Fight Aging!

The degree to which human longevity is inherited is one of a large number of interesting research topics that, while being related to aging, has little to no relevance to the question of how to treat aging as a medical condition. In developing means to repair or resist the cell and tissue damage that causes degenerative aging, the focus must be on the damage, not the differences from individual to individual. How it is that aging progresses somewhat differently from individual to individual will become increasingly irrelevant as therapies to slow and reverse aging emerge.

That said, today's open access paper on the heritability of longevity is quite interesting. The argument put forward by the authors is that previous efforts to quantify the degree to which individual variance in longevity is determined by one's immediate ancestry have produced underestimates because they failed to properly compensate for the effects of premature death resulting from accidents, infectious disease, and the like. If the strategy for assessment used in the paper is employed instead, then human heritability of longevity is higher than past results, and also more in line with the heritability of other physical traits.

At the same time, the big picture on the genetics of aging that has emerged in recent years, with the advent of very large population databases such as the UK Biobank, is that genetics plays only a small role in determining life expectancy. It is far outweighed by lifestyle choice in the vast majority of people. A high heritability but low contribution of genetic variance suggests that heritability largely exists as a result of the cultural transmission of lifestyle choices; parents that take better care of their health tend to have children who take better care of their health, and vice versa.

Heritability of intrinsic human life span is about 50% when confounding factors are addressed

Understanding the heritability of human life span is fundamental to aging research. However, quantifying the genetic contribution to human life span remains challenging. Although specific life span-related alleles have been identified, environmental factors appear to exert a strong effect on life span. Clarifying the heritability of life span could direct research efforts on the genetic determinants of life span and their mechanisms of action.

Previous studies have estimated the heritability of life span in various populations with results ranging from 15 to 33%, with a typical range of 20 to 25%. Recently, studies on large pedigree datasets estimated it at 6 to 16%. These studies contributed to growing skepticism about the role of genetics in aging, casting doubt on the feasibility of identifying genetic determinants of longevity. Current estimates for the heritability of human life span are thus lower than the heritability of life span in crossbred wild mice in laboratory conditions, estimated at 38 to 55%. They are also lower than the heritability of most other human physiological traits, which show a mean heritability of 49%.

Most life-span studies used cohorts born in the 18th and 19th centuries, with appreciable rates of extrinsic mortality. Extrinsic mortality refers to deaths caused by factors originating outside the body, such as accidents, homicides, infectious diseases, and environmental hazards. Another factor that varies between studies is the minimum age at which individuals must be alive to be included, referred to as the cutoff age. To our knowledge, these two factors - extrinsic mortality and cutoff age - have not been systematically investigated for their effect on heritability estimates of life span.

Here, we explored the effects of extrinsic mortality and cutoff age on twin study estimates of heritability. We used model-independent mathematical analysis and simulations of two human mortality models to partition mortality into intrinsic and extrinsic components. We tested our conclusions on data from three different twin studies, including the SATSA (Swedish Adoption/Twin Study of Aging) study, containing data from twins raised apart that have not been previously analyzed for life-span heritability. To test generalizability to non-Scandinavian cohorts, we also analyzed siblings of US centenarians. We found that extrinsic mortality causes systematic underestimates of the heritability of life span and that cutoff age has a mild nonlinear effect on these estimates. When extrinsic mortality is accounted for, estimates of heritability of life span due to intrinsic mortality rise to about 55%, more than doubling previous estimates.

This is an example of the very earliest stages of research leading to drug discovery, the identification of a potential target protein, here CUL5, that can be manipulated to change cell metabolism in a specific way, here meaning a reduction in the amount of tau protein in the cell. Aggregation of altered tau is a feature of late stage Alzheimer's disease, a cause of cell dysfunction and death in the brain. Reducing tau levels is one possible approach to the problem, though given that tau has a normal and necessary function in the brain, it may not be the best possible approach. At this stage, researchers do not know how CUL5 functions to affect tau levels, and thus a good deal of further work stands between the present discovery and the emergence of any practical outcome.

Aggregation of the protein tau defines tauopathies, the most common age-related neurodegenerative diseases, which include Alzheimer's disease and frontotemporal dementia. Specific neuronal subtypes are selectively vulnerable to tau aggregation, dysfunction, and death. However, molecular mechanisms underlying cell-type-selective vulnerability are unknown. To systematically uncover the cellular factors controlling the accumulation of tau aggregates in human neurons, we conducted a genome-wide CRISPR interference screen in induced pluripotent stem cell (iPSC)-derived neurons.

In comparison to other tau screens previously reported in the literature, our data have broadly similar patterns of hit genes. A previous genome-wide screen for modifiers of tau levels performed in SHY5Y cells has several shared classes of genetic modifiers. Surprisingly, this screen identified CUL5 as a negative modifier of tau levels. Since CUL5 regulates hundreds of substrates, it is not surprising that CUL5 knockdown has different phenotypes in different contexts.

