Fight Aging!

Senescent cells accumulate with age in tissues throughout the body. These cells cease replication and secrete a potent mix of pro-growth, pro-inflammatory signaling that is disruptive to tissue structure and function when maintained over the long term. Cells become senescent throughout life in response to various circumstances, but in youth are efficiently destroyed by the immune system. With old age, the immune system falters in this task for reasons that are still being explored in detail. While the increased damage and disarray found in aged cells and tissues likely accelerates the pace at which cells become senescent, present evidence suggests that immune dysfunction in the matter of senescent cell clearance is the dominant factor in the increased presence of lingering senescent cells in later life.

Various approaches to selectively removing senescent cells from aged tissues have been demonstrated in animal studies, such as the first generation of senolytic drugs (including the combination of dasatinib and quercetin) that sabotage mechanisms that senescent cells use to resist programmed cell death. A number of the biotech companies founded to develop senolytic drugs are focused instead on immunotherapies, ways to adjust the behavior of the immune system so that it can better target senescent cells for destruction. Today's scientific paper reports a novel basis for anti-senescence immunotherapy, based on removing an impediment to the ability of macrophages to destroy senescent neutrophils. Beyond the novel senolytic approach, the work is interesting for demonstrating that senescent neutrophils in and of themselves make up a sizable fraction of the entire problem of cellular senescence, at least in the liver and heart.

Restored clearance of senescent neutrophils by tissue-resident macrophages limits organ aging

Aging is accompanied by parallel functional decline across organs, but the cellular drivers remain unclear. Tissue-resident macrophages (TRMs), long-lived cells that comprise 60 to 90% of macrophages in major organs, maintain homeostasis through efferocytosis of apoptotic and senescent cells. Neutrophils, the most abundantly produced and shortest-lived leukocytes (more than 100 billion generated daily in humans), require continuous TRM clearance; uncleared aged neutrophils release proteases and extracellular traps that damage tissues and propagate aging. TRMs express the prostaglandin E2 (PGE2) receptor EP2, which suppresses macrophage metabolism and phagocytosis in aging. Whether impaired TRM efferocytosis drives the accumulation of senescent neutrophils that promote organ aging and whether inhibition of EP2 signaling can restore this process, remain unknown.

In aged mice, TRM-specific EP2 deletion restored mitochondrial fitness and immune homeostasis, and reversed cognitive decline, frailty, sarcopenia, adiposity, and cardiac dysfunction toward youthful states. Plasma proteomics identified the liver as a major source of age-associated immune changes. Single-cell RNA-seq of mouse liver and multiorgan flow cytometry revealed accumulation of senescent CXCR4+ neutrophils across efferocytic organs in aging. These cells exhibited the senescence-associated secretory phenotype (SASP), DNA damage response activation, cell cycle inhibitor induction, NETosis, and anti-apoptosis programs, and were efficiently cleared following EP2 deletion.

Liver multiplex imaging localized paracrine stress to parenchymal cells neighboring senescent neutrophils. Ex vivo efferocytosis assays showed that aged TRMs were most impaired in clearing senescent neutrophils relative to apoptotic substrates, with both functions restored by EP2 deletion or pharmacologic antagonism. Mechanistically, EP2 signaling suppressed integrin-dependent stabilization of senescent neutrophils on TRMs and downstream engulfment. Analyses of human liver and heart datasets revealed conserved EP2 up-regulation in aged TRMs, enrichment of senescent neutrophils, and reduced TRM-neutrophil interactions.

This work identifies EP2 signaling in TRMs as a central regulator of organ-wide aging through its control of senescent neutrophil clearance, reframing aging as a failure of active cellular clearance rather than passive degeneration. With age, neutrophils acquire senescence-associated features, and their accumulation drives tissue injury through two converging mechanisms: intrinsic degranulation and NETosis, and extrinsic paracrine stress on neighboring parenchymal cells. Pharmacological inhibition of EP2 restores TRM efferocytic capacity and promotes clearance of senescent neutrophils, positioning EP2 antagonism as a tractable therapeutic strategy for age-related organ and functional decline.

Microglia are innate immune cells of the brain, very similar to the macrophages found elsewhere in the body outside the central nervous system. Both microglia and macrophages do much more than defend against pathogens; both are deeply involved in tissue maintenance, function, and regeneration. It is by now well established that microglia become inappropriately inflammatory in old age, and researchers increasingly see this as an important component of age-related neurodegeneration. Here, researchers present provocative data to argue that the microglia of old age are not the same cell type as the microglia of youth; they are instead more like macrophages, derived from circulating monocytes outside the brain. This is a sizable departure from the present understanding, a wrench thrown into the works for several possible therapeutic approaches to microglial dysfunction in old age, so one should probably wait for confirmation before taking it at face value.

Prior studies have identified age-related shifts in gene expression, including increased inflammatory signaling and reduced synaptic function, implicating transcriptional dysregulation in brain aging. However, gene expression alone provides an incomplete view. To address this, we profiled gene expression and multiple layers of epigenetic regulation, including chromatin accessibility, DNA methylation, and three-dimensional (3D) genome organization at single-cell resolution across the adult lifespan.

Aging is associated with coordinated and often nonlinear changes in gene regulation across cell types, with a major transition occurring around midlife. A notable finding was a remodeling of the brain's immune cell landscape. Microglia underwent a nonlinear transition in which embryonically derived, brain-resident microglial cells were progressively replaced by a population with epigenetic features resembling blood-circulating monocytes. This transition was not readily detectable using gene expression alone but was revealed by DNA methylation, which preserves cellular lineage. These monocyte-like microglia exhibited epigenetic, transcriptional, and 3D genome features associated with proinflammatory programs, suggesting a potential driver of age-related neuroinflammation.

Link: https://doi.org/10.1126/science.adt8307

Atrial fibrillation is a disruption of normal heart rhythm. It becomes more prevalent with old age, and at its most severe end can contribute to cardiovascular mortality. Much of the incidence of atrial fibrillation is idiopathic, meaning the cause is obscure. Treatment tends to focus on the more severe cases and surgery to map the electrical connections in the heart and ablate regions that are causing issues, regardless of the underlying reasons as to why those regions might cause issues. Research suggests that the gut microbiome may play a role in idiopathic atrial fibrillation via generation of the metabolite TMAO, which is disruptive to the regulation of heart rhythm. Some people with idiopathic atrial fibrillation may be able to eliminate or dampen the severity of episodes by suitably altering their diet and thus adjusting the behavior and composition of the gut microbiome. A number of potential strategies for pharmaceutical inhibition of TMAO production exist, such as use of iodomethylcholine, but none of these compounds have been developed as drugs.

Gut microbiota-derived trimethylamine N-oxide (TMAO) plays a role in the pathogenesis of cardiovascular disease. The role of TMAO in the pathogenesis of atrial fibrillation (AF) remains uncertain. TMAO levels were quantified in plasma from serial subjects undergoing elective cardiac catheterizations (N=5,090) and shown to independently associate with prevalent AF following adjustment for risk factors (TMAO adjusted odds ratio 1.7).

Human cAMP response element modulator isoform IbΔC-X transgenic mice (CREM-IbΔC-X), a spontaneous mouse model of AF, supplemented with a TMAO diet developed AF sooner. C57BL/6J mice on and off a TMAO had more inducible AF via a transesophageal pacing study compared to chow controls. Dietary choline supplementation increased circulating TMAO levels and significantly accelerated AF onset in CREM-IbΔC-X mice. Iodomethylcholine (IMC), the gut microbial CutC/D inhibitor that suppresses choline to TMA(O) metabolic transformation, reduced circulating TMAO levels and choline induced AF onset.

Cecal metagenomic analyses showed that choline supplementation induced changes in microbial communities associated with AF, while many of these changes were attenuated by IMC. Choline supplementation promoted overall adverse atrial remodeling with left atrial dilation. Optical mapping studies showed that mice supplemented with choline exhibited reduced conduction velocity, shortened action potential duration at 80% repolarization, and decreased wavelength. TMAO inhibits muscarinic receptor 2 resulting in autonomic dysfunction that promotes AF. In summary, the gut microbial metabolite TMAO, independently associated with AF risk in subjects, enhances AF in multiple AF mouse models via autonomic dysfunction, and is a therapeutic target for prevention of AF.

Link: https://doi.org/10.1172/JCI201684

Cancer is a dark mirror to the normal processes of tissue maintenance, in which normally helpful processes run amok and become pathological when harnessed to make tumors grow. A cancer is a subversion of normal regeneration and maintenance. Aging, on the other hand, is a progressive disruptive failure of those same mechanisms of regeneration and maintenance. Thus many of the issues found in aging are also of interest to the cancer research community, and have been studied in that context for considerably longer than the modern longevity biotechnology community has existed. It is quite common to find that an existing class of drug that might be of interest in the context of aging was initially developed as a cancer therapy.

T cell exhaustion is a feature of aging. These adaptive immune cells become unresponsive and do not contribute to immune defense as they should. T cell exhaustion is also a well known feature of cancer, one of the ways in which the immune system falls short in its ability to destroy a growing tumor. T cell exhaustion also hinders the deployment of immunotherapies that depend on the immune system's anti-cancer capabilities. Immune cells engineered to attack a cancer and introduced into the patient as a therapy often burn out and become exhausted long before they can make a meaningful dent in the size of a tumor, a faster and more exaggerated version of what happens to native, unmodified immune cells.

Today's research materials discuss what happens under the hood in the exhaustion of T cells, and point to a regulator that can adjust the balance of activity versus exhaustion. Exhaustion of T cells is a metabolic collapse, the T cell has exhausted its supply of energy by conducting the energetically expensive process of making cytotoxic proteins to kill cancerous cells. The pace at which this weapons manufacture progresses determines whether the T cell can sustain its activity over time, or whether it will quickly become exhausted. Some cancers can be overcome by a short period of aggressive attacks by highly active T cells, but in other cases that is not enough, a longer period of lower intensity anti-cancer activity would produce better results.

