Fight Aging!

Regulatory systems in wealthier parts of the world ensure that a great many different compounds at different doses are entered into long-term toxicology studies primarily conducted in mice. Researchers here report on the results of looking through that data in search of compounds that improved health and extended life. Hormesis is the name given to the benefits to health and longevity resulting from mild exposure to stress, whether toxicity, heat, cold, lack of nutrients, and so forth. Cells have evolved to react with increased maintenance and defenses when placed under stress, and if the stress is mild and transient, then the overall outcome is a net benefit to cell and tissue function. It is thus reasonable to think in advance of checking that some toxicology studies incorporated doses that improved health rather than damaged it.

Efforts to extend longevity and healthspan have benefited from the use of in vitro systems, short-lived model organisms and computational approaches, but translation to humans depends on demonstrating efficacy and safety in mammalian in vivo models. However, rigorously controlled rodent lifespan studies are slow, costly, and low-throughput. Hormesis, the induction of adaptive stress response pathways by low-level toxic or metabolic challenges, provides a mechanistic means for improved resilience, but testing hormetic dose-response relationships in mammals is logistically challenging.

Regulatory long-term toxicity studies, mandated for chemical authorisation, routinely generate lifespan and chronic toxicity data from large cohorts across multiple dose groups and therefore represent an underused resource for detecting unexpected survival benefits. We mined a random subset of the German Federal Institute for Risk Assessment electronic archive for long-term rodent pesticide studies in ≥ 50 animals per dose and sex. From qualifying studies with 154 substances, we identified 27 substances (18% of entries) that significantly increased survival at study termination.

Fifteen publicly disclosable substances were examined further; roughly half perturbed mitochondrial oxygen consumption rates in mammalian cells, and bromoxynil acted as a mitochondrial uncoupler. Back-translation to Caenorhabditis elegans showed bromoxynil improved multiple healthspan indicators without compromising organismal health. Regulatory toxicity archives can thus be repurposed to identify candidate compounds, targets, and mechanisms for mammalian healthy ageing research, and complement conventional screening pipelines.

Link: https://doi.org/10.1111/acel.70797

Senescent cells accumulate with age and generate inflammatory secretions that are disruptive to tissue structure and function. Targeted clearance of some fraction of these lingering senescent cells in aged tissues via senolytic therapies has been shown to reverse aspects of aging and extend life in mice. The small human clinical trials conducted to date have shown, on balance, promising results. Spurred by the very impressive animal data, the research community has been searching for novel mechanisms for selective destruction of senescent cells and novel senolytics. Interesting new approaches emerge a few times every year, some of which are low cost supplements and plant extracts, such as the candidate noted here. Unfortunately low cost therapies do not tend to lead to compelling human data, as clinical trials are expensive to run; if there is no profit to be made, finding funding is challenging. Academic institutions can and do run trials, but relatively few of them, and rarely large ones. Indeed, most of the trials of low cost senolytic treatments conducted to date were both small and run by academic institutions.

Current intervention strategies targeting senescent cells are primarily categorized into two types: senomorphics (modulation of the senescent phenotype) and senolytics (elimination of senescent cells). Senomorphics aim to mitigate the inflammatory microenvironment by using drugs (e.g., the mTOR inhibitor rapamycin, metformin) to inhibit senescence-associated secretory phenotype (SASP)-related signaling pathways without affecting cell survival. In contrast, senolytics aim to solve the problem at its source by selectively inducing apoptosis in senescent cells to completely eradicate SASP production. Representative senolytics include the BCL-2 family inhibitor navitoclax and the classic combination of dasatinib and quercetin. The latter has been shown to effectively clear senescent cells and improve various age-related functional declines in animal models and has shown promising results in clinical trials for Alzheimer's disease (Phase I), idiopathic pulmonary fibrosis and diabetic kidney disease.

However, existing senolytic compounds still have room for optimization in terms of selectivity, potency or long-term safety. This has prompted researchers to turn to natural products with diverse structures and unique mechanisms to find a new generation of lead molecules, such as PCC1, fisetin, and halophyte extracts.

Based on this, our study first established a system for the quantitative screening of senolytic small molecules and identified a potential candidate - cepharanthine (CEP) - through high-throughput screening. CEP is a bisbenzylisoquinoline alkaloid extracted from plants of the Stephania genus, possessing a wide range of anti-inflammatory, antioxidant, and anti-tumor activities. Previous research suggested its potential to intervene in inflammation, hinting at its anti-aging value. However, whether CEP possesses clear senolytic activity and the unique molecular mechanisms underlying its selective clearance effect have not yet been systematically elucidated.

CEP selectively eliminates senescent cells by cooperatively and in parallel regulating the PI3K/AKT and PERK-ATF4-CHOP pathways, differentially inducing PUMA/NOXA and triggering mitochondrial intrinsic apoptosis. In zebrafish, C. elegans, naturally aged mice, and progeroid mice, CEP clears senescent cells, reduces SASP levels, improves organ function and prolongs lifespan.

