Fight Aging!

Intermittent mild hypoxia has been shown to slow aging and improve health in animal studies, and is used in medicine in some contexts. It is a form of stress and encourages a hormetic response from cells that on balance improves health. Long term hypoxia or severe hypoxia tips over into outright harm, overwhelming any beneficial mechanisms that attempt to compensate. Human data suggests that high altitude living, at the point where mild hypoxia is induced by the lower oxygen content of the air, results in accelerated aging. For example, researchers have shown that these populations exhibit accelerated immune aging. These populations are not yet large enough or well studied enough to go much beyond this sort of investigation of a few aspects of their physiology. Epidemiology for more solid evidence of accelerated aging is lacking, for example, and much of the existing data on mortality and age-related disease could be explained by comparative poverty rather than any sort of comprehensive acceleration of aging.

Recall that epigenetic age is usually assessed from a blood sample, and the only cells in a blood sample with nuclei and nuclear DNA are immune cells. Thus epigenetic age assays are really a measure of immune aging rather than systemic aging. To the degree that those two correlate, this is fine. But they are not the same thing, and the immune system is subject to pressures and mechanisms not relevant to other cell types in other tissues. Thus epigenetic age in those other cell types and tissues is more interesting in a research context.

Today's open access paper provides more evidence for intermittent hypoxia to accelerate epigenetic age, though the question remains as to whether aging is a good description for is actually occurring inside cells, meaning a shift in nuclear DNA structure in response to low oxygen levels. In mice, the researchers looked at a few different tissues, and found that epigenetic age acceleration only occurred in old mice, and went away when hypoxia treatment was halted. The researchers also note human data from the AltitudeOmics study, which involved blood samples rather than tissue samples, and so measured immune aging rather than tissue aging.

Intermittent hypoxia induces reversible epigenetic age acceleration in old mice

Epigenetic mechanisms are considered adaptive regulators of gene expression, yet mechanisms driving aging-associated DNA methylation remain unclear. Prior work hinted that epigenetic aging might reflect a response to oxygen availability, with age-differential methylation in immune cells enriched near binding sites for hypoxia-responsive factors ARNT and REST. To test this hypothesis, we exposed adult (11 months) and old (23 months) mice to 1 month of intermittent hypoxia (IH) followed by normoxic recovery.

IH induced epigenetic age acceleration in lungs, spleen, and heart in old mice only. This acceleration reversed upon return to normoxia. Reversible shifts were enriched at bivalent domains and PRC2 targets, indicating oxygen-sensitive chromatin remodeling.

Human translational validation from the AltitudeOmics project in which 19 young adults underwent baseline testing near sea level then again after rapid ascent to 5260m confirmed rapid, conserved epigenetic aging. Our findings establish oxygen availability as a primary, conserved modulator of epigenetic aging across tissues and species, showing that oxygen fluctuations are a potent, reversible driver of epigenetic aging.

Sadly, we live in an age in which the media likes to generate conflict, and in which the role of personal responsibility in most aspects of life (and certainly in the matter of medicine) is denigrated. It is a culture that rejects risks, costs, and benefits that cannot be quantified easily, and demands a centralized, legalistic approach as to who is and is not permitted to take those risks. On the other side of the fence, those taking the risk of trying new therapies that are not fully understood are in all too many cases doing it without sufficient forethought and planning. Too many people take wishful thinking and popularist rhetoric as fact. They don't want to understand the details, and look for quick, certain answers where quick, certain answers doesn't exist. This is not a great environment in which to try to promote a responsible attitude to medical self-experimentation and risk, such that self-experimentation is encouraged as a way to make progress towards a better world in which people are healthier than would otherwise be the case. But what is the alternative? Age to death on the normal schedule and not rock the boat? Sometimes the boat needs to be rocked.

Bryan Johnson often tinkers with his daily regimen of drugs, peptides in the form of both supplements and injections and other medical interventions in pursuit of a longer life. He's part of a growing crowd of tech entrepreneurs who are seeking extra years by hacking their own bodies - and sharing their exploits widely through social media and other channels. Wealthy longevity evangelists are often seen as translators of early-stage science to the public, who turn preliminary or anecdotal findings into so-called stacks that combine supplements, other compounds, protocols and therapies, long before FDA approval.

But there is a danger to this growing phenomenon: researchers who study ageing and longevity warn that these biohacks have not been clinically tested, meaning that it's unclear whether they work or might harm people. There is no medical intervention that is proven to extend human life by targeting ageing itself, says Andrew Steele: "There probably are things on our radars that might work, but nothing has ever been tried in humans." Nir Barzilai is torn about the impacts that the biohackers have. Take Johnson's tinkering with various supplements and drugs, which is usually based on some kind of evidence: "If you're asking, 'Is he taking something that doesn't make sense?' I would say, no, these things are based on biology but not on clinical evidence."