New Strategy Could Prevent T Cell Exhaustion and Boost Immunotherapy

A major pillar of cancer immunotherapy involves stimulating T cells, the specialized killers of the immune system, to attack tumors. But this strategy has been undermined by the tendency of T cells to tire out before finishing the job. When the cells reach the fatigued stage - called T cell exhaustion - these immune cells lose the ability to sustain the attack and keep cancer growth under control. T cells enter the exhausted state to save themselves. They stop fighting to avoid becoming overstimulated and dying. When a T cell is in attack mode and making cytotoxic proteins, the mitochondria must convert nutrients from food into adenosine triphosphate (ATP). ATP is the primary molecule used by all living cells to store and transfer energy.

Researchers have now identified a signaling molecule called MEK that plays a key role in T cell exhaustion. "Think of ATP as the currency in a fund that the cell spends down. If you spend ATP on one thing, you don't have enough to do something else. The exhaustion program is a sign that the cell's bank account is getting close to zero. MEK tells exhausted cells whether to conserve fuel or go for broke. What we found is that inhibiting MEK makes the cells more conservative - helping them live longer while reducing the rate at which they produce the proteins that actually kill cancer cells." So MEK is both the problem and part of the solution - it keeps T cells at full power but risks complete burnout. This means blocking MEK is a double-edged sword: It weakens the attack but keeps the soldiers alive.

MEK inhibitors could be used selectively to rev up T cells. Patients with large tumors or a small number of immune cells are unlikely to have a strong enough response to immunotherapy to finish off the tumor quickly. In those cases, a MEK inhibitor-induced slow burn - even in an exhausted state - allows T cells to persist, which is essential when when either the task at hand (the tumor) is large or the workforce (the number of T cells) is small.

MEK-dependent bioenergetic demand drives terminal CD8+ T cell exhaustion

Loss of mitochondrial function promotes CD8+ T cell dysfunction during persistent antigen encounter. Here, we examined the pathways whereby chronic antigen stimulation leads to metabolic dysfunction. Chronic T cell receptor (TCR) engagement increased ATP demand, leading to mitochondrial NADH accumulation, accumulation of reactive oxygen species, and subsequent mitochondrial dysfunction. Among TCR-dependent proximal signaling components, inhibiting the kinase MEK uniquely reduced nutrient uptake and mitochondrial NADH accumulation while restoring proliferation. Accordingly, MEK inhibition during chronic TCR stimulation reduced terminal T cell exhaustion.

Mechanistically, chronic MEK activation in T cells drove ATP demand by increasing global protein synthesis rates in vitro and in vivo. MEK inhibition reversed chronic TCR stimulation-driven increases in RNA polymerase II C-terminal domain phosphorylation, reducing transcription rates at loci encoding effector- and terminal-exhaustion-associated genes while maintaining transcription of genes associated with T cell memory. Thus, MEK-dependent metabolic demand is a driver of T cell exhaustion, providing insight into how MEK inhibition enhances immunotherapy efficacy.

Clonal hematopoiesis of indeterminate potential (CHIP) is arguably the most studied form of somatic mosaicism, in which stem cells accumulate mutations over time, and thus patterns of those mutations spread out into the tissue supported by those stem cells. In this case, the "tissue" is the immune system, made up of immune cells descended from the hematopoietic stem cell population that is resident in the bone marrow. There is evidence for CHIP to contribute to forms of age-related disease and aspects of aging more generally, which is an argument for somatic mosaicism in all tissues to contribute to degenerative aging.

Aging is associated with organ and tissue function deterioration and consequent increased risk of disease occurrence and mortality. Recent scientific advancements have succeeded in increasing the human life span and attempts are being made to enhance the longevity further. This stretched longevity exposes the organism to increased cellular stress and accumulation of DNA damage. Mutations in leukemia-associated driver oncogenes like DNMT3A, TET2, ASXL1, TP53, PPM1D, SF3B1, SRSF2, and IDH1/IDH2, provide selective growth advantage to the mutated clones over normal hematopoietic stem cells (HSCs). Altered bone marrow (BM) microenvironment and increased pro-inflammatory milieu further accelerates the clonal expansion and eventually reduces the hematopoietic heterogeneity.

Significant increase in clonal hematopoiesis with more than two percent of peripheral blood cells arising from single hematopoietic clone is termed as clonal hematopoiesis of indeterminate potential (CHIP). CHIP is increasingly recognized as an age-associated risk factor linked to cardiovascular and neurological disorders. While epidemiological and experimental studies suggest mechanistic involvement of inflammation, current human evidence primarily supports risk association rather than definitive causality, which may vary across mutation types. Here, we have discussed the intrinsic and extrinsic changes occurring in the hematopoietic system and its role in enhancing the clonal expansion during aging. We have further discussed the role of CHIP in various diseases and diagnostic tools being currently used for CHIP diagnosis. Finally, we also discuss the current CHIP management strategies and global status of CHIP related research.

Link: https://doi.org/10.21037/atm-2026-1-0030

The vessels of the glymphatic system run parallel to blood vessels entering the brain. Glymphatic vessels provide a path for drainage of cerebrospinal fluid into the body. This is a way to remove metabolic waste from the brain, such as the protein aggregates that contribute to neurodegenerative conditions. Loss of glymphatic flow is a feature of aging, allowing the build up of metabolic waste in the brain and consequent cellular dysfunction. Researchers here report on interesting results from a relatively simple approach to restore a greater drainage of cerebrospinal fluid through the glymphatic system, intermittently changing gas levels known to affect blood vessel contraction and dilation in order to encourage fluid flow in the glymphatic system close to those vessels. It remains to be seen as to whether this will affect disease progress, but animal studies of other ways to increase drainage of cerebrospinal fluid are encouraging.

A unifying feature of neurodegenerative conditions is the accumulation of unwanted proteins in the brain. For Alzheimer's disease it is amyloid beta and Tau proteins, while for Parkinson's disease it is alpha synuclein. Related conditions such as Lewy body dementia have a similar protein buildup. Normally, the body can clear these proteins, which are often the waste products of neuron activity, using a natural process called glymphatic clearance, which takes place when our bodies enter deep sleep.

During this process, the brain tells cerebral blood vessels to dilate and constrict, which allows the cerebrospinal fluid that surrounds the brain to flow deeper into the tissue as interstitial fluid. A cycle of blood vessel dilation and contraction pumps the interstitial fluid through the brain and then back out, flushing potentially harmful proteins, inflammatory mediators, and waste into the blood so the body can clear them out. This process takes place at night, when it will not impact more complex synaptic function, which is also when the brain's neurons dump out their waste products. Indeed, many scientists believe glymphatic clearance is one of the reasons we need to sleep in the first place.

In a study conducted with 30 patients with Parkinson's disease and 33 healthy controls, researchers used MRI brain scans during sleep to figure out the frequency of oscillation between blood vessel dilation and contraction during glymphatic clearance. They then had study participants breathe in a mixture of 5% carbon dioxide (CO2) and normal air, alternating with normal room air every 35-seconds. After just one half-hour session of the new treatment, the researchers detected higher concentrations of proteins such as beta amyloid, alpha synclein, and other byproducts of brain activity in the blood, indicating these waste products had been flushed out of the brain and into the blood, allowing the body to clear them.

If lowering the CO2 levels in blood constricts the vessels in the brain, the opposite could also be true. Increasing CO2 levels could cause the vessels to dilate, and alternating raising and lowering the CO2 level would generate the pumping action needed to propel the interstitial fluid across the brain.

Link: https://www.research.va.gov/currents/0426-Exciting-new-treatment-being-developed-for-Parkinsons-Alzheimers.cfm

A peptide is a short protein. There are countless such molecules present in the body. If used as a basis for therapy, a peptide is generally injected rather than taken orally as only a very small range of peptides can survive the digestive tract. Indeed, only a very small number of proteins more generally can survive outside of their specialized location inside a cell. So when people talk about peptides for therapy, they are talking about a tiny fraction of the peptides present in the body, largely those that are in some way involved in signaling between cells and thus can be found circulating through blood and tissues. Of that still very large number of peptides, a handful have been developed or are under development as potential therapies.

In recent years the same sort of people who enthusiastically sell dietary supplements on the basis of minimal data, cherry-picked studies, and a lot of hype and marketing have now discovered the existence of injectable peptides. There is something of a craze developing for a handful of known peptides that include a few approved for use with specific conditions outside the US, a few that have some animal studies and no human data whatsoever, and others in between those extremes. That GLP-1 receptor agonists are peptides has only fueled this hype cycle.

The US regulatory system for medicine has some quirks. One of those quirks is the existence of compounding pharmacies, regulated by states rather than the federal government. Very roughly, there is a whitelist of compounds that a compounding pharmacy is allowed to sell to patients, and that whitelist is largely determined by whether anyone has published a rigorous manufacturing protocol, regardless of whether or not the compound was approved for use in patients by the FDA. A lot of peptides being sold by the enthusiasts fall into this category. Further, the supplement industry is also in its own regulatory category, distinct from any sort of FDA drug approval, and also largely focused on manufacturing and quality control. Supplement industry lobbyists are apparently trying to have peptides included into their remit as well (a tough sell for injectable compounds to be called dietary supplements, but people do like to follow the money; a lot of self-interest at work there).

Needless to say, there are those on the more scientific and pro-regulation side of the house who are horrified by this sudden expansion of what they see as a blight upon the way things should be run. If they haven't been as vocal about the supplement industry in recent years, it is because they have been worn down by its excesses over the decades. Generally these commenters are in favor of the federal regulatory status quo for drugs to be more broadly applied. I think that the sane position is to be strongly against the present regulatory status quo, as it is clearly harmful to the pace of technological progress in medicine, while also recognizing that (a) it isn't great that some people are taking unnecessary and often ill-advised risks in the matter of peptides, and (b) education is an ethically better approach than regulation by force. People will sometimes do stupid things; freedom comes with responsibility. Trying to take away freedom of choice has side-effects that cause more harm over the long term, as we can see from the way in which the enormous and largely unnecessary costs imposed on medical development have impeded progress towards longer, healthier lives.

