Fight Aging!

The retina at the back of the eye is the one part of the central nervous system that can be readily visually inspected, including the state of the network of blood vessels that supports it. Capillary networks of tiny blood vessels are dense and actively maintained; as the character of angiogenesis changes for the worse with aging, these networks become less dense and exhibit other signs of damage. Thus imagery of the retina provides a lot of data that can be employed to, for example, produce aging clocks, or act as a proxy measure for other forms of vascular and nervous system aging.

For retinal imagery to be usefully employed as a proxy measure of any specific aspect of vascular aging or central nervous system aging, or specific form of age-related damage, a robust correlation must first be demonstrated. Thus we have papers such as today's example, in which researchers establish links between retinal imagery characteristics and vascular and brain aging. One might expect this to inform efforts to further advance retinal imaging as a relatively low cost diagnostic tool, a way to better establish risk and the need for more costly forms of assessment in older people.

Cross-organ analysis reveals associations between vascular properties of the retina, the carotid and aortic arteries, and the brain

Doctors often use eye scans to check for signs of heart and brain disease, but the exact link between the tiny blood vessels in the eye and those in major organs is unclear. We aimed to systematically map similarities between blood vessels across the entire body. We compared vascular image-derived phenotypes from the brain, carotid artery, aorta, and retina, using UK Biobank sample sizes ranging from 18,808 to 68,740 participants. We examined phenotypic and genetic correlations, as well as common associated genes and pathways.

Here we show that white matter hyperintensities are positively correlated with carotid intima-media thickness (r = 0.03), lumen diameter (r = 0.14), and aortic cross-sectional areas (r = 0.09), but negatively correlated with aortic distensibilities (r ≤ -0.05). Arterial retinal vascular density shows negative correlations with white matter hyperintensities (r = -0.04), intima-media thickness (r = -0.04), lumen diameter (r = -0.06), and aortic areas (r = -0.05), while positively correlating with aortic distensibilities (r = 0.04). Significant correlations also persist after correcting for hypertension.

In summary, we found strong connections with the health of retinal blood vessels mirroring the health of the brain and major arteries. This suggests that some of the same factors influence vessel health across the body. This suggests that an eye scan could be a fast, non-invasive way to get a complete snapshot of a person's overall cardiovascular and brain health. These findings could help doctors identify health issues, such as early artery stiffness or brain aging, much sooner.

Aging is an accumulation of cell and tissue damage, combined with the dysfunctions resulting from that damage. Damaged systems lose function in a haphazard, random fashion that, averaged out over time and across many systems, tends to be proportional to the burden of damage. This is the case whether the system is a simple mechanical device, an organ, or a human. In aging humans and animals one thus observes correlations between most different examples of lost and degraded function, including those that cause mortality.

We assessed the population distribution of age-related functional impairments (ARFIs) and their associations with mortality and life expectancy (LE). We included 12,906 participants (mean age: 62.6 years) from the China Health and Retirement Longitudinal Study. Visual impairment, hearing impairment, cognitive impairment, sleep disorder, depressive symptoms, and disability in activities of daily living (ADL) were assessed. Cox proportional hazards models were used to estimate the associations of ARFIs with all-cause mortality. Life expectancy at age 50 was estimated by the presence and number of key ARFIs.

The six ARFIs exhibit distinct distributions by ages and provinces across China. During the 9-year follow-up, ADL disability, cognitive impairment, and depressive symptoms are independently associated with 64%, 41%, and 20% higher risks of mortality, corresponding to LE losses of 4.45, 3.08, and 1.59 years at the age of 50 years. A greater number of key ARFIs is associated with higher mortality risk in a dose-response manner (hazard ratios: 1.23 for one, 1.42 for two, and 1.86 for three) and greater LE loss (1.63 years for one, 3.37 for two, and 4.96 for three).

Link: https://doi.org/10.1038/s43856-025-01350-3

Evolution optimizes for reproductive success, and thus it should be no surprise to find that reproductive organs influence the entire body, and thus their aging has sizable effects on the aging of other organs. Researchers here review the mechanisms of aging that act to degrade structure and function of the testes, and in turn affect the production of androgens that influence tissue function elsewhere in the body.

The testis, a male-specific organ, plays a critical role in maintaining spermatogenesis and androgen production. As men age, testicular function declines, compromising not only reproductive capacity but also overall health and quality of life. Testicular ageing is characterized by progressive degeneration of the seminiferous epithelium and interstitial compartments, leading to endocrine dysfunction, impaired spermatogenesis, and heightened risk of age-related disease.