Link: https://doi.org/10.1016/j.phymed.2026.158875

Writing a succinct few page introduction to present scientific thought on the driving mechanisms of aging and the present landscape of development of means of treating aging seems quite the tall order. The field is complex, aging is complex, much is in flux and important updates to present understanding arrive every few years. Where to start, what to include, and what to leave out? Today's open access paper is, for its short length, a good attempt. It is important for those on the inside who have access to every last fine detail to be able to summarize at least the shape of the field to those on the outside. Knowledge is a set of concentric rings, from the laypeople at the outside to researchers at the cutting edge in the very center. The primary task of those in each ring, often neglected, is not to look inward and learn, but to look outward and explain well.

The authors of today's paper put forward their view on what we should take away from the data obtained to date on mechanisms of aging and their treatment, which is that the growing burden of cellular senescence in aged tissues plays a central, important role in degenerative aging. While numerous companies are developing forms of senolytic therapy to selectively destroy senescent cells, few have yet undertaken clinical trials. While novel approaches to clearing senescent cells or modulating their harmful behavior are discovered every year, the number of startup biotech and pharmaceutical companies focused on cellular senescence seems to have plateaued for now. This is a part of the field that, while well funded, could justifiably be funded to a much higher level than is presently the case. The mountain of animal data, that repeatedly, in scores of studies, demonstrates the capacity to rejuvenate tissues throughout the body and turn back the progression of age-related conditions, should be justification enough.

Biological mechanisms of ageing and potential therapeutic targets

Ageing is a natural and complex process that can be generally characterized by a slow and progressive physical and cognitive decline during adulthood, leading to impaired autonomic functioning and increased vulnerability to disease and death. It results from a series of biological changes that drive the accumulation of molecular and cellular damage over time, affecting cells, tissues, organs, and ultimately the entire organism. Thus, the classic view of ageing is linked to disease: one is the door that leads to the other, to the point that, socially, we associate both concepts and we see old people as sick and frail by default. Separating ageing from disease, and thus promote healthy ageing, is one of the biggest challenges of both science and the health systems.

Despite the growing insights into the biology of the ageing process, our current understanding on the complexity of multi-organ ageing and its dynamics is still limited. The first challenge is defining biological ageing itself. Currently, there is no consensus set of markers that can produce a list of organ-specific figures related to their actual biological age. Measurements of telomere length or epigenetic clocks are routinely used to estimate biological ageing, despite only covering one of the many facets of ageing. Moreover, although these are powerful tools to describe health associations in large populations, they are not designed for prediction of health at individual level, mostly due to their large variability. Thus, better makers of biological ageing are needed in order to have predictive tests with clinical impacts, and this will only come with a better understanding of the enormous complexity of the underlying molecular mechanisms of ageing.

Two major groups of theories to explain the mechanisms that lead to ageing have been proposed: the error-based and the program-based theories. The first consider ageing as a stochastic process caused by the accumulation of errors and damage in cells and tissues, both as a consequence of intracellular and external damages, as well as a less-effective system repair with time. This would include molecular processes like DNA damage, mitochondrial dysfunction, or telomere attrition. On the other hand, the program-based theories consider that individuals are partly genetically and developmentally quasi-programmed organisms and that healthy ageing would be the result of extending this programmed correctly functioning phase. As an example, there would be developmental pathways that keep working even past adulthood or mechanisms that are beneficial during the reproduction stage, like genes or certain hormones, that can be detrimental in the later stages.

There have been several attempts to classify the molecular mechanisms and biological processes associated with ageing. A landmark paper proposed 9 initial hallmarks of ageing, which were later expanded to 12, defined as factors that manifest with ageing and that, when aggravated or ameliorated experimentally, worsen or improve the ageing process. These hallmarks cover a wide variety of biological processes (from DNA damage to loss of stem cells or shortening of telomeres), but must of them seem to converge in what could be considered one of the most relevant hallmarks: the accumulation of senescent cells.

Most of the hallmarks related to stress (such as increased genomic instability, telomere shortening, metabolic changes, epigenetic changes, etc.) are potent inducers of senescence. In turn, senescence contributes essentially to other hallmarks, such as the alteration in intercellular communication or the depletion of stem cells. Moreover, the accumulation of senescent cells provides a clinically relevant target and is currently the hallmark that has more advanced therapeutic options in study. Although significant improvement of ageing phenotypes will undoubtedly require multimodal approaches, strategies to address the buildup of senescent cells in organs is likely to be the first pharmacological intervention to delay biological ageing that will be available to treat age-related diseases.

The dominant forms of cancer therapy, chemotherapy and radiotherapy, induce senescence in cancer cells they cannot kill, as well as in non-cancerous cells exposed to the treatment. Entering the senescent state is a response to a high level of stress and damage that isn't sufficient to kill the cell. A senescent cancer cell no longer replicates, and so promoting senescence continues to be seen as an acceptable goal to hinder the cancer. Cancer survivors are left with a high burden of cellular senescence, however, and as a result exhibit accelerated aging: higher mortality, higher risk of age-related conditions, including other cancers. Senotherapeutics such as senolytic drugs to selectively destroy senescent cells offer the possibility of dramatically reducing the consequences of an increased burden senescence induced by cancer therapies.