We find CUL5 expression to be correlated with resilience in tauopathies along with genes encoding CUL5 interactors, including ARIH2 and SOCS4. However, the molecular mechanisms by which CUL5 affects neuronal vulnerability in AD remains to be identified. A broad distribution of CUL5 expression is seen in different neuronal subtypes in the Seattle Alzheimer's Disease Brain Cell Atlas suggesting that CUL5 may modulate disease vulnerability via multiple mechanisms. For instance, it is possible that CUL5 expression affects vulnerability via tau ubiquitination. But, considering CUL5's known role in immune signaling, another possibility is that CUL5 expression affects vulnerability via the neuro-immune axis.

Link: https://doi.org/10.1016/j.cell.2025.12.038

Parkinson's disease is driven by the spread of misfolded α-synuclein through the brain. The most evident symptoms result from the death and dysfunction of motor neurons, caused by the presence of misfolded α-synuclein. Once α-synuclein misfolds, it is capable of inducing other molecules of α-synuclein to misfold in the same way, and this dysfunction can slowly spread from cell to cell. In recent years, researchers have shown that in a sizable fraction of Parkinson's disease cases misfolded α-synuclein first emerges in the intestines and then spreads to the brain. Here, researchers uncover more of the mechanisms by which this transmission takes place, with an eye to finding ways to intervene in the earliest stages of the condition in order to prevent later consequences.

Emerging evidence suggests that Parkinson's disease (PD) may have its origin in the enteric nervous system (ENS), from where α-synuclein (αS) pathology spreads to the brain. Decades before the onset of motor symptoms, patients with PD suffer from constipation and present with circulating T cells responsive to αS, suggesting that peripheral immune responses initiated in the ENS may be involved in the early stages of PD. However, cellular mechanisms that trigger αS pathology in the ENS and its spread along the gut-brain axis remain elusive.

Here we demonstrate that muscularis macrophages (ME-Macs), housekeepers of ENS integrity and intestinal homeostasis, modulate αS pathology and neurodegeneration in models of PD. ME-Macs contain misfolded αS, adopt a signature reflecting endolysosomal dysfunction and modulate the expansion of T cells that travel from the ENS to the brain through the dura mater as αS pathology progresses. Directed ME-Mac depletion leads to reduced αS pathology in the ENS and central nervous system, prevents T cell expansion and mitigates neurodegeneration and motor dysfunction, suggesting a role for ME-Macs as early cellular initiators of αS pathology along the gut-brain axis. Understanding these mechanisms could pave the way for early-stage biomarkers in PD.

Link: https://doi.org/10.1038/s41586-025-09984-y

Aging research is not a field marked by its unity. At the high level there is some degree of consensus on the need to treat aging as a medical condition, and that this is a plausible goal given time and effort. But ask questions about any particular detail regarding the mechanisms of aging, how to progress towards therapies, the bounds of the possible, and the state of the field, and you will usually find almost as many opinions as there are researchers to hold them. This is characteristic of a field of study in which far more remains to be discovered than has been mapped to date. The research community cannot be said to fully understand the cell, let alone how an organism made up countless cells of many diverse types changes over time.

Still, enough is known to make inroads. We can target senescent cells for selective destruction. We can replace mitochondria. We can reprogram epigenetic patterns. And so forth. We can have opinions on how well any specific class of therapy will perform, but only by earnestly trying a given approach - building the therapies, conducting the clinical trials, and bringing drug into widespread use - will we actually find out how well that approach works.

As recent history demonstrates, the creation of novel therapies is a slow process in the present environment of medical regulation. Ten years is a rapid pace for the move from idea to first clinical trial. Another decade might pass between that first trial and commercial availability of the resulting drug for the average patient. Success for any given line of research is not inevitable. Viable therapies can be completely ignored because the drugs involved are generic, or the approach otherwise cannot be effectively patented and monopolized. A long road lies ahead, given the way in which medical research and development is presently conducted.

Past, present and future perspectives on the science of aging

Juan Carlos Izpisua Belmonte: In the next decade, I expect aging research to move from describing decline to restoring function. High-resolution human datasets, from single-cell and spatial maps to longitudinal studies, will provide a clearer picture of how aging progresses across tissues. At the same time, systemic biology will become even more important, with interorgan communication and circulating signals serving as key therapeutic entry points. Clinically, biological age measures will help to personalize prevention and allow earlier intervention. In the long term, I am hopeful that these developments will reshape medicine.

Steve Horvath: Over the next 10 years, I expect the field to shift decisively from measuring aging to modulating it in humans. I hope that epigenetic clocks will continue to mature into tools for evaluating interventions in individuals and even at population scale. My hope is that the aging field will identify safe, well-tolerated interventions that are capable of rejuvenating multiple human organ systems.

Bérénice A. Benayoun: In the next decade, I think the future of our field will be precision geroscience - understanding what shapes aging trajectories and which levers can be potentially acted upon to promote long-term health, not only based on private unique genetic variation but also other important factors that we are just beginning to appreciate/

Steve N. Austad: I see a takeover by massive omics. I am not suggesting this is a bad thing. It will certainly lead to a personalization of health and medical treatments, but I don't think it will lead to the kind of breakthrough that something like antibiotics represented. I think there will be more interventions on the market over that time (mostly supplements) - some might even be effective, although I doubt they will outdo what the best lifestyle choices do now. Real breakthroughs, if they come, will be further out than 5-10 years.