Neither Steele nor Barzilai are cynics. Both say that some of the protocols being tested and touted by Silicon Valley elites could have a meaningful impact on lifespan and healthspan - the time during which people are not affected by chronic disease and disabilities related to ageing. But the evidence isn't there yet. Matt Kaeberlein calls it "a signal-to-noise problem". In the limited available data about these interventions, he says, "there's signal there, but there's a whole lot of noise". That makes it hard for the public to separate the two.

Link: https://www.scientificamerican.com/article/silicon-valleys-longevity-biohackers-are-engaged-in-a-dangerous-experiment/

Hematopoietic cell populations reside in the bone marrow. A tree of ever more specialized progenitor cell populations descends from the root hematopoietic stem cell population, responsible for ultimately producing red blood cells and white blood cells. Hematopoietic stem cell populations are known to become damaged and dysfunction with age, and this is one of the contributions to immune system dysfunction in later life. It also produces effects such as platelets that are more prone to causing inappropriate clotting and thrombosis. Here, researchers provide evidence to suggest that the intermediate hematopoietic progenitor cell populations are much less impacted by aging than is the case for hematopoietic stem cells, and might be buffering the loss of stem cell function to allow for maintained hematopoietic function. It is a little early to understand what this might mean for approaches to therapy, and what the implications are for the importance of hematopoietic stem cell function in aging. It is certainly interesting, however.

Aging of the hematopoietic system has profound consequences for organismal health and longevity, attributed to the well-characterized functional aging of hematopoietic stem cells (HSCs). Here, we tested whether progenitor cells may demonstrate age resistance to enable hematopoietic homeostasis throughout life despite the functional decline of upstream HSCs. Strikingly, our results revealed unwavering reconstitution capacity by young and old progenitors, demonstrating that intermediate progenitors are functionally unaffected by aging and placing Flk2+ multipotent progenitors (MPPFs) as a potential source of age resilience.

This unique finding was emphasized by unchanged transcriptomic, proliferation, and mitochondrial capacity of young and old MPPFs, revealing remarkable similarities upon aging. Considering that HSCs functionally decline with age, yet intermediate progenitors remain unperturbed and "age resilient", we posit that MPPFs may play an essential role in protecting downstream progenitors from inheriting age-related properties from HSCs. We propose three potential mechanisms for how MPPFs maintain hematopoietic integrity and homeostasis with age.

Link: https://doi.org/10.1016/j.stemcr.2026.102965

Genes produce proteins at a pace determined by epigenetic control over nuclear DNA structure. That epigenetic control changes with age for reasons that are incompletely understood. A promising possibility is that repeated activation of DNA repair processes depletes specific factors needed for maintenance of DNA structure, but that needs further confirmation. The pace of protein production changes in a characteristic way with age for countless different proteins. Of that large number, some are known to cause harm, and are associated with aspects of degenerative aging. These are potential targets for gene therapies; I listed a large number of them some years ago, and that set has only grown since then.

Gene therapy technology has existed for decades, but is not yet very broadly used. A narrow subset of such therapies are becoming increasingly used in the medical tourism industry as potential treatments for aging. Why aren't we swimming in dozens of commercially available gene therapy implementations to dial up expression of gene X or dial down expression of gene Y to improve late life health? The short answer is that gene therapy has a delivery problem. It is somewhere between very hard and impossible to deliver gene therapies safely and effectively to most tissues in the body, given the tools presently available. The therapeutic applications being explored most aggressively these days largely fall into a small set of categories, where local delivery of a relatively small amount of a well-explored gene therapy vector (such as plasmids or AAV) does the job. For example, to turn a small number of fat cells into factories to produce a beneficial signaling protein that will circulate throughout the body - such as klotho, follistatin, and so forth. Or where a delivery mode can hit desired tissues with high specificity, such as intranasal delivery of AAV to reach parts of the brain.

Gene therapies that can reliably and selectively produce expression in a small inner organ require direct injection, which developers largely reject as an option outside the context of severe disease. Intravenous injection of gene therapy vectors that produce sufficient expression in a target inner organ without overloading the liver or bearing an unacceptably high risk of an immune reaction is an unsolved problem for near all target organs. Further, systemic injection of high dose gene therapy vectors has caused deaths in recent years, and is thus not in favor for anything but the most severe disease conditions. Being able to change gene expression in cells throughout the body with a single intravenous treatment (again without overloading the liver or provoking the immune system) also remains a pipe dream; while a few programs offer hope for progress on this front, no established gene therapy vectors are capable of doing this.

Partial epigenetic reprogramming is thought to offer the potential to bypass targeting of individual genes by rejuvenating the control over DNA structure and gene expression. But this approach still suffers from all of the delivery issues of gene therapy, alongside the likely need for different dosage and duration in different tissues. At the end of the day, yes, the technological capability exists to change the behavior of aging cells for the better. It is trivial to do so in a cell in a dish. The delivery challenges are what prevents the research and development communities from bringing this capability into patients in the near term. For now the field is focused on only a few genes, approaches, and tissues that are a good fit for the limited delivery capabilities that exist.

