' in electric fields. This means that if an electric field is placed in a petri dish with skin cells, the cells stop moving randomly and start moving in the same direction. The researchers investigated how this principle can be used to electrically guide the cells in order to make wounds heal faster. Using a tiny engineered chip, the researchers were able to compare wound healing in artificial skin, stimulating one wound with electricity and letting one heal without electricity. The differences were striking.

"We were able to show that the old hypothesis about electric stimulation can be used to make wounds heal significantly faster. In order to study exactly how this works for wounds, we developed a kind of biochip on which we cultured skin cells, which we then made tiny wounds in. Then we stimulated one wound with an electric field, which clearly led to it healing three times as fast as the wound that healed without electric stimulation."

In the study, the researchers also focused on wound healing in connection with diabetes, a growing health problem worldwide. "We've looked at diabetes models of wounds and investigated whether our method could be effective even in those cases. We saw that when we mimic diabetes in the cells, the wounds on the chip heal very slowly. However, with electric stimulation we can increase the speed of healing so that the diabetes-affected cells almost correspond to healthy skin cells."

Link: https://www.chalmers.se/en/current/news/mc2-how-electricity-can-heal-wounds-three-times-as-fast/

Bone tissue is constantly remodeled through the activity of osteoblast cells, depositing extracellular matrix, and osteoclast cells, breaking down extracellular matrix. With age, the balance between these two populations shifts to favor osteoclasts, and the result is loss of bone density leading to osteoporosis. The research community is actively engaged in finding better ways to shift this balance back towards osteoblast activity. Here, researchers describe an approach that inhibits the generation of osteoclast cells.

It is well-established that women experience disproportionately lower bone mass than men throughout their lives. Loss of bone mass accelerates with menopause, increasing the risk of osteoporosis and associated fractures for women as they age. To figure out why this happens, researchers looked at the differences in the ways bone is regulated in male and female mice, which share many similarities with humans and are important models for studying health and disease. They focused on specialized cells called osteoclasts, which help maintain bone health by breaking down and recycling old bone.

The researchers found reducing KDM5C disrupted cellular energy production in osteoclasts, which slowed down extracellular matrix resorption and preserved bone mass. Importantly, KDM5C is linked to X chromosomes, which means it is more active in females than in males. "Lowering KDM5C levels is like flipping a switch to stop an overactive extracellular matrix resorption process. The result is more bone mass, which ultimately means stronger bones. We're very excited about this work and look forward to carrying out future studies to refine our findings. At the end of the day, we hope these insights make a difference for people with osteoporosis."

Link: https://www.vai.org/article/osteoporosis-treatments-may-benefit-from-discovery-of-key-driver-of-low-bone-density/

Reading around the present state of research into the aging of skin and hair provides interesting insights into the gap between knowledge and understanding in complex biological systems. At this point, there is no complete understanding as to how skin and hair age, even while there is an enormous amount of data on the cellular biology and behavior on all of the different cell types involved. This is a microcosm of the bigger picture of aging in general: while well-researched lists of fundamental forms of damage and change exist, showing exactly how those processes interact to produce the decline of a larger system remains a work in progress. So while researchers understand a great deal about the building blocks involved in hair turning gray with age, much remains to be accomplished when it comes to describing how those building blocks lead to the outcome.

This is why it is important to advocate for more attention to be given to intervention, in parallel with observation. The state of the art in biotechnology allows the research community to repair the forms of damage thought to cause aging. We should do that, and not wait around for greater understanding of a highly complex system to emerge from observation. Further, it is likely that repair therapies will provoke that greater understanding, at least to the degree that they are successful. See, for example, the greatly increased understanding of cellular senescence in aging that has followed the development of senolytic treatments that selectively destroy these cells to produce rejuvenation in animal models.

Today's research materials are an example of an incremental advance in the understanding of age-related hair graying, involving a specific behavioral change in stem cells responsible for the production of melanocytes. Because this one of the early issues in aging, occurring quite independently of functional loss elsewhere in the body, it is quite possible that the mechanisms involved will be of little use understanding or intervening in other aspects of aging, but time will tell.

Study Links 'Stuck' Stem Cells to Hair Turning Gray

Certain stem cells have a unique ability to move between growth compartments in hair follicles, but get stuck as people age and so lose their ability to mature and maintain hair color. A new study focused on cells in the skin of mice and also found in humans called melanocyte stem cells, or McSCs. Hair color is controlled by whether nonfunctional but continually multiplying pools of McSCs within hair follicles get the signal to become mature cells that make the protein pigments responsible for color.

This means that during normal hair growth, such cells continually move back and forth on the maturity axis as they transit between compartments of the developing hair follicle. It is inside these compartments where McSCs are exposed to different levels of maturity-influencing protein signals. Specifically, the research team found that McSCs transform between their most primitive stem cell state and the next stage of their maturation, the transit-amplifying state, and depending on their location. The researchers found that as hair ages, sheds, and then repeatedly grows back, increasing numbers of McSCs get stuck in the stem cell compartment called the hair follicle bulge. There, they remain, do not mature into the transit-amplifying state, and do not travel back to their original location in the germ compartment, where WNT proteins would have prodded them to regenerate into pigment cells.

Dedifferentiation maintains melanocyte stem cells in a dynamic niche

For unknown reasons, the melanocyte stem cell (McSC) system fails earlier than other adult stem cell populations, which leads to hair greying in most humans and mice. Current dogma states that McSCs are reserved in an undifferentiated state in the hair follicle niche, physically segregated from differentiated progeny that migrate away following cues of regenerative stimuli. Here we show that most McSCs toggle between transit-amplifying and stem cell states for both self-renewal and generation of mature progeny, a mechanism fundamentally distinct from those of other self-renewing systems.

Live imaging and single-cell RNA sequencing revealed that McSCs are mobile, translocating between hair follicle stem cell and transit-amplifying compartments where they reversibly enter distinct differentiation states governed by local microenvironmental cues (for example, WNT). Long-term lineage tracing demonstrated that the McSC system is maintained by reverted McSCs rather than by reserved stem cells inherently exempt from reversible changes. During ageing, there is accumulation of stranded McSCs that do not contribute to the regeneration of melanocyte progeny. These results identify a new model whereby dedifferentiation is integral to homeostatic stem cell maintenance and suggest that modulating McSC mobility may represent a new approach for the prevention of hair greying.

In one sense, the accumulation of senescent cells with age is the same story in every tissue. These cells secrete pro-inflammatory, disruptive signaling that actively degrades tissue structure and function. The targeted destruction of lingering senescent cells produces aspects of rapid rejuvenation in aged mice. In another sense, every tissue is different and senescence in that tissue likely worthy of at least some degree of distinct study, perhaps leading to optimized therapies for clearance of senescent cells on a tissue by tissue basis, for example. Here, find a review that looks at cellular senescence in the context of skin and the known aspects of aging observed in skin tissue.

Despite the growing interest by researchers into cellular senescence, a hallmark of aging, its role in human skin remains equivocal. The skin is the largest and most accessible human organ, reacting to the external and internal environment. Hence, it is an organ of choice to investigate cellular senescence and to target root-cause aging processes using senolytic and senomorphic agents. This review presents different aspects of skin cellular senescence, from physiology to pathology and signaling pathways. Premature cellular senescence can underlie pathological skin conditions. However, its role is ambiguous, and it seems that a distinction needs to be made between acute and chronic senescence. It appears that the chronic accumulation of senescent cells can have a detrimental effect on skin function, health, and aging, while acute stimulation of transient senescent cells plays an important role in wound healing.

In contrast to acute wound healing, chronic, nonhealing ulcers (e.g., murine model of diabetes, venous ulcers, radiation ulcers) are characterized by higher levels of senescence. Clearance of senescent cells with senolytics (i.e., dasatinib plus quercetin) has been shown to mitigate radiation ulcers. Additionally, it is well known that the regenerative capacity of the skin declines with age in conjunction with increased accumulation of senescent cells. Delayed wound healing was reported in young 8-week-old mice after the subcutaneous transfer of irradiated fibroblasts. In this case, the kinetics of wound healing were similar to those observed in naturally aging 2-year-old mice.

On the other hand, researchers have reported different senescent responses in younger (30.2 ± 1.3 years) vs. older (75.6 ± 1.8 years) healthy subjects in punch biopsy wounds. The second biopsy, taken for analysis, was performed several days after the first one. Induction of p21 and p53 was observed during healing in younger but not older skin. Therefore, transient appearance of senescent cells may be needed for proper healing of acute wounds, but their chronic presence delays healing. Moreover, senescent fibroblasts have also been found in keloid scars - lesions that result from abnormal wound healing and can be classified as benign skin tumors. It is believed that the appearance of aging is a desirable phenomenon in keloids as a mechanism potentially responsible for stopping the proliferation of fibroblasts and the progression of lesions.

Hair disorders can also be affected by senescent pathways. In an experimental model of age-related hair loss, hair follicle dermal stem cells exhibited features of senescent cells (overexpression of p16INK4a and SA-β-Gal). Additionally, increased senescence-associated secretory phenotype (SASP) components were detected in the mesenchymal niche of the hair follicle. Moreover, clearing senescent cells by a possible senolytic, FOXO4-DRI, reduced hair loss in progeroid aging mice. Additionally, hair follicle dermal papillary cells from the male balding scalp showed the loss of proliferative capacity. This phenomenon was associated with increased SA-β-Gal and p16INK4a/pRb expression. Moreover, knocking out p16INK4a promoted faster growth of hair follicle dermal papillary cells.

Link: https://doi.org/10.1111/acel.13845

To what degree is the age-related decline in activity of important stem cell populations driven by intrinsic damage versus changes in the surrounding cells of the stem cell niche? Stem cells require the support of the niche, and there is evidence to suggest that the better studied types of stem cell (muscle, hematopoietic, neural) are more affected by the cell environment than by any damage to the stem cells themselves. Even so, it is quite clear that stem cells do suffer nuclear DNA mutations, as evidenced by the existence of somatic mosaicism. In that context, the research here is interesting: researchers find a way to regulate the behavior of the bone marrow hematopoietic niche that rejuvenates some measures of hematopoiesis in old mice.

Aging associated defects within stem cell-supportive niches contribute towards age-related decline in stem cell activity. However, mechanisms underlying age-related niche defects, and whether restoring niche function can improve stem cell fitness, remain unclear. Here, we sought to determine whether aged blood stem cell function can be restored by rejuvenating their supportive niches within the bone marrow (BM). We identify Netrin-1 as a critical regulator of BM niche cell aging. Niche-specific deletion of Netrin-1 induces premature aging phenotypes within the BM microenvironment, while supplementation of aged mice with Netrin-1 rejuvenates aged niche cells and restores competitive fitness of aged blood stem cells to youthful levels.

We show that Netrin-1 plays an essential role in maintaining active DNA damage responses (DDR), and that aging-associated decline in niche-derived Netrin-1 results in DNA damage accumulation within the BM microenvironment. We show that Netrin-1 supplementation is sufficient to resolve DNA damage and restore regenerative potential of the aged BM niche and blood stem cells to endure serial chemotherapy regimens.

Link: https://doi.org/10.1038/s41467-023-37783-4

Medin is one of a small number of proteins that can misfold in ways that encourage other molecules of the same protein to also misfold, linking to form solid aggregates. While medin aggregation seems near ubiquitous in old people, the harms caused by this form of amyloidosis are far less well studied than is the case for, say, the amyloid-β characteristic of Alzheimer's disease. Still, evidence supports a role for medin in causing age-related dysfunction of the cerebral vasculature, and it is also suggested that this can provoke greater pathology in neurodegenerative conditions such as Alzheimer's disease.

In the open access paper I'll point out today, researchers point out evidence for rising numbers of senescent cells in the aged vasculature to precede and encourage medin aggregation. These cells secrete disruptive signaling, some of which is encapsulated in extracellular vesicles. Here, the vesicles generated by senescent cells are found to contain medin in greater amounts than those generated by normal cells. This is one of many lines of research that support the use of senolytic therapies to clear senescent cells as a possible approach to the treatment of neurodegenerative conditions. Early senolytics are in clinical trials, but it remains to be seen as to whether that part of the longevity industry focused on building new senolytic therapies will pursue the rejuvenation of brain tissue with any great vigor, or any time soon.

Senescence and extracellular vesicles: novel partners in vascular amyloidosis

The most common human amyloid is aortic medial amyloid (AMA), caused by aggregation of a 50-amino acid peptide called medin, which is cleaved by an unknown mechanism from its parent protein, milk fat globulin EGF-factor 8 (MFGE8). Medin is present in the vessel wall of 97% of Caucasians aged over 50- years, yet despite its prevalence in the ageing population there is a very limited understanding of the mechanisms driving AMA. Despite several forms of amyloidosis, including AMA and Alzheimer's disease (AD), being frequently associated with ageing, there has been limited research to date on the effect of cellular 'ageing', termed senescence, on amyloidosis.

Senescent cells accumulate in the vasculature with age and undergo a range of phenotypic changes, including extracellular matrix (ECM) remodelling and increased secretion of inflammatory mediators. Researchers have confirmed a strong correlation between age and medin in the ECM of the medial layer of human aortic tissue. In vitro studies, using human vascular smooth muscle cells (VSMCs), demonstrated that the ECM synthesised by senescent cells contained medin in a fibril-like form. This was in contrast to the small, round aggregates found in the ECM from healthy, proliferative VSMCs, suggesting senescent cells create an environment permissive for medin aggregation. Further mechanistic studies found that small extracellular vesicles (sEVs) secreted from VSMCs carried medin as a cargo and were responsible for medin release and also its aggregation in the ECM. Importantly, senescent VSMCs showed enhanced sEV secretion and senescent sEVs could accelerate medin aggregation compared with sEVs from proliferative VSMCs.

The pathological effects of medin accumulation in the vasculature, as well as the forms of medin responsible for inducing damage, remain poorly understood. Studies have shown that small medin aggregates can induce endothelial cell dysfunction and inflammation while accumulation of fibrillar amyloid species can contribute to weakening and stiffening of the vessel wall. These effects may be particularly relevant to the cerebrovasculature as a recent study has shown that medin accumulates in the cerebral vessels with age and may enhance Aβ formation, leading to vascular stiffening in the brain and increased CAA burden. These data suggest that medin may represent a new therapeutic target for AD and CAA, to maintain a functioning and healthy cerebral environment during ageing.

The thymus is a small organ in which thymocytes mature into T cells of the adaptive immune system. Active thymic tissue atrophies with age, a process that appears to be accelerated by the usual suspects such as a poor lifestyle and chronic inflammation. As a result, the supply of new T cells diminishes, and the adaptive immune system becomes ever less functional and ever more inflammatory as a result, packed with exhausted, malfunctioning, and senescent cells.

Researchers here report on a study in which they assessed the pace at which new T cells left the thymus in a population of older people. They found that the lowest quartile, those with the lowest production of new T cells, exhibited a twofold increase in mortality risk in comparison to those in the normal range for their age. The immune system is important to health, but this likely also reflects a higher burden of age-related damage that encourages greater thymic atrophy.

Immunosenescence is a complex process characterized by an age-related remodelling of the immune system. The prominent effects of the immunosenescence process is the thymic involution and, consequently, the decreased numbers and functions of T cells. Since thymic involution results in a collapse of the T-cell receptor (TCR) repertoire, a reliable biomarker of its activity is represented by the quantification of signal joint T-cell receptor rearrangement excision circles (sjTRECs) levels. Although it is reasonable to think that thymic function could play a crucial role on elderly survival, only a few studies investigated the relationship between an accurate measurement of human thymic function and survival at old ages.

By quantifying the amount sjTRECs by real-time polymerase chain reaction (PCR), the decrease in thymic output in 241 nursing home residents was evaluated to investigate the relationship between thymic function and survival at old ages. The mean age of these patients was 78.4 years. We found that low sjTREC levels were associated with a significant increased risk of mortality at older ages. Nursing home residents with lower sjTREC exhibit a near 2-fold increase in mortality risk compared to those with sjTREC levels in a normal range.

In conclusion, thymic function failure is an independent predictor of mortality among elderly nursing home residents. sjTREC represents a biomarker of effective ageing as its blood levels could anticipate individuals at high risk of negative health outcomes. The identification of these subjects is crucial to manage older people's immune function and resilience, such as, for instance, to plan more efficient vaccine campaigns in older populations.

Link: https://doi.org/10.1186/s12979-023-00340-0

The abnormal generation of circular DNA as a mechanism of cancer, operating by greatly increasing the expression of genes that favor the growth and development of a particular type of cancer. It is a feature of established tumor tissue, but researchers here note that the early presence of extracellular circular DNA in precancerous tissue is a strong marker for the later development of cancer, in that study participants lacking circular DNA in tissue biopsies near all did not go on to develop cancer. The research is focused on one particular tissue and cancer type, but is likely broadly applicable across many varieties of cancer.

Circular DNA, known as extrachromosomal DNA or ecDNA, often harbor cancer-associated genes called oncogenes. Because they can exist in large numbers in a cell, they deliver a super-charged growth signal that can override a cell's natural programming. They also contain genes likely to dampen the immune system's response to a nascent cancer, the researchers found. Previous research had suggested that the circles, which are widespread in human cancers but rarely found in healthy cells, primarily arise in advanced tumors as the abnormal cells increasingly botch the intricate steps required to copy their DNA before each cell division. But the new study shows that the circles can be found even in precancerous cells - and their presence jump-starts a cancerous transformation. Blocking their formation, or their effect on the cells that carry them, might stop cancers from developing, the researchers believe.