Terrie E. Moffitt: Over the next 5-10 years, I envision aging research evolving into an era of close integration between basic and clinical sciences, much like what has been achieved in hypertension, diabetes and cancer research. As our understanding of the molecular mechanisms that regulate aging deepens, we will see the identification of diverse therapeutic targets and an acceleration in the development of drugs, vaccines and other interventional strategies.

Guang-Hui Liu: The coming decade will probably see a shift towards precision geroscience. Multidimensional aging clocks may become clinically useful tools for quantifying biological age and intervention effects. We anticipate early human trials targeting newly recognized aging drivers, and advances in gene and cell-based regenerative strategies. Critically, the field is moving towards a unified medical paradigm: targeting the root causes of aging to prevent multiple chronic conditions together, rather than individually.

Vadim N. Gladyshev: I expect to see organ- and systems-resolved aging maps and clinically qualified aging biomarkers; routine real-time biological age monitoring (omics, digital, wearables, and imaging); embryo-inspired rejuvenation cues; advances in replacement; insights from long-lived species on complex interventions that slow down aging; and advances in the theoretical understanding of aging.

Vera Gorbunova: I expect the first antiaging interventions to be approved and introduced to clinical practice. I see aging biomarkers to become a routine part of a health check-up linked to individualized recommendations on improving healthspan. I also expect the development of safe interventions focused on restoring a more youthful epigenome, and preventative strategies to enhance genome stability and improve DNA repair to become available.

David A. Sinclair: I expect the emergence of interventions that treat common diseases by resetting cellular age and allowing the body to heal itself. This will include Yamanaka factor mediated epigenetic reprogramming, due to be tested in humans in 2026, followed by epigenetic editing, small-molecule reprogramming drugs and AI-guided therapies. Within 10 years, I foresee whole-body rejuvenation.

George A. Kuchel: I firmly believe that the future of geroscience, and also its most important impact, will be in the prevention of multiple chronic conditions, which are among the most prevalent and typical features of aging in humans.

John W. Rowe: First, there will be a dramatic increase in the number of clinical trials focused on senescence and age-related disorders with interventions arising from geroscience. Second, we are lagging behind in care of older persons and geriatric medicine continues to suffer severe workforce inadequacies, especially for those with low or middle income. Societies must recognize the need and develop incentives, including financial, to bolster all facets of the eldercare workforce including public health, acute care and long-term care. Third, we have largely viewed aging as an accumulation of deficits and have systematically neglected the valuable capabilities that older people bring to society.

Oskar Hansson: In the space of neurodegenerative diseases, I think we are now moving into the therapeutic era, and I hope that the research community will develop several effective and safe interventions for these devastating brain diseases. Personally, I have especially high hopes for different genetic medicine approaches.

Anne Brunet: The field is moving forward very rapidly, and it is amazing to be part of it! I think there will be several translational breakthroughs in the next 5 to 10 years, notably for devastating age-related diseases such as Alzheimer's disease. Research-wise, it will be very cool to see what happens because so much more is feasible at the organismal level, and it will be an era of quantitative physiology that can be done at scale.

Ming Xu: In the next 5 to 10 years, I expect that the field of aging research will make incredible progress in these three directions. (1) I expect to see a significant rise in large-scale, human clinical trials for geroscience interventions. (2) Single-cell and spatial omics technologies will allow us to reveal the cellular and tissue-specific heterogeneity of aging. 3) AI will become an indispensable tool for aging research. AI and machine-learning models will be used to understand the complexity of multiomics data, identify novel aging targets and design personalized therapies.

Eiji Hara: Cellular senescence research is currently attracting considerable attention, with growing evidence that senescent cells are deeply involved in aging and various age-related diseases. Many studies suggest that targeting senescent cells could help to prevent or treat age-related conditions. Over the next 5-10 years, I expect we will gain a clearer understanding of several critical questions: which types of senescent cells drive specific pathologies, what are the optimal strategies for selective elimination versus functional modulation of these cells, and what are the potential risks of senolytic interventions.

Jing-Dong J. Han: I envision the next decade as the era when aging research becomes a predictive science. Big data will provide the 'language' of aging - a comprehensive, high-resolution dictionary of biological changes. AI models will be the 'translator', enabling us to read this language to forecast health trajectories, identify vulnerabilities and design personalized interventions long before clinical symptoms appear. The goal will be to move from treating age-related diseases to preemptively managing the aging process itself.

Felipe Sierra: As with all other areas of human activity, the field will be dominated by AI and other computer-based approaches to translate the biology of aging into interventions. In addition, I believe the field will succeed within the next 5 years at identifying predictive and clinically useful biomarkers that will take us into a more quantitative stage of research. I fear that, combined, AI and biomarkers will 'suck up the oxygen' from more basic mechanistic research, and this in turn will lead to progressively diminishing returns from AI and biomarkers.