Unregulated Peptide Use in the Age of Biohacking: Digital Promotion, Gray-Market Access, and Emerging Public Health Risks

The recent expansion of peptide-based medicines has been especially visible in metabolic disease. GLP-1 receptor agonists and related incretin-based therapies have reshaped the treatment of type 2 diabetes and obesity, with agents such as semaglutide and tirzepatide demonstrating substantial effects on body weight and cardiometabolic outcomes in clinical trials. However, the visibility of approved peptide therapies has coincided with rising nonclinical peptide experimentation. The public success of GLP-1 receptor agonists has made injectable metabolic therapies more visible and normalized in public discourse, particularly for goals related to weight, metabolism, and body composition.

This legitimacy appears to be spilling over into a less regulated consumer marketplace, where experimental, investigational, or weakly evidenced peptides are promoted for fat loss, injury recovery, longevity, cognition, libido, aesthetics, sleep, muscle gain, and performance enhancement. The concern is not that all peptides are equivalent, but that digital discourse and online access pathways may blur distinctions between approved medicines, compounded products, investigational drugs, research chemicals, context-specific clinical therapies, preclinical compounds, and products supported mainly by anecdote or marketing.

This blurring is amplified by biohacking culture, longevity medicine, wellness clinics, and influencer-led health optimization. Biohacking and do-it-yourself biology communities have been shaped partly through online forums and digital spaces where users exchange knowledge, techniques, protocols, and interpretations of biological self-experimentation. In peptide-related discussions, compounds are frequently framed as tools for optimization, recovery, performance, aesthetics, cognition, or longevity, with terms such as "stacks," "protocols," "research peptides," "tier lists," and "longevity peptides" creating a shared language of self-experimentation. These digital sources should not be interpreted as evidence of clinical efficacy or safety. However, they are relevant to public health because online creators, forums, and wellness communities can influence how health products are perceived, normalized, sourced, combined, and interpreted outside formal clinical supervision.

Gray-market access is central to this exposure pathway. Many peptide products are sold online with disclaimers such as "for research use only" or "not for human consumption," while being discussed in consumer spaces as substances for personal use. Certificates of analysis, purity claims, and biomedical language may provide reassurance, even when products have not undergone the regulatory review, manufacturing oversight, or postmarketing surveillance expected for approved medicines. In this gray-market environment, access may appear medically adjacent while remaining weakly accountable, poorly traceable, and difficult to monitor through conventional pharmacovigilance systems.

Sleep quality is well established to decline with age and age-related disease. A sizable medical and supporting industry is devoted to attempts to improve sleep quality via what are essentially compensatory approaches to intervention. As researchers note here, the evidence to hand does not demonstrate that reduced sleep quality causes an acceleration in the pace of aging. That the evidence for poor sleep to cause accelerated aging is very mixed suggests a complex relationship between this dysfunction and the broader scope of aging, in which only some of the circumstances and mechanisms associated with poor sleep may accelerate aging. Otherwise it is likely a downstream consequence of aging.

Sleep gets worse with age and is correlated with risk for disease and mortality. The possibility that poor sleep causes aging to accelerate has prompted interest in improving sleep to slow aging and prevent disease. However, the existing evidence on the link between poor sleep and accelerated aging is unclear. Here, we tested for correlation and causation between poor sleep and accelerated aging using five independent datasets of adults (total N > 64,000).

We found strong evidence for a correlation between poor sleep and fast aging that is consistent across young, middle, and late adulthood and across aging biomarkers derived from different tissues and modalities. We found that this correlation is robust to the influence of chronic disease burden, but not to the influence of shared genetic and early environmental factors among twins. Finally, we found mixed evidence for a causal influence of poor sleep on accelerated aging using Mendelian randomization. Our findings indicate that the correlation between poor sleep and accelerated aging is highly robust; however, the claim that poor sleep causes aging to accelerate is not consistently supported.

Link: https://doi.org/10.64898/2026.07.02.26357135

A useful side-effect of publishing under a copyleft license is that one can be lazy about formally publishing compilations of past material. Sooner or later someone else will get around to it. Thus Kris Borer, a longevity community advocate, recently let me know that he has assembled and tidied up a collection of some of my short essays and published it as a book. The pictures of me that end up on conference websites (and now on a book cover) are looking ever younger than the reality these days; a reverse Dorian Gray effect in which fortunate lighting at the time of capture and additional post-processing every time someone copies an picture of me for a new use conspire to hide the lines. For all the promise of medical technology to hand and medical technology to come, we're all still aging faster than we'd like.

Aging is damage. Damage is repairable. Get to work. For nearly a quarter century, a writer known only as Reason said this almost every day - to a world that mostly wasn't listening. He said it when curing aging was a punchline. He said it as the science caught up, the first companies formed, and the money and the clinical trials arrived. He built, without quite meaning to, the most complete record we have of a scientific field being willed into existence - and then, in 2018, he stopped writing about other people's companies and founded his own.

The Voice of Reason gathers sixty-nine of his best pieces: the science of why we age and how we might not; a blistering quarrel with everyone who calls death a gift; the politics of which cures get made; his own self-experiments with biohacking; and, beneath it all, an unblinking reckoning with mortality - his readers', and his own. He is clear, he is blunt, he is often very funny, and he is angrier than you expect about the hundred thousand people who die of aging every day. He is also, it turns out, a man whose quarter-century forecast is coming true.

Link: https://www.amazon.com/Voice-Reason-Quarter-Century-Fighting-ebook/dp/B0H96F89Z3

Every cell contains hundreds of mitochondria, the evolved descendants of what were once symbiotic bacteria. Much of the original mitochondrial DNA has migrated into the cell nucleus, and mitochondria have become essential components of the cell, subject to quality control mechanisms that recycle malfunctioning and worn mitochondria, as is the case for other organelles. Nonetheless, mitochondria still behave very much like bacteria. They divide to make up their numbers, fuse together, and readily exchange component structures and proteins. Mitochondria are vital to cell function in a number of ways, the most important of which is their production of the chemical energy store molecule adenosine triphosphate (ATP). Cells rely upon ATP to power the chemistry of life.

With advancing age, mitochondria throughout the body change in size, structure, and function. They generate a greater amount of damaging oxidative molecules in the course of making ATP, and the production of ATP declines. Quality control is impaired and malfunctioning mitochondria accumulate. Some are made to malfunction as a result of damage to the remnant mitochondrial genomes, other dysfunction appears to be a consequence of age-related changes in the level of expression of critical mitochondrial genes found in the cell nucleus. This mitochondrial dysfunction also generates continual inflammatory signaling via maladaptive interactions between damaged mitochondria and their debris and defense mechanisms in the cell.

In today's open access paper, the authors propose a quite different view of mitochondrial dysfunction. In their hypothesis, there is a decline in the ability of mitochondria to appropriately adapt to the lower demand for ATP in aged tissues. Without appropriate regulation, excess material for the production of ATP keeps on arriving to clutter up the environment, giving rise to the observed side-effect of increased production of oxidative molecules and other issues. It is an interesting point of view, and seems worthy of an attempt to produce supporting experimental evidence.

Rethinking frailty as a disorder of mitochondrial adaptability, from energetic congestion to systemic vulnerability

Frailty is a clinical syndrome of reduced physiological reserve and disproportionate vulnerability to stressors in older adults. The dominant cellular model attributes frailty to mitochondrial bioenergetic insufficiency, supported by convergent evidence of reduced mitochondrial respiratory capacity, lower mitochondrial DNA (mtDNA) content and altered substrate metabolism in frail individuals across multiple tissues. Several reproducible features of the phenotype are nevertheless difficult to reconcile with a strict bioenergetic deficit interpretation. Particularly consequential for the present proposal is that cellular energetic demand itself declines progressively with age. Sedentariness, reduced muscle mass, anabolic resistance and the involution of brown adipose tissue together reduce cellular ATP turnover, shifting the balance between substrate input and demand toward chronic excess of input relative to consumption.

Building on these considerations, we propose a complementary framework in which frailty originates in energetic congestion, a state in which a chronically reduced demand allows substrate to persist beyond utilisation, while substrate input itself remains broadly preserved, with the consequence that the regulatory coupling between substrate availability and cellular need is progressively lost. Mitochondrial dysfunction in this view is real but reframed in its directionality. The mitochondrion is not failing because fuel is scarce. It is failing because the fall in demand-driven ATP turnover is not matched by a comparable reduction in substrate delivery, so that oxidative flux is uncoupled from cellular need, while mitochondrial adaptability, the capacity of the organelle to coordinate output with fluctuating energetic demand, is progressively impaired.

The thymus is primarily noted as being the site of T cell maturation, essential to the supply of new T cells to maintain the adaptive immune system. It declines in function relatively early in aging; active tissue is largely replaced by fat in most 50 year olds. Like all organs, cells in the thymus also generate various factors that circulate throughout the body. The production of these factors also declines with age as the thymus atrophies. Researchers here identify one such factor, thymulin, which appears to meaningfully affect myeloid immune cells to help control inflammatory signaling and improve immune surveillance of cancer.

Chronic inflammation increases with age and contributes to cancer progression and therapeutic resistance, yet the mechanisms underlying this process remain incompletely understood. Here, we identify an increased frequency of pro-inflammatory myeloid cells in aged mice and humans, characterized by elevated production of IL-1α, IL-1β, IL-6, and TNF-α. These cells are enriched in the breast tumor microenvironment and are associated with accelerated tumor progression.

Using heterochronic parabiosis and bone marrow chimeras, we show that age-associated myeloid cell inflammatory activation is suppressed by non-bone marrow-derived circulating factors present in young hosts. Integrative analyses identify thymulin, a thymus-derived peptide that declines with age, as a mediator that suppresses pro-inflammatory cytokine production by inhibiting NF-κB signaling. Furthermore, thymulin enhances antitumor T-cell immunity, improves tumor control and survival, and sensitizes tumors to anti-PD-L1 therapy in an age-dependent manner.

Together, these findings uncover a thymus-myeloid cell regulatory axis linking aging, inflammation, and cancer immunity, and suggest thymulin as a potential strategy to improve cancer immunotherapy in older individuals.