Gene therapy for aging and longevity

Over 2000 genes have been linked to increased longevity in a variety of models, but the translation of these findings into clinical applications remains challenging. Gene therapy is a potential strategy for extending healthspan by targeting genes associated with longevity or age-related diseases. This approach involves transferring genetic material directly into target tissue using viral or nonviral vectors, thereby enabling the augmentation, suppression, or precise editing of genes. This review examines multiple gene therapy strategies and their respective technical challenges, with a particular focus on identifying the most promising genetic targets for future interventions.

Many different gene delivery vectors have been engineered in recent decades. They can broadly be divided into physical, chemical, and virus-based methods. All gene delivery vehicles must overcome the same set of issues: efficient delivery to target locations, evasion of host immune responses, sufficient packaging size, controlled expression levels, reversibility and stability, redosability, and cost-effectiveness. In other words, each vector represents a multidimensional optimization problem in which certain existing properties determine whether a vector is more suitable for some applications over others. In the context of longevity therapies, additional requirements include a broad distribution profile, very-long-acting and stable expression, and high safety standards, as such interventions must remain effective over extended periods and are also intended for use in individuals without overt disease.

The main obstacle longevity gene therapies need to overcome is the ability to deliver the genes of interest to many or all tissues in the body. Most of the genes known to extend longevity are expressed intracellularly and across numerous tissues in the body. In this review, we identified multiple gene candidates from animal and human studies as potential targets for longevity gene therapies. Based on its advantages in gene delivery, AAV-mediated gene therapy is currently the most suitable platform for longevity gene therapy, but technical challenges remain, such as whole-body delivery and biomechanical limitations.

To accelerate the longevity gene therapy field, several key technical advancements are desirable. These include new AAV serotypes or vehicles for broader delivery across the body; better systems for controlled expression in individual organs, compact, reversible, or controllable expression systems; improved immunosuppressors to prevent anti-vector or anti-transgene immunity; compact molecular tools for safe and controlled integration; and new (possibly automated) production and quality control pipelines to reduce manufacturing costs.

In mammals the male reproductive system outlasts the female reproductive system over the course of aging, but mechanisms of damage and dysfunction still eventually lead to a loss of fertility. The epididymis, where sperm cells mature, is a critical portion of the testes. As researchers here note, while observations of degeneration are readily available, there is relatively little understanding of the aging of the epididymis at the detailed level of cellular biochemistry. After better characterizing epididymal cells in young and aged non-human primates, the researchers found a proximate cause of problems: loss of FOXO1 expression drives cellular senescence, and senescent cells then disrupt structure and function in the surrounding tissue via their inflammatory secretions.

Aging of the male reproductive system is characterized by declining fertility, with epididymal dysfunction being a critical yet poorly understood contributor. Through a multimodal analysis in non-human primates that integrated histology and transcriptomics, we delineated a coherent epididymal aging phenotype encompassing epithelial senescence, chronic inflammation, fibrosis, and functional decline. Single-nucleus transcriptomics revealed principal cells (PCs) as the predominant and most transcriptionally perturbed epithelial cell type. Within PCs, the longevity-associated transcription factor FOXO1 was markedly downregulated with age.

Functional studies in human epididymal epithelial cells demonstrated that FOXO1 deficiency drives cellular senescence. Mechanistically, FOXO1 transcriptionally activates LHX1, and this axis is essential for counteracting senescence. Furthermore, intervention with senescence-resistant mesenchymal progenitor cells or their exosomes mitigated epididymal aging phenotypes and restored FOXO1 expression in vivo and in vitro. Our study establishes the FOXO1-LHX1 axis as a key protective pathway against primate epididymal aging, providing mechanistic insights and potential therapeutic targets for preserving male reproductive health.

Link: https://doi.org/10.1093/procel/pwag020

Senile lentigo, an age spot, is a form of photoaging in response to UV exposure featuring a darkening of the skin. An increased burden of cellular senescence is thought to play an important role in photoaging more generally, and here researchers show that age spots contain an increased number of senescent cells. It is likely that these senescent cells are an important driver of the altered structure of skin and altered behavior of skin cells in an age spot. It is also likely that intermittent use of senolytic drugs will slow skin aging and even improve function in already aged skin, based on research conducted to date, but there is surprisingly little published human data on this front despite a number of companies offering plausibly senolytic skin products, and the growing off-label use of senolytic drugs such as dasatinib and quercetin.