The researchers assessed the prevalence of ecDNA, and identified the genes they carried, in biopsies from nearly 300 people with Barrett's esophagus or esophageal cancer, where individual patients were studied as the cancer developed. They found that the prevalence of ecDNA increased from 24% to 43% in early- versus late-stage esophageal cancer, indicating the continual formation of the DNA circles during cancer progression. More tellingly, they found that 33% of people with Barrett's esophagus who developed esophageal cancer had ecDNA in their precancerous cells. In contrast, only one out of 40 people who didn't develop cancer had cells with ecDNA, and that individual passed away due to another cause.

Link: https://med.stanford.edu/news/all-news/2023/04/ecDNA-cancer.html

Regeneration from injury is an intricate dance of many different cell types: stem cells, somatic cells, cells that become senescent, and innate immune cells such as macrophages. This is true of every higher species, but what is the meaningful difference between species capable of regenerating entire limbs and internal organs, such as salamanders, and species that scar and exhibit only partial regeneration of lost tissue, such as near all mammals? In recent years, researchers have discovered that senescent cells and macrophages behave differently in injured tissues in species capable of proficient regeneration. Clearance of senescent cells is unusually efficient in salamanders, for example.

A characteristic of proficient tissue regeneration is a recapitulation of embryonic development, in which cells dedifferentiate to form a blastema in order to rebuild the structure of lost tissue. In today's open access paper, researchers find that salamander senescent cells produce signaling that encourages this dedifferentiation in muscle tissue during limb regeneration. Similar research in zebrafish, another highly regenerative species, has shown that senescent cells are necessary for regeneration of retinal tissues. While the senescence-associated secretory phenotype (SASP) produced by senescent cells is clearly different from species to species, identifying specific signal differences that may be involved in proficient regeneration, as here, is very much a work in progress.

Benefits of "Zombie" Cells: Senescent Cells Aid Regeneration in Salamanders

Senescent cells are cells that have permanently stopped dividing in response to cellular stress but have not died. As organisms age, the number of senescent cells in the body increases. This accumulation is currently considered one of the hallmarks of aging and has been linked to a variety of diseases, including cancer. A growing body of evidence suggests that senescent cells may also have beneficial effects, such as wound healing or preventing tissue scarring.

Salamanders have unique regeneration abilities and are able to re-grow many organs of their bodies, including lost limbs. To check if the presence of senescent cells influences the limb regeneration process, researchers found a way to modulate the number of senescent cells in the wound. The team observed that the presence of senescent cells enhanced the regeneration process. "When more senescent cells were present in the wound, the animals developed a larger regeneration bud, or - as we call it - blastema. This is a collection of cells that are going to form all the needed tissues in the new limb. The larger the blastema, the more cells are there to regrow the limb and the quicker the regeneration process. The presence of senescent cells seemed to 'fuel' the regeneration process."

"Our results show that senescent cells use cell-cell communication to influence the regeneration process. They secrete molecules that signal to mature muscle fibers to dedifferentiate into muscle progenitor cells. These cells can multiply themselves as well as differentiate into new muscle cells, thereby enhancing the regeneration process. This signaling appears to be an important part of promoting regeneration."

Senescent cells enhance newt limb regeneration by promoting muscle dedifferentiation

Salamanders are able to regenerate their entire limbs throughout lifespan, through a process that involves significant modulation of cellular plasticity. Limb regeneration is accompanied by the endogenous induction of cellular senescence, a state of irreversible cell cycle arrest associated with profound non-cell-autonomous consequences. While traditionally associated with detrimental physiological effects, here, we show that senescent cells can enhance newt limb regeneration.

Through a lineage tracing approach, we demonstrate that exogenously derived senescent cells promote dedifferentiation of mature muscle tissue to generate regenerative progenitors. In a paradigm of newt myotube dedifferentiation, we uncover that senescent cells promote myotube cell cycle re-entry and reversal of muscle identity via secreted factors. Transcriptomic profiling and loss of function approaches identify the FGF-ERK signalling axis as a critical mediator of senescence-induced muscle dedifferentiation. While chronic senescence constrains muscle regeneration in physiological mammalian contexts, we thus highlight a beneficial role for cellular senescence as an important modulator of dedifferentiation, a key mechanism for regeneration of complex structures.

Hyperphosphorylation of tau protein produces aggregation and neurofibrillary tangles in later stage Alzheimer's disease. Researchers here use a peptide to inhibit one of the mechanisms by which increased phosphorylation occurs in neurons in older individuals. The approach produces promising results in a mouse model of Alzheimer's disease, but - as is usually the case - one has to wonder as to whether or not this interaction of model and treatment in mice is relevant to the human condition. Old mice do not naturally develop any pathology resembling Alzheimer's disease, so all of the models are by their nature very artificial, and embody assumptions about which forms of pathology in the aging brain are most important. The outcome of this state of affairs is that many approaches to have worked well in mouse models went on to fail to achieve meaningful results in human patients, at great cost in time and funding.

Researchers have treated mice with a peptide that blocks the hyperactive version of an enzyme called CDK5, finding dramatic reductions in neurodegeneration and DNA damage in the brain. These mice also showed improvements in their ability to perform tasks such as learning to navigate a water maze. The CDK5 gene encodes a type of enzyme known as a cyclin-dependent kinase. Most of the other cyclin-dependent kinases are involved in controlling cell division, but CDK5 is not. Instead, it plays important roles in the development of the central nervous system, and also helps to regulate synaptic function.

CDK5 is activated by a smaller protein that it interacts with, known as P35. When P35 binds to CDK5, the enzyme's structure changes, allowing it to phosphorylate - add a phosphate molecule to - its targets. However, in Alzheimer's and other neurodegenerative diseases, P35 is cleaved into a smaller protein called P25, which can also bind to CDK5 but has a longer half-life than P35. When bound to P25, CDK5 becomes more active in cells. P25 also allows CDK5 to phosphorylate molecules other than its usual targets, including the Tau protein. Hyperphosphorylated Tau proteins form the neurofibrillary tangles that are one of the characteristic features of Alzheimer's disease.

Researchers have shown that transgenic mice engineered to express P25 develop severe neurodegeneration. In humans, P25 has been linked to several diseases, including not only Alzheimer's but also Parkinson's disease and frontotemporal dementia. Pharmaceutical companies have tried to target P25 with small-molecule drugs, but these drugs tend to cause side effects because they also interfere with other cyclin-dependent kinases, so none of them have been tested in patients. This team decided to take a different approach to targeting P25, by using a peptide instead of a small molecule. They designed their peptide with a sequence identical to that of a segment of CDK5 known as the T loop, which is a structure critical to the binding of CDK5 to P25. In tests in neurons grown in a lab dish, the researchers found that treatment with the peptide led to a moderate reduction in CDK5 activity. Those tests also showed that the peptide does not inhibit the normal CDK5-P35 complex, nor does it affect other cyclin-dependent kinases.

When the researchers tested the peptide in a mouse model of Alzheimer's disease that has hyperactive CDK5, they saw a myriad of beneficial effects, including reductions in DNA damage, neural inflammation, and neuron loss. These effects were much more pronounced in the mouse studies than in tests in cultured cells.

Link: https://news.mit.edu/2023/new-peptide-may-hold-potential-alzheimers-treatment-0413

Parkinson's disease is characterized by misfolding and aggregation of α-synuclein, a pathology that spreads from where it initially starts, frequently in the intestinal nervous system, spreading between nerve cells. Researchers here report on a technique to identify the presence of small amounts of misfolded α-synuclein, demonstrating that it allows for early detection of the condition. Near every disease is easier to treat or at least slow down in its earlier stages, and early detection may well be an essential part of efforts to prevent the development of common age-related neurodegenerative conditions, such as Parkinson's disease.

Parkinson's disease is characterized by deposits of a protein known as alpha-synuclein (aSyn) in the nervous system. This protein can become corrupted and start to change shape in a process called misfolding. These misfolded proteins will start to clump together and poison the surrounding healthy nerve cells that are responsible for brain function, particularly for motor skills.

Protein Misfolding Cyclic Amplification (PMCA) - also termed seed amplification assay (SAA) technology - is under development at Amprion Inc., a biotech company focusing on the commercial utilization of SAA for early diagnosis of Parkinson's, Alzheimer's, and other neurodegenerative diseases. Researchers at Amprion studied 1,123 participants who were enrolled at 33 facilities globally between July 2010 and July 2019, representing the largest analysis so far of aSyn-SAA for the biochemical diagnosis of Parkinson's disease. Of these, 545 had Parkinson's disease, 163 were healthy people with no evidence of Parkinson's, 54 had evidence of the disease on brain scans, 51 were in the early stages of the disease, and 310 had genetic mutations that are known to cause Parkinson's but hadn't yet done so.

Using aSyn-SAA as a test in early Parkinson's detected the disease 87% of the time. Among participants who did not have Parkinson's, the test showed the absence of the disease 96% of the time. Interestingly, 30% of participants with the LRRK2 gene mutation - which causes a disease that looks like Parkinson's - do not have misfolded aSyn, but instead appear to have a different biological disease. In a group of patients who had lost their sense of smell, which is another sign of Parkinson's, the disease was detected 98.6% of the time. Significantly, 86% of prodromal, or pre-symptomatic, cases of Parkinson's disease were positive for aSyn-SAA years before clinical symptoms of the disease appeared, opening the door for an early diagnosis before substantial damage in the brain.

Currently, misfolded aSyn can only be detected by taking a spinal tap, which is an invasive and painful procedure. However, researchers are optimizing the aSyn-SAA technology to be utilized to detect the protein in blood, a skin biopsy, or a swab of the nose.

Link: https://www.uth.edu/news/story/study-misfolded-alphasynuclein-protein-key-to-early-detection-of-parkinsons-disease

Some recent work on length-dependent issues in transcription of genes to RNA observed in aging have touched on the role of RNA polymerase II (Pol II), a protein that performs the initial work of moving along a DNA sequence in the genome, reading that sequence in order to assemble the precursor to a corresponding messenger RNA molecule. Do age-related changes in the maintenance of nuclear DNA structure and the activity of Pol II make it harder for longer genes to undergo accurate transcription? Today's open access paper is focused on fidelity of transcription in the context of Pol II behavior, but the work has relevance to those other discussions regarding a selective disadvantage applied to the transcription of longer gene sequences in later life.

The structural organization of nuclear DNA is exceedingly complex and dynamic, ever-changing as the result of a rapid interplay between histones, epigenetic structural additions, and other molecules to expose different regions to transcriptional machinery such as Pol II. At a high level, one might think of the genome as being wrapped around histones, with portions becoming unwrapped for transcription as needed. With age, a great deal changes in the epigenetic decorations placed upon DNA, and thus also in the arrangement of packaged DNA. It is not unreasonable to think that this has a range of effects on cell and tissue function.

A cell is state machine built upon a feedback loop: gene expression produces protein machinery that react to the environment to cause epigenetic changes that alter gene expression. Historically, we might have viewed epigenetic changes in aging as an issue that occurs far downstream of molecular damage and environmental change in tissues that causes aging, but recent discoveries have suggested that much of that epigenetic change characteristic of aging might result from depletion of specific resources following cycles of DNA repair, and thus be a direct consequence of stochastic damage to DNA. Much remains to be determined in certainty; the best approach to establishing the relevance of any specific mechanism involved in aging is to fix it in isolation of other mechanisms and observe the result.

Ageing studies in five animals suggests how to reverse decline

Researchers analysed genome-wide transcription changes in five organisms: nematode worms, fruit flies, mice, rats, and humans, at different adult ages. The researchers measured how ageing changed the speed at which the enzyme that drives transcription, RNA polymerase II (Pol II), moved along the DNA strand as it made the RNA copy. They found that, on average, Pol II became faster with age, but less precise and more error-prone across all five groups.

Previous research had shown that restricting diet and inhibiting insulin signalling can delay ageing and extend lifespan in many animals, so the researchers then investigated whether these measures had any effect on the speed of Pol II. In worms, mice and fruit flies that carried mutations in insulin signalling genes, Pol II moved at a slower pace. The enzyme also travelled more slowly in mice on a low-calorie diet. But the ultimate question was whether changes in Pol II speed affected lifespan. Researchers tracked the survival of fruit flies and worms that carried a mutation that slowed Pol II down. These animals lived 10% to 20% longer than their non-mutant counterparts. When the researchers used gene editing to reverse the mutations in worms, the animals' lifespans shortened.

The researchers wondered whether Pol II's acceleration could be explained by structural changes in how DNA is packed inside cells. To minimize the space that they take up, the vast threads of genetic information are tightly wound around proteins called histones into bundles called nucleosomes. By analysing human lung cells and umbilical vein cells, the researchers found that ageing cells contained fewer nucleosomes, smoothing the path for Pol II to travel faster. When the team boosted the expression of histones in the cells, Pol II moved at a slower pace. In fruit flies, the elevated histone levels seemed to increase their lifespans.

Ageing-associated changes in transcriptional elongation influence longevity

Physiological homeostasis becomes compromised during ageing, as a result of impairment of cellular processes, including transcription and RNA splicing. However, the molecular mechanisms leading to the loss of transcriptional fidelity are so far elusive, as are ways of preventing it. Here we profiled and analysed genome-wide, ageing-related changes in transcriptional processes across different organisms: nematodes, fruitflies, mice, rats and humans. The average transcriptional elongation speed (RNA polymerase II speed) increased with age in all five species. Along with these changes in elongation speed, we observed changes in splicing, including a reduction of unspliced transcripts and the formation of more circular RNAs.

Two lifespan-extending interventions, dietary restriction and lowered insulin-IGF signalling, both reversed most of these ageing-related changes. Genetic variants in RNA polymerase II that reduced its speed in worms and flies increased their lifespan. Similarly, reducing the speed of RNA polymerase II by overexpressing histone components, to counter age-associated changes in nucleosome positioning, also extended lifespan in flies and the division potential of human cells. Our findings uncover fundamental molecular mechanisms underlying animal ageing and lifespan-extending interventions, and point to possible preventive measures.

It is well established that the ε4 variant of APOE increases the risk of Alzheimer's disease, but there is no firm consensus as to why this is the case. Theories abound. Researchers here suggest that the mechanism of interest is increased neuroinflammation, as APOEε4 increases the tendency for the innate immune cells known as microglia to become activated and inflammatory in the aging brain. There has been an increased focus on chronic inflammation in Alzheimer's disease in recent years, particularly given the continued failure to produce meaningful patient benefits via clearance of amyloid-β, with some researchers going so far as to suggest it is the primary driving mechanism in the onset and progression of the condition.

Alzheimer's disease (AD) is a multifactorial disorder neuropathologically characterized by amyloid-β (Aβ) plaques and tau neurofibrillary tangles. Among the multiple pathogenic processes involved in AD etiology, neuroinflammation, commonly associated with microglial reactivity, has been increasingly recognized. Microglial activation plays a key role in the accumulation of AD hallmark proteinopathies, rather than being merely an epiphenomenon of their deposition. Specifically, recent observations from animal and human studies suggest that microglial activation precedes and may drive tau spread over the neocortex, from the medial temporal to association and primary sensory structures. Such microglial activation is synaptotoxic, affects brain connectivity, and predicts clinical decline. Aβ pathology can trigger microglial activation in AD, but Aβ plaques and activated microglia only partially overlap topographically in the human brain, and microglial activation may occur before demonstrable Aβ deposition.

Using complementary positron emission tomography (PET) radiotracers for the topographical quantification of microglial activation, Aβ, and tau accumulation across the brain, we investigated the association between the APOEε4 genotype, microglial activation, Aβ, and tau in a cohort of individuals across the aging and AD continuum. We hypothesized that APOEε4 is associated with microglial activation independently of AD hallmark proteinopathies. We then tested whether microglial activation mediates the effects of APOEε4 on tau accumulation, neurodegeneration, and clinical impairment.

We found that APOEε4 carriers presented increased microglial activation relative to noncarriers in regions within the medial temporal cortex accounting for Aβ and tau deposition. Furthermore, microglial activation mediated the Aβ-independent effects of APOEε4 on tau accumulation, which was further associated with neurodegeneration and clinical impairment. The physiological distribution of APOE mRNA expression predicted the patterns of APOEε4-related microglial activation in our population, suggesting that APOE gene expression may regulate the local vulnerability to neuroinflammation. Our results support that the APOEε4 genotype exerts Aβ-independent effects on AD pathogenesis by activating microglia in brain regions associated with early tau deposition.

Link: https://doi.org/10.1126/sciadv.ade1474

The lifespan of flies is especially sensitive to intestinal function, making them perhaps an interesting model in which to study mechanisms by which changes in the gut microbiome can affect health and longevity. It is clear that the gut microbiome changes with age, and different microbial populations can affect health in different ways. At the high level, it is thought that much of the harm done in later life is mediated by increased chronic inflammation, a reaction to harmful species or the metabolites that they produce. At the detail level, a lot of work remains to be accomplished when it comes to mapping the biochemistry underlying the way in which the presence of specific microbes can provoke a maladaptive response. In the work here, the issue appears a little more than just an immune response, extending to stem cell function and other determinants of metabolism.