Although mechanistic insights are advancing rapidly, most therapeutic studies remain rooted in reductionist single-cell models that overlook the integrated dynamics of the testicular microenvironment. In reality, testicular ageing reflects a coordinated decline of germ cells, Sertoli and Leydig cells, and their niches. This process is driven by interconnected mechanisms, including oxidative stress, defective DNA repair and autophagy, dysregulated endocrine homeostasis, impaired protein quality control, and aberrant activation of ageing-related signalling pathways, which act synergistically.

Testicular ageing is accompanied by a progressive collapse of energy metabolism. Impaired fatty acid utilisation, reduced glucose uptake, and widespread mitochondrial dysfunction collectively drive metabolic remodelling that deteriorates the testicular microenvironment. Moreover, senescent somatic cells acquire a senescence-associated secretory phenotype (SASP), releasing pro-inflammatory cytokines such as IL-6 and IL-1β, while testicular macrophages adopt a pro-inflammatory state that recruits adaptive immune cells. Together, these changes establish a chronic inflammatory microenvironment that reinforces cellular senescence and accelerates testicular ageing.

Priorities for future research include clarifying cell-microenvironment interactions, establishing non-invasive biomarkers for early detection, and resolving metabolic pathways that may guide senolytic strategies. As therapeutic paradigms evolve, emerging interventions - particularly stem-cell-based approaches - may extend beyond the limits of conventional pharmacology to enable more precise and effective mitigation of testicular ageing.

Link: https://doi.org/10.1080/07853890.2026.2624183

The peptide industry has been growing for some years now, becoming more vocal and visible. It occupies a similar space to the supplement industry, and seems likely to provoke many of the same battles with regulators such as the FDA. Peptide use is characterized by the same lack of rigorous supporting data that attends supplement use, and for many of the same reasons. The lines in the sand dividing peptide from drug are just as arbitrary as those dividing supplement and drug, and just as driven by funding and the high cost of regulatory compliance. Peptides that can be effectively monopolized via intellectual property become drug candidates, as only with that monopoly is it possible to raise enough funding to engage with regulators and run clinical trials. Peptides that cannot remain on the outside, without the robust human data needed to support greater interest.

Against the background of this broader context of a growing market for the use of peptides, you might recall that the peptide FOXO4-DRI was one of the early potential senolytic therapies to be validated in animal studies, back in the mid-2010s. FOXO4-DRI interferes in the interaction between FOXO4 and p53 that normally inhibits apoptosis of senescent cells, and thus results in the selective destruction of senescent cells with very little impact on other cells. Clearance of senescent cells is well demonstrated to improve health in aged animal models, but only relatively small clinical trials of a few senolytic small molecules have yet taken place to validate use in humans.

A company, Cleara Biotech, was formed to commercialize the early academic work on FOXO4-DRI, and appears to still be a going preclinical concern focused more on the FOXO4-p53 interaction than on FOXO4-DRI per se. Other groups have since become involved, such as Numeric Biotech, and it has long been the case that anyone so minded can just up and buy FOXO4-DRI for personal use from any number of peptide sellers. It is unclear as how many people are choosing to do that, and certainly we'll never see any sort of useful data resulting from that use. Meanwhile, academic research groups continue to work with FOXO4-DRI as a tool to explore the FOXO4-p53 interaction in the context of cellular senescence as a driver of degenerative aging.

FOXO4-DRI regulates endothelial cell senescence via the P53 signaling pathway

Endothelial cell dysfunction during aging is a key driver of vascular aging and related diseases; however, effective strategies to selectively eliminate senescent endothelial cells and restore vascular function remain lacking. FOXO4-DRI, a novel peptide-based intervention, specifically disrupts the interaction between FOXO4 and P53, thereby inducing apoptosis in senescent cells. This study innovatively focuses on the mechanism by which FOXO4-DRI induces apoptosis in senescent endothelial cells, demonstrating that it functions by activating the p53/BCL-2/Caspase-3 signaling pathway to promote selective apoptosis of these cells. FOXO4-DRI significantly improves vascular function and delays vascular aging.