In the dermal and epidermal layers of the skin, various manifestations of aging have been associated with an accumulation of senescent cells, namely fibroblasts, keratinocytes, and melanocytes. We and others have previously reported an accumulation of senescent cells in chronologically aged epidermis upon exposure to chronic low-dose UV radiation and in the epidermis of precancerous actinic keratosis, age-associated lesions that frequently occur in sun-damaged skin. Since the prevalence of photoaging in Asian populations commonly results in skin hyperpigmentation, we here extended our investigation to senile lentigo (SL), a common age-associated hyperpigmentation disorder caused by chronic UV exposure.

Facial skin biopsy samples from 9 donors of Korean ethnicity, classified under type III or IV on the Fitzpatrick scale, were collected from both perilesional and lesional sites. Expectedly, we observed a higher degree of pigmentation and more melanocytes. To determine whether SL lesions are associated with an accumulation of senescent cells, we stained sections for well-characterized hallmarks of senescence: p16INK4A, lamin B1, and increased nuclear size.

Using these markers we found an accumulation of senescent cells in SL epidermis. This is of particular interest because we and others have previously observed an accumulation of senescent keratinocytes in actinic keratosis lesions and in chronically UV-exposed skin. Moreover, it is noteworthy that patients with Hutchinson-Gilford progeria, a premature aging syndrome caused by an altered form of lamin A that triggers cellular senescence, exhibit widespread hyper- as well as hypopigmentation. However, the extent to which different cell types within the skin contribute to this phenotype remains unclear. Importantly, while the senescence-associated secretory phenotype in senescent human fibroblasts is well characterized, very little is known about the senescence-associated secretory phenotype in keratinocytes.

Link: https://doi.org/10.1016/j.jid.2026.04.024

Blood contains countless different proteins secreted from different cell populations throughout the body. Different cell types tend to secrete different mixes of proteins. Researchers have recently made inroads into constructing organ-specific aging clocks from protein levels in blood, using machine learning to identify patterns that predict the health, disease risk, and disease status of specific organs. This is still in the relatively early stages when compared to other clocks, but it seems to be going fairly well so far. The results are as useful as more general aging clocks, which is to say that there are still hurdles to overcome before they can be used by an individual to reliably assess health or in a study to rapidly assess outcomes of a new therapy.

Senescent cells accumulate with age in tissues throughout the body, and secrete a pro-inflammatory, disruptive mix of proteins that actively degrades tissue structure and function. Animal studies demonstrate that cellular senescence is an important contributing cause of degenerative aging. Researchers here make use of the approach taken to produce organ-specific proteomic aging clocks to attempt to map the burden of cellular senescence in different tissues using only a blood sample. This is possible because senescent cells of different types and origins produce meaningfully different mixes of secreted proteins, just like other cells. Only here, those secretions are much more harmful when sustained over the long term.

Circulating cell type senescence signatures track distinct dimensions of health status and trajectories in human longitudinal cohorts

Cellular senescence becomes more common with age as healthy cells encounter sublethal environmental and genotoxic stress or accrue other types of damage, and is implicated in age-related decline. Senescence is characterized in part by proteomic expression changes, including the secretions of pro-inflammatory cytokines and other proteins. These senescence-associated proteins (SAPs) have since proven to be heterogeneous by cell type and senescence-inducing stimulus.

In this study, senescence signatures from the Senescence Catalog (SenCat), including 14 human cell types were examined in circulation for clinical relevance in two longitudinal studies - 1,275 participants of the Baltimore Longitudinal Study of Aging (BLSA) and 997 participants of the Invecchiare in Chianti (InCHIANTI) study. This study undertook the first investigation of cell type-specific (senotype-specific) senescence signatures and their possible clinical relevance across two human cohorts. SAPs were associated with diverse aging phenotypes in the BLSA and InCHIANTI cohorts, and outperformed other circulating non-SAPs in predicting many clinical parameters, including age, walking pace, and hypertension.

Overall, this study comprehensively evaluates and identifies clinically relevant "core" and cell type senescence signatures with cross-study validation and lays a foundation for future exploration of cell type senescence biomarkers in circulation. We demonstrate that senescence markers generally outperformed non-senescence markers in predicting clinical traits and illustrate key examples of cell type senescence signatures with unique relevance to corresponding organ systems and functions. This study highlights the potential translational use of senescence markers.

The challenge inherent in present approaches to reduce unwanted inflammation and immune activation, such as by targeting circulating tumor necrosis factor (TNF) with monoclonal antibodies in the context of autoimmune conditions, is that this signaling is also used in the normal, desirable immune response. Suppression thus has side-effects on immune competence. Nonetheless, researchers continue to try to improve the approaches to this class of therapy, as it is certainly better than prior alternatives. Here, researchers turn chimeric antigen receptor technology to the clearance of TNF: engineered T cells equipped with suitable engineered receptors casn live in the body for years while continually clearing excessive TNF in circulation.