Matt Kaeberlein: I am optimistic that the importance of geroscience will continue to gain recognition, and lead to greater investment from both public and private sectors. I expect substantial engagement from major pharmaceutical companies and anticipate the first FDA approval for a drug that slows aging, probably in companion animals. That milestone would mark a turning point for translational geroscience. Clinically, the landscape will remain frothy for a while. Some longevity clinics already practice evidence-based medicine, whereas others promote unproven or even unsafe interventions. Over time, I expect consolidation around data-driven, ethical standards.

The development of atherosclerosis is very different in males versus females. In the commonly used mouse models that develop atherosclerotic plaque in response to a high fat diet this is very evident. Interestingly, ovariectomized female mice develop plaque in a very similar way to male mice, indicating the importance of hormones to the mechanisms of atherosclerosis. In humans, atherosclerosis is broadly a male condition up to the age of menopause, at which point women start to catch up to the male extent of atherosclerotic plaque and subsequent cardiovascular disease and mortality.

Cardiovascular disease (CVD) is the leading cause of death for both men and women in the United States, though the age of onset differs by sex. Historical estimates suggest men experience earlier onset of coronary heart disease (CHD) by about 10 years as compared with women. Sex-specific differences in CVD are attributed to multiple different pathways, including hormonal influences, differences in cardiovascular health behaviors and factors, and exposure to adverse social determinants of health. Historically, men had higher rates of smoking, diabetes, and hypertension. However, population shifts in cardiometabolic risk phenotypes have resulted in similar or higher rates of obesity, diabetes, and hypertension in women than men. Additionally, the overall prevalence of smoking has decreased and is similar among men and women.

This study analysed data from the CARDIA (Coronary Artery Risk Development in Young Adults) study, a prospective multicenter cohort study. US adults aged 18 to 30 years enrolled in 1985 to 1986 and were followed through August 2020. Sex differences in the cumulative incidence functions of premature CVD (onset earlier than 65 years), were compared overall and for each subtype (CHD, heart failure, stroke).

Among 5,112 participants with a mean age of 24.8 ± 3.7 years at enrollment and a median follow-up of 34.1 years, men had a significantly higher cumulative incidence of CVD, CHD, and heart failure, with no difference in stroke. Men reached 5% incidence of CVD 7.0 years earlier than women (50.5 versus 57.5 years). CHD was the most frequent CVD subtype, and men reached 2% incidence 10.1 years earlier than women. Men and women reached 2% stroke and 1% heart failure incidence at similar ages. Sex differences in CVD risk emerged at age 35, persisted through midlife, and were not attenuated by accounting for cardiovascular health.

Link: https://doi.org/10.1161/JAHA.125.044922

A recent human trial of α-ketoglutarate supplementation failed to show benefits, but researchers continue to show interest in α-ketoglutarate based on results in cells and animal studies. In this example, researchers link α-ketoglutarate availability to the regulation of cellular senescence via TET. It may be that this interaction is not as important to cellular senescence in humans as it is in mice, or that middle aged people (40 to 60) don't have a large enough burden of senescent cells to make effect sizes resulting from α-ketoglutarate supplementation easily visible, or that the optimal dose is higher than the trial dose. Regardless, it seems a poor substitute for senolytics if the goal is to influence the burden of senescence in older people.

Cellular senescence, a state of stable cell-cycle arrest associated with aging, is characterized by a distinct pro-inflammatory secretome. This study systematically interrogates the critical role of the α-ketoglutarate (AKG)-Ten-eleven translocation (TET) axis in regulating senescence in human somatic cells. Downregulating TET expression and activity, either genetically (siRNA) or pharmacologically (via C35), or limiting AKG bioavailability through a targeting peptide, trigger widespread epigenetic reprogramming, amplify pro-inflammatory signaling, and enhance the senescence-associated secretory phenotype (SASP), ultimately driving cells toward replicative senescence.

Conversely, augmenting AKG bioavailability or TET expression and activity significantly enhances cellular resilience to stress, effectively preventing and reversing senescent phenotypes. These findings not only position the AKG-TET axis as a critical regulatory nexus of cellular senescence but also challenge the traditional view of senescence as a fixed endpoint, revealing its dynamic and plastic nature susceptible to therapeutic intervention.

Link: https://doi.org/10.1016/j.isci.2025.114298

Amyloid is a category, referring to proteins that clump together and precipitate from solution to form solid fibrils or other structures. At least hundreds of different proteins are capable of forming amyloids given suitable alterations to their structure or surrounding conditions, but most of the research attention given to this activity is directed towards toxic, pathological amyloids that form in great excess in the context of neurodegenerative conditions (such as amyloid-β, α-synuclein, and tau), followed by the few amyloids outside the brain that do the same to contribute to severe cardiovascular and other conditions (such as transthyretin or medin).

In today's research materials, researchers provide evidence for a specific type of amyloid formation to be involved in the creation and maintenance of long-term memory. This is very different from the basis for pathological amyloidosis, and involves different proteins, but given the research community focus on that amyloidosis, there has perhaps been a tendency to write off all forms of amyloid as harmful byproducts of cellular metabolism. A brief glance at the history of our understanding of biochemistry suggests that this sort of viewpoint is usually mistaken; if a process exists, evolution will eventually lead to its incorporation into some necessary aspect of cell function.