Therapy-induced senescence (TIS) has emerged as a central biological response to anticancer therapies, extending beyond tumor suppression to influence long-term tissue homeostasis, cardiovascular (CV) remodeling, and accelerated biological aging. Chemotherapy, radiotherapy, targeted therapies, and emerging immune-activating treatments can induce senescence not only in malignant cells, where it may initially contribute to tumor growth arrest and immune-mediated clearance, but also in non-malignant CV tissues. Persistent accumulation of senescent cells and sustained release of the senescence-associated secretory phenotype (SASP) represent a double-edged sword that may promote chronic inflammation and endothelial dysfunction while contributing to the exacerbation of multifactorial CV outcomes, including myocardial fibrosis, vascular stiffness, and progressive CV dysfunction.

Increasing evidence suggests that TIS-associated mechanisms - including persistent DNA damage response activation, p53/p21- and p16INK4a-mediated cell-cycle arrest, NF-κB-driven inflammatory signaling, mitochondrial dysfunction, oxidative stress, and metabolic rewiring - overlap with pathways involved in CV toxicity and systemic tissue remodeling. Through chronic inflammatory and immune-vascular crosstalk, TIS may contribute to a broader phenotype of inflammaging and therapy-associated premature biological aging.

Emerging senescence-targeting strategies, including senolytic and senomorphic therapies, represent promising approaches to mitigate long-term CV injury while preserving antitumor efficacy, although their clinical benefit and safety remain to be fully established. This review summarizes current knowledge regarding the dual and systemic role of TIS in cancer and CV disease, considering TIS as a candidate, non-exclusive mediator acting alongside direct therapy-related injury, and discusses its translational implications for integrated precision cardio-oncology strategies.

Link: https://doi.org/10.3389/fcvm.2026.1951892

Rentosertib is a TNIK inhibitor developed by In Silico Medicine in the course of the company's efforts to find drugs that can affect aging, shown to be anti-fibrotic, and thus recently in a phase 2 trial for the treatment of idiopathic pulmonary fibrosis. Here, the researchers provide evidence from multiple proteomic aging clocks to bolster the claim that this isn't just another anti-fibrotic drug candidate attempting to incrementally improve on what has come before, but does actually affect mechanisms of aging. There are of course already drugs that clearly affect mechanisms of aging to some degree - rapamycin and related rapalog molecules are perhaps the most robust when it comes to available data. But one can't raise the funds needed to run large trials to quantify and prove effects on aging in humans for a low-cost drug with no patent protection, as that drug cannot produce a large enough return on investment to motivate investors to fund the very expensive regulatory process. Thus the first drugs with robust data for modest effects on aging in humans will most likely be expensive, novel therapies. This is unfortunately the way the world works, or at least the way it works given the present approach to regulation of medicine.

Decades of progress in identifying mechanisms of aging and therapeutic targets to modulate them have revealed a tremendous overlap with central regulators of disease. Consequently, recent efforts in developing therapies to treat aging-related diseases often identify regulators of aging as promising disease targets. Drug repurposing efforts have highlighted the potential of treatments developed for one aging-related disease to modulate other aging-related diseases or longevity more generally, due to shared underlying pathway dysregulation coalescing around the hallmarks of aging. The aging field now faces a critical methodological question in translating biological insights into actionable clinical results: how best to measure the effects of an intervention on biological aging from data collected in clinical trials.

Proteomic clocks, by tracking the immediate effectors of biological change, may excel in providing aging biomarkers or mechanistic insight. Here we compare six proteomic clocks (ProtAge, OrganAgemortality, OrganAgechrono, PAC, ipfP3GPT and PAOPAC) on serum proteomes from a published 12-week phase 2a trial of the candidate anti-fibrotic drug rentosertib in idiopathic pulmonary fibrosis. We measure the variance between the clocks and find that all six clocks consistently predicted lower biological age in treated arms. However, proteomic clocks alone cannot deconvolute aging- and disease-specific effects. We addressed this issue indirectly through pathway analyses that identified potential anti-aging shifts in senescence and metabolic processes alongside the anti-fibrotic activity of rentosertib.

Link: https://doi.org/10.1038/s41587-026-03286-y

Do we need to fully understand aging, how exactly it works in fine detail, in order to create rejuvenation therapies that are effective enough to make the effort worthwhile? One would expect not, based on the present state of field, but also expect that the process of creating rejuvenation therapies should become ever easier as knowledge accumulates. One can find dead ends and failures by falling into them, or by knowing in advance not to go that way. The former requires considerably greater effort and expense. The present understanding of aging is much advanced over past decades, but still woefully incomplete: it is impossible to determine in advance whether any given mechanism is more or less important than any other; everything interacts with everything else, and researchers do not yet have a full map of those interactions; and what is cause and what is effect is often up for debate. Yet this incomplete state of knowledge exists in parallel with the generation of, for example, a mountain of preclinical data in aged mice for meaningful degrees of rejuvenation achieved via partial clearance of senescent cells.

Today's open access paper by a senior figure in the field of aging research is something of a complaint against engineering, against moving ahead with partial knowledge, and along the way a denial of meaningful progress to date via single interventions. Or at the very least, the author opposes the rhetoric of engineering ("we think we have it this time!") percolating back into the scientific community. A few fair points are made in there about the state of affairs in aging research, but it does represent a very conservative scientific viewpoint: understanding before action, and much of what presently looks promising in terms of addressing causative mechanisms of aging is a mirage. Both of these points can be strongly argued against. For the first, understanding before action is just not the way things work in the messy real world we live in. Partial understanding followed by many attempts at actions likely to fail is the usual path ahead - and we are almost certainly better off because eager engineers convince themselves that something is worth a shot, pick up incomplete science, and try to make it work, even if they talk about this process and gather support for their efforts in ways that annoy scientists.