Extracellular factors, such as cytokines, are implicated in various diseases. Utilizing biologics to functionally neutralize these extracellular factors is a valid therapeutic approach in the clinic. While biologics have shown effectiveness in disease treatment, they have inherent limitations that require further improvement. Due to their short half-lives, biologics must be administered repeatedly to maintain therapeutic efficacy, leading to increased costs, reduced patient compliance, and decreased quality of life. For example, the widely used anti-tumor necrosis factor (TNF) antibody (adalimumab, Humira) requires bimonthly injections for indications like rheumatoid arthritis.

Chimeric antigen receptor (CAR)-T cells, as an exogenous entity, traditionally target surface antigens on tumor or pathogenic cells rather than soluble factors like TNF. Unlike all existing targeted protein degradation approaches, CAR-T cells do not rely on any component of the host's endogenous protein degradation machinery. Moreover, CARs undergo receptor-mediated endocytosis upon antigen engagement and are continuously replenished by CAR-T cells, enabling iterative and sustained target degradation.

In this study, we exploited these properties to engineer a TNFR1 ectodomain-based CAR-T platform for specific, durable degradation of soluble TNF. To overcome the critical barrier of poor CAR-T expansion in immunocompetent hosts, we further applied CRISPR-mediated Bcor/Zc3h12a double knockout to generate long-lived TNFR1-bearing T cells that persist in vivo without preconditioning. We demonstrate that a single infusion of cells confers durable rheumatoid arthritis remission in mouse models, establishing a host-machinery-independent cellular targeted protein degradation platform and a paradigm shift from chronic repeated drug administration to single-infusion intervention for inflammatory disease.

Link: https://doi.org/10.1016/j.hlife.2026.05.003

Degenerative aging, as one might expect, is largely studied in the old. Aging happens in younger people, but doesn't kill or greatly inconvenience them, and is thus not a high priority for the research community. Thus far less is known of how exactly aging proceeds in younger adults, such as which mechanisms are more important. So it is always interesting to see researchers attempting to make some inroads into what is happening to younger adults as a result of those mechanisms of aging. Here, researchers present evidence for measures aging provided by aging clocks in younger adults to have accelerated since the 1950s; one might immediately think of the rising prevalence of obesity as the first place to look for a cause, but there are any number of other possible candidates.

Researchers analyzed data from more than 154,000 young adults in the UK Biobank, a large biomedical dataset containing biological, health and lifestyle data, and from more than 10,000 individuals in the U.S. participating in the National Institutes of Health's (NIH) All of Us Research Program, an effort to build a comprehensive health dataset on more than 1 million people living in the U.S. To estimate the level of biological aging - or age gap - the researchers examined aging at two levels: across the body as a whole, known as systemic aging, and within individual organs, known as organ-specific aging.

For systemic aging, the researchers used established measures, including clinical biomarker-based measures such as PhenoAge and the Klemera-Doubal Method, as well as a metabolomic age score, which provides a measure of individual metabolism. For organ-specific aging, the researchers used blood proteomic data, which measure levels of multiple proteins linked to specific organ systems, to estimate biological aging in individual organs.

The researchers found that individuals in the UK born between 1965 and 1974 had systemic aging that was 23% of one standard deviation higher compared with those born between 1950 and 1954, after accounting for chronological age. In other words, people in the younger birth cohort showed a modest shift toward older biological profiles than people in the older birth cohort when at the same chronological age. The researchers observed a similar pattern in the U.S cohort. Participants born between 1990 and 1999 had systemic aging that was 92% of one standard deviation higher compared with those born between 1965 and 1969.

Link: https://medicine.washu.edu/news/faster-aging-in-younger-generations-linked-to-rise-in-early-onset-cancer/

Loss of muscle mass and strength with age is universal, leading both to physical frailty and to a harmful disruption of metabolism more generally. Muscle doesn't just exist to provide motive power, it is also a metabolically active tissue. The signals it provides are important to insulin metabolism, for example, in addition to the systemic benefits that result from exercise. The causes of age-related muscle decline are complex and layered. For example, low-level molecular damage of the sort described in the Strategies for Engineered Negligible Senescence (SENS) and the Hallmarks of Aging disrupt the function of neuromuscular junctions linking the nervous system to muscle fibers, and those nerve signals are necessary for the normal adaptive response of muscle tissue. But completely separately, muscle stem cells become progressively less active with age, and the somatic muscle cells produced by those stem cells are needed for muscle growth and regeneration.

All of this is attended by altered levels of expression of countless genes, some of which are more important than others when it comes to regulating the behavior of muscle cells. In today's open access paper, for example, researchers discuss the role of NOX4 in muscle adaptation to use. In youth, using muscle will grow muscle. In later life this becomes less the case. NOX4 appears to occupy an important position in the regulation of this response to exercise, and its levels decline with age. Energetic use of muscle generates oxidative stress through increased activity of mitochondria, and this increase in the production of oxidative molecules as a side-effect of energy metabolism is the primary signal triggering a cascade of protective and adaptive responses. NOX4 is necessary to that process as a producer of specific forms of oxidative molecule; having less of it doesn't just prevent muscle growth, but paradoxically increases the harms done by oxidative signaling as the protective response is attenuated.