Commensal microbes in animals have a profound impact on tissue homeostasis, stress resistance, and ageing. We previously showed in Drosophila melanogaster that Acetobacter persici is a member of the gut microbiota that promotes ageing and shortens fly lifespan. However, the molecular mechanism by which this specific bacterial species changes lifespan and physiology remains unclear. The difficulty in studying longevity using gnotobiotic flies is the high risk of contamination during ageing. To overcome this technical challenge, we used a bacteria-conditioned diet enriched with bacterial products and cell wall components. Here, we demonstrate that an A. persici-conditioned diet shortens lifespan and increases intestinal stem cell (ISC)/a> proliferation. Feeding adult flies a diet conditioned with A. persici, but not with Lactiplantibacillus plantarum, can decrease lifespan but increase resistance to paraquat or oral infection of Pseudomonas entomophila, indicating that the bacterium alters the trade-off between lifespan and host defence.

A transcriptomic analysis using fly intestine revealed that A. persici preferably induces antimicrobial peptides (AMPs), while L. plantarum upregulates amidase peptidoglycan recognition proteins (PGRPs). The specific induction of these genes by peptidoglycans from two bacterial species is due to the stimulation of the receptor PGRP-LC in the anterior midgut for AMPs or PGRP-LE from the posterior midgut for amidase PGRPs. Heat-killed A. persici also shortens lifespan and increases ISC proliferation via PGRP-LC, but it is not sufficient to alter the stress resistance. Our study emphasizes the significance of peptidoglycan specificity in determining the gut bacterial impact on healthspan. It also unveils the postbiotic effect of specific gut bacterial species, which turns flies into a "live fast, die young" lifestyle.

Link: https://doi.org/10.1371/journal.pgen.1010709

In today's open access paper, researchers report the discovery of differences in the synaptic ultrastructure of aging primates, differences that are connected to loss of memory function. The working hypothesis is that faltering mitochondrial activity inhibits correct formation of synapses, and that this issue is one of the important factors to distinguish individuals that go on to develop worse memory performance in later life.

Every cell contains hundreds of mitochondria, descendants of ancient symbiotic bacteria. Mitochondria are responsible for generating the chemical energy store molecules, adenosine triphosphate, that power cellular processes. It is well known that this activity declines with age, perhaps largely due to failing quality control of damaged mitochondria. Autophagy targeted to mitochondria, known as mitophagy, recycles worn and damaged mitochondria, but is shown to become less effective with age. This occurs for a variety of proximate causes that include changes to mitochondria themselves, as well as failures in parts of the complex autophagy mechanisms.

In energy-hungry tissues like the brain and muscles, loss of mitochondrial activity likely produces a sizable contribution to age-related dysfunction. Many different cellular processes will be affected, and the example in today's paper is but one of these. Restoration of mitochondrial function in older individuals is an important goal for the research community, but so far the range of available interventions have struggled to outperform the effects of exercise and calorie restriction. This includes mTOR inhibition, mitochondrially targeted antioxidants, NAD+ precursor supplements, and so forth. One might hope that the next generation of interventions, including transplantation of functional mitochondria, will produce more impressive outcomes.

Mitochondria power-supply failure may cause age-related cognitive impairment

Brains are like puzzles, requiring many nested and codependent pieces to function well. The brain is divided into areas, each containing many millions of neurons connected across thousands of synapses. These synapses, which enable communication between neurons, depend on even smaller structures: message-sending boutons (swollen bulbs at the branch-like tips of neurons), message-receiving dendrites (complementary branch-like structures for receiving bouton messages), and power-generating mitochondria. To create a cohesive brain, all these pieces must be accounted for.

Prior studies had found that brains lose synapses as they age, and the researchers saw this pattern in their non-human primate model, too. But when they looked at the synapses that remained, they found evidence of a breakdown in coordination between the size of boutons and the mitochondria they contained. A fundamental neuroscientific principle, the ultrastructural size principle, explains that whenever one part of the synaptic complex changes in size, so too must all the other parts. The synapse, the mitochondria, the boutons - all these parts must scale in accordance with one another. The team found that adherence to the ultrastructural size principle was essential for avoiding working memory impairment with age. By viewing violation of the ultrastructural size principle and mitochondria-related failures as the key to age-related cognitive impairment, the study ushers in a new era for aging research.

Violation of the ultrastructural size principle in the dorsolateral prefrontal cortex underlies working memory impairment in the aged common marmoset (Callithrix jacchus)

Here, we tested the hypothesis that changes to synaptic ultrastructure that affect synaptic efficacy stratify marmosets that age with cognitive impairment from those that age without cognitive impairment. We utilized electron microscopy to visualize synapses in the marmoset dorsolateral prefrontal cortex (dlPFC) and measured the sizes of boutons, presynaptic mitochondria, and synapses. We found that coordinated scaling of the sizes of synapses and mitochondria with their associated boutons is essential for intact working memory performance in aged marmosets. Further, lack of synaptic scaling, due to a remarkable failure of synaptic mitochondria to scale with presynaptic boutons, selectively underlies age-related working memory impairment.

We posit that this decoupling results in mismatched energy supply and demand, leading to impaired synaptic transmission. We also found that aged marmosets have fewer synapses in dlPFC than young, though the severity of synapse loss did not predict whether aging occurred with or without cognitive impairment. This work identifies a novel mechanism of synapse dysfunction that stratifies marmosets that age with cognitive impairment from those that age without cognitive impairment. The process by which synaptic scaling is regulated is yet unknown and warrants future investigation.

Researchers here demonstrate that there is still room to improve the accuracy of epigenetic clocks based on patterns of DNA methylation. It could be argued that more effort should go towards generating a sufficient understanding of DNA methylation to allow the use of existing clocks to assess potential rejuvenation therapies, however. The long-term promise of epigenetic clocks is to provide a way to rapidly determine whether or not a given intervention is producing a meaningful reversal of aging, a replacement for time-consuming, expensive life span studies. Because researchers do not at present understand how underlying processes of aging are reflected in specific DNA methylation changes, it is impossible to take clock data at face value for any given intervention that targets only one aspect of aging. A clock may be insensitive to that mechanism of aging or it may give it too much weight. There is no way to know without undertaking life span studies to calibrate the clock against the intervention, defeating the point of the exercise.

"First generation" epigenetic ageing clocks, including those by Horvath and Hannum, were trained on chronological age (cAge), with near-perfect clocks expected to arise as sample sizes grow. However, cAge clocks hold limited capability for tracking and quantifying age-related health status, also termed biological age (bAge). To address this, "second generation" clocks have been trained on other age-related measures, including a phenotypic biomarker of morbidity (PhenoAge), rate of ageing (DunedinPACE), and time to all-cause mortality (GrimAge). Regressing an epigenetic clock predictor (whether trained on cAge or bAge) on chronological age within a cohort gives rise to an "age acceleration" residual with positive values corresponding to faster biological ageing.

Here, we sought to improve the prediction of both cAge and bAge. We first present large-scale epigenome-wide association studies (EWAS) of cAge (for both linear and quadratic CpG effects) and time to all-cause mortality as a proxy for bAge. A predictor of cAge is then generated using DNA methylation data from 11 cohorts, including samples from more than 18,000 participants of the Generation Scotland study. Through data linkage to death records in Generation Scotland, we develop a bAge predictor of time to all-cause mortality, which we compare against GrimAge, in four external cohorts. Our bAge predictor was found to slightly outperform GrimAge in terms of the strength of its association to survival. These analyses highlight the potential for large DNA methylation resources to generate increasingly accurate predictors of (i) cAge, with potential forensic utility, and (ii) bAge, with potential implications for risk prediction and clinical trials.

Link: https://doi.org/10.1186/s13073-023-01161-y

Senescent cells accumulate with age, largely due to cells reaching the Hayflick limit, but a range of cell stresses can also induce senescence. Senescent cells are rapidly cleared by the immune system in youth, but the balance between creation and destruction shifts with advancing age. The immune system becomes less capable, but it is also likely that the aged environment inflicts greater stress that leads to more cells becoming senescent.

Clearance of senescent cells via senolytic compounds that provoke these cells into self-destruction is presently a well funded and promising area of development. Fisetin is one such senolytic, interesting for being a cheap, safe, and widely used plant-derived supplement, but only animal data has so far been published on its ability to rapidly clear senescent cells. As noted in this paper, it may be that fisetin can to some degree also prevent cells from becoming senescent in response to stress, which might slow the accumulation of senescent cells over time. As is always the case, it is worth remembering that just because a mechanism is demonstrated to exist in cell cultures doesn't mean that it does provide a meaningfully large contribution to the balance of creation and destruction of senescent cells in living animals, however. That remains to be shown.

Reactive oxygen species (ROS) are a key risk factor of cellular senescence and age-related diseases, and protein kinase C (PKC) has been shown to activate NADPH oxidases (NOXs), which generate ROS. Although PKC activation induces oxidative stress, leading to the cellular dysfunction in various cell types, the correlation between PKC and senescence has not been reported in vascular smooth muscle cell (VSMC). Several studies have indicated cellular senescence is accompanied by phosphatase and tensin homolog (PTEN) loss and that an interaction exists between PTEN and PKC. Therefore, we aimed to determine whether PTEN and PKC are associated with VSMC senescence and to investigate the mechanism involved.

We found hydrogen peroxide (H2O2) decreased PTEN expression and increased PKCδ phosphorylation. Moreover, H2O2 upregulated the NOX1 subunits, p22phox and p47phox, and induced VSMC senescence via p53-p21 signaling pathway. We identified PKCδ activation contributed to VSMC senescence through activation of NOX1 and ROS production. However, fisetin inhibited cellular senescence induced by the PTEN-PKCδ-NOX1-ROS signaling pathway, and this anti-aging effect was attributed to reduced ROS production caused by suppressing NOX1 activation. These results suggest that the PTEN-PCKδ signaling pathway is directly related to senescence via NOX1 activation and that the downregulation of PKCδ by flavonoids such as fisetin provides a potential means of treating age-associated diseases.

Link: https://doi.org/10.1016/j.archger.2023.104927

Random mutational damage to nuclear DNA occurs constantly. While near all of it is restored by the highly efficient suite of DNA repair mechanisms present in the cell, some is not. This damage accumulates over time. Fortunately, near all of it occurs in DNA that is unused in that cell type, or occurs in genes that are not all that important, or occurs in somatic cells that have few replications remaining before hitting the Hayflick limit. In other words, most DNA damage isn't all that important, and even where it sticks, it will be cleared from the body via the normal processes of replacement of cells in a tissue.

How does DNA damage contribute to aging? Firstly, cancer risk: an unlikely combination of mutations occurring in any cell can give rise to a cancerous cell capable of unfettered replication. It is a risk throughout life, but that risk grows as the immune system ages and as the aged, ever more inflammatory tissue environment becomes more hospitable to the growth of a nascent cancer. Beyond cancer, it is likely that damage to stem cells is the primary problem, as lingering mutations in stem cells can spread throughout tissues to form patterns of overlapping mutational damage called somatic mosaicism. A minor loss of function in one cell is not a disaster. A minor loss of function in half of an organ may be a meaningful contribution to degenerative aging.

Is DNA damage really random in its effects on genes, however? Today's open access paper is one of a number to point out that longer genes are more vulnerable, and that an examination of changes in gene expression shows a greater loss of expression of longer DNA sequences than shorter DNA sequences. It is interesting to speculate on the degree to which this shapes the details of changes in cell behavior observed in aging, as compared to the contributions of the many other issues resulting from forms of damage. It is hard to do much more than speculate, however. Metabolism is ferociously complex, and the best way forward to answer any question is to repair a specific form of damage and see what happens as a result. Repair random mutational damage on a cell by cell basis is not a near term prospect, however, given the present state of genetic engineering.

It is worth noting that a different group of researchers has suggested that a reduction in the expression of longer DNA sequences with advancing age is the result of age-related changes in regulation of transcription, not DNA damage. It will be interesting to see how this debate over mechanisms progresses as more data emerges.

Age or lifestyle-induced accumulation of genotoxicity is associated with a length-dependent decrease in gene expression

DNA damage has long been proposed as a primary molecular driver of aging. Aging has also been associated with a series of transcriptional changes, most of which are highly tissue- and cell type-specific. Even though the search for a global aging signature has been the goal of much research, meta-analyses have shown that very few genes are consistently upregulated or downregulated with aging across different tissues. It appears that, at the mRNA level, aging signatures are not defined by the overexpression of particular sets of genes, but rather an overall decay in transcription.

Genetic material is constantly challenged throughout the lifespan of the organism, both by endogenous and environmental genotoxins. Some of this damage happens in the form of transcription-blocking lesions (TBLs), which impede transcriptional elongation. Accumulation of TBLs provokes a genome-wide shutdown of transcription, which also affects undamaged genes through poorly understood mechanism. Assuming a constant TBL incidence, meaning that any base pair in the genome has a similar probability of suffering damage that results in a lesion, a greater accumulation of TBLs is to be expected in longer genes. In fact, a gene length-dependent accumulation of other forms of genetic damage, like somatic mutations, has already been reported in conditions like Alzheimer's disease. Hence, TBLs, just like somatic mutations are expected to accumulate with aging, and their accumulation should be dependent on gene length. However, unlike somatic mutations, TBLs have a strong and direct impact on mRNA production, and their gene length-dependent effects are likely to be measurable from RNA sequencing data of aged tissues.

So far, a potential relationship between age-related transcriptional changes and gene length has received relatively little attention. Here, we aimed to extend these early observations, which were based on bulk microarray and RNA sequencing data to the existing aging datasets based on single cell RNA sequencing technology. We also extended our gene length analyses to mouse and human datasets of lifestyle-induced genotoxic exposure (UV, smoke) and progeroid syndromes (Cockayne syndrome and trichothiodystrophy).

We found a pervasive age-associated length-dependent underexpression of genes across species, tissues, and cell types. Furthermore, we observed length-dependent underexpression associated with UV-radiation and smoke exposure, and in progeroid diseases, Cockayne syndrome, and trichothiodystrophy. Finally, we studied published gene sets showing global age-related changes. Genes underexpressed with aging were significantly longer than overexpressed genes. These data highlight a previously undetected hallmark of aging.

Researchers here take a high level tour of what is known of age-related changes in the gut microbiome and how they influence health. Accumulating evidence shows a loss of beneficial populations that generate useful metabolites such as butyrate, accompanied by an increase in harmful populations that can provoke chronic inflammation. This is a likely a meaningful contribution to the onset and development age-related conditions, making it a priority to develop ways to reset the balance of populations in the gut microbiome. The best of the available approaches, given the evidence to date, is fecal microbiota transplantation from a young donor. This has been shown to rejuvenation the aging microbiome, improve health, and even extend life span in short-lived laboratory species.

The trillions of microorganisms found in and on the human body (the microbiota) offer tremendous potential in understanding aging. The microbiome (the aggregate genetic content of the microbiota) exceeds the human genome by multiple orders of magnitude. Microorganisms colonize numerous sites in and on the body, with the greatest extent of colonization occurring within the gastrointestinal (GI) tract. Extensive and rigorous prior research has emphasized the key role that the gut microbiota has in host health and disease, including contributions to diseases associated with aging such as cancer, Parkinson's disease, obesity, and type 2 diabetes. Yet, despite remarkable progress in understanding the cellular and molecular mechanisms through which the microbiome contributes to individual diseases linked to aging, the net effects of the microbiome for the aging process or the potential for manipulating the microbiome to promote healthy aging remain unclear.

The overall association between the human microbiome and age is strong enough that it is possible to predict biological age with striking precision with the microbiome. An initial proof-of-concept was demonstrated in early life, in which a "microbiota maturity index" established in healthy individuals was delayed in the context of malnutrition. More recently, machine learning tools have enabled the accurate prediction of age in adults from distal gut metagenomic data with a mean absolute error of 6 to 8 years. The composition of the microbiota found in other body habitats, including the skin and oral cavity, is also linked to age.

In animal studies, the microbiome can decrease life span in older animals. In C. elegans, GI accumulation of Escherichia coli contributes to age-related death. Removal of germ-free D. melanogaster from sterile conditions reduces life span in adults. More recently, the detrimental effects of the microbiome in aging animals has been studied using the African turquoise killifish. Middle-aged (9.5-week-old) killifish treated with antibiotics outlived untreated fish, suggesting that the microbiota impairs life span in older killifish. Remarkably, inoculation with the GI microbiota of 6-week-old killifish significantly increased the life span of middle-aged killifish groups.

These findings are also relevant to mammals. Work in two mouse models of progeria (a human premature aging syndrome) supports the potential for microbiome-based interventions to extend life span. The gut microbiota was altered in prematurely aging mice, including a significant decrease in Akkermansia muciniphila in a model of the most common human progeria syndrome. As in killifish, fecal microbiota transplantation (FMT) from wild-type mice significantly increased the life span of transgenic prematurely aging recipient mice. Even more excitingly, the Verrucomicrobium A. muciniphila, a common member of the human gut microbiota, was sufficient to extend life span in the mice. These results provide a major step towards identifying the cellular and molecular mechanisms responsible for microbiota-dependent changes in life span as well as an important step towards the potential translation of these results to humans.