The point here is that, in most fields, the fastest path to understanding is to repeatedly build and fail, and occasionally build and succeed, well before the point of sufficient understanding to succeed at the outset. To return to senescent cells, the sizable rejuvenation resulting from clearing senescent cells in aged mice was surprising to just about everyone in the aging field, and caused a sizable reallocation of resources towards this approach to aging. If no-one had forged ahead to try, then today the field of senescence in aging would still consist of a small number of researchers debating whether or not senescence was a meaningful contribution to degenerative aging.

Seven ways not to think carefully about aging

The principal theme of this polemic is that developing a consistent, defensible conceptual framework about aging and its control is the most important step towards developing ways to promote human health by postponing aging. Alas, the field is rife with indefensible, but highly influential conceptual frameworks and latent assumptions whose pursuit is leading to dramatic progress in the wrong directions. In this article, I will use "aging" to refer to the process that converts a healthy young adult, such as a college sophomore, into an aged person, perhaps 60 to 80 years old, with diminished functional performance in many domains, a growing collection of health concerns, and a progressively increasing risk of death.

It is important to note a key element of this definition. It defines aging as something that happens to a whole organism (mouse, worm, fly, human). This form of aging does not happen to something that is not a whole organism, like, for example, a cell in culture or a cell in an aging person. It is entirely possible, within this proposed definition, that aging (of a mouse or person) might lead to changes in their constituent cells, or might be caused by changes in their constituent cells. Those are interesting, empirical, testable questions. But to discuss them cogently, one cannot use the word "aging" in two different senses, i.e., to refer to a process that alters intact organisms and also to things that can occur in individual cells.

The underlying observation here is that among any representative set of older people, e.g., a batch of 70-year-olds, some will have strong evidence of age-related problems in multiple functional domains, and others will have escaped, to an impressive degree, most of the ill consequences that afflict those in the same age cohort. It is tempting to say that members of the latter group are "biologically younger" than average, and that they have a "biological age" that is less than their calendar age of 70 years. But the introduction of a construct like "biological age" to discussions of the biology of aging is a distinct step backward, a serious obstacle to thinking carefully about the biology of aging. The fundamental error here is "reification," the mistake of treating an abstract idea as though it were a real thing, as though the map were the territory.

"Aging clocks" appear to have value to researchers, to research administrators, to laypersons, and to worried people who are tempted to purchase a commercial estimate of their own biological age. This complacent acquiescence leads to acceptance of claims that "Taking Drug X made the treated population younger" based solely on clock data, without parallel evidence on well-validated age-sensitive functional outcomes. The use of some clock-branded metric as though it were measuring a real thing, i.e., measuring "biological age," has become a very common feature of modern biogerontological discourse, with major effects on the choice of problem by researchers and the choice of investment strategy by those with funds to allocate.

It is now common for scientific administrators and many researchers to endorse the solemn pledge that they are focused on healthspan, and definitely not on lifespan. Newcomers to the field quickly absorb the notion that research on how to keep old people healthy is good, and research on how to keep people alive for longer is bad, perhaps shameful. The error here is the assumption that there is a trade-off to be made between enduring health and increasing lifespan-the "seesaw" model in which improvements in lifespan require diminished health. But in the context of research aimed at extending healthy lifespan by modulating the pace of aging, both logic and experimental data support models in which good health and longer lifespan go hand in hand, more like an elevator than a seesaw. This is entirely to be expected because prolongation of good health is the most direct and obvious way to increase life expectancy in adults.

Far too many talks, pitches, and grant proposals begin with an image of a wheel showing purported hallmarks of aging, based initially on a series of papers that attempted to tabulate key aspects of cell and molecular biology that supposedly were the main elements of aging. The criteria themselves are highly problematic: processes that change with age, for example, are much more numerous and easier to discover than the very small subset of processes known to retard aging in mammals. They are also much less likely to be related to the factors that can retard the aging process, and are a relic of the attitude that discovering "the cause of aging" was a worthwhile endeavor.

But in addition to these conceptual weaknesses, the Hallmarks movement represents a significant obstacle to aging research, both for what it includes and for what it fails to include. A researcher trying to choose a new area for research, or an administrator or reviewer asked to judge the significance of a specific research proposal, is very often rendered complacent by the imprimatur conferred by Hallmark designation. If, for example, the authors of the Hallmarks table have decided that cellular senescence, or genetic instability, or changes in gut bacterial populations are important enough to include on their list, this designation tempts readers to avoid thinking about the nature, source, strength, and consistency of the evidence underlying Hallmark designation.

For many decades, biogerontologists devoted their careers to testing specific ideas about the (supposed) cause of aging. The hope was that once the cause of aging had been identified (perhaps it was cellular senescence, or mitochondrial mutations, or stem cell exhaustion, or somatic mutations...), this might point to identification of drugs that would slow aging by blunting its cause. Pointing out the weaknesses in this conceptual scheme has been a central goal of this review. Blocking any one of the dozens of insults that cause aspects of late-life decline would not be expected to retard the overall aging process to an important degree.