Link: https://doi.org/10.1038/s41467-026-75383-0

A magnetic resonance imaging (MRI) approach known as diffusion tensor image analysis along the perivascular space (DTI-ALPS) can be used to measure the flow of cerebrospinal fluid leaving the brain via the glymphatic system, a network of vessels that parallels blood vessels passing out of the brain. This drainage of cerebrospinal fluid allows metabolic waste to leave the brain, but becomes progressively ever more impaired with advancing age. It is thought that this loss of drainage leads to a build up of protein aggregates such as misfolded amyloid-β that contribute to the onset and progression of neurodegenerative conditions. Here researchers review the evidence for a reduced drainage rate measured via DTI-ALPS to correlate with established measures of the progression of Alzheimer's disease. One might recall that some animal studies have shown that forcing an increase in glymphatic flow of cerebrospinal fluid has produced a reduction in neurodegenerative pathology.

Although the diffusion tensor image analysis along the perivascular space (DTI-ALPS) index is widely utilized as a proxy for glymphatic function in Alzheimer's Disease (AD) research, its association with core AD pathological biomarkers remains inconclusive due to inter-study heterogeneity. This systematic review aimed to investigate associations between the DTI-ALPS index and AD biomarkers and to elucidate potential sources of heterogeneity.

Thirty-six studies were included. Meta-analyses revealed significant correlations between the DTI-ALPS index (N = 22) and amyloid-β positron emission tomography (PET) deposition (N = 9), Mini-Mental State Examination (MMSE) (N = 15), and Montreal Cognitive Assessment (MoCA) (N = 10) scores. Conversely, the association with tau PET deposition (N = 3) was not significant after adjusting for publication bias. Regarding clinical staging, indices were significantly lower in AD and mild cognitive impairment groups compared to controls but no difference was found between the two patient groups. Based on meta-regression and narrative synthesis results, we identified methodological variability and AD pathological complexity as primary sources of heterogeneity.

Link: https://doi.org/10.3389/fnagi.2026.1832525

As the name might suggest, aquaporin proteins facilitate the transfer of water molecules across cell membranes. This is important in a broad range of contexts, such as the operation of the blood-brain barrier that wraps blood vessels that pass through the brain, and in the drainage of cerebrospinal fluid from the brain into the body. One of the paths by which cerebrospinal fluid exits the brain, carrying away metabolic waste with it, is the glymphatic system. Glymphatic vessels run parallel to the blood vessels that enter and exit the brain. Research is making it increasingly apparent that drainage of cerebrospinal fluid is vital to the health of the brain. Unfortunately this drainage becomes progressively ever more impaired with advancing age, and this is thought to contribute to the buildup of protein aggregates and other forms of metabolic waste in the brain, contributing to inflammation, cell dysfunction, and neurodegenerative conditions.

In today's open access paper, researchers build on past work on the manipulation of aquaporin 4 (AQP4) activity in the glymphatic system. A small molecule compound TGN-073 increases the activity of AQP4 via a mechanism that isn't understood, but may involve altering the structure of AQP4 to broaden the size of the pores it creates in the cell membrane. Other work has shown that different isoforms and thus structures of AQP4 are more effective than the usual version, for example. Here, researchers show that this increased AQP4 activity does in fact help to reduce neurodegenerative pathology in mice, supporting the importance of failing cerebrospinal fluid drainage in the development and progression of neurodegenerative conditions.

AQP4-dependent enhancement of glymphatic function attenuates tau pathology and neurodegeneration in PS19 mice

The glymphatic system facilitates cerebrospinal fluid-interstitial fluid exchange and contributes to the clearance of pathogenic proteins from the brain. Glymphatic dysfunction has been associated with Alzheimer's disease and related tauopathies; however, whether impaired glymphatic transport causally drives tau accumulation and neurodegeneration, and whether its enhancement confers therapeutic benefit, remains unclear.

Glymphatic water dynamics in PS19 tau transgenic mice were assessed using JJVCPE, a novel MRI-based approach for evaluating brain water exchange. The effect of pharmacological activation of aquaporin-4 (AQP4) with TGN-073 on glymphatic cerebrospinal fluid influx was examined in wild-type mice using dynamic contrast-enhanced MRI. Tau pathology, neurodegeneration, and cerebrospinal fluid tau levels were analyzed in PS19 mice following chronic TGN-073 treatment. AQP4-deficient PS19 mice were examined to determine target specificity.

PS19 mice exhibited significant impairment of glymphatic water exchange at early disease stages, which progressively worsened with ageing. Pharmacological activation of AQP4 with TGN-073 robustly enhanced glymphatic-related tracer influx, reduced tau accumulation, neuronal loss, and gliosis, and was accompanied by increased cerebrospinal fluid tau levels. TGN-073 also restored perivascular AQP4 enrichment without significantly altering overall AQP4 abundance. Importantly, these beneficial effects were abolished in AQP4-deficient PS19 mice, demonstrating that both glymphatic enhancement and suppression of tau pathology and neurodegeneration are AQP4-dependent.

Our findings support a mechanistic contribution of impaired glymphatic function to tau accumulation and neuronal vulnerability in tauopathy. Pharmacological activation of AQP4 enhances glymphatic function, restores perivascular AQP4 organization, and ameliorates tau pathology, neurodegeneration, and gliosis. These findings identify AQP4-mediated glymphatic modulation as a disease-relevant and therapeutically tractable pathway for tau-related neurodegenerative disorders.

The immune system and its supporting organs and structures throughout the body, such as bone marrow, spleen, lymphatic system, and thymus, are collectively make up a very complex system. The way in which the immune system ages is thus also very complex. Different specialized cell populations change in number and function. Immune cells are influenced into maladative inflammatory behavior by some combination of internal molecular damage and disarray on the one hand coupled with external damage to tissue on the other. The supply of many types of immune cell is much reduced from youthful levels, allowing malfunctioning and senescent immune cells to accumulate. The immune system is crucial to health, not just as a defense against pathogens and potentially cancerous cells, but also due to its role in day to day tissue maintenance. Improving immune function in older people is likely to produce meaningful benefits. There are certainly many, many distinct issues to provide starting points for those who wish to develop novel therapies with that goal in mind.

Aging is accompanied by complex structural and functional immune system changes driven by genomic instability, epigenetic alterations, mitochondrial dysfunction, telomere attrition, loss of proteostasis, deregulated nutrient sensing, and the accumulation of senescent cells exhibiting a senescence-associated secretory phenotype, which altogether lead to severe consequences including altered antimicrobial defense, the overproduction of autoantibodies, and chronic, low-grade inflammation (inflammaging).

In this article, we summarize age-related alterations in the function of primary and secondary lymphoid organs, including the bone marrow, thymus, spleen, and lymph nodes. The involution of these organs leads to impaired hematopoiesis, reduced production of naïve lymphocytes, and immune microenvironment disruption. We also describe aging-related impairment of the activity of neutrophils, macrophages, dendritic cells, and natural killer cells, as well as dysregulation of T lymphocyte and B lymphocyte responses. Specifically, these alterations include a decline in naïve cell populations, an accumulation of memory and exhausted cells, and a reduction in the diversity of antigen receptors. Consequently, older individuals exhibit increased susceptibility to infections, cancer, and autoimmune diseases, along with diminished vaccine efficacy.

Link: https://doi.org/10.3390/ijms27136037

Clonal hematopoiesis of indeterminate potential (CHIP) is a form of somatic mosaicism in the immune system. Hematopoietic stem cells and progenitor cells in the bone marrow responsible for producing immune cells acquire random mutations over time, and patterns of these mutations slowly spread out into the immune system as a result. There is evidence for CHIP to correlate with accelerated progression of a number of age-related conditions and other aspects of degenerative aging, making it a good place to start if trying to understand how important somatic mosiacism is to the progression of aging. While the research community largely agrees that DNA damage is important in aging, based on the existence of accelerated aging conditions in which DNA repair mechanisms operate poorly, it is by no means concretely established as to how much of a contribution DNA damage makes to normal aging. Expect to see further investigation of CHIP and its effects on measures of aging and age-related dysfunction as an approach to answering that question.

Clonal haematopoiesis of indeterminate potential (CHIP) represents somatic mutations in haematopoietic stem cells that drive clonal expansion. Epigenetic age acceleration (EAA), estimated from DNA methylation (DNAm) clocks, may capture age-related changes in haematopoiesis. This systematic review and meta-analysis was conducted to synthesise evidence on associations between CHIP and EAA and explore shared biological mechanisms that may underlie this relationship. Five studies comprising 7,483 individuals (ages 55-79, 67.1% female) assessing associations between CHIP and DNAm clocks were included.

Across studies, CHIP individuals had higher EAA than no-CHIP individuals, and larger clones were associated with higher EAA. Meta-analysis of three cross-sectional studies (n=6,946) showed that CHIP had higher EAA versus no-CHIP for Horvath1Age IEAA (mean difference, MD=2.84 years), HannumAge EEAA (MD=2.31 years), PhenoAge (MD=1.84 years), and GrimAge (MD=1.20 years,). Both DNMT3A- and TET2-mutated CHIP were associated with higher EAA with TET2-mutated CHIP showing larger effect sizes and more consistent associations than DNMT3A-mutated CHIP across DNAm clocks tested. Higher EAA may also act as an effect modifier for morbidity and mortality in CHIP. Larger longitudinal studies are needed to verify a temporal relationship and determine whether EAA provides incremental prognostic value for morbidity and mortality in CHIP.

Link: https://doi.org/10.1016/j.arr.2026.103259

The thymus is a tiny organ near the heart responsible for generating T cells of the adaptive immune system. Thymocyte cells are made in the bone marrow, migrate to the thymus, and undergo a process of exposure and selection that leads to mature T cells. The adaptive immune system needs a supply of new cells to make up the losses incurred due to damage and the Hayflick limit on replication. Unfortunately, the thymus atrophies with age; it is one of the earliest organs to reach a significant loss of function. Most 50-year olds have little active thymus tissue left, and a sizable component of the subsequent accelerating decline of the adaptive immune system takes place because it is denied sufficient reinforcements. It becomes ever more populated by senescent, exhausted, and malfunctioning T cells.