Link: https://doi.org/10.1371/journal.pbio.3002087

This recent article from the SENS Research Foundation discusses calcium chelation and, separately, the tailored cyclodextrin molecules developed by Cyclarity to sequester 7-ketocholesterol. This altered form of cholesterol is toxic to cells, and may provide a significant contribution to a range of age-related conditions, including atherosclerosis. Cyclarity will be conducting initial human trials in the near future. Since the best way to determine exactly how important 7-ketocholesterol is in the context of atherosclerosis in humans is to remove it, it will be interesting to see how this goes. It is vital to progress that more programs of this nature make it to human trials, rather than becoming bogged down in academic questions over ways to determine the likely degree of efficacy in advance of clinical development.

Cyclarity's UDP-003 is a small molecule LysoSENS therapy that directly removes damaged cholesterol products that turn macrophages into foam cells and thus drive atherosclerosis. Researchers set out to design a molecular precision tool that would remove 7-ketocholesterol (7KC) selectively while leaving normal physiological cholesterol untouched. Using a combination of experimentation with existing cyclodextrins, trial-and-error virtual experiments in existing molecular modeling software, and eventually a new VR molecular modeling and design system, Cyclarity constructed a novel cyclodextrin dimer in virtual space and tested it in silico against native and oxidized cholesterol before testing it in actual lab conditions - and then back again to the virtual system in an iterative optimization cycle.

This dimer is comprised of two different cyclodextrins, one of them "scoop-like" and the other a "gripper" complex, linked together in a configuration where the two can cooperate to create a binding cavity. It's a bit like a reusable coffee pod or a shaker cup for protein shakes, with a chamber to take in the desired material and then a sealable cap to hold the contents in place. This dual structure allows UDP-003 to first capture 7KC and then surround it, holding on to it with extremely high affinity. Trapped in the UDP-003 core, 7KC can't interact or react with anything else in the body, allowing UDP-003 to passively carry it out of the cell, through the circulation, and harmlessly out of the body via excretion.

In experimental systems, UDP-003 sucks very high amounts of 7KC from cultured cells and blood cells, as well as from surgically captured atherosclerotic plaque, with no corresponding effect on free unmodified cholesterol in blood. A useful safety test is to see if a cyclodextrin will extract cholesterol out of the membranes of red blood cells, causing them to lyse; on such tests, UDP-003 has extremely little hemolytic activity.

In 2021, the UK's Medicines and Healthcare products Regulatory Agency (MHRA - their equivalent of FDA) awarded Cyclarity an Innovation Passport under its Innovative Licensing and Access Pathway (ILAP), which is a new program designed to help shepherd truly innovative therapies more quickly through the regulatory process by giving awardees early and ongoing contact and feedback with the regulators. Thanks to this and a solid scientific foundation, UDP-003 trials are coming up fast in the UK. As of this writing (late winter of 2023), Cyclarity is finishing up its animal safety data and getting ready to produce enough UPD-003 at pharmaceutical grade to run their first human trial. While only a safety trial, it will be a critical first-in-human test of the new molecule.

Link: https://www.sens.org/clarifying-cyclarity-edta-vs-udp-003/

The path to understanding that pharmacological inhibition of mTOR replicates some of the calorie restriction response to cause a slowing of aging started with studies of rapamycin. The primary mechanism of interest is upregulation of autophagy, a cellular housekeeping mechanism that is involved in a range of interventions that slow aging in short-lived species. Other mechanisms may well turn out to be involved, as altering metabolism is a complex business and still incompletely understood.

The various mTOR inhibitors are collectively one of the most studied, and arguably best of the existing approaches to alter metabolism in order to modestly slow aging in mammals. This isn't rejuvenation, and isn't anywhere near as good as the effects of first generation senolytics when it comes to rapidly reversing aspects of aging in old animals. Rapamycin and other mTOR inhibitors are quite robust in their effects in comparison to many of the other alleged calorie restriction mimetics, however, so there is that.

Rapamycin, the only drug that has been consistently demonstrated to increase mammalian longevity. An update.

Prior to 2009 the consensus of scholars was that aging could not be treated or if it could be it must be a youth factor (e.g., growth hormone). Numerous advertised non-scientific approaches absconded with people's funds, mostly confused people, and were counterproductive for the field. However, there were two scientific settings in which aging could be reproducibly delayed. Unfortunately, neither was optimal for use in people. They were restrictions of diet and/or growth factors by genetic means. Since people do not like restricting anything, especially food, progress toward a deeper understanding of aging and potential ways to delay its effects was slow.

In recognition of this bottleneck, the National Institute of Aging established the Interventions Testing Program (ITP) to identify compounds that could be tested for aging effects under rigorous and standard conditions. To date, the ITP website indicates they have tested or in the process of testing 64 different compounds, some at varied doses and in combination. Twenty publications from the ITP have reported increases in lifespan from ten compounds. Importantly, the ITP also reports compounds that do not extend lifespan.

Here we focus of the ITP 2009 test of what was then an unlikely candidate drug called rapamycin. Results showing increased median and maximum lifespan in advanced aged males and females in this paper reset the paradigm for aging studies. It suggested that pharmacological agents can prevent, delay, and/or reduce the severity of age-caused morbidities. We will first briefly remind readers about the biology of the cell systems affected by rapamycin, better known as mTOR. Next, we will review the results of several studies on the effects chronic rapamycin has on lifespan in both sexes including our recollection of the first study. Following that, we will relate selected examples of the effects chronic rapamycin has on age-caused diseases.

We conclude with our view of what rapamycin effects are telling us about aging and how it might be working. We confess at the outset that we have only a faint picture of rapamycin's function as an anti-aging agent and suggest that it will be as complicated and mysterious as the studies to determine how restriction of food and growth factors work, which after half a century still have a way to go.

Covalent Bioscience develops catalytic antibodies, a way to bind and neutralize target molecules in the body without consuming the antibody molecule itself. A given dose of catalytic antibody can thus remove many times more target molecules than is the case for standard monoclonal antibodies. This offers the potential for highly efficient removal of age-related amyloids present outside cells, perhaps the most interesting of the many possible use cases, such as those related to suppression of specific signal molecules. Like most biotech companies, the backstory behind the science emphasizes the point that progression of any given technology from academia to industry is slow indeed.

Covalent Bioscience was incorporated in 2010 by Dr Sudhir Paul and Dr Richard Massey based on catalytic antibody technology and several exciting potential products for unmet medical needs. The technology and potential products were developed in Dr. Sudhir Paul's group at the University of Texas (UT). Dr Richard Massey and Dr Sudhir Paul have worked together on the field of catalytic antibody (or catabody) when Dr Massey was in Igen in the late 80s. I have worked with Dr. Paul since 1999 and am one of the co-founders of Covalent Bioscience. We, the founders of Covalent Bioscience, share the same conviction that our platform technology holds the potential to generate superior immunotherapeutic drugs and vaccines.

Today, Covalent Bioscience has grown to a preclinical stage company holding significant assets. Our broad technology platform can be applied to generate novel lead products for unmet needs across multiple areas of medicine. We have three promising lead products for diseases that proved very difficult to treat and prevent by conventional means. Two of them are catabodies for treating age-associated diseases such as Alzheimer's disease and transthyretin amyloidosis. The products are expected to remove toxic aggregates that cause diseases in a more efficient and safe manner than conventional antibodies.

In 2018, Dr Paul and I moved full time to Covalent Bioscience. Our lab is located at the skirt of the Houston Medical Center, biggest medical center in the world. In 2020, Covalent Bioscience received from The University of Texas the commercial rights to all inventions and research materials/tools Paul's team generated there. With our current funding, we are generating new catabodies and working in collaboration with a pharma company to advance one of our lead products closer to human trials.

Link: https://medium.com/@arielf/interview-with-stephanie-planque-from-covalent-bioscience-9a2b49e74f49

In this study, researchers show that mice lacking a functional ATF4 gene show little to no loss of grip strength and treadmill performance into late life; it is quite an impressive effect size. Assessments of muscle biochemistry do show age-related declines, but to a lesser degree than the controls. How ATF4 knockout functions to produce this outcome is an interesting question. The researchers point out a range of possible downstream and upstream targets that have been implicated in the regulation of muscle growth, but it will clearly require further work to identify the important mechanisms involved.

Aging slowly erodes skeletal muscle strength and mass, eventually leading to profound functional deficits and muscle atrophy. The molecular mechanisms of skeletal muscle aging are not well understood. To better understand mechanisms of muscle aging, we investigated the potential role of ATF4, a transcription regulatory protein that can rapidly promote skeletal muscle atrophy in young animals deprived of adequate nutrition or activity.

To test the hypothesis that ATF4 may be involved in skeletal muscle aging, we studied fed and active muscle-specific ATF4 knockout mice (ATF4 mKO mice) at 6 months of age, when wild-type mice have achieved peak muscle mass and function, and at 22 months of age, when wild-type mice have begun to manifest age-related muscle atrophy and weakness. We found that 6-month-old ATF4 mKO mice develop normally and are phenotypically indistinguishable from 6-month-old littermate control mice. However, as ATF4 mKO mice become older, they exhibit significant protection from age-related declines in strength, muscle quality, exercise capacity, and muscle mass.

Furthermore, ATF4 mKO muscles are protected from some of the transcriptional changes characteristic of normal muscle aging (repression of certain anabolic mRNAs and induction of certain senescence-associated mRNAs), and ATF4 mKO muscles exhibit altered turnover of several proteins with important roles in skeletal muscle structure and metabolism. Collectively, these data suggest ATF4 as an essential mediator of skeletal muscle aging and provide new insight into a degenerative process that impairs the health and quality of life of many older adults.

Link: https://doi.org/10.1007/s11357-023-00772-y

Supplementation with the non-essential amino acid glycine has been shown to modestly slow aging in short-lived laboratory species. In today's open access review paper, researchers note glycine supplementation as essentially a calorie restriction mimetic approach that works primarily through effects on methionine sensing. Much of the broadly beneficial metabolic response to lowered calorie intake occurs because cells react to low levels of the essential amino acid methionine in ways that increase efficiency of protein production and reuse of materials. For example, this increases the activity of cellular housekeeping activities such as autophagy. More housekeeping means better functioning cells and tissues, and kept up over the long term this has the desirable outcome of lengthening healthy life span.

Unfortunately we know that while short-term benefits to health metrics achieved via this sort of approach are much the same in mice versus humans, and thus some form of calorie restriction seems a sensible health practice, long-term effects on life span are much smaller in long-lived species. It remains to be understood as to exactly why this is the case, but from an evolutionary perspective one might argue that many of the metabolic changes taking place in response to calorie restriction in a short-lived mammals are already permanently turned on in a long-lived mammal in order to enable individuals of that species to be long-lived in the first place.

Glycine and aging: Evidence and mechanisms

The restriction of calories, branched-chain amino acids, and methionine have all been shown to extend lifespan in model organisms. Recently, glycine was shown to significantly boost longevity in genetically heterogenous mice. This simple amino acid similarly extends lifespan in rats and improves health in mammalian models of age-related disease. While compelling data indicate that glycine is a pro-longevity molecule, divergent mechanisms may underlie its effects on aging.

Glycine is abundant in collagen, a building block for glutathione, a precursor to creatine, and an acceptor for the enzyme Glycine N-methyltransferase (GNMT). A review of the literature strongly implicates GNMT, which clears methionine from the body by taking a methyl group from S-adenosyl-L-methionine and methylating glycine to form sarcosine. In flies, Gnmt is required for reduced insulin/insulin-like growth factor 1 signaling and caloric restriction to fully extend lifespan. The geroprotector spermidine requires Gnmt to upregulate autophagy genes and boost longevity. Moreover, the overexpression of Gnmt is sufficient to extend lifespan and reduce methionine levels. Sarcosine, also known as methylglycine, declines with age in multiple species and is capable of inducing autophagy both in vitro and in vivo.

Taken all together, existing evidence suggests that glycine prolongs life by mimicking methionine restriction and activating autophagy. In this review, we provide a detailed overview of the current evidence that glycine is a pro-longevity molecule, a so-called geroprotector. By exploring and synthesizing available data, we also offer a tentative mechanistic explanation for how this simple amino acid may target biological aging and prolong life.

With advancing age, the intestinal barrier responsible for keeping pathogens out of tissues becomes ever less effective. This contributes to rising levels of chronic inflammation. Researchers here note that intestinal barrier dysfunction correlates with markers of ribosomal stress, and that this form of cell stress can be induced by metabolites generated by microbes present in the intestine. It is one of the ways in which age-related shifts in the prevalence of different microbial species in the gut can become harmful to health.

The interaction between the gut microbiome and aging is becoming a well-studied area, so one might expect to see a growing focus on specific mechanisms in the years ahead, and potentially ways to interfere more specifically. For now, only very general approaches exist to adjust the gut microbiome populations towards a more youthful configuration, such as fecal microbiota transplantation and flagellin immunization.

Upon exposure to internal or environmental insults, ribosomes stand sentinel. In particular, stress-driven dysregulation of ribosomal homeostasis is a potent trigger of adverse outcomes in mammalians. The present study assessed whether the ribosomal insult affects the aging process via the regulation of sentinel organs such as the gut.

Analyses of the human aging dataset demonstrated that elevated features of ribosomal stress are inversely linked to intestinal barrier maintenance biomarkers during the aging process. Ribosome-insulted worms displayed reduced lifespan, which was associated with the disruption of gut barriers. Mechanistically, ribosomal stress-activated Sek-1/p38 signaling, a central platform of ribosomal stress responses, counteracted the gut barrier deterioration through the maintenance of the gut barrier, which was consistent with the results in a murine insult model. However, since the gut-protective p38 signaling was attenuated with aging, the ribosomal stress-induced distress was exacerbated in the gut epithelia and mucosa of the aged animals, subsequently leading to increased bacterial exposure.

Moreover, the bacterial community-based evaluation predicted concomitant increases in the abundance of mucosal sugar utilizers and mucin metabolic enzymes in response to ribosomal insult in the aged host. All of the present evidence on ribosomal insulting against the gut barrier integrity from worms to mammals provide new insights into the roles of ribosomes in the regulation of human longevity and susceptibility to gut-associated chronic diseases.

Link: https://doi.org/10.1016/j.redox.2022.102565

Brown fat and beige fat are involved in generating heat, while white fat is not. In white fat deposits, some fraction of fat cells become beige, behaving like brown fat in generating heat. That fraction increases in a cold environment. Because of this direction of energy towards heat production, and related behavior of beige fat cells, having a greater proportion of beige fat rather than white fat is metabolically favorable in this era of excess calories and metabolic disorders. With age, there is less beneficial production of beige fat and more production of white fat tissue, however. Researchers are thus interested in finding a way to bias the body towards beige fat production, or at least reduce the loss of beige fat with age. It is unclear as to whether such an approach can be any better than exercise and diet, but that can be said for most of the research programs intended to produce interventions into aspects of aging at the present time.

Perivascular adipocyte progenitor cells (APCs) can generate cold temperature-induced thermogenic beige adipocytes within white adipose tissue (WAT), an effect that could counteract excess fat mass and metabolic pathologies. Yet, the ability to generate beige adipocytes declines with age, creating a key challenge for their therapeutic potential. Here we show that ageing beige APCs overexpress platelet derived growth factor receptor beta (Pdgfrβ) to prevent beige adipogenesis. We show that genetically deleting Pdgfrβ, in adult male mice, restores beige adipocyte generation whereas activating Pdgfrβ in juvenile mice blocks beige fat formation.

Mechanistically, we find that Stat1 phosphorylation mediates Pdgfrβ beige APC signaling to suppress IL-33 induction, which dampens immunological genes such as IL-13 and IL-5. Moreover, pharmacologically targeting Pdgfrβ signaling restores beige adipocyte development by rejuvenating the immunological niche. Thus, targeting Pdgfrβ signaling could be a strategy to restore WAT immune cell function to stimulate beige fat in adult mammals.

Link: https://doi.org/10.1038/s41467-023-37386-z

Strategies shown to modestly slow aging have quite different outcomes in short-lived versus long-lived mammals. Every intervention that touches on the mechanisms associated with calorie restriction, the stress responses that dial up the activities of cellular housekeeping mechanisms such as autophagy, has a larger effect on mouse life span than human life span most likely because these mechanisms evolved in the context of seasonal famine. The reproductive life span of a short-lived species must lengthen considerably to pass through an additional season of famine into the comparative plenty that follows, but that isn't true of a long-lived species such as our own.

What are the mechanisms that mediate this difference between species, however? This question is comparatively little explored, in large part because cellular metabolism is ferociously complicated, even before one layers the interplay of different organs and tissues on top of the complexity of cellular processes. Then there is the question of our fellow travelers, the microbial populations of the intestine. The activities of the gut microbiome are attracting more attention of late, and as today's open access paper suggests, the microbiome may turn out to play a role in species differences in response to potentially age-slowing interventions.