A great many proteins and other molecules might be capable of mild geroprotective effects, slightly slowing aging, or slightly improving late life health. As a general rule, proposed mechanisms for potentially geroprotective effects found in the literature are usually correct. The open question is always the size of the effect produced by those mechanisms in humans. Firm data is usually lacking, and the only practical way to determine outcomes is to run expensive, lengthy clinical studies. Those expensive, lengthy studies are not usually put together for low-cost interventions, and thus the state of uncertainty continues, fueling a supplement industry and anti-aging medical community that runs on marketing rather than facts. This paper discusses lactoferrin supplementation, a good example of a basis for therapy that falls into this category. There is lot of interesting and suggestive mechanistic evidence, but very little beyond that when it comes to outcome measures that might shed light on the impact on aging.

Lactoferrin (LF) is an iron-binding glycoprotein composed of two homologous lobes, each capable of binding one ferric iron ion. LF varies based on iron saturation, with apo-LF representing the iron-depleted form and holo-LF the iron-saturated form. LF is best understood as a multifunctional protein, with pleiotropic biological effects, including prebiotic activity, facilitation of iron absorption, and support of immune function. Clinical studies further indicate that LF promotes the growth of beneficial gut microorganisms and supports intestinal health and immunity. Because LF has been well tolerated in human trials, without a meaningful increase in adverse effects, it has the potential to benefit aging populations.

LF has traditionally been studied in the context of host defense, iron regulation, gastrointestinal health, and immune function. Evidence of LF's effect on healthy aging remains limited. LF demonstrates regulatory activity that aligns with key drivers of biological aging: preservation of epithelial barrier function, modulation of microbial composition, regulation of iron trafficking, attenuation of NF-κB-IL-6 signaling, enhancement of antioxidant defenses, and support of autophagic and mitochondrial quality control pathways. Although much of the mechanistic evidence remains preclinical, emerging human studies suggest favorable effects on inflammatory biomarkers, immune activation profiles, and iron parameters. However, whether these mechanistic and biomarker effects translate to meaningful functional outcomes in older adults remains to be established.

Link: https://doi.org/10.3390/nu18203319

Fatty liver disease, or at least the non-alcohol induced side of fatty liver disease, more properly known as metabolic dysfunction-associated steatotic liver disease (MASLD) is largely an outcome of obesity. Obesity is now known to promote an accelerated age-related accumulation of senescent cells in many tissues. It is not surprising to find cellular senescence in liver cells as an important mechanism in the progression of MASLD to more severe and ultimately fatal liver conditions. Treating the consequences of obesity with senotherapeutics does not appear a priority for the research and development community, but in fairness a great many more severe conditions have not yet made it onto that still short priority list either. There are only so many researchers and entrepreneurs in the field, and senotherapeutics can in principle treat a very large number of conditions, given the importance of cellular senescence in aging.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is sustained not only by lipid overload and hepatocellular injury but also by maladaptive responses to persistent metabolic stress. Cellular senescence has emerged as a candidate mechanism linking metabolic stress to persistent inflammation and fibrosis. This short review aims to examine how hepatocyte senescence develops and persists in MASLD, how senescent hepatocytes interact with immune surveillance, and how senescence-associated secretory phenotype (SASP) signaling contributes to fibrotic remodeling. We synthesized recent human, animal, and in vitro evidence, prioritizing mechanistic studies directly addressing hepatocyte senescence, immune cell interactions, SASP signaling, and fibrosis, while retaining landmark studies where they provided essential mechanistic context.

Current evidence indicates that senescent hepatocytes accumulate in experimental and human MASLD and can influence macrophages, hepatic stellate cells, liver sinusoidal endothelial cells, and neighboring hepatocytes. Under conditions of effective immune surveillance, senescence may remain transient and contribute to the removal of damaged cells. In a chronically injured liver, however, continued generation of senescent hepatocytes, altered immune-cell function, and persistent SASP signaling may favor their retention and promote inflammatory and fibrogenic remodeling. Important uncertainties remain, including the lack of universal senescence markers, limited direct evidence for defective senescent-hepatocyte clearance in human MASLD, and the context-dependent effects of senescence across hepatic cell types.

Overall, available evidence supports hepatocyte senescence as a plausible contributor to MASLD progression, but its pathogenic importance appears to depend on cellular context, immune competence, and the duration of the senescent state. Defining these conditions will be important for developing senescence-directed therapies without disrupting beneficial repair responses.

Link: https://doi.org/10.3389/fimmu.2026.1982821

Nuclear DNA structure determines which genes are transcribed into RNA. The molecules making up the machineries of transcription move around the nucleus to interact with every sequence of DNA they can reach. Regions of DNA that are spooled onto histone molecules and compacted are hidden, and those genes are thus silenced and not expressed. Regions of DNA that are unspooled are accessible to transcription machinery, and those genes are actively expressed. Nuclear DNA structure changes constantly, controlled by the addition and removal of decorating molecules at specific locations on DNA and histones. This is known as epigenetic regulation, a highly complex layer of interaction between cell state and pattern of gene expression.