There are strategies that will absolutely, definitely regenerate the aged thymus, well demonstrated in animal models. None of them are all that practical for widespread use in medicine, or at least not palatable to those in charge of the regulation of medicine. Upregulation of FOXN1 via gene therapy regrows the thymus, but no delivery system other than direct injection has emerged to enable sufficient delivery to such a small organ without overloading and harming other tissues. Direct injection is not palatable because any sort of introduction of a needle into the inner organs of an aged individual has a small but meaningful rate of severe complications. This also rules out the use of KGF protein therapy, shown to regenerate the thymus in animal studies, but which cannot be introduced into humans at high enough levels via intravenous injections without causing unacceptable side-effects in other tissues.

Currently those working in the field of thymus regeneration are focused on a few different strategies. Firstly there are potential cell therapies that use cell populations known to home to the thymus, such as thymocytes and thymic epithelial cells. One can even engineer the cells, say to secrete KGF for example. Then there are a range of quieter and not yet successful efforts to find some clever way to use a small molecule or a biologic to tweak the metabolism of the thymus without upsetting any of the other tissues in the body. Existing targets, particularly those close to FOXN1, make that difficult to achieve. Lastly there is the Intervene Immune approach of tailored growth hormone therapy, which produces thymic restoration to a similar degree as observed following long term mild calorie restriction.

The good news for today is that someone is claiming to have found a viable small molecule approach to regeneration of the aged thymus that works via intraperitoneal injection in mice, a popular stand-in for intravenous injection. The treatment duration was quite short, only a few weeks. The number of mice per group is sadly low, 5 for some of the data, as low as 3 for some of the rest. That is low enough that I would want to see this replicated with 12 or more mice per group before taking it at face value. The small molecule in question is a free fatty acid receptor agonist, with the free fatty acid receptor GPR40 as the target; this agonism appears to compensate for a reduction in expression in this receptor, but how exactly this interacts with what is known of the FOXN1-centered biochemistry regulating thymic growth and activity remains to be seen. It could be as simple as reduced inflammation in thymic tissue, as reductions in inflammatory signaling are a known outcome of GPR40 agonism, but very little in biology tends towards being simple.

GW9508-Induced Activation of GPR40 in Thymic Epithelial Cells: A Therapeutic Strategy to Delay Thymic Aging

The thymus plays a crucial role in T-cell development and the establishment of cellular immunity. Thymic epithelial cells (TECs), which constitute the predominant stromal cell population in the thymus, are vital for maintaining thymic structure and function. With aging, the thymus undergoes gradual involution, characterized by a reduction in thymic volume, a decline in TEC numbers, and an accumulation of fibroblasts, adipocytes, and senescent cells within the thymic microenvironment. These changes result in decreased production of naïve T cells and reduced diversity of peripheral T-cell receptors (TCRs), ultimately compromising immune function in the elderly.

GW9508 is a selective agonist of GPR40, a receptor extensively studied in the context of metabolic diseases, and more recently, in relation to age-associated disorders. GPR40, also known as free fatty acid receptor 1 (FFAR1), is predominantly expressed in pancreatic β-cells and insulin-secreting cell lines, as well as in enteroendocrine cells, gustatory cells, immune cells, splenocytes, and the brain. Within immune system, GPR40 is implicated in regulating the functions of various immune cell, including keratinocytes, macrophages, and neutrophils. However, the role of GPR40 in senescent TECs has not been documented.

Here, GW9508, a selective agonist of GPR40, was used to treat aged C57BL/6J mice and aged iTECs model. The results indicated that targeted activation of GPR40 can activate the AMPK signaling pathway while inhibiting the ERK1/2-MAPK pathway, thereby enhancing the viability and restoring the function of aged iTECs. In vivo experiments in 17-month-old mice confirmed the effects of GW9508, consistent with cellular assays results, demonstrating that GW9508 effectively restored thymic function and facilitated structural recovery. Although thymus dysfunction begins relatively early in life, a recent study showed that it retains substantial protective capacity in adults, strongly supporting the notion that enhancing thymus function holds significant potential for improving T-cell function in older adults.

A number of neurodegenerative conditions, including Alzheimer's disease, are characterized by a pervasive chemical alteration of tau protein that causes tau to cease its normal function and aggregate into structures known as neurofibrillary tangles. This is harmful to neurons and their normal, necessary function. The feedback loop between maladaptive inflammation and tau aggregation drives the end stages of Alzheimer's disease, causing widespread cell death in the brain and the eventual death of the patient. Researchers here identify a compensatory maintenance process in neurons that can be made to operate more efficiently by increasing the expression of a protein called SORLA. In mice engineered to develop tau pathology, greater SORLA expression slows the progression of neurodegeneration.

Recent genome-wide association studies have linked multiple gene variants with altered Alzheimer's disease (AD) risk, including the class I membrane receptor endosomal trafficking factor, SORLA, or "Sortilin-related receptor containing LDLR class A repeats" (encoded by the SORL1 gene, also known as LR11). SORLA is a component of the retromer endosomal trafficking complex. Expression of retromer components have been shown to be down-regulated in AD and reduced SORLA expression was also linked to AD.

A role for SORLA in reducing amyloid-β (Aβ) levels has been well established; however, relatively little is known with respect to whether and how SORLA can potentially affect tau pathology in vivo. Here, we show that SORLA up-regulation can attenuate pathological effects in aged PS19 tauopathy mouse brain, including tau phosphorylation and seeding, ventricle dilation, synapse loss, long-term potentiation (LTP) impairment, and glial hyperactivation. These results indicate that SORLA confers neuroprotection against tau toxicity in the PS19 mouse brain.

Link: https://doi.org/10.1126/sciadv.aed6825

One of the hallmarks of dysfunctional lipid metabolism in the brain the context of age-related neurodegenerative disease is an increase in lipid droplets in brain cells. This is seen in a number of different neurodegenerative conditions. Evidence suggests lipid metabolism dysfunction to be involved in the inflammatory behavior of the innate immune cells known as microglia, thought to be an important contributing cause of neurodegeneration. Here, researchers provide evidence for lipid droplet formation to be associated with cellular senescence, a state in which cells cease to replicate and secrete inflammatory signals. Senescent cells are not cleared efficiently in aged tissues, and their numbers grow to disrupt tissue structure and function. It is already known that some fraction of overly inflammatory microglia in the aging brain are senescent; it remains to be seen as to the degree to which lipid metabolism dysfunction contributes to the burden of cellular senescence or vice versa.

Senescent cells (SnCs) are growth-arrested yet remain metabolically active and undergo extensive reprogramming to support their survival and the Senescence-Associated Secretory Phenotype (SASP). SnCs undergo key metabolic changes, including increased glycolysis, altered mitochondrial function and dysregulated lipid metabolism. While these metabolic changes are increasingly recognized, a comprehensive understanding of how they contribute to the pathophysiological effects of SnCs is still lacking.

Here, through metabolic profiling, we identified elevated levels of glycolytic metabolites in SnCs, which coincided with an increased presence of lipid metabolites, specifically triacylglycerol derivatives, the precursors of lipid droplets (LDs). We show that SnCs accumulate LDs in a classical primary human fibroblast model, and that senescent microglia upregulate LDs markers in a mouse model of Alzheimer's disease (AD), where they play a pathological role. Single-nucleus analysis of brains from AD patients further revealed an elevated levels of LDs markers in senescent brain cells, including microglia. Previous studies implicated both lipid droplet-containing microglia and senescent microglia in AD pathology.

Our findings provide evidence that these may represent the same cell population, in which the co-occurrence of LDs accumulation and the senescent state jointly contribute to their disease-promoting properties.

Link: https://doi.org/10.18632/aging.206390

The gut microbiome changes with age in ways the provoke chronic inflammation and tissue dysfunction. Animal studies demonstrate that restoring a youthful gut microbiome to old individuals extends life and improves health. Thus we would expect favorable changes to the gut microbiome to be reflected in any good alternative measure of aging, such as aging clocks. With that in mind, in today's open access paper the authors report on the development of algorithms based on gut microbiome composition that are predictive of epigenetic clock results. This allows identification of specific microbial species that may be harmful or helpful in the matter of the pace of aging.

The eventual destination for this field of research is to produce probiotic or other forms of therapy that can permanently adjust the composition of the gut microbiome in a controlled way. Reduce the numbers of bad species, increase the numbers of good species, and do this for at least hundreds of different species. At present a number of approaches can rejuvenate the gut microbiome with a single treatment, but in an uncontrolled way. For example, fecal microbiota transplantation from a young donor. Animal studies show that fecal microbiota transplantation produces sizable benefits, but for human medicine, given the present regulatory environment, widespread use of such a gut microbiome altering therapy is only likely given complete control over both the contents of the therapy and the outcomes of the therapy.

Gut microbiome signatures associate with DNA methylation-based biological aging

Recent advances in machine learning have applied novel tools to aging research, yet the relationship between the gut microbiome and epigenetic aging remains underexplored. This proof-of-concept study investigates whether gut microbial composition is associated with biological aging pace independent of chronological age. Using paired 16S rRNA gene sequencing and DNA methylation data from 123 monocyte-enriched samples in a cohort including Native Hawaiian and Pacific Islander participants, we developed "EpiBiome" models to predict epigenetic age acceleration residuals and DunedinPACE, a DNA methylation biomarker that estimates the instantaneous pace of biological aging.

Models predicting residuals of traditional clocks (Horvath, Levine, GrimAge2) showed no predictive signal at either taxonomic rank. By contrast, the EpiBiome-Accel model for DunedinPACE reached statistical significance at both the species level (R2 = 0.152) and the genus level (R2 = 0.099,). Adding chronological age as a feature did not improve performance (ΔR2 = -0.046 at species level), indicating age-independence. SHAP analysis of the species-level ElasticNet model identified Bifidobacterium adolescentis as the dominant contributor and the strongest predictor of decelerated aging, with Succinivibrio dextrinosolvens showing the strongest association with accelerated aging. These findings reveal specific gut taxa as hypothesis-generating candidates for mechanistic follow-up, rather than as individual-level diagnostic markers.

The biochemistry of aging is enormously complex, and it is very hard to pick apart which changes are definitively cause versus effect, and which changes are definitively more important than others. The only robust approach is to build a therapy that fixes just one change in isolation, and observe the results. This is not always possible or practical. When it can be done, a great deal is learned, however. See the outcome of the development of the first senolytic drugs on the state of knowledge regarding the role and relative importance of senescent cells in degenerative aging, for example. But the lack of such targeted and relatively effective therapies for most other potentially important mechanisms of aging allows a wide diversity of viewpoints to arise, as any new hypothesis regarding the importance of any given form of damage or dysfunction is hard to prove or disprove.