This study aims to analyze the vascular function and aging status of the aorta in naturally aged mice and progeroid model mice following FOXO4-DRI injection. Additionally, it investigates changes in endothelial cell function in senescent endothelial cells induced by oxygen-glucose deprivation (OGD), as well as the protein expression and interaction in the FOXO4-P53 signaling pathway. To assess the impact of FOXO4-DRI on endothelial cell senescence, the senescent endothelial cells were treated with FOXO4-DRI, followed by immunofluorescence and Western blotting experiments.

Injection of FOXO4-DRI in both naturally aged and induced aging mice effectively suppressed aortic aging and improved aortic function. Additionally, we found that FOXO4-DRI alleviates endothelial cell senescence induced by OGD, thereby enhancing endothelial cell function. Through co-immunoprecipitation (CO-IP) experiments, we discovered that FOXO4-DRI prevents the binding of FOXO4 to P53, facilitating the phosphorylated P53 nuclear exclusion, which subsequently trigger BAX and cleaved caspase-3, leading to the apoptosis of senescent cells. Ultimately, this mechanism achieves the goal of inhibiting vascular aging.

There are so many detrimental age-related changes in gene expression that it will always be possible to pick out any one gene exhibiting altered expression and spend years on research and development aimed at fixing this one specific issue. Restoring youthful expression of any one gene in any one tissue is an achievable goal for present day medical research and development, though costs and regulatory hurdles remain challenging. Expression can be increased via gene therapy vectors, or reduced via various approaches, such as small interfering RNA, that attack some part of the process of gene expression. The most productive future will not be one of picking through thousands of changes one by one, however, but instead a matter of attempts to restore youthful gene expression more generally, for most or all genes, through some form of reprogramming. Still, the one by one approach remains the primary focus of the research community, as this example illustrates, though at least researchers now tend to favor regulatory genes that influence the expression of large numbers of other genes.

O-GlcNAc Transferase (OGT) is responsible for the addition of β-O-linked N-acetyl-D-glucosamine (O-GlcNAc) to serine and threonine residues, thereby regulating more than 8000 human proteins through O-GlcNAcylation. In the brain, reduced O-GlcNAc levels, which can arise from insufficient OGT activity, have been increasingly linked to aging-related neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis.

While current strategies focus on restoring O-GlcNAc levels via O-GlcNAcase (OGA) inhibition, recent discoveries highlight transcript-level regulation of OGT as a direct and promising therapeutic target. This concept article explores the role of intron detention and decoy exon-mediated splicing repression in limiting OGT pre-mRNA maturation and proposes the use of antisense oligonucleotides or selective splicing factor degraders to promote productive splicing and nuclear export of OGT mRNA. By enhancing OGT expression independently of O-GlcNAc feedback, these approaches aim to restore proteostasis and improve resilience to neurodegeneration, offering a novel therapeutic approach for aging-related neurodegenerative diseases.

Link: https://doi.org/10.1002/cbic.202500774

Researchers here provide evidence for glycogen produced by the gut microbiome to contribute to age-related neurodegeneration. A mutation associated with amyotrophic lateral sclerosis and frontotemporal dementia appears to make the inflammatory consequences of microbiome-derived glycogen worse, thus potentially explaining its relevance to disease. But the prevalence of the microbes involved in the production of glycogen in the gut microbiome of patients with these conditions suggests that every older person is impacted by this mechanism to some degree, with that degree being dependent on the exact composition of the gut microbiome. This is one of a range of studies showing at least some correlation between gut microbiome composition and specific age-related conditions, and as illustrated here, researchers are starting to move beyond correlation to explore the mechanisms responsible.

Gut dysbiosis and neural inflammation occur in patients with amyotrophic lateral sclerosis (ALS), including those with a causal mutation in chromosome 9 open reading frame 72 (C9ORF72). How gut commensals interact with common ALS genotypes to impart risk of neural degeneration remains unclear. Here, we identify 10 phylogenetically diverse bacterial strains that promote cytokine release in a C9orf72-dependent manner. Metatranscriptomics implicated the glycogen biosynthesis pathway as a driver of inflammation.

Colonization of germ-free C9orf72-deficient mice with Parabacteroides merdae that produced inflammatory glycogen enhanced monocytosis, blood-brain barrier breakdown, and T cell infiltration into the central nervous system. Enzymatic digestion of glycogen in the gut promoted survival of C9orf72-deficient mice and dampened microglial reactivity in the brain.