Epigenetic control of DNA structure changes with age. Some of this may be a consequence of repeated cycles of DNA repairrand consequent depletion of molecules needed to maintain the normal status quo. The rest is a downstream consequence of other age-related changes, some of it useful, some of it maladaptive. Searching for age-related changes in epigenetic marks that are both important and harmful is not a bad strategy at this point in the state of knowledge regarding epigenetics and aging, but it is complicated by the context-dependent nature of much of epigenetics. Nonetheless, by this point in the study of epigenetics some epigenetic decorations are well studied enough to have recognizable names, which largely means the methylation of specific locations on specific histone molecules, as these affect the expression of large numbers of genes. Today's open access paper is any example of a successful foray into this part of the field, yielding a possible approach to therapies for neurodegenerative conditions.

H3K9me3 inhibition reverses Alzheimer's progression by restoring synaptic and immune proteostasis across the brain-retina axis

Epigenetic dysregulation is increasingly linked to aging and neurodegeneration, yet its contribution to retinal and brain pathology in Alzheimer's disease (AD) remains unclear. We quantified the repressive epigenetic mark histone H3 lysine 9 trimethylation (H3K9me3) in post mortem retinas and brains from donors spanning normal cognition, mild cognitive impairment, and AD dementia. H3K9me3 increased early across the AD continuum in both brain and retina, correlating with cognitive impairment and neuropathological burden. H3K9me3 levels were strongly correlated between matched brains and retinas.

We characterized the in vitro inhibitory activity of ETP69, an epidithiodiketopiperazine, against suppressor of variegation 3-9 homologue 1 (SUV39H1) and other methyltransferases. In two transgenic AD mouse models (APPswe/PS1dE9 and APPswe/tauP301L/PS1tm1Mpm), we assessed ETP69 effects on cerebral H3 methylation, behavior, AD-like pathology, synaptic integrity, and proteomic profiles. This pharmacological H3K9me3 reduction consistently reduced cerebral H3K9me3 relative to other histone marks assessed, mitigated AD-like pathology, preserved synapses, and improved short-term and long-term cognitive and visual performance. Proteomics revealed that H3K9me3 derepression re-established retinal and brain proteostasis and remodeled innate immune pathways and brain-derived neurotrophic factor/nerve growth factor-inducible protein (BDNF/VGF)-granin signaling.

Hormone replacement therapy is a popular treatment for women leading up to or following menopause. Manipulating sex hormones is a very blunt strategy, with potentially significant downsides, and a high variation in outcomes between patients, but the medical community has accumulated a great deal of experience in delivering this class of therapy. In the matter of assessing how this sort of approach affects aging, the research community is presently engaged in a process of gathering as much data as possible on how aging clocks interact with various therapies thought to influence aging or age-related disease. The accuracy of the clocks in the environment of any given therapy is unknown, and the effect of the therapy on the clock is unknown, and so the way forward is to obtain as much data as possible to illuminate the space of the possible and enable better judgements on how to move ahead. The clocks and the therapies are being calibrated against one another simultaneously.

Epigenetic age acceleration (EAA) is a critical biomarker of aging. Hormone replacement therapy (HRT) is commonly used to alleviate age-related diseases, while glycemic status also influences the aging process. We aimed to investigate the association between estrogen and EAA, and the effects of HRT, EAA, and glycemic status on mortality. Mendelian randomization (MR) established causal relationships between genetically predicted estrogen receptor expression and EAA markers (HorvathAA, HannumAA, PhenoAA, and GrimAA). Using data from the National Health and Nutrition Examination Survey, we employed Cox proportional hazards models to analyze the association between HRT and mortality, exploring whether it was modified by EAA and glycemic status.

Elevated estrogen receptor α (ESR1) expression significantly decelerated PhenoAA (β -1.26). HRT significantly correlated with a reduced risk of all-cause (hazard ratio, HR: 0.65) and cardiovascular (HR: 0.52) mortality. Additionally, there was a significant three-way interaction among HRT, two types of EAA (HorvathAA and PhenoAA), and abnormal glucose status. Stratified analyses showed no significant interaction in the normal glucose subgroup; however, a significant antagonistic interaction emerged between HRT and both HorvathAA and PhenoAA in the abnormal glucose subgroup. Consequently, although HRT exhibited a protective main effect in patients with abnormal glucose, its survival benefits were significantly attenuated as their epigenetic aging accelerated.

Link: https://doi.org/10.1186/s13293-026-00959-w

It is by now well established that senescent cells promote senescence in neighboring cells. This is a useful and necessary part of the benefits of the transient presence of senescent cells in the contexts of cancer suppression and coordination of wound healing. But when senescent cell clearance falters in later life, and senescent cells begin to linger and accumulate, this promotion of further senescence makes matters worse. One of the ways in which senescent cells promote senescence is via relatively well mapped and well understood inflammatory signaling. Here, however, researchers note that there are other pathways involved, in which the signaling involves the contents of small extracellular vesicles. Interfering in senescent cell signaling as a basis for therapy is likely a more challenging path forward than selective destruction of senescent cells, but efforts are being made in both directions regardless.

Senescent cells accumulate during both physiological and pathological processes, including aging. They are characterized by the expression of the cell cycle inhibitor p16INK4A and the senescence-associated secretory phenotype (SASP). However, fibroblasts ectopically expressing p16INK4A do not exhibit a canonical SASP, leaving the mechanisms by which they communicate with their microenvironment largely unknown. Here, we show that human primary fibroblasts ectopically expressing p16INK4A release significantly more small extracellular vesicles (sEVs) than proliferating cells. Furthermore, we demonstrate that sEVs isolated from p16INK4A-expressing fibroblasts are biologically active and can mediate paracrine senescence in proliferating cells.