Nicotinamide riboside (NR) is a supplement derived from vitamin B3 that acts to make up for age-related shortfalls in the production of nicotinamide adenine dinucleotide (NAD), thereby improving mitochondrial function. NAD is essential to the mitochondrial process of packaging chemical energy store molecules, the adenosine triphosphate (ATP) used to power cellular operations. With age the various pathways for synthesizing and recycling NAD become less efficient, and some effort has been put towards assessing ways to restore this portion of mitochondrial biochemistry. So far the results have not been all that impressive, no better than structured exercise programs at best, and a number of failed clinical trials at worst. Still, perhaps this can shed some light on why we might expect results in rodents to be materially different from results in people for this class of intervention.

Oral supplementation of nicotinamide riboside alters intestinal microbial composition in rats and mice, but not humans

The gut microbiota impacts systemic levels of multiple metabolites including NAD+ precursors through diverse pathways. Nicotinamide riboside (NR) is an NAD+ precursor capable of regulating mammalian cellular metabolism. Some bacterial families express the NR-specific transporter, PnuC. We hypothesized that dietary NR supplementation would modify the gut microbiota across intestinal sections. We determined the effects of 12 weeks of NR supplementation on the microbiota composition of intestinal segments of high-fat diet-fed (HFD) rats. We also explored the effects of 12 weeks of NR supplementation on the gut microbiota in humans and mice.

In rats, NR reduced fat mass and tended to decrease body weight. Interestingly, NR increased fat and energy absorption but only in HFD-fed rats. Moreover, 16S rRNA gene sequencing analysis of intestinal and fecal samples revealed an increased abundance of species within Erysipelotrichaceae and Ruminococcaceae families in response to NR. PnuC-positive bacterial strains within these families showed an increased growth rate when supplemented with NR. The abundance of species within the Lachnospiraceae family decreased in response to HFD irrespective of NR.

Alpha and beta diversity and bacterial composition of the human fecal microbiota were unaltered by NR, but in mice, the fecal abundance of species within Lachnospiraceae increased while abundances of Parasutterella and Bacteroides dorei species decreased in response to NR. In conclusion, oral NR altered the gut microbiota in rats and mice, but not in humans. In addition, NR attenuated body fat mass gain in rats, and increased fat and energy absorption in the HFD context.

One might naively think that studying the effects of exercise on human aging is fairly straightforward. This isn't the case, as illustrated by the authors of this commentary. Very little is simple when it comes to making use of existing epidemiological data, or trying to construct studies that shed light on the question of how exactly exercise interacts with aging. It seems very clear that exercise is a good thing, and that most of us should be undertaking more of it, but once down in the weeds, at the detail level, it is all too easy to find large gaps in present knowledge and contradictory or poorly designed studies.

Preserving functional health and quality-of-life in old age is a major goal and global challenge in public health. The high rate of sedentary behavior that is characteristic of the older adult population exacerbates impairments of physiological and structural systems that are typically seen in the aging process. Achieving an understanding of the profound influence of physical activity on all aspects of health in old age is the driving force behind the emergence of "physical activity in old age" as a growing area of research. Accumulated evidence implies that being physically active and exercising is far superior to other optimal aging facilitators. Yet this area of research faces numerous constraints and obstacles.

Compared to other age groups, old age is typified by increased heterogeneity, which complicates research and renders practice harder to conduct. This heterogeneity is typical of physical performance as well as cognitive and behavioral performance. With respect to physcial activity (PA) in old age, a reductionist approach is often adopted. For example, PA programs may be developed to affect specific types of performance (e.g., muscle strength, aerobic endurance, and balance), by manipulating parts of an intact physiological movement system. However, one typical manifestation of aging is a heterogenous decline in these physiological systems. In healthy organs, these systems communicate with one another to maintain homeostasis; yet aging causes the breakdown of different physiological systems, which in turn may affect other more intact physiological systems, thereby interfering with this homeostasis. As such, this individual pattern of aging could imply the need for critically rethinking PA training principles for aging populations.

Due to the large heterogeneity of evaluation methods and PA interventions, standardized guidelines are lacking for assessing the benefits of PA programs for specific groups of older adults. While the literature presents numerous reports that employed specific criteria for assessing physical fitness, the PA programs that were used for such interventions are not always clearly described. Moreover, in addition to the lack of standardized assessment tools and intervention details, research studies fall short in providing guidelines for the standardized reporting of PA protocols - in terms of the type of PA, intensity, number of repetitions, and more. With exercise and other types of PA, there is clearly no "one-size-fits-all," especially in the diverse aged population. Yet, research on older populations is typically biased towards healthy and relatively young older adults, with certain groups of older individuals frequently being excluded from research on aging - especially in studies with PA interventions.

Despite evidence on the benefits of PA in advanced age, public health initiatives often fail to examine clinically relevant effects of PA on physical and cognitive health. For example, it has been hypothesized that the highly controlled environments in which some PA research is conducted limit its replicability in real-world community settings. While the efficacy of the PA intervention may perhaps be more clearly demonstrated in laboratory settings, there is a dearth of research that indicates its effectiveness when conducted in real-world conditions as well. In addition, the effect of PA in clinical populations may vary, based on the stage of the disease, the nature of a concomitant medical treatment, and the patients' current lifestyle.

Link: https://doi.org/10.1186%2Fs11556-023-00318-3

There are a great many genes that one might target with gene therapies to treat aspects of aging. The review here is quite narrow in scope, and only looks at a few approaches to gene therapy, and a few of the genes that might be targeted, those that have arguably received more attention in this context and are either the subjects of small clinical trials or might be entering trials in the near future. It even omits follistatin and myostatin in favor of telomerase, klotho, VEGF, and APOE. The latter is probably not all that interesting as a target, but it is very well researched as a result of the strong focus on funding Alzheimer's disease programs over the past few decades.

The telomerase reverse transcriptase (TERT) gene encodes the rate-limiting catalytic TERT protein, a subunit of telomerase. Studies on telomeres and telomerase have been conducted since the start of research on aging. Many studies have shown that defects in telomeres or telomerase exert a substantial influence on the development of aging-related diseases. Some in vivo experiments have already reported that TERT gene therapy exhibits exciting efficacy for treating diverse diseases. Researchers tentatively introduced AAV-mouse Tert into 12- and 24-month-old mice, and they found noticeable improvements in various aging-related molecular biomarkers. Interestingly, an increase in median lifespan was also observed. Later, researchers designed an AAV9 vector that expressed Tert in heart tissue to treat heart failure after myocardial infarction (MI). Intravenous injection of this vector into mouse models of myocardial infarction showed that mice with the vector expressing TERT had less damage to the cardiac indices of both structure and function, decreased mortality and improved biomarkers.

KL, another classic aging-related gene, has a much shorter research history than that of the TERT gene, just over twenty years. Exploring concrete mammalian models (mostly mouse models) of aging-related diseases has revealed the therapeutic effect of enhancing KL expression in neurodegenerative diseases, chronic kidney diseases, cardiovascular diseases, etc. Preclinical evidence has demonstrated that KL has broad therapeutic promise for treating various aging-related diseases. However, no interventional clinical trials have been conducted to assess the clinical potential of KL.

The entire human body is widely affected by vascular endothelial growth factor (VEGF), and the formation and function of blood vessels are highly reliant on VEGF. VEGF is negatively associated with aging, and its high VEGF expression has a protective effect on the cardiovascular system. However, many studies have identified it as a potential target in malignant tumors and it is regarded as a promoting factor. Therefore, it remains a concern whether it will induce cancer when applied in anti-aging gene therapy. Researchers conducted an experiment based on the hypothesis that vascular aging is a founding factor in organismal aging. Over an experimental period of more than 30 months, they reported increased lifespans and physiological function after applying the gain-of-function system of transgenic VEGF and AAV-assisted VEGF transduction. Thus, VEGF seems to play a paradoxical role in aging similar to the telomerase gene, which inspires further systematic and careful exploration of potential treatments.

Gene therapies, especially in the field of aging provide new hopes for treating diseases. However, not all aging-related genes have the potential to be the targets. Satisfactory efficacy is only achieved by combining them with an adaptive operational strategy and efficient carriers. Additionally, some genes may simply be predictors of prognosis or capable of screening out effective medications for diseases. To be a therapeutic target, the candidate gene should have a relatively distinct and clear role.

Link: https://doi.org/10.14336/AD.2022.00725

Dasatinib, a tyrosine kinase inhibitor, was one of the first drugs shown to selectively destroy senescent cells and thereby reverse aspects of aging, particularly when used in combination with the plant flavonoid quercetin. Strangely, little attention was given to the question of whether other tyrosine kinase inhibitors can target senescent cells until recently. A number of these compounds have in the past undergone clinical trials, or even been approved for use by regulators, for the treatment of conditions that researchers now suspect to be connected with cellular senescence to a significant degree. Nintedanib, for example, in the context of pulmonary fibrosis, or masitinib in the context of Alzheimer's disease.

In today's open access paper, researchers report on another tyrosine kinase inhibitor that may act to reduce the age-related burden of cellular senescence. It is, as one might expect, an approved cancer drug. The dasatinib and quercetin combination remains one of the more effective senolytic therapies in terms of reducing the burden of senescent cells in animal studies. There is no particular reason as to why dasatinib should be the best in its class, however. It is possible that other tyrosine kinase inhibitors are better, either overall, or for specific use cases. Certainly, by analogy, the class of bcl-2 family inhibitors (including navitoclax, one of the other early senolytic drugs) that selectively destroy senescent cells vary widely in effectiveness.

Defining regorafenib as a senomorphic drug: therapeutic potential in the age-related lung disease emphysema

Senescence, a hallmark of aging, is a factor in age-related diseases (ARDs). Therefore, targeting senescence is widely regarded as a practicable method for modulating the effects of aging and ARDs. Here, we report the identification of regorafenib, an inhibitor of multiple receptor tyrosine kinases, as a senescence-attenuating drug. We identified regorafenib by screening an FDA-approved drug library.

Treatment with regorafenib at a sublethal dose resulted in effective attenuation of the phenotypes of βPIX knockdown-induced and doxorubicin-induced senescence and replicative senescence in IMR-90 cells; cell cycle arrest, and increased SA-β-Gal staining and senescence-associated secretory phenotypes, particularly increasing the secretion of interleukin 6 (IL-6) and IL-8. Consistent with this result, slower progression of βPIX depletion-induced senescence was observed in the lungs of mice after treatment with regorafenib.

Mechanistically, the results of proteomics analysis in diverse types of senescence indicated that growth differentiation factor 15 and plasminogen activator inhibitor-1 are shared targets of regorafenib. Analysis of arrays for phospho-receptors and kinases identified several receptor tyrosine kinases, including platelet-derived growth factor receptor α and discoidin domain receptor 2, as additional targets of regorafenib and revealed AKT/mTOR, ERK/RSK, and JAK/STAT3 signaling as the major effector pathways. Finally, treatment with regorafenib resulted in attenuation of senescence and amelioration of porcine pancreatic elastase-induced emphysema in mice.

Based on these results, regorafenib can be defined as a novel senomorphic drug, suggesting its therapeutic potential in pulmonary emphysema. Senescence is a factor in the pathogenesis of chronic pulmonary diseases, including emphysema. Thus, senotherapy based on senolytics, senomorphics, and their combination has been recognized as a practicable strategy for the treatment of these diseases. Previous studies have reported on the efficacy of regorafenib in animal models of Alzheimer's disease and bleomycin-induced fibrosis. The role of regorafenib in the attenuation of senescence may provide an explanation for its beneficial effects in these disease models.

Cells become senescent constantly throughout life, largely those that reach the Hayflick limit on cellular replication. Near all such cells rapidly self-destruct or are removed by the immune system. With age, the immune system becomes less efficient and senescent cells begin to linger in ever-increasing numbers, the balance between creation and destruction thrown off. These cells produce inflammatory signaling that, when sustained over the long term, causes cell and tissue dysfunction, contributing to age-related disease.

If interested in how lifestyle interventions might impact the process, a sensible place to look is tissues with rapid cell division and turnover of cells, such as the intestinal barrier, as effects should appear more rapidly. In this study, researchers show that long-term exercise does reduce signs of cellular senescence in this tissue, though this appears to be a matter of reducing the proportion of the study population exhibiting high biomarker values rather than moving the average for everyone. Whether this outcome is similar in other tissues is an open question. While exercise is beneficial, one can't exercise one's way out from under degenerative aging, only somewhat slow its progression.

Regular endurance exercise training is an effective intervention for the maintenance of metabolic health and the prevention of many age-associated chronic diseases. Several metabolic and inflammatory factors are involved in the health-promoting effects of exercise training, but regulatory mechanisms remain poorly understood. Cellular senescence - a state of irreversible growth arrest - is considered a basic mechanism of aging. Senescent cells accumulate over time and promote a variety of age-related pathologies from neurodegenerative disorders to cancer. Whether long-term intensive exercise training affect the accumulation of age-associated cellular senescence is still unclear.

Here, we show that the classical senescence markers p16 and IL-6 were markedly higher in the colon mucosa of middle-aged and older overweight adults than in young sedentary individuals, but this upregulation was significantly blunted in age-matched endurance runners. Interestingly, we observe a linear correlation between the level of p16 and the triglycerides to HDL ratio, a marker of colon adenoma risk and cardiometabolic dysfunction. Our data suggest that chronic high-volume high-intensity endurance exercise can play a role in preventing the accumulation of senescent cells in cancer-prone tissues like colon mucosa with age. Future studies are warranted to elucidate if other tissues are also affected, and what are the molecular and cellular mechanisms that mediate the senopreventative effects of different forms of exercise training.

Link: https://doi.org/10.1038/s41514-023-00100-w

Naked mole rats are an extreme example of compression of morbidity in mammals, in that individuals show few signs of aging until very late in life. Their biochemistry is peculiar in a number of ways when compared with other mammals. Their senescent cells do little harm to surrounding tissues; their protein synthesis is highly efficient; the are better at repairing DNA damage; they exhibit impressive cancer suppression mechanisms; and so forth. Will it be possible to build human enhancements or medical technologies from what is learned of naked mole rat metabolism? It is plausible that this is a very complicated extremely long-term project; equally any part of naked mole rat biochemistry could turn out to inform a comparatively simple, targeted intervention. It is too early to say.

The species Heterocephalus glaber, commonly known as the naked mole-rat, is a eusocial mammal endemic to the arid and semi-arid regions of northeast Africa. In the wild, naked mole-rats live an almost completely subterranean lifestyle, in colonies of up to 295 animals (average size is 60 animals/colony) that cohabitate a network of tunnels that the mole-rats dig themselves with their large, ever-growing incisors. Naked mole-rats are notable for their extreme lifespans, living longer than any other documented rodent, with the longest previously-reported lifespan of 37 years and many animals living beyond 30 years. These values are notable in the context of this species' small body size due to the strong correlation across species between that value and mammalian lifespan: maximum lifespan potential (MLSP) increases by 16% for each doubling of average species body mass.

For most mammalian species, lifespan is limited by an exponential increase in the per-day risk of death (i.e. mortality hazard) with age in accord with a statistical distribution first defined by Gompertz based on human mortality. The increase in mortality hazard with age is referred to as "demographic aging". We have previously shown H. glaber to achieve its exceptional longevity through defiance of this trend, exhibiting near constant mortality hazard across the full spectrum of observed lifespans, with no hazard increase evident even many-fold beyond their expected MLSP. For naked mole-rats, the lack of demographic aging is accompanied by seemingly-indefinite maintenance of many physiological characteristics that typically change with age. Naked mole-rats are resistant to age-related diseases such as cancer, neurodegeneration, and cardiovascular disease and show signs of tissue regeneration and remodeling preventing the deterioration of age-associated physiological function.

Here, we re-visited the demographic analysis of our naked mole-rat collection, with husbandry data now extended by five years across an expanded set of animals. We found our original conclusions of naked mole-rat mortality hazard being age-independent to be reproduced, using either the total sum of all historical data or only those data collected after our previous study - the latter qualifying as a replication study.

Link: https://doi.org/10.1101/2023.03.27.534424

Verifying the ages of those who claim to be extremely old is rarely as easy might be the case. Many parts of the world are lacking any sort of suitable records infrastructure dating back far enough to help. Particularly past the age of 110, the small number of verified individuals makes any attempt to learn from epidemiological data quite difficult. This in today's open access paper, researchers here report on the construction of epigenetic clocks using data from the oldest living people, with the hope of producing a tool that can help to verify claims of exceptional old age, and thus expand the databases.

While this is certainly interesting science, and will hopefully solve a logistical problem for other scientists, it is far from clear the study of survival to extreme old age will actually teach us anything useful. Long-lived individual share their gene variants and biochemistry with countless others who didn't make it. If a given variant gene doubles the ~1% chance of living to 100 for someone born a century ago, then you will see a lot of centenarians with that variant, but their survival is still overwhelmingly a matter of luck in the random distribution of life expectancy. Further, centenarians are not in good shape, and supercentenarians even less so, with a ~50% yearly mortality rate and greatly diminished physical capabilities. This is not the outcome that we should be seeking to emulate in later life.