A survey of human fecal samples demonstrated that inflammatory forms of glycogen were present in gut contents from 15/22 patients with ALS, 1/1 patient with C9ORF72 frontotemporal dementia (FTD), and 4/12 healthy controls. Together, the results of this work identify bacterial glycogen as a modifiable mediator of immune homeostasis in the gut and brain.

Link: https://doi.org/10.1016/j.celrep.2025.116906

The composition of the gut microbiome, the relative sizes of the various microbial populations, changes with age in ways that promote chronic inflammation and dysfunction throughout the body. The production of beneficial metabolites decreases, while microbes capable of provoking a constant inflammatory reaction increase in number. Studies of fecal microbiota transplantation have demonstrated that the unfavorable composition of the gut microbiome in old animals can be rejuvenated via the introduction of donor material from young animals. One treatment produces lasting rejuvenation, though presumably the processes of aging will slowly degrade the gut microbiome over time, just as they did before. Health is improved and life span increased.

Fecal microbiota transplantation sees enough use in medicine for researchers and clinicians to broadly understand the safety profile of the treatment, and for a body of work to have evolved regarding best practices for sourcing, screening, storing, and using donor material. But the most common use case, to treat C. difficile infections in which hostile bacteria have overrun the intestine, is not focused on older people, and donors do not necessarily tend to be younger people. Clinical trials that do provide evidence specifically for the use of young donor material to treat old patients are thin on the ground. So it is good to see that at least one group is making the effort to run such a trial; we might expect to see results in a few years.

Aging Resilience Through Microbiota Optimization and Regulation (ARMOR)

It has been proposed that changes in the gut microbiota in aging individuals, known as gut dysbiosis, contribute to sarcopenia. Species diversity decreases, and bacterial representation is altered, which could impair muscle function through various pathways, such as mitochondrial dysfunction, chronic inflammation, and disruption of protein synthesis. Muscle function loss is strongly associated with cognitive and metabolic impairment in older adults.

Recently, it has been demonstrated that fecal microbiota transplantation (FMT) is an effective procedure for modulating gut microbiota and has proven highly effective in managing cases of Clostridium difficile-associated chronic diarrhea. The main objective of this project is to carry out FMT from young, physically active donors to a cohort of older adults to evaluate its effect on muscle, cognitive, and metabolic function.

Why donors who exercise? There is growing evidence that gut microbiota diversity is increased in young, physically active individuals. The FMT is planned to be administered through lyophilized microbiota capsules. By restoring microbial diversity, it is expected to improve the quality and function of skeletal muscles, leading to greater cognitive and metabolic resilience.

Randomized, double-blind, placebo-controlled trial of fecal microbiota transplantation from young physically active donors to promote resilient aging: clinical trial protocol (ARMOR study)

Sarcopenia, characterized by the progressive loss of skeletal muscle mass and strength in older adults, is a key determinant of frailty and functional decline. Affecting up to 15% of individuals aged 65-80 years and more than 50% of those over 80, sarcopenia not only compromises physical autonomy but also increases the risk of metabolic dysfunction and cognitive decline. Emerging evidence suggests that age-related gut microbiota dysbiosis contributes to these impairments by reducing microbial diversity and altering host metabolic signaling, leading to chronic inflammation and mitochondrial dysfunction. The present study aims to evaluate the safety, tolerability, and preliminary efficacy of oral fecal microbiota transplantation derived from young, physically active donors administered to older adults, focusing on outcomes related to functional autonomy, muscle performance, metabolism and cognition.

This is a double-blind, randomized, placebo-controlled clinical trial involving community-dwelling adults aged 65-84 years. Participants will be randomized 1:1 to receive either FMT capsules or placebo following a short course of oral rifaximin (or placebo). Assessments will be performed at baseline and at 4, 8, and 20 weeks post-intervention. The primary outcomes are safety and tolerability, as well as changes in the Global Index of Functional Autonomy (GDLAM battery) and muscle strength. Secondary outcomes include gait speed, body composition (DXA), metabolic biomarkers, gut microbiota composition (shotgun metagenomics), cognitive performance, and psychological well-being.

By restoring microbial diversity and function, FMT from young, active donors may enhance muscle quality, cognitive resilience, and metabolic health in older adults. This study introduces a novel, non-invasive therapeutic approach based on lyophilized and encapsulated microbiota, offering a feasible and scalable strategy to promote healthy aging.