Specifically, treatment with these sEVs induces proliferative arrest, upregulates p16INK4A expression, and activates a DNA damage response in recipient cells. Notably, sEVs from p16INK4A-expressing cells do not induce the expression of the canonical SASP factors IL-6 and IL-8, suggesting that they promote senescence independently of a classical inflammatory response. We further demonstrate sEV-mediated transmission of paracrine senescence in two cellular models of aging: progerin expression and telomere dysfunction induced by a dominant-negative telomere mutant. In addition, sEVs isolated from fibroblasts derived from aged donors induce paracrine senescence in fibroblasts from young donors. Collectively, these findings identify sEVs released by senescent and aged cells as an important mechanism of intercellular communication and a key mediator of paracrine senescence.

Link: https://doi.org/10.18632/aging.206425

It is easier and less costly to theorize about aging than it is to run studies in mice and cells. Uncertainty also tends to inspire the generation of hypotheses, and our understanding of the fine details of degenerative aging remains in a state of considerable uncertainty. For all that biological data can now be accumulated with a level of accuracy and at rates that would shock the last generation of researchers, assembling that data into a coherent whole - in which it is fully understood and concretely proven as to how mechanisms of aging interact with one another, what is cause, what is consequence, what is more important, and what is less important - remains beyond present capabilities. There are certainly consensus views, but they are not yet set in stone. In this environment one can advance any number of reasonable novel views of how exactly aging progresses that more or less fit the data; this is a golden era for the generation of theories of aging.

Today's open access paper is an attempt to unify the traditional damage accumulation view of aging, in which forms of cell and tissue damage produce dysfunction that eventually overwhelms the organism, with the more recent hyperfunction view of aging, in which developmental programs run off the rails by continuing to operate into later life, producing dysfunction that eventually overwhelms the organism. Where these two viewpoints share common ground is around the evolutionary arguments as to why aging is near universal, in that natural selection operates more strongly on features of early life than on features of late life. Early reproductive success at the cost of later dysfunction tends to win out, so evolution near always produces biological systems that work well in early life but then fall apart. Exceptions exist, but are few and far between.

From hyperfunction to systemic amplification: reframing the logic of late-life rejuvenation

Aging is often modeled, and interventions prioritized, as the near-linear accumulation of cell-intrinsic lesions; yet the exponential acceleration of late-life mortality under the Gompertz law points to an active, program-like component shaping the trajectory. Furthermore, systemic interventions - including therapeutic plasma exchange and extracellular-vesicle-based therapies - together with the transient embryonic rejuvenation phase, can induce rapid, broadly coordinated organism-level rejuvenation on timescales difficult to attribute to gradual repair alone.

Here, we propose an integrative-first load-gain framework in which primary lesions provide the damage load, while the systemic communication architecture sets the gain: a systemic hyperfunction of intercellular signaling that converts slow cellular inputs into self-amplifying late-life acceleration. This architecture provides a mechanistic basis for both the embryonic biological-age reset and Gompertzian late-life acceleration by positioning organism-level coupling as a central gain-setting layer governing aging trajectories. It further implies regime-dependent therapeutic leverage: cell-autonomous approaches are most effective as early-life prevention and may slow progression in midlife, but durable late-life reversal requires systemic signaling reset that suppresses amplification and restores buffering capacity.

By treating rejuvenation as a shift in the organism's regulatory state rather than local lesion repair, the framework positions partial reprogramming and other cell-autonomous strategies as complementary to systemic recalibration and most effective within a rejuvenated systemic milieu.

The state of the gut microbiome is at least as influential on long term health as lifestyle choices like exercise. The composition of the gut microbiome changes with age for reasons yet to be fully explored. Inflammatory populations grow at the expense of populations producing metabolites necessary for tissue function. Connections can be drawn between near every organ and system in the body and specific metabolites or specific microbial populations influencing them. In turn the immune system and other organs influence the gut microbiome. Fortunately, it is possible to produce the lasting restoration of a more youthful gut microbiome via strategies such as flagellin immunization and fecal microbiota transplantation. Unfortunately, probiotic and related strategies are as yet incapable of producing such sizable and lasting changes, though there is hope that much more complex and carefully designed probiotic mixes could in the future approach the results obtained via fecal microbiota transplantation.

The intestine engages in communication with various distant organs through neural, immune, and endocrine pathways. This systemic interconnection mechanism is referred to as the gut-organ axis, in which gut microbiota play a central role. This review systematically examines the complex and bidirectional interactions between the gut microbiota and the brain, liver, lungs, kidneys, bones, heart, skin, germline, and immune system. Central to these interactions are microbial metabolites - fatty acids, secondary bile acids, and tryptophan derivatives - that act as crucial systemic signals engaging key receptors in the brain, liver, and beyond.

Studies demonstrated that the composition of the gut microbiota and alterations in its metabolites can directly or indirectly regulate the physiological and pathological processes of various organs. Biological therapies, such as fecal microbiota transplantation and probiotic interventions, can establish a healthy intestinal environment by reshaping the intestinal microecology, thereby positively influencing related diseases. The therapeutic landscape is rapidly evolving, with next-generation probiotics, postbiotics, and engineered strains now enabling precise, targeted remodeling of the gut ecosystem to restore host homeostasis and treat multi-organ diseases. This review articulates how the gut microbiota integrates environmental cues into a multi-organ regulatory network, underscoring its potential as a therapeutic target for systemic diseases.