How Brain May Deliberately Form Amyloids to Turn Experiences Into Memories

The prevailing model of memory hypothesizes that a change in synaptic strength is one of the mechanisms through which information is encoded in neuronal circuits. While changes in synaptic strength require alterations in the synaptic proteome, the mechanisms that initiate and maintain these changes in synaptic proteins remain unclear. Molecular chaperones play a critical role in proteome function, and act as an interface between the environment and the proteome. Chaperones guide proteins to attain the correct folded state. It has long been thought that in the nervous system, chaperones help proteins to either fold correctly or prevent proteins from harmful misfolding and clumping.

A new study found that in Drosophila, one of a family of J-domain protein chaperones, CG10375, which they named "Funes", does something unexpected - it allows proteins to change their shape and form functional amyloids that house long-term memory. "This expands the idea of a protein's capacity to do meaningful things, and suggests there is an unknown universe of chaperone biology that we've long been missing." Thus amyloids are not always harmful unregulated byproducts as previously thought. Amyloids can be carefully controlled - serving as tools the brain uses to store information. Ultimately, the research reveals for the first time a critical step in the process of how long-lasting memories endure.

In fruit flies, a prion-like protein called Orb2 (and its relative protein CPEB in mammals) must undergo self-assembly at the synapses, the gap between two neurons, to maintain a memory. Orb2 belongs to a class of nonpathological amyloids, where amyloid formation enables a protein to acquire a new function. Over time, the researchers began to hypothesize that the difference between a harmful and a helpful amyloid may depend on whether Orb2's assembly process is tightly regulated by other proteins.

The researchers discovered Funes by manipulating the concentrations of 30 different chaperones in the fly's memory centers. Flies with increased levels of Funes showed a remarkable ability to remember an odor-reward link after 24 hours - a standard proxy for long-term memory. But the most surprising discovery came at the molecular level. Researchers engineered Funes variants that could bind Orb2 but could not trigger its transition into amyloid and found the flies' long-term memory failed. This indicated that Funes is an essential component for long-term memory formation.

Diseases of the eye are often the indication of choice for new, advanced forms of medicine, particularly gene therapies. Delivery to the eye is straightforward and proven, effective doses can be very low, and the structures of the interior of the eye are relatively isolated from the rest of the body. All told, the risk to patients is much lower than would be the case for targeting, say, the liver, which makes it a great deal easier to convince investors and regulators to support such a program. Thus we shouldn't be all that surprised to see that the first clinical trial of partial reprogramming to rejuvenate epigenetic control over nuclear DNA structure and gene expression will focus on regeneration of the damaged retina.

The FDA has given the go-ahead for the first ever human trial of a partial epigenetic reprogramming therapy. The FDA's decision clears an investigational new drug application for Life Bioscience's ER-100, a gene therapy designed to rejuvenate damaged retinal cells in people with serious, age-related eye diseases. The biotech is now preparing to commence a Phase 1 first-in-human study to show its therapy can be delivered safely in patients with open-angle glaucoma and non-arteritic anterior ischemic optic neuropathy (NAION).

As a first-in-human trial, Life Bioscience's study is primarily focused on safety and tolerability. Instead of using all four Yamanaka factors, ER-100 employs three of the factors (Oct4, Sox2, and Klf4) delivered transiently to reset age-associated epigenetic markers while keeping cells committed to their original function. By excluding c-Myc, a factor associated with uncontrolled growth, the strategy is intended to lower the risk of tumors that has historically concerned regulators and clinicians. From a safety perspective, the company's preclinical studies in non-human primates demonstrated that ER-100 was well tolerated in NHPs, with no systemic toxicities.

"The therapy uses a doxycycline-inducible system, giving us precise control over when the genes are active and allowing treatment to be paused or stopped if needed. In addition, ER-100 is delivered locally to the eye, limiting systemic exposure. Multiple preclinical animal models have demonstrated controlled gene expression, favorable biodistribution, restoration of epigenetic markers, and improvements in visual function which has collectively provided the foundation for FDA clearance."

Link: https://longevity.technology/news/fda-clears-first-human-trial-of-epigenetic-reprogramming-therapy/

Ferroptosis is a form of programmed cell death associated with iron metabolism. A body of evidence supports a role for excessive ferroptosis in the progression of Alzheimer's disease and other age-related conditions, a maladaptive reaction to forms of age-related damage present in the brain, such as mitochondrial dysfunction, an increased burden of senescent cells, chronic inflammatory signaling, and so forth. Researchers are starting to consider suppression of ferropotosis as an approach to treating neurodegenerative conditions, which leads to papers such as this one, a discussion of the mechanisms by which exercise acts to reduce ferroptosis. That is a step along the road to identifying potential targets for drug development. Attempting to mimic specific outcomes of exercise, calorie restriction, or other environmental effects on metabolism is a widely employed strategy, though it seems unlikely to be capable of more than modestly slowing disease progression or modestly reducing severity.

Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has emerged as a critical link between cellular senescence and Alzheimer's disease (AD). Senescent cells disrupt iron metabolism, promote peroxidation-prone lipid remodeling, and suppress antioxidant defenses, creating a pro-ferroptotic environment that accelerates neuronal degeneration. This review integrates recent mechanistic evidence demonstrating that these senescence-induced changes heighten ferroptotic susceptibility and drive AD pathology through pathways involving protein aggregation, autophagic failure, and inflammatory synaptic loss.

Importantly, physical exercise has emerged as a pleiotropic intervention that counteracts these ferroptotic mechanisms at multiple levels. Exercise restores iron homeostasis, reprograms lipid metabolism to reduce peroxidation risk, reactivates antioxidant systems such as GPX4, enhances mitochondrial and autophagic function, and suppresses chronic neuroinflammation. Moreover, systemic adaptations through muscle, liver, and gut axes coordinate peripheral support for brain health. By targeting ferroptosis driven by cellular senescence, exercise not only halts downstream neurodegenerative cascades but also interrupts key upstream drivers of AD progression.

These findings position ferroptosis as a therapeutic checkpoint linking aging biology to neurodegeneration and establish exercise as a mechanistically grounded strategy for AD prevention and intervention.

Link: https://doi.org/10.3389/fcell.2025.1742209

Autophagy is the name given to a complex collection of processes responsible for identifying and recycling damaged or otherwise unwanted structures in the cell. Typically, a structure flagged for recycling is engulfed by an autophagosome, which is transported to and fuses with a lysosome, and the structure is broken down inside the lysosome by enzymes. An optimal level of autophagy for the maintenance of cell function only occurs in response to stress, including heat, cold, lack of nutrients, toxins, oxidative damage to important molecules, and so forth. Thus mild stresses that inflict relatively little damage to a cell can improve the function of cells, tissues, and organs, leading to a greater resistance to the damage and dysfunction of aging. Most of the well studied interventions shown to modestly slow aging and extend life in animals involve an increased operation of autophagy.

Researchers and the longevity industry continue to work towards the development of drugs capable of upregulating autophagy to produce health benefits in older people. These efforts include examples in the well studied category of mTOR inhibitors, drugs that can mimic some of the beneficial metabolic response to exercise and calorie restriction, as well as a good number of unrelated programs at various stages of preclinical and clinical development. Meanwhile, there is a continued effort to better understand and measure autophagy. One of the challenges is that autophagy consists of many different steps, an assay can only obtain insight into one step, and increased activity in any given step can be a sign of increased function, but it can also be a sign that autophagy is dysfunctional and backed up.

Links between autophagy and healthy aging

Several if not all manifestations of aging can be postponed by a healthy lifestyle involving a balanced diet coupled with regular exercise and sufficient sleep. Similarly, various genetic and pharmacological longevity interventions can exert beneficial effects across species in a conserved manner, extending both lifespan and healthspan. While all these interventions-ranging from genetic perturbations to pharmacological supplementation to lifestyle changes-affect diverse biological processes, a common candidate mechanism underpinning at least some of their benefits is autophagy, a cellular recycling process essential for maintaining cellular homeostasis.

In this review, we summarize how autophagy is affected by various pharmacological and lifestyle factors, with a focus on studies in which autophagy has been shown to play a causal role in promoting healthy aging. Specifically, we review the molecular mechanisms through which pharmacological agents, dietary restriction, exercise, sleep adjustments, as well as temperature modulation affect autophagy to extend lifespan and often also healthspan in model organisms and humans.

Still, major gaps remain in human research due to limited assays to monitor autophagy and the scarcity of longitudinal studies linking autophagy dynamics to health outcomes. Closing this gap is a key challenge in converting discoveries from model organisms into interventions that consistently enhance healthy aging in humans. By summarizing current findings and highlighting remaining uncertainties, this review aims to provide a roadmap for translating insights on autophagy from model organisms into strategies to promote healthy aging in humans.

The best thing that researchers can do with the presently established aging clocks, such as Phenotypic Age, is to gather as much data as possible on the relationship between the clock output and meaningful outcomes such as disease risk and mortality. Hence the existence of studies such as the one reported here. Even now, going on twenty years into the use of aging clocks, it remains unclear as to whether any of the existing, relative well-used clocks will produce a reasonable assessment of the effects of any novel potentially age-slowing or age-reversing therapy. An understanding of the links between what is measured in the clocks and the underlying processes of aging have not been established and will be very challenging to establish, and thus it is impossible to predict whether a clock will overestimate, underestimate, or just fail when it comes to assessing the quality of any given intervention in aging. This is the case even for clocks such as Phenotypic Age that use clinical chemistry rather than omics measures. In this environment, gathering more data is probably the best path forward.

Accelerated biological aging serves as a risk factor for age-related diseases, its role in the prognosis of Parkinson's disease (PD) remains ambiguous. This study investigates the association between biological aging and the mortality in PD patients. Data were sourced from the UK Biobank. Independent prognostic factors for mortality in PD patients were assessed by Cox regression model, and a nomogram was developed to predict the survival of PD patients. A total of 569 PD patients were enrolled in this study.