Aging is by far the greatest cause of human suffering and mortality. Yet is it in human nature to resist every change whether or not it is beneficial. It is also in human nature to accept what is. So the development of means to treat aging in order to prevent the present toll of suffering and death will be resisted, and then these means will come into being, exist, and be accepted. Along the way, a lot of ink will be spilled on why we should or should not make the world a better place in this way. Such is the way of things. Ignoring the debate to focus on building rejuvenation biotechnologies is probably the fastest way to create (a) therapies for aging that most people will choose to use and (b) a world in which most people accept this state of affairs as a good thing.

Humanity has long sought to mitigate the challenges of ageing and extend the span of healthy life. But for centuries, a story of resignation shaped the moral imagination: ageing and death were inevitable, so ethics concerned how best to accept them. This narrative is crumbling. Over the past few decades, biogerontology has revealed that ageing is not immutable. Lifespan has been extended by tenfold in nematodes and by 50% in mice. Cellular reprogramming, senolytic drugs, and genetic insights suggest that at least parts of the ageing process can be modified.

Due to the profound implications of such progress, ethical debate has followed close behind. However, most discussions have been dominated by consequentialist framings: balancing hoped-for benefits (e.g., reduced healthcare costs, productivity gains) against feared harms (e.g., overpopulation, inequality, loss of meaning). Both critics and advocates tend to treat longevity as a matter of projected outcomes, reducing the ethical question to a contest of demographic forecasts. What remains underexplored is a deeper foundation: whether anti-ageing research is justified independent of its consequences, rooted instead in duties, autonomy, and the intrinsic value of life itself.

We seek to further this discussion by grounding the case for longevity research not only in outcomes but also in respect for autonomy, self-ownership, and the intrinsic value of life itself. On this basis, we address three kinds of critiques: philosophical appeals to "naturalness", societal concerns about resources, justice, and stagnation, and individual worries about meaning and boredom, showing that none provide decisive objections. Beyond rebuttal, we highlight neglected benefits: longevity research drives technological integration like the Apollo program, affirms the priority of existing persons over abstractions, and liberates individuals from rigid age-based expectations. The moral baseline must flip: the burden now falls on defenders of forced ageing to explain why preventable suffering should continue.

Link: https://doi.org/10.1016/j.arr.2026.103054

The supporting cells of the brain are collectively known as glia. This category includes astrocytes, microglia, and oligodendrocytes, among others, cells that are responsible for maintenance of an environment in which neurons can function, or directly aiding neuron function in various ways. Researchers here discuss how age-related changes in the interactions between neurons and glia may both arise from neurodegeneration and drive neurodegeneration. Manipulating some of these interactions can slow aging and extend life span in flies.

Aging is often discussed as something that happens inside cells: DNA is damaged, mitochondria stop working, and proteins are misfolded. But aging also changes how cells communicate with each other. For example, neurons in the brain rely on neighboring cells, called glia, for nutrients, waste handling, and local repair. Dysregulation of the interactions between neuron and glia is considered a hallmark of brain aging, but the consequences of disrupting neuron-glia communications are still being uncovered.

Researchers compared glial cell-surface proteomes in young (5 day) and old (50 day) flies to examine how signaling molecules are regulated in the aging brain, and identified a set of 872 proteins that exhibited age-specific differences in abundance. Proteins that became more abundant with age were enriched for functions related to localization and transport, which supports the idea that older brains may need stronger homeostasis and trafficking control. In contrast, many proteins that became less abundant with age were associated with synapse organization, axon guidance, and related processes.

The researchers chose 48 genes that exhibited the greatest changes between the glial surface proteomes of young and old flies, and tested whether manipulating these genes in adult glia altered lifespan. One candidate from the screen, a cell adhesion protein called DIP-β, was found to extend lifespan in both males and females when overexpressed in glia. Older flies with higher levels of DIP-β in their glia also climbed better than controls, suggesting improved late-life function in addition to longer lifespan. Analysis suggested that DIP-β overexpression was associated with increased signaling between glia and neurons, and between glia and fat cells, with prominent shifts in a number of signaling pathways (such as the TGF-beta, Wnt, FGFR, and EGFR pathways). This is an appealing model because it connects a surface protein found in glia to broader tissue coordination during aging.