Link: https://doi.org/10.1016/j.tmed.2026.100042

The only viable way to definitively establish the importance of any given mechanism of action is to create a therapy that selectively prevents or repairs that mechanism without touching the other mechanisms of aging, and then observe the outcomes in aged animals. This is a challenge, and typically the results are a surprise; until the development of senolytic therapies, no-one expected clearance of senescent cells to be so very effective at reversing age-related disease in animal models, for example. Because it is hard to determine the relative importance of mechanisms of aging, much of the aging research community often resembles a collection of small fiefdoms, each advocating for the importance of their small portion of degenerative aging, in the absence of concrete proof of that importance. This is worth bearing in mind when looking at new viewpoints, such as the concept of ferro-aging advanced here.

In recent years, with increasing research on ferroptosis, abnormal iron metabolism has gradually been recognized as an important pathological basis for aging-related diseases. Iron is an essential trace element for oxygen transport, energy metabolism, and DNA synthesis. However, excess free iron can generate large amounts of reactive oxygen species (ROS) through the Fenton reaction. This induces lipid peroxidation, DNA damage, and cellular dysfunction.

Traditionally, iron overload has been thought to promote tissue damage primarily by triggering ferroptosis; Nevertheless, recent studies have proposed a new concept distinct from ferroptosis - ferro-aging. Ferro-aging is not an acute form of cell death but rather a chronic pre-pathological state characterized by persistent lipid peroxidation and progressive cellular dysfunction. Although cells in the ferro-aging state retain membrane integrity, they can sustain irreversible damage and continuously affect the local microenvironment through the formation of the senescence-associated secretory phenotype (SASP), ultimately contributing to tissue functional decline and systemic aging,

This review systematically summarizes the molecular basis of ferro-aging, with a focus on the central role of ACSL4 in promoting membrane lipid remodeling and sustaining chronic lipid peroxidation. We discuss how ACSL4-associated ferro-aging contributes to the pathogenesis of osteoporosis (OP), osteoarthritis (OA), and intervertebral disc degeneration (IVDD) by disrupting local microenvironmental homeostasis, driving metabolic reprogramming, amplifying inflammatory SASP signaling, and impairing the function of key cell types such as osteoblasts, chondrocytes, and nucleus pulposus cells.

Link: https://doi.org/10.1186/s12964-026-03194-3

Cells contain hundreds of mitochondria, constantly fusing together, replicating by splitting apart, and swapping component parts. Mitochondrial function is vital to cell health, and declining mitochondrial function is an important component of degenerative aging. Some of the answers as to why mitochondrial function declines with age are likely buried somewhere in the complex interactions of mitochondrial structure, the dynamics of mitochondrial fusion and fission, and the operation of the mitochondrial quality control processes of mitophagy. Mitophagy is both necessary to maintain function by destroying worn mitochondria, but it also seems quite sensitive to changes in structure and size of mitochondria, as happens when the dynamics of fusion and fission change.

In today's open access paper, researchers demonstrate that compounds that improve the activity of mitofusin, a protein that is important in mitochondrial fusion, lead to improved mitochondrial function and slowed aging in short-lived nematode worms. This is perhaps more interesting than the average result of this nature because at least one mitofusin activator is somewhere in the process of development as a human therapy. Nonetheless, when it comes to modulating mitochondrial dynamics, a survey of the literature will show papers in which benefits arise from inducing greater fission, greater fusion, and greater equilibrium. In short, it is complicated, and one shouldn't take any individual result as promising without looking at contradictions that characterize the broader field of such efforts.

Mitofusin Activation Delays Aging in Caenorhabditis elegans

Age-linked tissue dysfunction is associated with mitochondrial degeneration manifested as organelle fragmentation and respiratory dysfunction. Efforts to mitigate downstream consequences of mitochondrial degeneration, as with reactive oxygen species (ROS) scavengers, have not translated to the human condition. We posit that intrinsic fusion-mediated mechanisms for mitochondrial protection modulate aspects of aging linked to mitochondrial abnormalities. In C. elegans roundworms mitochondrial fusion is mediated by the mitofusin ortholog Fuzzy Onion-1 (fzo-1).

Here, the addition of a mitofusin inhibitor, MFI8, to cultures of age-synchronized C. elegans shortened worm lifespan in a concentration-dependent manner. Reciprocally, the mitofusin activators Chimera and 8015-P2 prolonged worm survival in a dose-dependent manner. The pro-survival effect of Chimera was absent in worms lacking its protein target, FZO-1, and at lower concentrations Chimera-amplified survival was further increased by absence of the mitochondrial fission protein that acts in opposition to fzo-1, DRP-1. The mitofusin activator 8015-P2, which is more potent than Chimera, exhibited greater anti-aging effects on lifespan and improved worm healthspan measured as forced swimming activity and resistance to thermal and oxidative stresses.

These proof-of-concept worm studies identify aging phenotypes reciprocally related to fzo-1/mitofusin activation status. As 8015-P2 is under development for use in human neurodegenerative diseases, it might alleviate aging phenotypes evoked by mitochondrial degeneration in higher species.