Centenarian clocks: epigenetic clocks for validating claims of exceptional longevity

Clouding this debate over limits to human lifespan is poor record keeping in the early twentieth century, and extreme age claims made for secondary gain. Norris McWhirter of the Guinness Book of World Records, wrote, "No single subject is more obscured by vanity, deceit, falsehood, and deliberate fraud than the extremes of human longevity". Mistakes in age claims can also arise due to dementia or confabulations. The maximum life span of humans is currently determined by Jeanne Calment, documented to have lived for 122 years. Controversy still exists over Jeanne Calment's age despite verified documentation. Although a sample of her blood is stored and analyses might help resolve the controversy, to date, it has not been allowed due to ethical constraints surrounding the informed consent signed at the time of sample donation. Even with proper documentation, Jeanne Calment's age is doubted because documentation alone can be falsified or misattributed to an heir as some have suggested

Highly accurate age estimators can be built based on DNA methylation levels. The high accuracy of epigenetic clocks has been replicated numerous times and would be one way to verify the age of individuals too old to have been counted accurately by nascent census methods. However, most current epigenetic clocks underestimate the ages of older individuals (due to the well-known regression to the mean effect) and lead to relatively low age correlations in the oldest old.

Here, we present three DNA methylation-based age estimators (epigenetic clocks) for verifying age claims of centenarians. The three centenarian clocks were developed based on 7,039 blood and saliva samples from individuals older than 40, including 184 samples from centenarians, 122 samples from semi-supercentenarians (aged 105+), and 25 samples from supercentenarians (aged 110+). The oldest individual was 115 years old. Our most accurate centenarian clock resulted from applying a neural network model to a training set composed of individuals older than 40. An epigenome-wide association study of age in different age groups revealed that age effects in young individuals (younger than 40) are correlated (r = 0.55) with age effects in old individuals (older than 90).

We further present a chromatin state analysis of age effects in centenarians. Our chromatin state analysis reveals that mean methylation of PRC2 target sites continue to increase late in life while exhibiting increased variability. Similarly, the mean methylation levels of two negatively age-related chromatin states (EnhA1, TxEx4) do not exhibit any leveling off effect late in life. These results suggest that one will be able to build accurate centenarian clocks for people who live beyond 120 years. The centenarian clocks are expected to be useful for validating claims surrounding exceptional old age.

Low environmental temperature has been shown to modestly extend life, and there are a number of examples of similar species in which those dwelling in a colder environment exhibit a longer life span. Some thought has gone into identifying mechanisms responsible for this effect, but the effect size really isn't large enough for a great deal of interest to be devoted to the development of therapies based on these mechanisms. Similarly, there is some suggestion that lower body temperature might slow aging in warm blooded species. The work here notes one of the potential mechanisms linking environmental temperature with protein aggregation, a feature of aging. It is again a question as to whether effect sizes are large enough to be in any way interesting as a basis for further investigation.

Extreme low temperatures are detrimental, but a moderate decrease in body temperature can have beneficial effects for the organism. In fact, lowering body temperature extends longevity in both poikilotherms (for example Caenorhabditis elegans, Drosophila melanogaster, and distinct fish species) and homeotherms such as rodents. Aging is a primary risk factor for neurodegenerative disorders that involve protein aggregation. Because lowering body temperature is one of the most effective mechanisms to extend longevity in both poikilotherms and homeotherms, a better understanding of cold-induced changes can lead to converging modifiers of pathological protein aggregation.

Here, we find that cold temperature (15 °C) selectively induces the trypsin-like activity of the proteasome in Caenorhabditis elegans through PSME-3, the worm orthologue of human PA28γ/PSME3. This proteasome activator is required for cold-induced longevity and ameliorates age-related deficits in protein degradation. Moreover, cold-induced PA28γ/PSME-3 diminishes protein aggregation in C. elegans models of age-related diseases such as Huntington's and amyotrophic lateral sclerosis. Notably, exposure of human cells to moderate cold temperature (36 °C) also activates trypsin-like activity through PA28γ/PSME3, reducing disease-related protein aggregation and neurodegeneration. Together, our findings reveal a beneficial role of cold temperature that crosses evolutionary boundaries with potential implications for multi-disease prevention.

Link: https://doi.org/10.1038/s43587-023-00383-4

Excess visceral fat generates inflammatory signaling through a range of mechanisms, including DNA debris from stressed and dying fat cells that triggers innate immune sensors, and an additional burden of senescent cells producing the senescence-associated secretory phenotype (SASP). Chronic inflammatory signaling is disruptive to cell and tissue function throughout the body, and, as illustrated here, joints are no exception.

Osteoarthritis (OA) is a major cause of disability and globally the most common musculoskeletal health issue with more than 30% of those over 45 years of age having sought treatment. In recent attempts to develop new treatments for patients it is now emerging that the multifaceted clinical pathology of OA is underpinned by particular molecular endotypes defined by distinct molecular mechanisms and signaling pathways, which may overlap. In OA these include 'low repair', 'bone cartilage', 'metabolic' and 'inflammatory' endotypes.

In attempting to understand the drivers of these endotypes, it is notable that obesity is a major risk factor for the development of OA. Excessive mechanical loading of the joint is often cited as the cause of the association between obesity and OA. However, studies also find that obesity increases the risk of developing OA in the hands, a non-load bearing joint, illustrating that the association is not solely due to pathological loading on the articular cartilage but may also be due to the chronic inflammatory metabolic effects of obesity.

Hand, hip, knee, and foot joint synovial tissue was obtained from OA patients (n = 32) classified as obese (BMI over 30) or normal weight (BMI 18.5-24.9). Targeted proteomic, metabolic, and transcriptomic analysis found the inflammatory landscape of OA synovial fibroblasts are independently impacted by obesity, joint loading, and anatomical site with significant heterogeneity between obese and normal weight patients, confirmed by bulk RNAseq. Further investigation by single cell RNAseq identified four functional molecular endotypes including obesity specific subsets defined by an inflammatory endotype related to immune cell regulation, fibroblast activation, and inflammatory signaling.

These cell types draw similarity to fibroblast subsets reported in rheumatoid arthritis (RA), suggesting OA pathogenesis in obese patients may be akin to the more inflammatory RA joint. Obese OA specific clusters are involved in the activation and recruitment of immune cells, which are reminiscent of 'immune-effector fibroblasts' reported in RA known to regulate and recruit immune cells. In conclusion, these findings demonstrate the significance of obesity in changing the inflammatory landscape of synovial fibroblasts in both load bearing and non-load bearing joints.

Link: https://doi.org/10.1002/ctm2.1232

Researchers here report on evidence for CD4+ T cells to be important in keeping senescent cell numbers under control in later life, an interaction mediated by the presence of cytomegalovirus (CMV). CMV is a persistent viral infection that is near ubiquitous in the older population, and which coerces ever more of the immune system to become specialized to fight it, to the detriment of other functions.

We know that the number of senescent cells in tissues grows with age, slowly, and that the immune system appears to become less efficient at removing these cells, leading to an imbalance between creation and destruction. A lingering burden of senescent cells produces inflammatory, disruptive signaling that harms cell and tissue function, contributing to degenerative aging.

One point here is that while researchers show CD4+ T cells to be capable of destroying senescent cells, and a higher count of these cells correlating with lesser numbers of senescent cells, this is not a conclusive proof that CD4+ T cells are the ones undertaking most of the work. CD4+ T cell counts could well be a reflection of the health and capacity of other components of the immune system that are also attacking senescent cells.

Boosting the body's anti-viral immune response may eliminate aging cells

Researchers found more senescent cells in the old skin compared with young skin samples. However, in the samples from old individuals, the number of senescent cells did not increase as individuals got progressively older, suggesting that some type of mechanism kicks in to keep them in check. Experiments suggested that once a person becomes elderly, certain immune cells called killer CD4+ T cells are responsible for keeping senescent cells from increasing. Indeed, higher numbers of killer CD4+ T cells in tissue samples were associated with reduced numbers of senescent cells in old skin.

When they assessed how killer CD4+ T cells keep senescent cells in check, the researchers found that aging skin cells express a protein, or antigen, produced by human cytomegalovirus, a pervasive herpesvirus that establishes lifelong latent infection in most humans without any symptoms. By expressing this protein, senescent cells become targets for attack by killer CD4+ T cells. "Our research enables a new therapeutic approach to eliminate aging cells by boosting the anti-viral immune response. We are interested in utilizing the immune response to cytomegalovirus as a therapy to eliminate senescent cells in diseases like cancer, fibrosis, and degenerative diseases."

Cytotoxic CD4+ T cells eliminate senescent cells by targeting cytomegalovirus antigen

Senescent cell accumulation has been implicated in the pathogenesis of aging-associated diseases, including cancer. The mechanism that prevents the accumulation of senescent cells in aging human organs is unclear. Here, we demonstrate that a virus-immune axis controls the senescent fibroblast accumulation in the human skin. Senescent fibroblasts increased in old skin compared with young skin. However, they did not increase with advancing age in the elderly.

Increased CXCL9 and cytotoxic CD4+ T cells (CD4 CTLs) recruitment were significantly associated with reduced senescent fibroblasts in the old skin. Senescent fibroblasts expressed human leukocyte antigen class II (HLA-II) and human cytomegalovirus glycoprotein B (HCMV-gB), becoming direct CD4 CTL targets. Skin-resident CD4 CTLs eliminated HCMV-gB+ senescent fibroblasts in an HLA-II-dependent manner, and HCMV-gB activated CD4 CTLs from the human skin. Collectively, our findings demonstrate HCMV reactivation in senescent cells, which CD4 CTLs can directly eliminate through the recognition of the HCMV-gB antigen.

Immunotherapies offer great potential, but are not without side-effects as presently implemented. This is well demonstrated in the cancer field, where a chance of severe short-term, or even lasting immune-related issues is a risk that patients are willing to take given the alternatives on the table. Here, researchers suggest that the immunotherapies tested against Alzheimer's disease in clinical trials are producing an accelerated shrinkage of brain tissue, perhaps because of raised inflammation. In recent years, these immunotherapies have succeeded in clearing extracellular amyloid-β, but have not improved patient outcomes. Alzheimer's disease is complex, and it remains to be seen as to whether amyloid-β is truly important in the disease process, or whether it is a side-effect of the real disease processes. Immunotherapies will remain an important part of clinical development for neurodegenerative conditions, and so I'm sure it is concerning to many in this part of the field to see potential issues of this nature.

Researchers identified 31 published clinical trials of so-called antiamyloid Alzheimer's drugs. All aim to eliminate beta amyloid, whose buildup many consider a driver of the disease. The drugs fell into two categories. One, secretase inhibitors, are traditional small-molecule drugs that target an enzyme that produces beta amyloid from a larger protein. These compounds have largely been abandoned because they didn't pan out in trials. The second category included monoclonal antibodies like lecanemab that directly target various forms of beta amyloid. Another antiamyloid antibody in the analysis, aducanumab, was approved in 2021 amid much controversy, and still others are in trials. Sixteen of the 31 trials researchers analyzed involved these lab-generated immune proteins.

Alzheimer's disease frequently causes the brain to shrink as the illness progresses. But the researchers found both types of antiamyloid drugs generally caused clinical trial participants to lose more brain volume than what was seen in Alzheimer's patients on a placebo. Lecanemab and another antibody, donanemab, currently in late-stage trials, both accelerated whole brain volume loss. People in two large lecanemab trials on the highest drug dose recorded, on average, a 28% greater brain volume loss relative to placebo after about 18 months. This translated to a loss of an extra 5.2 milliliters (mL) in brain matter. The authors also reported that the antiamyloid antibodies - but not the secretase inhibitors - led to an increase in the size of brain ventricles, indicating they were filling with extra fluid. This can happen when nearby brain tissue atrophies. In people taking the now-approved dose of lecanemab, brain ventricle size increased by 36% more that it did in people on placebo - or an additional 1.9 mL.

Researchers then studied whether a type of brain swelling and bleeding called amyloid-related imaging abnormalities (ARIA), a well-documented side effect of the antibodies, was associated with the other brain changes. ARIA occurred in 21% of the 898 people taking lecanemab in a pivotal trial (as well as 9% on a placebo); most had no symptoms, but some did become severely ill and at least two died after extensive brain swelling and bleeding. Researchers found the experimental therapies with a higher rate of ARIA also generated a bigger average increase in the size of the ventricles. There's a logic behind this, though the connections haven't been proved. ARIA shows up on brain scans as inflammation, and generally, it's not controversial that neuroinflammation would lead to neurodegeneration.

Link: https://www.science.org/content/article/promising-alzheimer-s-therapy-and-related-drugs-shrink-brains

Olfactory clues can be added to the many items that influence the highly plastic life span of short-lived species. You might recall that flies respond to the scent of food in ways that accelerate aging, while here researchers show that female odors slow development and extend life in female mice by 8% to 9%, give or take. This mechanism is one of many reasons as why one should be skeptical of any life span study in mice that shows effect sizes of much less than 20%, and was conducted in anything less than a very rigorous, controlled manner, with a large number of mice. The life span of short lived species is just very sensitive to environmental circumstances, as well as interventions that stimulate the same metabolic responses.

Several previous lines of research have suggested, indirectly, that mouse lifespan is particularly susceptible to endocrine or nutritional signals in the first few weeks of life, as tested by manipulations of litter size, growth hormone levels, or mutations with effects specifically on early-life growth rate. The pace of early development in mice can also be influenced by exposure of nursing and weanling mice to olfactory cues. In particular, odors of same-sex adult mice can in some circumstances delay maturation. We hypothesized that olfactory information might also have a sex-specific effect on lifespan.

We show here that the lifespan of female mice can be increased significantly by odors from adult females administered transiently, that is from 3 days until 60 days of age. The presence of odors from adult females produced an 8% increase in median lifespan of female mice, compared to the control group, and a 9% increase in the age at 90th percentile. Female lifespan was not modified by male odors, nor was male lifespan susceptible to odors from adults of either sex. Conditional deletion of the G protein Gαo in the olfactory system, which leads to impaired accessory olfactory system function and blunted reproductive priming responses to male odors in females, did not modify the effect of female odors on female lifespan.

Our data provide support for the idea that very young mice are susceptible to influences that can have long-lasting effects on health maintenance in later life, and provide a potential example of lifespan extension by olfactory cues in mice.

Link: https://doi.org/10.7554/eLife.84060

Remaining life expectancy at 65 has increased by a year with every passing decade since at least the middle of the 20th century, an improvement that has occurred without deliberate targeting of the mechanisms of aging. To what degree is this observed trend in human life expectancy due to (a) a general slowing of aging that will carry on throughout the entire life span, and thus lengthen maximum observed life span, or (b) a more selective slowing of processes of aging that does not meaningfully impact lifespan-limiting mechanisms that operate in late life, and thus does not lengthen maximum life span?

For example, we know that supercentenarians (the tiny fraction of people who live to be age 110 and older) exhibit significant degrees of transthyretin amyloidosis, and this may be the majority cause of death in that age category. Much earlier in old age, this form of amyloidosis is present but probably not a major killer in comparison to other mechanisms of aging. It is entirely plausible that positive effects on life span resulting from past improvements in medical technology and changing lifestyle choices could have limited effects on this one specific issue, and thus would have a limited effect on maximum human lifespan.

Whether or not this is the case or is an open question, however. This is an interesting area of scientific inquiry, and today's open access paper is a worthy and novel addition to the literature regarding historical trends in life expectancy, but this work is of limited relevance to efforts to extend human life. We have a list of causative mechanisms of aging to target for repair, and a biotechnology community advanced enough to undertake that work. The best approach to the treatment of aging as a medical condition is to start fixing issues and see how it goes: clearance of senescent cells, for example, is performing exceptionally well in animal models, and will hopefully see greater progress into human use in the years ahead.

Mortality postponement and compression at older ages in human cohorts

A key but unresolved issue in the study of human mortality at older ages is whether mortality is being compressed (which implies that we may be approaching a maximum limit to the length of life) or postponed (which would imply that we are not). We summarize historical mortality data in 19 currently-industrialized countries by birth cohort using a variant of the Gompertz mortality law, and find that it fits cohort mortality data extremely well. Using this law, we identify the youngest age at which individuals in each cohort reach an assumed mortality plateau, which we call the Gompertzian Maximum Age (GMA). We find that over much of the period covered by our data, there was no increase in the GMA. Historical improvements in life expectancy were therefore largely the result of mortality compression. We demonstrate, however, that there have been episodes where the GMA increased. The presence of these episodes of mortality postponement suggests that the maximum length of a human life is not, in fact, fixed.

The first episode of mortality postponement that we identify occurred for cohorts born in the early part of the second half of the 19th century, and was more pronounced for females than for males. Over this period, the GMA increased by around 5 years. We can only speculate as to the causes of this increase, but as the first of these cohorts reached age 50 just after 1900 and the last reached age 100 in 1980, this may be related to a first wave of improvements in public health and medical technology. We identify a second, and much more significant, episode of mortality postponement, which is affecting cohorts born between 1910 and 1950 (so those currently aged between 70 and 110). We estimate that the GMA for these cohorts may increase by as much as 10 years, and remaining life expectancy at age 50 by as much as 8 years, depending on the country.