Link: https://doi.org/10.7554/eLife.110158

Nuclear DNA is surrounded by transcriptional machinery, protein structures that will attempt to transcribe any gene sequence they encounter. Where DNA is compacted into regions of heterochromatin by being spooled onto histones, genes are silenced because their sequences are hidden from transcriptional machinery. Whether a given stretch of DNA is compacted or not is determined by epigenetic mechanisms, largely decorations (such as methyl groups) attached to DNA and histones that alter their structural behavior. A general feature of aging is a loss of heterochromatin and increasing expression of genes and other sequences that are usually silenced in youth. This leads to, for example, the expression of transposons that can drive DNA damage and inflammation, but also disruption and change in normal cell function.

Some time ago, researchers established a way to visualize whether or not a given region of DNA is compacted into heterochromatin. Flies can be genetically engineered with suitably placed genes that change the color of some of their features, such as eye segments, depending on whether or not they are expressed. Thus just by looking at the fly, researchers will know whether or not the region of DNA containing the inserted gene is compacted. A number of different fly lineages have been constructed over the years, as researchers needed a solution for one region or another. This approach is called position effect variegation.

Today's open acccess paper is a discussion of position effect variegation as a tool to inspect changes in DNA compaction into heterochromatin that occur with age and their correlation with high level outcomes such as mortality risk and longevity. Since increased loss of heretochromatin appears to correlate with longevity in flies, position effect variegation could be used to build aging clocks (in flies at least) that primarily reflect alterations to DNA structure rather than other mechanisms.

Position effect variegation (PEV) as an aging clock: visualization of age-dependent loss of heterochromatin and longevity associated with enhanced heterochromatin

The heterochromatin loss model of aging suggests there is an age-dependent reduction in epigenetic factors that form and maintain the heterochromatin state of chromosomes. Position Effect Variegation (PEV) can visually report phenotypes of heterochromatin mediated silencing in Drosophila Melanogaster eyes and we use PEV to examine the association between heterochromatin state changes and aging.

Pericentric inserts causing PEV showed suppressed variegation phenotypes in old age compared to young age and were confirmed to be associated with progressively increasing transcription, indicating loss of heterochromatin mediated silencing. Within a single population, animals with enhanced PEV phenotypes live longer than those with more suppressed PEV phenotypes, suggesting that small differences in environmental or genetic factors within this population could be responsible for differences in heterochromatin and lifespan.

Environmental factors could enhance heterochromatin, reduced nutrient diet and lower temperature coincided with enhanced heterochromatin and longer life. Furthermore, genetic variants associated with long life, including chico mutants, lead to increased heterochromatin and enhanced PEV phenotypes. Therefore, aging can be linked to heterochromatin loss and developmental increases in heterochromatin are associated with longevity. Thus, PEV reporters act as aging clocks demonstrating loss of heterochromatin that progresses with age and epigenetic alterations that can promote longevity.

The addition and removal of methyl groups from specific locations on the genome is one of the epigenetic mechanisms used to control the structure of DNA in the cell nucleus, such as which sequences are hidden via compaction into heterochromatin and which remain accessible to allow the expression of genes. That the pattern of DNA methylation changes with age in characteristic ways is what allows the existence of epigenetic clocks, the use of DNA methylation status to assess biological age. That epigenetic control over gene expression changes with age also makes it a potential target for the development of therapies to treat aging, particularly now that partial reprogramming studies have amply demonstrated that reversing age-related epigenetic changes is possible in principle.

As individuals age, the precise regulation of DNA methylation gradually deteriorates, leading to widespread epigenetic drift. This loss of control results in both global hypomethylation and site-specific hypermethylation, disrupting normal gene expression patterns. Global hypomethylation can lead to genomic instability, activation of transposable elements, and oncogene expression, while localized hypermethylation may silence tumor suppressor genes or genes critical for immune regulation and metabolic function. These changes are increasingly recognized as contributors to the development of chronic diseases. For example, aberrant DNA methylation patterns have been implicated in cancer, cardiovascular disease, type 2 diabetes, and neurodegenerative disorders such as Alzheimer's disease.

One of the most promising trends is the integration of DNA methylation data with other layers of biological information, such as transcriptomics, proteomics, metabolomics, and microbiomics. This multi-omics approach offers a holistic view of aging by capturing complex molecular interactions/network that DNA methylation alone cannot fully explain. Combining these datasets can refine biological age estimates, identify novel aging biomarkers, and uncover mechanisms driving age-related functional decline.

