Fight Aging!

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Contents

• A Role for Cellular Senescence in Medin Amyloidoisis
• Impaired Melanocyte Stem Cell Migration Implicated in Hair Graying
• More Age-Related Conditions, Greater Risk of Frailty
• Plasma Transfer Lowers Epigenetic Age and Mortality in Rats
• Nobody is Counting on the Near Term Emergence of a Regulatory Path to Approval for Therapies to Treat Aging
• Extrachromosomal Circular DNA Implicated in Early Development of Cancer
• Low Thymic Function Correlates with a Twofold Risk of Mortality in Old People
• Netrin-1 Upregulation Restores Bone Marrow Niche Cells to Rejuvenate Aspects of Hematopoiesis
• Cellular Senescence in Aging Skin
• KDM5C Inhibition Reduces Osteoclast Activity, Increasing Bone Density
• Towards Electromagnetic Guidance of Cells in Wound Healing
• Quantifying the Effects of Exercise on a Transcriptomic Aging Clock
• Exercise and Alternative Mechanisms of Telomerase
• Current Aging Clocks are Arguably Too Sensitive to Transient Stresses
• Targeting an Imbalance of Inflammatory Factors Induces Regeneration in Osteoarthritic Joints

A Role for Cellular Senescence in Medin Amyloidoisis
https://www.fightaging.org/archives/2023/04/a-role-for-cellular-senescence-in-medin-amyloidoisis/

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.

Impaired Melanocyte Stem Cell Migration Implicated in Hair Graying
https://www.fightaging.org/archives/2023/04/impaired-melanocyte-stem-cell-migration-implicated-in-hair-graying/

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.

More Age-Related Conditions, Greater Risk of Frailty
https://www.fightaging.org/archives/2023/04/more-age-related-conditions-greater-risk-of-frailty/

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.

Plasma Transfer Lowers Epigenetic Age and Mortality in Rats
https://www.fightaging.org/archives/2023/04/plasma-transfer-lowers-epigenetic-age-and-mortality-in-rats/

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 has 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.

Nobody is Counting on the Near Term Emergence of a Regulatory Path to Approval for Therapies to Treat Aging
https://www.fightaging.org/archives/2023/04/nobody-is-counting-on-the-near-term-emergence-of-a-regulatory-path-to-approval-for-therapies-to-treat-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 permitted 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."

Extrachromosomal Circular DNA Implicated in Early Development of Cancer
https://www.fightaging.org/archives/2023/04/extrachromosomal-circular-dna-implicated-in-early-development-of-cancer/

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.

Low Thymic Function Correlates with a Twofold Risk of Mortality in Old People
https://www.fightaging.org/archives/2023/04/low-thymic-function-correlates-with-a-twofold-risk-of-mortality-in-old-people/

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.

Netrin-1 Upregulation Restores Bone Marrow Niche Cells to Rejuvenate Aspects of Hematopoiesis
https://www.fightaging.org/archives/2023/04/netrin-1-upregulation-restores-bone-marow-niche-cells-to-rejuvenate-aspects-of-hematopoiesis/

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.

Cellular Senescence in Aging Skin
https://www.fightaging.org/archives/2023/04/cellular-senescence-in-aging-skin/

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.

KDM5C Inhibition Reduces Osteoclast Activity, Increasing Bone Density
https://www.fightaging.org/archives/2023/04/kdm5c-inhibition-reduces-osteoclast-activity-increasing-bone-density/

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."

Towards Electromagnetic Guidance of Cells in Wound Healing
https://www.fightaging.org/archives/2023/04/towards-electromagnetic-guidance-of-cells-in-wound-healing/

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."

Quantifying the Effects of Exercise on a Transcriptomic Aging Clock
https://www.fightaging.org/archives/2023/04/quantifying-the-effects-of-exercise-on-a-transcriptomic-aging-clock/

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.

Exercise and Alternative Mechanisms of Telomerase
https://www.fightaging.org/archives/2023/04/exercise-and-alternative-mechanisms-of-telomerase/

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.

Current Aging Clocks are Arguably Too Sensitive to Transient Stresses
https://www.fightaging.org/archives/2023/04/current-aging-clocks-are-arguably-too-sensitive-to-transient-stresses/

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.

Targeting an Imbalance of Inflammatory Factors Induces Regeneration in Osteoarthritic Joints
https://www.fightaging.org/archives/2023/04/targeting-an-imbalance-of-inflammatory-factors-induces-regeneration-in-osteoarthritic-joints/

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.