The timing of these episodes of mortality postponement explain why longevity records have been so slow to increase in recent years - cohorts old enough to have broken longevity records were too old to experience the current bout of postponement - and identifies significant potential for longevity records to rise by the year 2060 as younger cohorts, who did experience it, reach advanced old age. Our results on the division of changes in remaining life expectancy at age 50 across cohorts between compression and postponement are robust to our modelling choices. Likewise, our conclusion that longevity records will likely be broken in the coming decades is also robust to a wide range of possible assumptions. But our predictions of precisely by how much these records will rise, and when, depend on our modelling assumptions, in particular on the maximum mortality rate we assume.

We emphasise further that cohorts born before 1950 will only have the potential to break existing longevity records if policy choices continue to support the health and welfare of the elderly, and the political, environmental and economic environment remains stable. The emergence of Covid-19 and its outsize effect on the mortality of the elderly provides a salutary warning that none of this is certain. If, however, the GMA does increase as the current mortality experience of incomplete cohorts suggests is likely, the implications for human societies, national economies, and individual lives will be profound.

TDP-43 is one of the more recently discovered protein aggregates involved in neurodegenerative conditions. A few proteins in the body are capable of misfolding or otherwise becoming altered in ways that encourage other molecules of the same protein to do the same. Toxicity results, and it can spread as these altered proteins move from cell to cell. The condition most clearly associated with TDP-43 pathology is amyotrophic lateral sclerosis (ALS), but it appears to be involved in other forms of neurodegenerative disease as well. Researchers have made inroads into understanding how these aggregates form and disrupt normal cellular operations, but as yet little progress has been made towards development of a viable approach to therapy.

TAR DNA binding protein 43 kDa (TDP-43) plays an important role in several essential cell functions. However, TDP-43 dysfunction has been implicated in the development of various brain diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and limbic predominant age-related TDP-43 encephalopathy (LATE). Recent investigations into the individual components of TDP-43 pathology show how broader TDP-43 dysfunction may precede these disease end states, and therefore could help to explain why TDP-43 dysfunction continues to be implicated in a rapidly expanding category of neurodegenerative diseases.

TDP-43 pathology is usually characterized by insoluble, hyperphosphorylated and ubiquinated aggregates of TDP-43 in the cytoplasm, nucleus, and cell processes of neurons and glia. Mislocalization of TDP-43 within cellular compartments is also characteristic of the pathology. Normally TDP-43 is tightly auto-regulated and is almost entirely located in the nucleus. Consequently, depletion of TDP-43 in the nucleus, in association with abnormally high levels in the cytoplasm, is considered to be pathological. Indeed, TDP-43 mislocalization alone appears capable of causing mRNA instability, impaired gene regulation, mitochondrial dysfunction, impaired protein turnover, among other issues. However, the underlying causes of TDP-43 mislocalization and aggregation remain unclear.

The literature reviewed in this article suggests that dysregulation of TDP-43 initiated by some environmental and/or genetic insults can lead to a snowballing dysfunction across the cell, involving impaired gene expression, mRNA stability, as well as the function and coordination of those pathways directly regulated by TDP-43. Furthermore, the hallmarks of TDP-43 pathology, such as hyperphosphorylation and insoluble cytoplasmic accumulation of the protein may actually be artifacts of an upstream impairment in TDP-43's normal function.

Link: https://doi.org/10.3389/fnagi.2023.1142617

Centenarians exhibit some different immune systems characteristics when compared against the general population in earlier old age. Whether this offers any meaningful degree of protection is an open question. Even if these differences are protective, one should expect that biochemical characteristics that are found to a greater degree in centenarians will only slightly improve the small odds of living to be this old in the context of the medical technology and lifestyle choices of the last century. It doesn't take much of a change, say 1.25% survival odds rather than 1% survival odds, to see a lot more of that mechanism operating in the living population very old people, when compared to the population at large. That doesn't make the underlying mechanism a desirable basis for an enhancement therapy - it is achieving far too little to be worth the time and effort.

Using a multi-modal, single cell approach, we generated cell composition and transcriptional profiles from the peripheral blood mononuclear cells (PBMCs) of 7 centenarians using CITE-seq. We integrated this novel data set with publicly available single cell RNA-seq datasets of aging and longevity across the human lifespan to characterize cell type composition and gene expression profiles unique to centenarians. The peripheral blood immune cell repertoire of individuals is known to change with age. Previous transcriptional studies have shown decreases in lymphocytes and increases in myeloid cells with age, which we also observed in the peripheral blood of centenarians. However, in addition to these common changes across aging, our analysis identified patterns of immune cell profiles and compositional alterations that are unique to centenarians.

We observed expected shifts in the composition of centenarians' PBMCs from non-cytotoxic (e.g., naive CD4+ T cells and memory CD4+ T cells) to cytotoxic lymphocytes (e.g., cytotoxic CD4+ T cells) that have been observed previously in studies of human longevity. Similarly, the decrease of naive B cells with aging and longevity has also been reported previously. However, we also discovered novel compositional patterns of extreme old age including aging-related changes (e.g. a significant increase of CD14+ monocytes in older age that continues in the centenarian group), centenarian-specific changes (e.g. myeloid dendritic cells and plasmacytoid dendritic cells display no significant change among the three younger age groups but a unique, significant decrease occurs in extreme longevity), and aging-specific changes independent of extreme longevity (e.g. a significant increase of CD16+ monocytes in older age that then decreases in the centenarian age group).

The extent to which these unique patterns in centenarians are the drivers of extreme longevity or just the consequence of having reached an extreme old age remains an open question, since not everything we see in centenarians is necessarily important to reach extreme old ages. Additional data are needed to understand the effect of these patterns on human longevity. Overall, these findings display age-related changes in composition and transcription in both lymphocyte and myeloid cell types that collectively reflect immunocompetent profiles that may in part account for centenarians' ability to reach extreme ages.

Link: https://doi.org/10.1016/j.ebiom.2023.104514

Researchers consider that the state of late life health in humans, and the mechanisms involved, are a balance between risk of death by cancer and risk of death by loss of tissue function. Cancer risk is increased by the activity of damaged cells, particularly stem cells, in a dysfunctional tissue environment, while loss of tissue function is accelerated by suppressing that activity. Tissue must be maintained, such as via a supply of new cells to replace losses, and cells must be active in order for that maintenance to occur.

Cellular senescence is a part of this balance of benefit and harm. Cellular senescence is a cancer suppression mechanism, halting the replication of cells at risk of becoming cancerous, as well as attracting the attention of the immune system to the local area via inflammatory signaling. Too much cellular senescence, and a lasting burden of cellular senescence when senescent cells are not efficiently destroyed by the immune system, disrupts tissue function and accelerates degenerative aging via that very same inflammatory signaling, however.

The advent of senolytic therapies to selectively destroy senescent cells will allow us to have our cake and eat it. If senescent cells are only periodically removed by treatment, then the short-term benefit of cellular senescence in suppression of immediate cancer risk resulting from cell damage will be retained, while the long-term downside of lingering senescent cells will be eliminated.

Modeling of senescent cell dynamics predicts a late-life decrease in cancer incidence

Current oncogenic theories state that tumors arise from cell lineages that sequentially accumulate (epi)mutations, progressively turning healthy cells into carcinogenic ones. While those models found some empirical support, they are little predictive of intraspecies age-specific cancer incidence and of interspecies cancer prevalence. Notably, in humans and lab rodents, a deceleration (and sometimes decline) of cancer incidence rate has been found at old ages. Additionally, dominant theoretical models of oncogenesis predict that cancer risk should increase in large and/or long-lived species, which is not supported by empirical data.

Here, we explore the hypothesis that cellular senescence could explain those incongruent empirical patterns. More precisely, we hypothesize that there is a trade-off between dying of cancer versus dying of other ageing-related causes. This trade-off between organismal mortality components would be mediated, at the cellular scale, by the accumulation of senescent cells. In this framework, damaged cells can either undergo apoptosis or enter senescence. Apoptotic cells lead to compensatory proliferation, associated with an excess risk of cancer, whereas senescent cell accumulation leads to ageing-related mortality.

To test our framework, we build a deterministic model that first describes how cells get damaged, undergo apoptosis, or enter senescence. We then translate those cellular dynamics into a compound organismal survival metric also integrating life-history traits. We address four different questions linked to our framework: can cellular senescence be adaptive, do the predictions of our model reflect epidemiological patterns observed among mammal species, what is the effect of species sizes on those answers, and what happens when senescent cells are removed? Importantly, we find that cellular senescence can optimize lifetime reproductive success. Moreover, we find that life-history traits play an important role in shaping the cellular trade-offs.

Blood vessel density declines with age, alongside other detrimental changes in the microvasculature, such as small areas of tissue damage following microbleeds. All of this can be readily imaged in the retina, and retinal imaging is already in widespread use in clinical practices. Thus it is interesting to see progress towards an aging clock that uses this aspect of degenerative aging as a marker. A number of potential therapeutic strategies may meaningfully increase angiogenesis and thus microvascular density in later life, such as increased circulating VEGF via gene therapy, or use of existing FDA-approved CLCX12 agonists, all of which have yet to be robustly assessed as better or worse than the effects of, say, six months of a structured exercise program. A good, accessible way to measure results will hopefully speed up progress here.

The blood vessel-rich tissue in the retina, can be used to track human aging in an aging clock called eyeAge, in a way that is noninvasive, less expensive and more accurate than other aging clocks that are currently available. A growing body of evidence suggests that the microvasculature in the retina might be a reliable indicator of the overall health of the body's circulatory system and the brain. Changes in the eye accompany aging and many age-related diseases including age-related macular degeneration (AMD), diabetic retinopathy, and Parkinson's and Alzheimer's disease. Ophthalmologists can often detect early symptoms of AIDS, chronic high blood pressure and certain tumors in the eyes, a utility that is not surprising given that any subtle changes in the vascular system first appear in the smallest blood vessels, and capillaries in the retina are among the smallest in the body.

But subtle changes in these small blood vessels often go undetected by even the most sophisticated instruments, necessitating the use of deep learning, an effort spearheaded by Google Research. Researchers from Google and elsewhere developed models to predict diabetic retinopathy from retinal images and have gone on to use retinal images to identify at least 39 eye diseases including glaucoma, diabetic retinopathy, and AMD, as well as non-eye diseases such as chronic kidney disease and cardiovascular disease. Google researchers trained and tuned the model for eyeAge using their well-studied EyePACS data set which involves more than 100,00 patients and applied it to patients from the UK Biobank, which involved more than 64,000 patients.

"This type of imaging could be really valuable in tracking the efficacy of interventions aimed at slowing the aging process. The results suggest that potentially, in less than one year we should be able to determine the trajectory of aging with 71% accuracy by noting discernable changes in the eyes of those being treated, providing an actionable evaluation of geroprotective therapeutics. Our study emphasizes the value of longitudinal data for analyzing accurate aging trajectories. Through EyePACS longitudinal dataset involving multiple scans from individual people over time our results show a more accurate positive prediction ratio for two consecutive visits of individual rather than random, time-matched individuals."

Link: https://www.buckinstitute.org/news/retinal-scans-a-non-invasive-inexpensive-method-to-track-human-aging/

Researchers here discuss an interesting approach to transdifferentiation as a basis for therapy. In transdifferention, a cell of one type is reprogrammed to become another type directly, without passing through an intermediary stage of dedifferentiation to pluripotency. There has long been interest in directly converting scar tissue cells into heart muscle cells following a heart attack or similar injury, as animal studies have been promising. How do cells hold on to their state and resist a change of cell identity, however? If the mechanisms holding cell state firm can be identified and inhibited, then cells can be more readily changed into other cell types. That is demonstrated here in heart tissue, a novel approach to the challenge of enhancing regeneration in this normally poorly regenerative organ.

Defining the mechanisms safeguarding cell fate identity in differentiated cells is crucial to improve 1) our understanding of how differentiation is maintained in healthy tissues or altered in a disease state, and 2) our ability to use cell fate reprogramming for regenerative purposes. Here, using a genome-wide transcription factor screen followed by validation steps in a variety of reprogramming assays (cardiac, neural and iPSC in fibroblasts and endothelial cells), we identified a set of four transcription factors (ATF7IP, JUNB, SP7, and ZNF207, collective AJSZ) that robustly opposes cell fate reprogramming in both lineage and cell type independent manners.

Mechanistically, our approach revealed that AJSZ oppose cell fate reprogramming by 1) maintaining chromatin enriched for reprogramming transcription factor motifs in a closed state and 2) downregulating genes required for reprogramming. Finally, knockdown of AJSZ in combination with overexpression of cardiac reprogramming factors Mef2c, Gata4, and Tbx5, collectively MGT, significantly reduced scar size and improved heart function by 50%, by reprogramming fibroblasts into cardiomyocytes, as compared to MGT alone post-myocardial infarction.

Collectively, our study suggests that inhibition of barrier to reprogramming mechanisms represents a promising therapeutic avenue to improve adult organ function post-injury.

Link: https://doi.org/10.1038/s41467-023-37256-8

The hypothesis that aging is a genetic program that is to some degree selected has always been a vocal minority view in the research community. There are just as many quite diverse theories of programmed aging as there are more mainstream evolutionary theories of aging that orbit the concept of antagonistic pleiotropy, the idea that lesser selection pressure in late life, because early reproduction means greater evolutionary fitness, allows for the evolution of mechanisms that are beneficial in youth and harmful in late life. There is even a fusion of the two sides: the hyperfunction theory of programmed aging suggests that aging is a consequence of developmental processes that fail to shut down.

One modern way of framing programmed aging is to consider the operations of cellular biochemistry derived from the genome as analogous to computer software, and aging the consequence of flaws in that software. If such software was evolved rather than designed, as some software is these days. That said, it is important to note that calling, say, the ability of a biological system to accumulate a specific form of damage and dysfunction a flaw (or a bug, or some other appropriate term for software that isn't behaving as desired) says nothing of how hard it might be to produce a better version that lacks this flaw.

It seems self-evident that at some point in the future our not entirely biological descendants, possessing some system for specifying the seed of an individual that is derived from or incorporating DNA, will be engineered to be functionally immortal. Immortal lower animals exist, such as the hydra that is essentially a steady state embryo, an ambulatory bundle of stem cells. Reconciling (a) the necessary mechanisms of constant growth, repair, and replacement to sustain an organism indefinitely with (b) the need for a central nervous system that maintains memory and state over time seems a challenging project, to say the least, however. At present it would be a major undertaking to alter one gene in the human genome while having any confidence that the outcomes are fully understood, let alone producing an entirely new functionally immortal higher species.

Thus for now it seems that the best approach to aging is based on repair. Don't try to alter the biochemistry that we have; accept its flaws, and attempt to repair the well-known forms of damage that accumulate with age as a result of those flaws. Comparatively little effort has so far been put towards building therapies capable of damage repair, while the specific desired forms of repair are quite well understood, that pursuing repair seems a much better use of time than building incremental first steps towards a distant future of an engineered, ageless genome.

Ageing as a software design flaw

Many theories of why we age have been proposed, including damaged-based and programmatic theories, with the former currently more widely accepted and studied. Most damage-based theories postulate that inefficient repair mechanisms result in singular or multiple, and often interacting, forms of damage accumulation. Although damage can be broadly defined as any change that affects function, here I refer more specifically to molecular damage hypothesized to drive ageing, such as by-products of metabolism, unwanted chemical modifications, and other types of molecular damage affecting crucial cellular components like the genome, telomeres, mitochondria, and proteins. By contrast, programmatic theories argue that ageing results from predetermined mechanisms encoded in the genome, rather than stochastic damage accumulation.

The concept of information in biology has a long history, and biological systems can be seen as highly complex information systems. Likewise, the idea that ageing could be linked to information decay or loss has been proposed, in particular in the context of the information theory of ageing. According to this theory, loss of genetic or epigenetic information with age, driven by DNA damage, is the primary cause of ageing. One hypothesis is that errors accrue in the DNA, corrupting the information in the genome and ultimately disrupting tissue homeostasis and causing ageing. More broadly, the idea that errors or damage to one or more biological types of hardware, including the DNA, accumulate and drive the process of ageing has been prevalent for decades. By hardware I encompass all elements of biological systems, including organs, tissues and the basic unit of life, the cell, and its structures (mitochondria, telomeres, proteins, DNA, and so on), most of which have at some point been hypothesized to be important in ageing.

What if, however, the processes that cause ageing are not a product of inevitable molecular damage but rather intrinsic features of the software? In this context, I define software as the genetic program, the DNA code that orchestrates how a single cell becomes an adult human being capable of reproducing, ultimately our evolutionary purpose. Herein, I present and explore the hypothesis that perhaps ageing is not a result of inevitable wear and tear or accumulated molecular damage in the hardware but rather that ageing is caused by design flaws in the software itself. I discuss manipulations of ageing and how they support this hypothesis, acknowledge exceptions, and lastly, propose areas of future study.

Researchers here discuss some of the details involved in present efforts to adjust the behavior of inflammatory microglia in the aging brain. Microglia are innate immune cells of the central nervous system, analogous to macrophages elsewhere in the body. A sizable body of evidence implicates the ever more inflammatory activities of microglia in the onset and progression of neurodegenerative conditions. Innate immune cells react in this way to molecular signs of damage and cell stress produced by other aspects of aging, but when a state of inflammatory signaling persists for the long-term, it becomes harmful in and of itself, altering cell behavior for the worse throughout tissue, and producing dysfunction.