Parallel to these analytical advances, there is growing interest in interventions targeting epigenetic aging. Lifestyle modifications, including diet, exercise, and stress management, have demonstrated potential to modulate DNA methylation patterns and slow epigenetic age acceleration. Pharmacological approaches, such as senolytics, epigenetic modulators, and novel small molecules, are under investigation for their ability to reverse or delay methylation-based biological aging. Clinical trials integrating methylation clocks as endpoints are beginning to evaluate the efficacy of these interventions, potentially enabling real-time monitoring of biological age and intervention impact.

Link: https://doi.org/10.3389/fmolb.2025.1734464

Rapamycin is the most well studied of the mTOR inhibitors. It produces immunosuppression at high doses, and has been used in this context in the clinic for more than twenty years. At lower doses it mimics aspects of the beneficial metabolic response to calorie restriction, om particular an increased operation of the cellular maintenance processes of autophagy. In animal studies this has been demonstrated to slow aging and extend healthy life. Human clinical trial data for this lower dose anti-aging usage remains relatively sparse, unfortunately, but the results that do exist are interesting.

Rapamycin is one of the most intensively studied compounds with potential effects on longevity. Available experimental data indicate that inhibition of the mTOR pathway and activation of autophagy lead to improved cellular homeostasis, reduced oxidative stress, and a slowing of aging processes across multiple model organisms.

Current clinical studies in humans, although limited in number and involving small populations, suggest that low doses of rapamycin may enhance immune function, reduce visible signs of skin aging, and positively influence well-being and metabolic parameters.

Despite these promising findings, knowledge regarding the long-term safety, efficacy, and optimal dosing regimens of rapamycin remains limited. Further, multicenter, randomized clinical trials are needed to determine whether modulation of the mTOR pathway can represent an effective and safe strategy to support healthy human aging.

Link: https://doi.org/10.7759/cureus.98514

Rapamycin and other mTOR inhibitors mimic some of the mechanisms making up the response to calorie restriction. Their most interesting effect is to increase the operation of autophagy in cells. Autophagy is a collection of processes responsible for recycling damaged or unwanted proteins and structures in the cell. A large proportion of the approaches shown to modestly slow aging in yeast, worms, flies, and mice are characterized by increased or more efficient autophagy; it is a universal response to stress of any sort placed upon a cell. Too much autophagy can be a bad thing, but a modest increase improves health in the context of the dysfunctional, damaged environment of aged tissues.

Another feature of mTOR inhibitors, and the age-slowing interventions that are characterized by upregulated autophagy, is that the burden of harmful, inflammatory senescent cells that linger in aged tissues is reduced. The present thinking on this topic is that this reduction does not occur because senescent cells are destroyed by the intervention, but rather that the pace at which cells become senescent is reduced. This seems sensible: more autophagy allows cells to better maintain function and resist damage, and thus fewer cells will be tipped over the line into senescence in response to damage.

Here, however, researchers argue that, at least in immune cells, the effects of mTOR inhibition on cellular senescence do not emerge from autophagy. Instead, there is a direct effect on the burden of DNA damage in these cells, and it is that reduced DNA damage that leads to a reduced number of cells becoming senescent. Further work will have to be conducted in order to fully understand how exactly mTOR inhibition produces this outcome.

Rapamycin Exerts Its Geroprotective Effects in the Ageing Human Immune System by Enhancing Resilience Against DNA Damage

mTOR inhibitors such as rapamycin are among the most robust life-extending interventions known, yet the mechanisms underlying their geroprotective effects in humans remain incompletely understood. At non-immunosuppressive doses, these drugs are senomorphic, that is, they mitigate cellular senescence, but whether they protect genome stability itself has been unclear. Given that DNA damage is a major driver of immune ageing, and immune decline accelerates whole-organism ageing, we tested whether mTOR inhibition enhances genome stability.

In human T cells exposed to acute genotoxic stress, we found that rapamycin and other mTOR inhibitors suppressed senescence not by slowing protein synthesis, halting cell division, or stimulating autophagy, but by directly reducing DNA lesional burden and improving cell survival. Ex vivo analysis of aged immune cells from healthy donors revealed a stark enrichment of markers for DNA damage, senescence, and mTORC hyperactivation, suggesting that human immune ageing may be amenable to intervention by low-dose mTOR inhibition.