A decline in skeletal muscle NOX4 abrogates exercise-induced adaptive homeostasis and exacerbates biological aging

Adaptations to stressors can increase resilience and allow organisms to manage damaging insults. The ability of organisms to transiently adapt to otherwise harmful stressors is known as adaptive homeostasis. A quintessential example of adaptive homeostasis is the response to oxidants, namely, reactive oxygen species (ROS). ROS are highly reactive chemicals generated in response to stressors and as byproducts of life in an aerobic environment. While evolution has harnessed specific ROS, for example, H2O2 for physiological roles such as cellular signaling, stressors resulting in redox imbalance and excess ROS can damage essential macromolecules including proteins, lipids, and DNA to promote cell death and inflammation and contribute to disease.

A decline in both nuclear factor erythroid 2-related factor 2 (NFE2L2)-orchestrated adaptive homeostasis and consequently greater oxidative distress are thought to be key features of aging. In contracting skeletal muscle, the reactive oxygen species-producing enzyme NADPH oxidase 4 (NOX4) is a potent inducer of NFE2L2 adaptive homeostasis. Here, we report that skeletal muscle NOX4 levels decline in aged mice and humans, resulting in abrogated NFE2L2 adaptive homeostasis, increased protein oxidative damage, and decreased muscle function.

We show that deleting NOX4 in skeletal muscle exacerbates the physiological decline associated with aging, resulting in overt sarcopenia and frailty, characterized by physical inactivity, increased adiposity, systemic inflammation, whole-body insulin resistance, and advanced liver disease in aged chow-fed mice. The systems-wide physiological decline in aged skeletal muscle NOX4-deficient mice could be corrected by restoring NOX4 using viral approaches or activating NFE2L2 downstream with sulforaphane and reinstating adaptive homeostatic responses otherwise induced by exercise. Our findings provide important insights into the basis for the decline in NFE2L2-orchestrated adaptive homeostasis that accompanies physical inactivity with age and identify key mechanisms by which exercise may promote healthy aging.

Researchers here review the state of stem cell therapies for the treatment of age-related degenerative conditions, with particular attention to more recently emerged areas of the field such as efforts to rejuvenate old patient-derived stem cells before their use in therapy. Partial epigenetic reprogramming is not much mentioned in this context as, unlike the use of senolytics, it has not yet advanced to the point of ease of use for the average stem cell clinic. Treating a stem cell culture with cheap and well-established senolytic compounds is very much more feasible in comparison to the time, expertise, and expense needed to safely and reliably partially reprogram cells in that same culture.

Rejuvenation strategies for ageing stem cells focus on restoring their regenerative capabilities, which decline with age, to improve tissue homeostasis and potentially extend health and lifespan. Various pathways regulate the rejuvenation process in the body, but impairment of these pathways can lead to poor stem cell function. Although the body has various pathways, recent trends have new approaches to managing stem cells via new rejuvenation strategies. The primary methods for rejuvenation strategies for stem cells include (a) preconditioning and senolytics, and (b) biomaterials and engineered niches.

Environmental or chemical preconditioning can help in the regeneration of stem cells by increasing proliferation, differentiation, and stress resistance. Hypoxic culture, growth factor priming, and expansion on youth-mimicking matrices, such as decellularised extracellular matrix, are among the techniques to boost mesenchymal stem cells (MSCs) and other stem cell types for renewal. Senolytic drugs, for example, quercetin, fisetin, and dasatinib, selectively remove the senescent cells, and thus lower senescence-associated secretory phenotype (SASP) levels while restoring stem cell and their lineage potential. The drug quercetin showed the removal of senescent MSCs, leading to the enhancement of their proliferating and osteogenic capability, simultaneously inhibiting adipogenesis, adding other strong evidence to the senolytic approach of stem cell rejuvenation. Additionally, MSC exosomes exhibit immunomodulatory, antioxidant and reparative potential on senescent cells.

Engineered niches like scaffolds, decellularized matrices, and hydrogels, can replicate a juvenile extracellular environment to keep the stem cells viable. MSC-loaded chitosan hydrogels, along with MSC exosomes, enhanced fibroblast function, thereby increasing proliferation and collagen formation while reducing matrix metalloproteinases and SASP factors and rejuvenating skin in older mice. Biomaterial carriers enhance transplanted cell survival by mimicking extracellular matrix signals like adhesion ligands, sequestered growth factors, and mechanical stiffness that ultimately led to better engraftment and regenerative efficiency.