Aging is often framed as the gradual erosion of proteostasis, driven by declining chaperone capacity, impaired degradation, and dysregulated protein synthesis. Yet this view implicitly assumes that proteins fail primarily because they misfold or escape clearance. Increasing evidence instead points to a more fundamental problem: aging disrupts the spatial management of the proteome. Gradually, proteins are misplaced, signaling pathways are uncoupled from their compartments, and condensates that were once dynamic become pathological.

At the center of this spatial collapse lies nucleocytoplasmic protein partitioning. Nucleocytoplasmic protein transport has long been treated as a background housekeeping process, that is, essential but largely passive. However, this assumption is no longer reasonable. Karyopherins, the importins, exportins and biportins that mediate selective transport across the nuclear pore complex (NPC), are emerging as active regulators of proteostasis, phase behavior, and signaling fidelity. Rather than simply responding to cargo demand, karyopherins shape intracellular protein solubility, suppress aberrant condensation, and buffer age-associated stress. Their dysfunction therefore constitutes a primary, not secondary, driver of aging phenotypes.

Here, I argue that karyopherins should be repositioned at the core of aging biology. I propose that age-dependent failure of karyopherin-mediated transport represents a unifying mechanism linking proteostasis collapse, altered gene regulation, and the emergence of age-associated diseases. This perspective redefines nucleocytoplasmic protein transport from a logistics challenge into a central regulatory layer and highlights karyopherins as emerging targets for aging interventions.

Link: https://doi.org/10.1111/acel.70634

Microglia are innate immune cells resident in the brain, analogous to macrophages elsewhere in the body. Like macrophages, microglia are deeply involved in tissue maintenance as well as defense against pathogens and destruction of potentially cancerous, malfunctioning cells. Microglia adopt different packages of behaviors, called polarizations. In an aged tissue environment, microglia have a greater tendency to adopt an inflammatory polarization focused on defense rather than an anti-inflammatory polarization that aids in tissue maintenance. This shift towards maladaptive inflammatory signaling and immune behavior is characteristic of aging more generally. In the brain, microglia-driven inflammation harms tissue function, contributing to the onset and progress of neurodegenerative conditions.

Microglia, the resident innate immune cells of the central nervous system, are central players in brain development, healthy aging, and degenerative pathology, including Alzheimer's disease (AD). Aging is a major risk factor for AD, and various studies have identified alterations in microglial molecular signatures and morphological patterns that overlap with microglial states during aging. However, the mechanisms underlying the divergence of aging trajectories toward disease remain unclear. Thus, understanding the molecular changes in microglia during aging and AD pathology is crucial to elucidating the mechanisms that drive disease progression.

In this review, we examine current advances in understanding the phenotypic alterations in human microglia, highlighting gene signatures and morphological changes that may aid in defining microglia's molecular and functional programs in healthy aging and over the course of AD. We further explore the roles of oxidative stress and cellular senescence in driving the development of a chronic reactive state in microglia during aging, which may also contribute to the complex process underlying the onset and progression of AD pathology. This review highlights the advancements in therapeutic strategies focused on targeting pertinent pathological microglial changes during aging and in disease to mitigate the AD neurodegenerative process.

Link: https://doi.org/10.3390/cells15131159

The first predictive blood tests for future risk of Alzheimer's disease were developed in recent years based on correlations between marker proteins in the blood and disease risk derived from large epidemiological studies. One such marker is phosphorylated tau 217 (p-tau217), a modified variant of the tau protein involved in Alzheimer's disease pathology. People with higher levels in a blood sample have a greater chance of developing Alzheimer's disease symptoms in the years ahead, as the mechanisms of neurodegeneration are already operating at a higher than average level in their brain cells. Tau becomes pathological and damaging when it is hyperphosphorylated, aggregating and provoking chronic inflammation in brain tissue.

The medical community is somewhat reluctant to engage with this sort of testing because there is no easy prescription to follow up with. But the interesting question remains: what should one do if a blood test shows a high level of p-tau217? The obvious first answer is to look at all of the lifestyle factors that correlate with risk of Alzheimer's disease, based on epidemiological studies, and modify one's lifestyle choices appropriately. More speculatively, get vaccinated, based on the ongoing discussion over the evidence for late life vaccinations of various sorts to reduce the risk of dementia via trained immunity. The same might be said for taking antiviral drugs, based on similar discussions centered on the possible role of persistent viral infections in neurodegenerative conditions. After than, one might look at what else can be done to reduce age-related chronic inflammation, given its prominent role in neurodegenerative conditions, but all such strategies are probably things one should be undertaking regardless.

Prognostic Value of Blood-Based P-Tau217 Levels for Progression to Cognitive Impairment

Blood-based biomarkers have fundamentally transformed Alzheimer disease research and have become a common feature of observational cohorts and prevention trials. Does plasma phosphorylated tau 217 (p-tau217) predict absolute long-term risk of clinical progression in cognitively unimpaired older adults across multiple aging and Alzheimer disease cohorts?

In this pooled multicohort study of 2,684 cognitively unimpaired participants across 6 selected longitudinal studies, higher baseline plasma p-tau217 levels were significantly associated with increased risk of progression to cognitive impairment over up to 13.5 years of follow-up. Individuals with very high p-tau217 levels (more than 2.5 standard deviations above the mean) had an estimated 38% absolute risk of progression over 5 years, with higher risk over 10 years, although longer-horizon estimates were constrained by sparsity of data.

These findings support the potential of p-tau217 for prognostic model development and estimation of long-term risk of cognitive decline among cognitively unimpaired individuals, although further research in unselected and more generalizable populations is needed.

Health is like art; one knows it if one sees it. But that isn't good enough for the development of therapies. Health must be pinned down and actually measured. Numerous bodies have offered guidelines to this end, and those guidelines have been interpreted in countless different ways by the scientists who conduct studies. Everyone has their own definition at the detail level, which makes comparison between studies a sizable challenge. This is the usual picture for any area of human endeavor in which standards would be useful. Coordination is not a solved problem, and about the best one can hope for is a few competing standards that are fairly rigorously adhered to. In the matter of assessing and treating degenerative aging, even that remains an aspirational goal.

For the first time in human history, we may be able to measure health directly, rather than infer it from the presence or absence of disease. Doing so could enable earlier detection of age-related declines and catalyze new interventions to extend healthy longevity. But this shift will require a clear and operationalizable definition of "health" and rigorous methods to assess it. The World Health Organization's (WHO) healthy ageing framework introduced intrinsic capacity (IC) - "the composite of all the physical and mental capacities of an individual."

As a measure of individual level functioning, intrinsic capacity could become a transformative outcome for geroscience research, clinical practice, and population health. From the outset, however, intrinsic capacity has been interpreted inconsistently. While ambiguity was acceptable in a policy context, it has become problematic as IC is increasingly applied in clinical care and biological research.

In 2017, WHO-affiliated investigators identified five subdomains - locomotor, cognitive, sensory, psychological, and vitality - as "pivotal" to intrinsic capacity. While the first four comprise overt measures of functioning consistent with traditional approaches to capacity, vitality was conceptualized as describing the biological attributes required to maintain homeostasis. Vitality emerged within these biological analyses with a biologically grounded profile, including DHEAS, IGF-1, hemoglobin, FEV1, and grip strength. This 5 subdomain pattern (with variation in the specific measures used) has since been replicated in cohorts across continents and found to predict subsequent mortality and incidence of specific diseases.

Yet despite broad acceptance of the five-domain structure, methodological inconsistency remains high. Studies differ in scoring approaches, data sources, and measurement tools, particularly for vitality. As IC increasingly becomes a candidate outcome for clinical trials and aging biology studies, lack of standardization poses serious risks - misinterpretation, non-comparability, and potential loss of credibility.

Link: https://doi.org/10.1016/j.tjfa.2026.100175

Advanced glycation endproducts (AGEs) are a broad class of sugar-modified molecules that have harmful effects in the body. They are involved in generating the chronic inflammation characteristic of the abnormal metabolism of obesity and diabetes, but more persistent AGEs generate cross-links between molecules in the extracellular matrix, impairing tissue properties such as elasticity. Revel Pharmaceuticals was founded to develop early candidate enzymes to break down glucosepane cross-links in the extracellular matrix, but has since focused instead on CML, a different AGE. There remains some debate over which of the better studied forms of AGE are in fact important in aging versus important in diabetes, and that seems unlikely to be settled absent means of breaking down and clearing these unwanted metabolic byproducts. To that end, the Revel researchers here report on their development of an enzyme to break down CML AGEs.

The accumulation of advanced glycation end products (AGEs) in long-lived proteins is a hallmark of mammalian aging and implicated as a driver of metabolic dysfunction. Among these adducts, Nε-carboxymethyl-lysine (CML) is particularly abundant in aging tissues, where it modifies proteins and acts as a ligand for the receptor for advanced glycation end products (RAGE), thereby perpetuating chronic inflammation and oxidative stress. While endogenous detoxification systems exist for reactive precursors, the stable CML adduct has historically been considered irreversible.

Here, we report the development of CMLase - an enzyme engineered through the directed evolution of over 500 million variants to specifically oxidize CML and restore the native lysine residue. We demonstrate that CMLase effectively reverses CML modifications in model proteins in vitro and in human tissue samples from elderly donors, providing proof-of-concept that protein damage previously deemed irreversible is amenable to enzymatic repair. Collectively, our approach establishes a platform for developing enzymes to reverse age-related molecular damage and ultimately repair tissue proteins compromised by aging and disease.

Link: https://doi.org/10.1038/s41467-026-75141-2

As for all tissues, bone derives its structural properties from the composition and structure of its extracellular matrix. This matrix constantly undergoes dynamic modification: osteoclast cells break down the matrix, while osteoblast cells build it up. Throughout much of adult life, a sufficient balance exists between these processes of creation and destruction to ensure that bones remain structurally sound. With old age, however, the balance shifts slowly to favor osteoclasts. The result is a loss of bone mineral density over time, leading eventually to osteoporosis, brittle bones, and fracture or breakage in an already frail elderly individual.