To test this in vivo, we conducted a placebo-controlled experimental medicine study in older adults administered with low-dose rapamycin. p21, a marker of DNA damage-induced senescence, was significantly reduced in immune cells from the rapamycin compared to placebo group. These findings reveal a previously unrecognised role for mTOR inhibition: direct genoprotection. This mechanism may help explain rapamycin's exceptional geroprotective profile and opens new avenues for its use in contexts where genome instability drives pathology, ranging from healthy ageing, clinical radiation exposure and even the hazards of cosmic radiation in space travel.

Structures of the endoplasmic reticulum are where the folding of newly synthesized proteins takes place in the cell. The endoplasmic reticulum is also involved in a range of other activities relevant to the manufacture of proteins and other molecules, such as quality control and recycling of misfolded proteins. Researchers here describe how the endoplasmic reticulum changes in structure with age, and link this to changes in the recycling of endoplasmic reticulum structures via autophagy. They suggest that these changes are compensatory, but become maladaptive in later life.

The morphological dynamics of the endoplasmic reticulum (ER) have received little attention in the context of ageing. Here we established tools in C. elegans for high-resolution live imaging of ER networks in ageing metazoans, which revealed profound shifts in ER network morphology that are driven by autophagy of ER components (ER-phagy). Across a variety of tissues, we consistently found a decrease in ER protein levels and cellular ER volume, and a structural shift from densely packed sheets to diffuse tubular networks. The ER content also declined in yeast and mammalian systems, and proteomic atlases of the ageing process in worms and mammals showed that age-onset collapse in ER proteostasis function is a broadly conserved aspect of the ageing process

We found that Atg8-dependent ER-phagy is the key mechanism driving turnover and remodelling of the ER network during ageing. A targeted screen for mediators in C. elegans revealed that the physiological triggers of ER-phagy in an ageing metazoan model are cell-type specific. Tissue-specific roles of ER-phagy receptors may help to explain why the ubiquitous macroautophagy machinery seems to be a universal requirement for longevity assurance in metazoan genetic studies, whereas the importance of selective ER-phagy mediators has been slower to emerge. Subsequently, we demonstrate that the two pathways capable of blocking age-associated ER-phagy, TMEM-131 and IRE-1-XBP-1, are required for mTOR-dependent lifespan extension in C. elegans.

Importantly, not all changes that occur during ageing reflect pathogenesis. The earliest remodelling events are likely to be adaptive responses to the cessation of developmental programmes and rising metabolic and cellular damage. We propose a model where age-dependent ER remodelling serves as an adaptive step in the ageing process associated with reprogramming of the proteostasis network. However, although data indicate that the net effect of ER-phagy on lifespan is positive, we speculate that early pronounced remodelling of ER structures is likely to trigger pleiotropic trade-offs later, especially in longer-lived cells and animals.

Link: https://doi.org/10.1038/s41556-025-01860-1

In recent years, researchers have established that a great many proteins can aggregate to some degree in cells of the aging brain, and that this likely contributes to loss of function. This issue is distinct from the few well-known proteins such as amyloid-β that aggregate to a very large degree in the context of neurodegenerative conditions. Here, researchers provide evidence for this generalized aggregation across more than a thousand proteins to contribute to impaired maintenance of synapses in the aging brain.

Neurodegenerative diseases affect 1 in 12 people globally and remain incurable. Central to their pathogenesis is a loss of neuronal protein maintenance and the accumulation of protein aggregates with ageing. Here we engineered tools that enabled us to tag the nascent neuronal proteome and study its turnover with ageing, its propensity to aggregate and its interaction with microglia. We show that neuronal protein half-life approximately doubles on average between 4-month-old and 24-month-old mice, with the stability of individual proteins differing among brain regions. Furthermore, we describe the aged neuronal 'aggregome', which encompasses 1,726 proteins, nearly half of which show reduced degradation with age.

The aggregome includes well-known proteins linked to diseases and numerous proteins previously not associated with neurodegeneration. Notably, we demonstrate that neuronal proteins accumulate in aged microglia, with 54% also displaying reduced degradation and/or aggregation with age. Among these proteins, synaptic proteins are highly enriched, which suggests that there is a cascade of events that emerge from impaired synaptic protein turnover and aggregation to the disposal of these proteins, possibly through microglial engulfment of synapses. These findings reveal the substantial loss of neuronal proteome maintenance with ageing, which could be causal for age-related synapse loss and cognitive decline.

Link: https://doi.org/10.1038/s41586-025-09987-9