As individuals age, microglia, the resident immune cells of the central nervous system (CNS), become less effective at preserving brain circuits. Increases in microglial inflammatory activity are thought to contribute to age-related declines in cognitive functions and to transitions toward mild cognitive impairment (MCI) and Alzheimer's disease (AD). As microglia possess receptors for communicating with the CNS environment, pharmacological therapies targeting these pathways hold potential for promoting homeostatic microglial functions within the aging CNS.

Preclinical and early phase clinical trials investigating the therapeutic effects of pharmacological agents acting on microglia, including reactive oxygen species, TREM2, fractalkine signaling, the complement cascade, and the NLRP3 inflammasome, are currently underway; however, important questions remain unanswered. Current challenges include target selectivity, as many of the signaling pathways are expressed in other cell types. Furthermore, microglia are a heterogenous cell population with transcriptomic, proteomic, and microscopy studies revealing distinct microglial states, whose activities and abundance shift across the lifespan. For example, homeostatic microglia can transform into pathological states characterized by markers of oxidative stress.

Selective pharmacological targeting aimed at limiting transitions to pathological states or promoting homeostatic or protective states, could help to avoid potentially harmful off-target effects on beneficial states or other cell types. In this mini-review we cover current microglial pathways of interest for the prevention and treatment of age-related cognitive decline and CNS disorders of aging focusing on MCI and AD. We also discuss the heterogeneity of microglia described in these conditions and how pharmacological agents could target specific microglial states.

Link: https://doi.org/10.3389/fphar.2023.1125982

Most cancers would become manageable if metastasis could be eliminated. A robust way to fully suppress metastasis across all forms of cancer would not be a cure in and of itself, but it would greatly reduce mortality and allow cancers to be managed or eliminated more readily, and with less trauma for the patient. On the way to a hypothetical end to metastasis, researchers are making inroads towards approaches that may at least reduce metastasis to some degree. These approaches often, as here, involve ways to enlist the immune system to more aggressively target and destroy metastatic cells before they can build a new tumor.

Even when a primary tumor is successfully treated, cells that have broken away from the tumor often linger in the body in a dormant state that allows them to evade detection by the immune system for years at a time. Then, after the dormant cells have developed new traits to help them survive, they can wake up and start their runaway growth again. "These tumor cells are not in a supportive environment at the beginning. So they have to adapt and develop their own self-supporting niche until they're ready, eventually, to wake up and start a fast-growing metastasis. The interaction with the person's immune system is very important to this process."

Using mouse models of early-stage metastasis from lung cancer, the research team conducted a genetic screen to look at the activity of genes in the tumor cells that are important for interactions with the host's immune system. That's how they identified the STING pathway - an acronym for stimulator of interferon genes - as a suppressor of metastatic outbreaks. Importantly, the researchers found that STING expression changes across different stages of metastasis. In the dormant stage, STING activity is low - and the dormant cells excel at hiding out from immune defenders. Moving out of the dormant stage and into an awakened, proliferative stage, the metastatic cells start to have increased STING activity. This makes them more vulnerable to attack by the immune system. But cells that survive this bottleneck to generate larger clusters, called macrometastastes, again show reduced STING levels, which makes them more resistant to the immune system.

Using STING activators in conjunction with that window of increased STING activity in the reawakened cancer cells could be an opportunity to help the body's immune defenders destroy them. Indeed, when scientists artificially increased STING signaling in those aggressive metastatic cells, they attracted more immune defenders like natural killer cells and T cells, which swooped in to kill them off. And when the scientists activated STING in mice lacking key immune cells, metastasis still developed - pointing to a critical role for STING in recruiting the immune cells to attack the cancer cells.

Link: https://www.mskcc.org/news/msk-scientists-identify-potential-new-strategy-against-metastasis

Most of the research relevant to the question of whether localized clearance of senescent cells can effectively treat age-related conditions has taken place in the context of osteoarthritis. While adding senescent cells to a joint is sufficient to provoke the onset of osteoarthritis, clearing senescent cells from only the joint region is not sufficient to produce significant patient benefits. The present consensus is that the senescent cells present in the rest of the body are producing a significant contribution by their signaling: those cells may be more distant, and their contributions thus more dilute, but there are a lot more of them.

UNITY Biotechnologies chose to pursue localized administration of senolytics in their initial phase 1 and phase 2 trials for both knee osteoarthritis and macular degeneration. Adopting a localized injection strategy is a time-worn approach intended to make things easier with regulators, as the much lower, localized dose means that there is a greatly reduced risk of side-effects. Unfortunately for UNITY investors, the outcome has been a demonstration, first in the knee, and now in the eye, that localized removal of senescent cells produces some benefit, but not as much as hoped, and not enough to show a clear advantage in human trials.

The conclusion adopted by the rest of the industry is that systemic, whole-body clearance of senescent cells is required to remove enough of the harmful effect of the senescence-associated secretory phenotype (SASP) on tissue function to produce meaningful gains for patients.

UNITY Shares Nearly Halved after Lead Asset Fails to Match Regeneron's Eylea

UNITY Biotechnology's lead asset, UBX1325, failed to show non-inferiority to Regeneron's anti-VEGF drug aflibercept in a Phase II wet age-related macular degeneration (wAMD) trial. This sent the biotech's shares tumbling 46% in premarket trading on Monday. The 24-week data are from the Part A portion of the proof-of-concept Envision study of UBX1325, a Bcl-xL inhibitor. The trial involved 51 patients with wAMD who received either two 10 mcg doses of UBX1325 at week zero and week four or anti-VEGF agent aflibercept 2 mg every eight weeks.

The trial used the Early Treatment Diabetic Retinopathy Study (ETDRS) to assess the therapies, which revealed an early and unexpected visual gain of 3.5 ETDRS letters with aflibercept, according to Unity. The 3.5-letter gain with aflibercept was mostly maintained for the study's duration. UBX1325 monotherapy, meanwhile, reduced letters by 0.8 from baseline.

Patients were already receiving aflibercept when they enrolled in the trial, but benefit from the therapy was not optimal, according to the press release. More than half (52%) of patients who received UBX1325 did not require anti-VEGF treatment throughout the 24 weeks of the trial, UNITY reported.

UNITY Biotechnology Announces Results from Phase 2 ENVISION Study of UBX1325 in Patients with Wet Age-Related Macular Degeneration

UNITY Biotechnology, Inc. ("UNITY"), a biotechnology company developing therapeutics to slow, halt, or reverse diseases of aging, today announced results from Part A of the Phase 2 ENVISION study of UBX1325 in patients with wet age-related macular degeneration (AMD) who were not achieving optimum benefit with their ongoing anti-VEGF therapy. UBX1325 treatment generally maintained visual acuity for 6 months (change of -0.8 ETDRS letters from baseline), with a majority of patients not requiring any anti-VEGF rescue. Patients in the every 8-week aflibercept arm had an early and unexpected gain of 3.5 letters at week 2 which was mostly maintained for the duration of the study. As a result of the strength on the control arm, the study did not meet the non-inferiority threshold compared to aflibercept through 24 weeks.

"Maintenance of visual acuity in hard-to-treat patients with active disease after withdrawal of their anti-VEGF therapy suggests that UBX1325 had an active treatment effect in wet AMD. We continue to be impressed with the durability of effect of UBX1325 in this patient population. Following a full analysis of ENVISION results, we will assess and optimize our resource allocation for future development of UBX1325. In the weeks ahead we will provide an update on Part B of the ENVISION study, and importantly, share 48-week data from the Phase 2 BEHOLD DME study. In DME, UBX1325 showed strong evidence of biologic activity and improvement in visual acuity - and, as a result, we plan to initiate a Phase 2b study in the second half of this year."

While rising numbers of senescent cells in the brain, particularly microglia, are thought to contribute to age-related neurodegeneration, researchers here report on data that strongly suggests senescent cells in the rest of the body collectively produce a larger harmful effect. Two senolytic treatments, one that can readily access the brain, and one that cannot, produce quite similar outcomes in an animal study of neurodegeneration. We might add this data to other indications that senescent cell pro-inflammatory signaling is a body-wide phenomenon, and thus removing senescent cells locally will likely be insufficient to help patients.

We examine similar and differential effects of two senolytic treatments, ABT-263 and dasatinib + quercetin (D + Q), in preserving cognition, markers of peripheral senescence, and markers of brain aging thought to underlie cognitive decline. Male F344 rats were treated from 12 to 18 months of age with D + Q, ABT-263, or vehicle, and were compared to young (6 months). Both senolytic treatments rescued memory, preserved the blood-brain barrier (BBB) integrity, and prevented the age-related decline in hippocampal N-methyl-D-aspartate receptor (NMDAR) function associated with impaired cognition.

Compared to older controls, senolytic treatments decreased transcription of dentate gyrus genes linked to oxidative stress and immune response, and increased the expression of synaptic genes. However, D + Q had a greater effect on brain transcription categories associated with cellular senescence, decreasing expression of genes linked to apoptosis, regulation of apoptosis, and microglial activation that were not significant for ABT-263 treatment. Dissimilarities associated with brain transcription indicate divergence in central mechanisms, possibly due to differential brain access. Previous work indicates that dasatinib enters the central nervous system to clear senescent cells. In contrast, ABT-263 does not cross the BBB, which may explain differential effects.

Link: https://doi.org/10.1111/acel.13817

Every cell contains hundreds of mitochondria, each with its own genome, mitochondrial DNA separate from that of the cell nucleus. The primary role of mitochondria is to generate chemical energy store molecules, adenosine triphosphate (ATP), used to power cell activities. Mitochondrial dysfunction with aging isn't just a loss of ATP generation and production of a harmful amount of reactive oxygen species, however. It can also be connected with chronic inflammation, as mislocalization of mitochondrial DNA can trigger sensors of the innate immune system to provide inflammatory signaling. Mitochondria are the descendants of ancient symbiotic bacteria, and there is a certain degree of overlap in the evolved mechanisms that detect the presence of bacteria and those that detect cellular damage and dysfunction. This is all the more reason for a greater focus on the development of ways to reverse the mitochondrial dysfunction observed in older individuals.

In addition to constituting the genetic material of an organism, DNA is a tracer for the recognition of foreign pathogens and a trigger of the innate immune system. cGAS functions as a sensor of double-stranded DNA fragments and initiates an immune response via the adaptor protein STING. The cGAS-STING pathway not only defends cells against various DNA-containing pathogens but also modulates many pathological processes caused by the immune response to the ectopic localization of self-DNA, such as cytosolic mitochondrial DNA (mtDNA) and extranuclear chromatin.

In addition, macrophages can cause inflammation by forming a class of protein complexes called inflammasomes, and the activation of the NLRP3 inflammasome requires the release of oxidized mtDNA. In innate immunity related to inflammasomes, mtDNA release is mediated by macropores that are formed on the outer membrane of mitochondria via VDAC oligomerization. These macropores are specifically formed in response to mitochondrial stress and tissue damage, and the inhibition of VDAC oligomerization mitigates this inflammatory response. The rapidly expanding area of research on the mechanisms by which mtDNA is released and triggers inflammation has revealed new treatment strategies not only for inflammation but also, surprisingly, for neurodegenerative diseases such as amyotrophic lateral sclerosis.

Link: https://doi.org/10.1038/s12276-023-00965-7

I've posted in the past on a two year followup of a single-person self-experiment, a successful attempt to favorably adjust the balance of populations in the aging gut microbiome via a single treatment with flagellin immunization. This approach was intended to motivate the immune system into more aggressively destroying problematic microbes that tend to grow in number with age. As assessed using the Viome service, the intervention appeared to produce a sizable, lasting benefit to the quality of the gut microbiome in a basically healthy 50-ish individual. You can look back at those posts for the details of the protocol and further references regarding this use of flagellin.

As is the case for flagellin immunization, there is animal data to show that fecal microbiota transplantation from a young individual to an old individual rejuvenates the gut microbiome. There is a lot more of this animal data for fecal microbiota transplant, however, produced in varied species, and demonstrating that the improvement lasts for a lengthy period of time, and even results in improved health and extended life span.

Thus the same 50-ish individual mentioned above later undertook a fecal microbiota transplant, using donor material provided by a healthy, athletic 20-year-old volunteer, and further assessed the effects of this intervention on the gut microbiome. Stool samples were tested beforehand, one month afterwards, and six months afterwards. All of the measurements were again made using the Viome service. In the charts below, marks indicate that the flagellin immunization was conducted in 05/2020, and fecal microbiota transplant at the end of 08/2022. The dates marked on the horizontal axis are the dates of Viome testing.

In summary, while the flagellin intervention greatly reduced microbial diversity in the process of greatly improving other metrics, that diversity was restored by fecal microbiota transplant from a young individual. That restoration appears lasting as of the six month mark. The transplant produced small gains in some of the other metrics assessed by Viome, though not to the same degree as the flagellin immunization. That may well be because much of the potential scope for improvement was already achieved. Interestingly, neither intervention did much for Metabolic Fitness. According to Viome, half of the population falls into the 22-28 range for Metabolic Fitness (on a scale of 0 to 100!) which makes one wonder a little regarding the algorithm used in the construction of this value.

The protocol for conducting a fecal microbiota transplant at home is almost too simple to talk about, but there are a few points that are worthy of thought. The mechanics of it are straightforward. A fresh stool sample is provided by the donor, and that material is mixed with water. A few fluid ounces of the result are delivered as an enema. The recipient then lies in a suitably sloped position, abdomen higher than chest, for 30 minutes or so, in order to encourage the enema fluid to flow as deeply as possible into the intestine. Repeat this process for two to three times a few days to a week apart.

As to the points worth of thought: when fecal microbiota transplantation is conducted in the clinic as a treatment for C. difficile infection, colonic cleansing and colonoscopy equipment may be used, but more importantly, donor stool samples are screened for potentially pathogenic microbes that an older individual may respond poorly to. This screening is wise for an older recipient, as the aged immune system is far less competent than a young immune system, and that is an important factor when it comes to suppressing undesirable microbial species in the gut. What is innocuous to a young person may be much less innocuous to an old person. Rather than going through the process of finding a willing, healthy volunteer, and rolling the dice on potential issues, one can use services that will sell screened and characterized stool samples from young individuals, such as Human Microbes. This is recommended.

Senescent cells accumulate with age throughout the body, and evidence is increasingly supportive of a role for cellular senescence in the development of Alzheimer's disease. This is particularly the case for senescent supporting cells in the brain, such as microglia and astrocytes, but the inflammatory signaling produced by senescent cells elsewhere in the body may well be just as influential on dysfunction in brain tissue. Given the capacity to clear senescent cells, and at least one recently launched trial of senolytic therapies to clear senescent cells in Alzheimer's patients, we should see some progress in the years ahead, towards a better understanding of the relevance of cellular senescence to age-related neurodegeneration.

Alzheimer's disease (AD) predominantly occurs as a late onset (LOAD) form involving neurodegeneration and cognitive decline with progressive memory loss. Risk factors that include aging promote accumulation of AD pathologies, such as amyloid-beta and tau aggregates, as well as inflammation and oxidative stress. Homeostatic glial cell states regulate and suppress pathology buildup; inflammatory states exacerbate pathology by releasing pro-inflammatory cytokines. Multiple stresses likely induce glial senescence, which could decrease supportive functions and reinforce inflammation.

In this perspective, we hypothesize that aging first drives AD pathology burden, whereafter AD pathology putatively induces glial senescence in LOAD. We hypothesize that increasing glial senescence, particularly local senescent microglia accumulation, sustains and drives perpetuating buildup and spread of AD pathologies, glial aging, and further senescence. We predict that increasing glial senescence, particularly local senescent microglia accumulation, also transitions individuals from healthy cognition into mild cognitive impairment and LOAD diagnosis. These pathophysiological underpinnings may centrally contribute to LOAD onset, but require further mechanistic investigation.

Link: https://doi.org/10.1038/s41467-023-37304-3

Researchers here describe a mechanism that appears to reduce DNA repair efficiency, and which can be suppressed to improve DNA repair. This is interesting, to say the least. It might be a path to determining just how much of a contribution to the pace of aging is produced by efficiency of DNA repair. The interaction between this and the finding that repeated cycles of double strand break repair induce epigenetic changes characteristic of aging is also an intriguing question. Mammalian studies sooner rather than later are called for.

The DNA-repair capacity in somatic cells is limited compared with that in germ cells. It has remained unknown whether not only lesion-type-specific, but overall repair capacities could be improved. Here we show that the DREAM repressor complex, formed by the Dp/Retinoblastoma(Rb)-like/E2F and the MuvB subcomplexes, curbs the DNA-repair capacities in somatic tissues of Caenorhabditis elegans. Mutations in the DREAM complex induce germline-like expression patterns of multiple mechanisms of DNA repair.

Consequently, DREAM mutants confer resistance to a wide range of DNA-damage types during development and aging. Similarly, inhibition of the DREAM complex in human cells boosts DNA-repair gene expression and resistance to distinct DNA-damage types. DREAM inhibition leads to decreased DNA damage and prevents photoreceptor loss in progeroid Ercc1-/- mice. We show that the DREAM complex transcriptionally represses essentially all DNA-repair systems and thus operates as a highly conserved master regulator of the somatic limitation of DNA-repair capacities.

Link: https://doi.org/10.1038/s41594-023-00942-8