Phenotypic age (PhenoAge) and PhenoAge acceleration (PhenoAgeAccel) were found to affect the survival in PD patients. Independent risk factors for PD mortality included age, male gender, smoking, underweight, depressive mood, low-density lipoprotein, and higher genetic susceptibility. The nomogram constructed based on PhenoAge showed robust prediction performance for mortality in PD patients. PhenoAge emerges as a pivotal PD mortality predictor, enabling the identification of individuals experiencing accelerated biological aging and implementing targeted interventions.

Link: https://doi.org/10.1038/s41531-026-01268-0

Adult life expectancy has exhibited a slow upward trend over the course of past decades, perhaps a year of increased life expectancy every decade, but the pace varies from year to year, region to region, and between socioeconomic groups. The trend exists as a result of improvements in medicine that impact the pace of aging as a side-effect, as therapies that deliberately target the mechanisms of aging have yet to reach widespread use. The contribution of medical advances is then layered with the effects of lifestyle differences, particularly the prevalence of obesity, public health programs such as efforts to reduce smoking, and other line items that can differ between populations and regions. Researchers here use European data to illustrate this point, and also note differences over time in the life expectancy trend.

This study makes several potential contributions to the ongoing debate on life expectancy trends in high-income countries. Our study examines these trends using data at the level of subnational regions: in total, we cover 450 regions in 13 Western European countries. We believe that addressing life expectancy at a fine geographical level is paramount in understanding the potential to further improve human longevity, as national aggregates mask large differences within countries. For example, in France, there are stark contrasts between laggard regions in the north and vanguard regions in the south and east. The disparities between eastern and western Germany, and northern and southern Belgium are equally pronounced. Together, they tell a compelling story of uneven regional progress.

Our study identified two distinct phases in the evolution of life expectancy gains over the past three decades. The first phase, from 1992 to 2005, was characterized by stable and substantial life expectancy gains in Western Europe (about 2.5 months per year for females and 3.5 months per year for males). Over this period, the pace of gains across regions quickly converged. In contrast, the second phase, from 2005 to 2019, marked a period of declining life expectancy gains. By 2018-2019, annual gains had decreased to about one month per year for females and two months for males.

During the earlier 'golden era', it was laggard regions that made the greatest gains in life expectancy. By contrast, the period 2005-2019 was much less favourable, as laggard regions saw shrinking gains in life expectancy. The driving forces behind this impressive reversal of fortunes can be better understood through the convergence-divergence framework, which explains the mechanisms leading mortality levels across populations to either converge or diverge. According to this theory, major innovations (e.g., drugs that reduce blood pressure) may initially trigger divergence, as some countries or groups are better positioned to benefit from them. Once access broadens, convergence tends to follow.

Link: https://doi.org/10.1038/s41467-026-68828-z

In today's open access paper, researchers review the evidence for exercise to slow the aging of muscle tissue in part because it improves DNA repair mechanisms. How exactly damage to nuclear DNA contributes to aging beyond creating a raised risk of cancer remains a debated topic, despite recent conceptual advances. Nuclear DNA damage occurs constantly, near all of which is repaired. Yet the remaining damage largely occurs in genes that are not used or that are not all that important, and in cells with few replications remaining. Thus the ability to cause harmful alterations to cellular metabolism throughout a tissue was thought to be limited.

The first way in which nuclear DNA damage could meaningfully impact aging is via somatic mosaicism. When mutations occur in stem cells, those mutations spread slowly throughout a tissue over time via the descendants of the somatic daughter cells created by the mutated stem cells. A mosaic of combinations of mutations is established over years and decades, and there is at least some reasonably convincing evidence for this to increase the risk of a few age-related conditions.

More recently, researchers have provided evidence for the repeated repair of DNA double strand breaks, whether successful or not, and wherever the break occurred in the genome, to cause epigenetic changes characteristic of aging. These epigenetic changes alter the structure of nuclear DNA and thus the expression of genes. If support for this mechanism continues to accumulate, it provides a way for random molecular damage to DNA to produce the consistent outcome of harmful age-related epigenetic changes that is observed to occur in all cells.

In this second viewpoint, interventions such as exercise that are thought to slow aging in part by improving the operation of DNA repair mechanisms may not in fact be working as hypothesized. They may indeed be changing the operation of DNA repair, but the primary outcome of interest is to reduce the negative effects of double strand repair on the epigenetic control of nuclear DNA structure and gene expression, rather than improving the efficiency of DNA repair more generally.

Impact of exercise-induced DNA damage repair on age-related muscle weakness and sarcopenia

Sarcopenia, the progressive and generalized loss of skeletal muscle mass, strength, and function with aging, poses a significant public health challenge. A key contributor to sarcopenia is the accumulation of DNA damage, both nuclear and mitochondrial, coupled with a decline in DNA repair efficiency. This genomic instability, exacerbated by chronic oxidative stress and inflammation, impairs critical cellular processes including protein synthesis, mitochondrial function, and satellite cell regenerative capacity, ultimately leading to myofiber atrophy and weakness. Intriguingly, regular physical exercise, while acutely inducing transient DNA damage, concurrently activates and enhances DNA damage repair pathways, serving as a powerful physiological modulator of genomic integrity.