Link: https://doi.org/10.3389/fcell.2026.1830358

Therapies that increase muscle tissue regeneration following injury, and possibly also normal maintenance and growth of muscle tissue, are of great interest at present. The widespread use of GLP-1 receptor agonists to induce calorie restriction causes loss of muscle mass as well as fat mass, and so there is a strong financial incentive for the research and development of means to force the body to build more muscle. There was already a strong financial incentive in the sense that everyone loses muscle with age, and frailty is a prevalent and harmful state of poor health, but for some reason that was never as motivating to the development community. Nonetheless, recent years have seen a number of interesting new discoveries in the regulation of muscle regeneration and growth. We will see whether any of them make it to the clinic in some form.

Muscle regenerative capacity declines with aging and disease, which leads to muscle loss and reduced lifespan. Muscle regenerative failure is related to a disrupted network orchestrated by multiple muscle-harbored cell types; whether and how the interplay between macrophages and myofibers contributes to this process is largely unknown. Herein, we report upregulation of histone methyltransferase G9a in both aged human muscle and mouse muscle after injury. Deletion of G9a in either myeloid cells or myofibers accelerates muscle regeneration.

Mechanistically, G9a down-regulates macrophage-derived interleukin 13 (IL13) and suppresses myofiber-derived myokine musclin, respectively, to inhibit myogenesis and macrophage phenotype transition during muscle regeneration. Either IL13 or musclin, per se, accelerated muscle regeneration, and their combined administration showed synergistic effects with therapeutic potentials for muscle degeneration disorders. Collectively, we highlight a crosstalk between macrophages and myofibers through IL13-Stat6 signaling and musclin, both regulated by G9a, which steers a pro-recovery microenvironment after muscle injury, with therapeutic potentials for muscle degeneration disorders.

Link: https://doi.org/10.1038/s41419-026-08944-2

Epigenetic control over nuclear DNA structure determines which sequences of DNA are exposed to transcription machinery in the cell nucleus, and thus which genes are expressed. As epigenetic decorations to DNA and its structural helpers are constantly added and removed, structure changes and so does gene expression. Which proteins are produced from their genetic blueprints, and in what amounts, is an important determinant of cell behavior. Epigenetic patterns and the structure of DNA changes with age, and so does gene expression. There are any number of examples of age-related changes in the level of expression of a specific protein that are clearly harmful, as animal studies have shown that health improves when the change is reversed.

If one thinks that aging is essentially epigenetic aging, which many people do judging from the vast funding flowing into the development of partial epigenetic reprogramming therapies intended to reset epigenetic decorations to a youthful pattern, then one should probably be very interested in which other interventions are known to reduce epigenetic age in human trials. People with other opinions on the nature of aging should still find the list interesting. Still, it has to be said that it is far from clear that there is a usefully comprehensive mapping of aging to epigenetic aging, or that even the better epigenetic clocks are actually measuring biological age, or measuring aspects of it in a way that will accurately reflect any given specific change to biochemistry produced by potential treatments for aging. There are clearly mechanisms of aging that cannot be fixed by reprogramming, such as accumulation of metabolic waste that cannot be effectively broken down by even youthful cells, or mutational damage to DNA.

Turning back time: a comprehensive list of interventions that decrease next-generation epigenetic aging clocks in humans

Epigenetic aging clocks estimate age from DNA methylation patterns and have become central tools in longevity research. More recently, next-generation clocks have been developed to better compensate for the known divergence between chronological age and epigenetic age in ways that relate to lifestyle, health, and age-related disease. Although epigenetic clocks represent investigational biomarkers, these newer models are more strongly associated with all-cause mortality risk than first-generation clocks. As such, interventions that modify them are of interest. To test this, we performed a series of systematic searches and identified 41 human studies reporting the effects of interventions on at least one next-generation epigenetic clock.

Our data suggest that a diverse range of pharmaceutical, lifestyle, supplementation, non-pharmaceutical clinical, and psychosocial interventions can decrease epigenetic age, including exercise, a plant-rich diet, the GLP-1 receptor agonist semaglutide, caloric restriction, ketamine, omega-3 fatty acids, a multivitamin-multimineral supplement, umbilical cord plasma, and the cholesterol-lowering drug pitavastatin. Nicotinamide riboside, rapamycin, senolytics, and several other interventions showed no detectable effect, whereas plasmapheresis and other therapeutics accelerated epigenetic aging. We also summarize reported effect sizes and compare next-generation clocks with respect to their frequency of use and responsiveness to intervention.

Mitochondria are power plants, hundreds of them in every cell working to create the chemical energy store molecule adenosine triphosphate (ATP) used to power cellular processes. They are the evolved descendants of ancient bacteria, and still act like bacteria in many ways. They are also very complex, and while a great deal is known of their structure and biochemistry, a complete and detailed answer as to why exactly their function declines with age is lacking. It is well established that exercise improves mitochondrial function, both in the short term and over the long term of maintaining physical fitness. This in turn explains some fraction of the beneficial effects of exercise and fitness when it comes to slowing the pace of degenerative aging.