The aging of the immune system is one of the contributing factors to this erosion of bone tissue maintenance. Chronic inflammation on the part of the immune system is a feature of aging, driven by maladaptive reactions to damage and dysfunction, and this is disruptive to the balance between osteoblasts and osteoclasts. There are other issues besides this. For example, innate immune cells are deeply involved in tissue maintenance, but too many of these cells relinquish these necessary tasks to adopt other, less helpful behaviors in aged tissues. Today's open access paper reviews the aging of the immune system through the lens of bone tissue, the links between what is known of immune aging and what is known of the declining maintenance of bones.

Immune cell senescence and chronic bone diseases: osteoimmune mechanisms and therapeutic perspectives

Immune cell senescence is an important intermediary linking organismal ageing, chronic low-grade inflammation, and disordered bone metabolism. With advancing age, immune cells undergo systemic functional remodeling and exhibit a series of characteristic alterations, including reduced proliferative capacity, skewed differentiation, abnormal migration and homing, impaired phagocytic and clearance functions, and changes in their secretory profile. These changes persistently disrupt the osteoimmune microenvironment and ultimately promote enhanced bone resorption, suppressed bone formation, and deterioration of bone quality.

This review centers on the immunological basis of bone homeostasis and systematically summarizes the major biological features of immune cell senescence, with a particular focus on the key cellular mechanisms through which it drives chronic bone disease. It further analyses its pathological manifestations and disease-specific differences in osteoporosis, osteoarthritis, rheumatoid arthritis, and diabetes-related bone disease. Current evidence indicates that the contribution of immune cell senescence varies across different diseases: its pathogenic association appears to be relatively more direct in osteoporosis and rheumatoid arthritis, whereas in osteoarthritis and diabetes-related bone disease it more often acts as a contributor to inflammatory amplification and microenvironmental deterioration.

At present, intervention strategies targeting immune cell senescence mainly focus on modulation of macrophage polarization, immune-mediated clearance of senescent cells, restoration of adaptive immune homeostasis, and mesenchymal stem cell (MSC)-related improvement of the local microenvironment, but overall these approaches remain at the preclinical or early translational stage. Future studies should integrate single-cell sequencing, spatial transcriptomics, and multi-omics approaches to define local immune cell senescence landscapes and establish robust biomarker systems, thereby promoting the transition from mechanistic research to precision intervention in chronic bone diseases.

Twenty years ago or so, researchers were investigating the possibility of building therapies based on upregulation of TFAM expression to improve mitochondrial function in aged tissues. While some initial results were promising, as it turned out the mitochondrial biochemistry of TFAM is complicated and too much is as bad as too little. This makes it a poor target for gene therapy, and a challenging target for small molecules. The field moved on to easier possibilities, as often happens. Still, nothing ever really stops entirely in the life sciences. Here find a review of the present state of knowledge regarding TFAM, and some speculation as to what future therapies might look like.

Mitochondrial transcription factor A (TFAM) is a nuclear-encoded mitochondrial protein that directly binds mitochondrial DNA (mtDNA) and contributes to mitochondrial genome maintenance. Beyond its established roles in mitochondrial transcription, mtDNA packaging, nucleoid organization, replication support, and copy number control, TFAM is increasingly recognized as a potential regulator of aging-related mitochondrial stress responses. Because mtDNA instability, respiratory dysfunction, reactive oxygen species imbalance, impaired autophagy, cellular senescence, and chronic inflammation are closely interconnected during aging, TFAM may occupy a proximal position linking mitochondrial genome homeostasis to broader aging biology.

However, TFAM should not be viewed as a uniformly protective factor. Its effects appear to depend on TFAM abundance, TFAM-to-mtDNA stoichiometry, tissue type, metabolic state, mitochondrial import, LONP1-mediated turnover, and mitochondrial quality-control capacity. TFAM deficiency may compromise mtDNA maintenance, impair oxidative phosphorylation, increase mitochondrial ROS production, and promote mtDNA-driven innate immune activation. Conversely, excessive or dysregulated TFAM accumulation may lead to mtDNA hypercompaction, reduce mtDNA accessibility, and potentially produce maladaptive effects in specific disease contexts.

In this review, we discuss the structural basis of TFAM-mtDNA interaction, the role of TFAM in mtDNA transcription, copy number control, genome protection, damage handling, inflammatory signaling, cellular senescence, systemic aging, and age-related diseases. We also highlight therapeutic opportunities, limitations, and unresolved questions, emphasizing that future strategies should aim to restore TFAM homeostasis rather than simply increase TFAM expression.

Link: https://doi.org/10.3389/fragi.2026.1830839

Like many age-related conditions, Parkinson's disease is associated with uncommon mutations and genetic variants that increase its likelihood, severity, and pace of progression. PINK1 is a protein involved in identifying damaged mitochondria to be broken down by the quality control mechanisms of autophagy. Loss of effective PINK1 function clearly accelerates mitochondrial dysfunction and increases cell death in neurons placed under the stress induced by the aggregation of misfolded α-synuclein that is characteristic of Parkinson's disease. PINK1 in Parkinson's disease is also an example of the way in which identifying genetic contributions to an age-related condition may not actually help all that much. The interactions between disease mechanisms and mitophagy are sufficiently complex for knowledge of the role of PINK1 mutations to illuminate relatively little about the rest of the problem, and for interventions targeting PINK1 to fail.

Mitochondrial dysfunction is a central feature of Parkinson's disease (PD) and contributes to the selective vulnerability of dopaminergic (DA) neurons. Among the pathways that maintain mitochondrial integrity, PINK1/Parkin-mediated mitophagy has been extensively characterized as a stress-responsive mechanism for the recognition and removal of damaged mitochondria. However, despite robust activation of this pathway in experimental systems, translation of these findings into effective disease-modifying strategies has remained limited.

Here, we propose that a conceptual distinction may help account for this gap. Current research has largely focused on pathway activation as a surrogate for functional recovery, yet mitochondrial quality control depends on the maintenance of functional continuity across multiple sequential steps, from damage recognition and ubiquitin signaling to autophagosome formation and lysosomal degradation. Disruption at any of these stages may compromise overall pathway output. Accumulating evidence suggests that, under PD-relevant conditions, upstream signaling and downstream mitochondrial clearance can become partially uncoupled, such that activation of the PINK1/Parkin pathway does not necessarily ensure effective completion of mitophagy. Within this framework, mitochondrial dysfunction interacts with α-synuclein (α-syn) accumulation, lysosomal impairment, and neuroinflammatory signaling to form a self-reinforcing pathological network.

This perspective provides a mechanistic basis for understanding why strategies that enhance upstream signaling alone have shown limited translational success. Finally, we discuss key challenges for therapeutic development, including the need for readouts that distinguish pathway engagement from pathway completion, the limitations of current model systems, and the importance of aligning patient stratification and intervention timing with pathway biology. We suggest that restoring functional continuity across the mitophagic process, rather than focusing exclusively on increasing pathway activation, may offer a more productive conceptual basis for targeting mitochondrial dysfunction in PD.

Link: https://doi.org/10.3389/fnagi.2026.1865383

Sarcopenia is the name given to later, more severe stages of the characteristic loss of muscle mass and strength that takes place with age. The loss is universal, ultimately leading to physical frailty. Since muscle is metabolically active, loss of muscle is also disruptive to overall metabolism, worsening insulin resistance and chronic inflammation. Like many aspects of degenerative aging, the underlying causes of sarcopenia form a web of interacting mechanisms. It is challenging to determine their relative importance, as well as which mechanisms are largely upstream versus largely downstream in the chain of cause and effect. As is usual, tracing a direct path from root causes of aging to proximate causes of disease is a work in progress, and very incomplete. Most research effort focuses on the proximate causes.

For sarcopenia, the most plausibly important and well studied proximate causes are (a) loss of muscle stem cell activity, reducing the supply of new muscle cells needed to replace losses, and (b) degeneration of the neuromuscular junctions that link the nervous system to muscle fibers. Without innervation, muscle lacks the signaling needed to provoke normal maintenance and growth in response to use. These proximate causes are of course far downstream of issues closer to the roots of aging, such as mitochondrial dysfunction, epigenetic change, senescent cell accumulation, and so forth.

Today's open access paper is an example of ongoing efforts to better understand how neuromuscular junctions falter in their function. The researchers focus in on a loss of postsynaptic excitability driven by reduced expression of the NaV1.4 sodium channel, and suggest inhibition of the CLC-1 chloride channel as a compensatory strategy to promote greater postsynaptic excitability without directly addressing the NAV1.4 issue. They found this approach to improve muscle function in aged mice.

Neuromuscular junction failure in sarcopenia is linked to NaV1.4 loss and reversed by ClC-1 inhibition

Sarcopenia is the age-related loss of muscle strength and size that leads to mobility limitations and loss of independence in older adults. The underlying cellular mechanisms remain unclear, and treatments are limited. As the critical interface between the nervous system and muscle, the neuromuscular junction (NMJ) is essential for muscle activation and force production. Here, we demonstrate that weak older individuals exhibit NMJ transmission failure that correlates with muscle weakness severity.

Preclinical experiments showed similar NMJ transmission failure in aged rodents that was associated with localized loss of muscle fiber excitability at the NMJ. This excitability defect, distinct from potential synaptic cholinergic transmission abnormalities, represents a novel disease mechanism of sarcopenia. Across species, immunohistochemistry identified a localized reduction in the voltage-gated sodium channel specific for skeletal muscle (NaV1.4) at the post-synaptic NMJ membrane. Acute NaV1.4 inhibition in adult rats reproduced findings of NMJ transmission failure observed in aged rodents and humans.

In a recent study on myasthenia gravis, inhibition of the ClC-1 channel was found to enhance NMJ transmission and improve muscle function in both animal models and patients with myasthenia gravis. Our current findings demonstrate that small molecule inhibition of ClC-1 can similarly enhance muscle contractile function and improve motor function assessments in aged, weak rats with confirmed NMJ dysfunction. The ClC-1 ion channel is specific to skeletal muscle, expressed along the entire muscle fiber membrane, including at NMJ, sarcolemma, and t-tubular system. This channel plays a critical role in modulating skeletal muscle excitability, especially during intense muscle activity, through cellular signaling systems activated during muscle activity.