This review comprehensively explores the intricate interplay between exercise, DNA damage, and DNA repair in the context of age-related muscle decline. We delve into the molecular hallmarks of DNA damage (e.g., 8-OHdG, single and double strand breaks) and the major repair mechanisms (base excision repair, nucleotide excision repair, mismatch repair, homologous recombination, non-homologous end joining), detailing how acute exercise modalities (e.g., high-intensity interval training, resistance training) induce specific damage types primarily via reactive oxygen species. Crucially, we synthesize emerging evidence suggesting that chronic exercise training may upregulate the efficiency and capacity of DNA repair enzymes, particularly OGG1 in base excision repair, thereby mitigating the accumulation of deleterious genomic lesions. This exercise-induced enhancement of DNA repair directly contributes to maintaining mitochondrial health, preserving muscle stem cell function, and combating cellular senescence and inflammation, ultimately delaying or ameliorating sarcopenia and improving muscle functional outcomes in older adults.

Researchers have been publishing more data of late from the CALERIE trial of human calorie restriction that took place over the course of a few years. The participants aimed at a 25% reduction in calorie intake, and ended up achieving something more like 12-15%. The trial started nearly 20 years ago at this point. It is often the case that tissue samples and data remain intact and potentially useful long after the study is complete, awaiting greater funding and interest, as well as the existence of more advanced analysis technologies.

Small non-coding RNAs (smRNAs), approximately 20-35 nucleotides in length, represent a diverse class of regulatory molecules that include microRNAs (miRs) and piwi-interacting RNAs (piRs). These nanoscale molecules are key regulators of gene expression, orchestrating complex networks to maintain genome stability and contribute to post-transcriptional gene regulation and cellular homeostasis.

Caloric restriction (CR) extends lifespan and enhances healthspan across species. In humans, the CALERIE Phase 2 trial demonstrated that CR improves inflammation, cardiometabolic health, and molecular aging. To explore underlying mechanisms, we examined CR-induced changes vs. ad libitum (AL) in smRNAs across plasma, muscle, and adipose tissue. Using smRNA sequencing, we analyzed miRs and piRs over 12 and 24 months, comparing CR levels (%CR) and group assignments (CR vs. AL).

We identified 16 smRNAs associated with %CR and 41 with CR vs. AL. Although tissue-specific expression varied, shared pathways emerged, including insulin signaling, circadian rhythm, cell cycle regulation, and stress response. Cross-species analysis revealed 17 miRs altered by CR in both humans and rhesus monkeys. These findings suggest smRNAs are key molecular mediators of CR's effects on aging and longevity, offering insight into biological mechanisms of CR and potential targets for age-related interventions.

Link: https://doi.org/10.1016/j.isci.2025.114514

The immune system is made up of many specialized populations of cells. Even within well recognized categories such as T cells of the adaptive immune system, there are numerous subcategories, defined by surface markers, that exhibit meaningfully different behaviors. The example for today is γδ T cells, known to be involved in the clearance of senescent cells. Unlike other T cells, γδ T cells behave more like innate immune cells, able to attack pathogens and potentially harmful cells without the need for other components of the adaptive immune system to process antigens for recognition. The γδ T cell population is relatively poorly understood, but like the rest of the immune system, it changes with age in ways that are likely in part dysfunctional, in part compensatory.

The transcription factors of the forkhead box O (Foxo) family, particularly Foxo1, play a pivotal role in regulating α/β T-cell key cellular processes. Interestingly, we recently found that the age-related decline in Foxo1 expression in mouse α/β T cells may drive the disruption of their peripheral homeostasis and contribute to the aging of this T-cell compartment. γ/δ T cells form a distinct subset of lymphocytes, differing from NK cells, B cells, and α/β T cells by combining adaptive properties with rapid, innate-like responses. Findings related to Foxo1 in α/β T cells prompted us to investigate how the functional capacities of γ/δ T cells are affected by aging, as well as whether Foxo1 expression could be modulated in this T-cell compartment with age.

In this study, we demonstrate that, as observed for α/β T cells, the homeostasis of the peripheral γ/δ T-cell compartment is markedly altered with age. Indeed, a comparison of the γ/δ T-cell compartment within the secondary lymphoid organs of old (18-month-old) and young (3-month-old) adult mice reveals that aging promotes the expansion of innate-like γ/δ T cells and enhances their capacity to produce IL-17. Notably, we found that these age-related changes were associated with the loss of Foxo1 expression within this T-cell compartment.

Finally, as observed in α/β T cells, our results indicate that the age-related decline in Foxo1 expression in γ/δ T cells is likely driven by a similar T cell-extrinsic factor. In this context, we identify type I IFNs as a key regulator that down-regulates Foxo1 in IL-17-producing γ/δ T cells with age and enhances the capacity of Ly-6C- CD44hi γ/δ T lymphocytes to mount a rapid in vivo response during aging.

Link: https://doi.org/10.1111/acel.70389