Brain aging is a complex biological process characterised by progressive neuronal and synaptic decline, in which disruption of mitochondrial quality control plays a central role. This system encompasses multiple synergistic components, including mitochondrial biogenesis, dynamic equilibrium, autophagic clearance, and energy metabolism. Aging induces dysfunction across these processes, precipitating mitochondrial fragmentation, functional decline, and energy crises, ultimately driving cognitive deterioration.

Exercise is a promising non-pharmacological intervention for preserving brain health during aging, and its benefits may be mediated, at least in part, through modulation of mitochondrial quality control. Specifically, exercise has been shown to activate key signaling pathways such as AMPK/SIRT1/PGC-1α, thereby promoting mitochondrial biogenesis and metabolic adaptation. It may also regulate mitochondrial dynamics and mitophagy via pathways including cAMP/PKA/Drp1 and AMPK/mTOR. In addition, emerging evidence indicates that exercise may influence brain mitochondrial function through activity-dependent regulation of mitochondrial gene expression and systemic signaling factors.

Link: https://doi.org/10.3390/biology15110854

Members of the life insurance industry have typically been far ahead of the rest of the general public outside the life sciences when it comes to an appreciation of progress towards therapies to treat aging as a medical condition. It is a very large industry, and thus has significant funding to direct towards analysis and prediction of trends in medicine. The prospect of increasing healthy human longevity, of a change in the way in which aging is addressed by medical research and development, is both an existential threat and opportunity for the life insurance industry. Those who predict correctly will thrive, and those who do not will suffer.

Thus it is always interesting to see how insurance industry researchers and analysts react to developments in the medical life science space. Here, the focus is on aging clocks, ways to combine biological data that predict mortality risk across populations. If biological age could be measured accurately for an individual via any specific variety of aging clock, and thus a good estimate of intrinsic mortality risk derived that individual, one would imagine that the life insurers would adopt this technology very rapidly. They have every motivation to do so. The reasons why they have not so far done are the same reasons as to why clocks are not yet the gold standard for assessing the quality of potential rejuvenation therapies: the clocks are not accurate for individuals, and their underlying connections to biological age are not fully understood.

Biological Clocks: Ready for Prime Time?

John Smith is a 50-year-old male applying for a life insurance policy. His medical history is unremarkable, and his recent medical visits record good health. He exercises regularly and is an enthusiastic member of several wellness programs. A recent test from a longevity company reports a biological age of 46, and records that he is aging at 0.7 years per year. Both the company and Mr. Smith are excited that his life expectancy is well above normal. Are they right? And if they are, should life insurers be excited too?

Chronological age is the widely accepted starting point of mortality assessment. It is also time-honored, having first appeared in insurance life tables in the 17th century. Yet it is a blunt metric: two 50-year-olds may have quite different health statuses and life expectancies. Biological age is a term that is widely used in the aging literature. But curiously, it has no accepted definition. This reflects both the complexity of aging and the lack of any gold-standard metric. It reflects how old the body has become, functionally and biologically. It incorporates dimensions of health, such as current physiological state, and the cumulative molecular and cellular damage that has accrued over time. Thus, at face value, biological age would seem to provide more useful underwriting information than chronological age. If one of our 50-year-olds had a biological age of 46 and the other 54, mortality projections would be quite different, and premiums could reflect these.

So, where did John Smith's biological age determination come from? It was likely provided by an "epigenetic clock." which is an algorithm that estimates chronological age from patterns of cellular DNA methylation. Epigenetic clocks are statistical models, trained on methylation status of selected subsets of CpG sites - typically ranging from a few hundred to a few thousand - chosen to optimize predictive performance.

What are the rubs against epigenetic clocks? There are quite a few. Epigenetic clocks are not trained to provide reliable predictions at the individual level. Rather, they are statistical models designed to minimize error across thousands of samples. Consequently, when applied to a single person, their estimates are biologically noisy. Epigenetic age is not a traditional biomarker, such as BMI or serum glucose, which can generate reliable individual-level information. Thus, to equate a younger predicted epigenetic age with a younger biological age, even though this is common practice, is an overextension. Epigenetic clocks are highly dependent on the training data and the populations from which they are derived. If a clock is applied to different populations - such as the very fit (Mr. Smith) or self-selected individuals (those likely to buy a commercial test) - the predictions may be inaccurate.

Are epigenetic clocks of value to life insurers? Not at present. While biological age, to the extent it is equated with epigenetic age, does predict mortality, it does not outperform traditional mortality risk predictors such as age, sex, smoking, blood pressure, BMI, and medical history. Similarly, pace-of-aging, although an outwardly attractive metric, does not outperform traditional measures of current health status. One exception might be the young or apparently healthy, where traditional risk factors are absent, and early deterioration might be captured. Another might be the small number of older individuals where all traditional risk markers are negative; epigenetic clocks may provide better insight into current health. But both scenarios would require longitudinal analyses to prove clock utility.