The research community regularly produces quite fascinating data regarding the ways in which diet influences health. Take this paper, for example. Plant cells have mitochondria, we consume raw plants, and it turns out that some fraction of those plant mitochondria are making their way out of the gut, into the body, into cells, and interacting with our mitochondria to favorably alter mitochondrial function. Perhaps there is an approach to therapy here that looks like mitochondrial transfusion, or looks like an oral therapy but with extracted plant mitochondria. But knowing the degree to which diet impacts health and life expectancy suggests that the size of effect is not large enough to be very interesting. Therapies that cannot much improve on the benefits of a good set of lifestyle choices are not where we should be spending our time. If we want truly effective treatments for aging, interventions that add decades of healthy life, mimicking lifestyle choice is not a good strategy.

Intercellular mitochondrial transfer is pivotal in both healthy and pathological states. Supplementing healthy mitochondria is emerging as a promising therapeutic approach for various diseases. Non-immunogenic edible plants, which contain mitochondria, offer a novel avenue for such therapies. Mitochondria were isolated from several commonly consumed edible plants (P-Mit). The distribution of P-Mit, particularly in the brain, was examined with a mitochondrial membrane-potential dye and an imaging system.

As a proof of concept, the molecular interactions underlying turmeric-derived mitochondria (T-Mit) uptake by microglia were elucidated through affinity precipitation coupled with mass spectrometry. By labeling with gold-nanoparticles in a distinct triangular or spherical shape followed by electron microscopy and energy dispersive spectroscopy analysis, we demonstrated the physical fusion of T-Mit and animal mitochondria in microglia. Mitochondrial functions such as superoxide levels, ATP-linked mitochondrial respiration, glycolysis and electron transport chain activity were assessed to determine the impact of T-Mit on aging-related microglial dysfunction. Next-generation small RNA sequencing revealed the underlying mechanism by which T-Mit-derived small RNAs modulate the expression of NADH dehydrogenase (ND) genes in microglia.

Orally administered T-Mit travelled from the gut to the brain in aged male mice, where they fused with microglial mitochondria (M-Mit), reprogramming M-Mit energy metabolism and reversing aging-related cognitive dysfunction. Specifically, T-Mit was taken up by microglia via the phagocytic receptor TREM2. Subsequently, T-Mit fused with M-Mit in a mitofusin 1-dependent manner. The T-Mit microRNAs Tae-miR319 and Osa-miR166a-3p then integrated into M-Mit, inhibiting the expression of complex I subunits ND4 and ND5. This inhibition alleviated reverse electron transport (RET) at complex I, reducing reactive oxygen species (ROS) production and facilitating ATP production, ultimately rescuing aging-related cognitive decline.

Link: https://doi.org/10.1186/s40035-026-00565-1

Microglia are innate immune cells of the brain, analogous to macrophages elsewhere in the body. Both cell types are deeply involved in the intricate processes of tissue maintenance and regeneration. The central nervous system has only limited regenerative capacity, but it can regain some lost function following injury, such as that caused by a stroke. Researchers here find a way to improve the regenerative activities of microglia, and demonstrate that this intervention can improve outcomes following stroke in animal models.

After a stroke, the brain launches a coordinated repair program that involves several types of cells. Among these, microglia, the brain's resident immune cells, play a pivotal role. Immediately after an injury, microglia are activated to trigger inflammation, but thereafter, they rapidly transition into a reparative state and produce growth factors, such as insulin-like growth factor 1 (IGF1), which support remyelination, strengthen neural connections, and promote functional recovery. But this only lasts for two months, limiting the brain's capacity to repair further.

To uncover the molecular mechanism responsible for diminishing microglial reparative functions the researchers identified a specific transcription factor called ZFP384, which increases as the brain's spontaneous repair functions diminish. They discovered that ZFP384 diminished the expression of genes associated with microglial reparative functions. Mechanistically, ZFP384 disrupts the chromatin interactions mediated by the protein YY1 that are necessary for the gene expression associated with neural repair. As a result, the microglia lose their reparative properties despite the brain's ongoing recovery needs.

To investigate whether preventing this loss of reparative properties in microglia could help improve recovery, the team first genetically deleted the Zfp384 gene specifically from microglia in mouse models of stroke. Interestingly, these animals maintained their recovery-associated gene expression for a much longer period than normal mice. Sustaining the reparative state of microglia enhanced remyelination of damaged nerve fibers and promoted synaptic plasticity, resulting in significantly better long-term neurological function.

Based on these findings, the researchers developed a therapeutic antisense oligonucleotide (ASO), a short, synthetic strand of nucleic acids that specifically decreases expression of a targeted gene. ASO-Zfp384 was designed to suppress Zfp384 expression. Remarkably, the treatment sustained microglial reparative functions and remained therapeutic even when administered 1 week or 1 month after stroke onset. Rather than simply reducing inflammation, the ASO-Zfp384 helped retain the brain's own reparative program, enhancing post-stroke recovery from neurological deficits.

Link: https://www.eurekalert.org/news-releases/1135664

Mitochondrial transplantation is under development as a class of therapy to treat aging. Mitochondrial dysfunction is a feature of aging, and evidence from animal studies suggests that lasting improvements in health result from replacement of a fraction of native mitochondria with new, functional mitochondria delivered via intravenous infusion. Cells readily take up mitochondria from their surroundings if given the chance. The biggest challenge remains scaling up manufacture, being able to harvest from cell cultures the vast numbers of mitochondria needed to produce a reasonable level of replacement in a human patient. Work has progressed to a first in human demonstration conducted recently, but a few other companies are also moving towards human trials at some pace.

One of the most interesting questions is that of how vital it is that mitochondrial DNA haplotype matches nuclear DNA haplotype. Mitochondria are the evolved descendants of ancient symbiotic bacteria, and carry their own genome, the mitochondrial DNA. There are more than 20 distinct groupings of human mitochondrial DNA haplotypes. Over evolutionary time, most mitochondrial genes migrated into nuclear DNA, so some components of the molecular machinery in a mitochondrion come from mitochondrial DNA, some from nuclear DNA. What happens when mitochondria with a different DNA haplotype are introduced into an adult individual? What if researchers construct a much better synthetic mitochondrial DNA haplotype that outperforms all natural haplotype when it comes to producing adenosine triphosphate (ATP) with a low burden of oxidative stress, and increases the efficiency of mitochondrial quality control as well? Are there roadblocks to implementing this goal?

There is some evidence to suggest that mixing and matching between haplotypes, or changing mitochondrial haplotype in an adult individual, is modestly harmful. Today's open access paper provides more data on this front, looking at outcomes on the lifespan of flies resulting from mismatches between mitochondrial genes in nuclear DNA versus mitochondrial DNA. The effect size is around a 10% reduction in median life span, which is not all that large in a species like the fruit fly, where life span is very plastic in response to circumstances. Still, it seems likely that companies developing mitochondrial transplantation therapies will choose to be cautious and match haplotype to patient.

Mitonuclear discordance modulates mitochondrial ageing dynamics in natural Drosophila populations

Mitochondria lie at the center of cellular metabolism and are key determinants of organismal ageing. Because the oxidative phosphorylation (OXPHOS) complexes are encoded by both nuclear and mitochondrial genomes, compatibility between these genomes is essential for efficient energy production and eukaryotic life. Disruption of this intergenomic coordination, via mismatches between mitonuclear genotypes, has been shown to impair metabolism with severe life-history consequences across diverse taxa. Yet, the role of mitonuclear compatibility in shaping ageing trajectories in natural populations remains poorly understood, with evidence largely limited to inbred laboratory lines.

Hormesis describes the process where mild stress can trigger protective adaptations against ensuing perturbations. In this context, mitohormetic interventions can represent a protective strategy to promote metabolic homeostasis and healthy ageing. Here, we leveraged natural genetic variation in wild Drosophila melanogaster populations to test how mitonuclear compatibility interacts with early-life metabolic stress to shape ageing phenotypes. Two mitochondrial haplotypes coexist in D. melanogaster populations along the Australian cline: "t" (most common in the north) and "m" (most common in the south), differing by 15 single-nucleotide polymorphism (SNPs) across protein-coding genes. We generated a panel of outbred populations carrying putatively coevolved ("tT," "mM") and mismatched ("mT," "tM") mitonuclear genomes.

We demonstrate that mitonuclear mismatch accelerates age-related mitochondrial decline, elevates reactive oxygen species production, and shortens lifespan. Strikingly, early-life mitochondrial stress induced by dietary modulation counteracts these effects, promoting mitochondrial homeostasis and longevity. Our findings reveal mitonuclear interactions shaping ageing trajectories in natural populations and provide unique evidence that targeted interventions can act as a buffer against the detrimental impact of genetic discordance.

You might recall that last year researchers demonstrated an age-related decline in peroxisome number in cells. Peroxisomes carry out a range of functions related to oxidative and lipid metabolism, but are relatively poorly researched in the context of aging. The decline in number of peroxisomes modestly accelerates the pace of aging, as researchers found that forcing a normalization of the number of peroxisomes via prx-11 inhibition extended life in nematode worms. Here, the same researchers provide an update on how they think that this all works under the hood, providing evidence for peroxisome counts to affect life span via mitochondrial function.

Peroxisomes execute essential functions in cells, including detoxification and lipid oxidation. Despite their centrality to cell biology, the relevance of peroxisomes to aging remains understudied. We recently reported that peroxisomes are degraded en masse via pexophagy during early aging in the nematode Caenorhabditis elegans, and we found that downregulating the peroxisome-fission protein PRX-11/PEX11 prevents this age-dependent pexophagy and extends lifespan. Here, we further investigated how prx-11 inhibition promotes longevity.

Remarkably, we found that reducing peroxisome degradation with age led to concurrent improvements in another organelle: the mitochondrion. Animals lacking prx-11 function showed tubular, youthful mitochondria in older ages, and these enhancements required multiple factors involved in mitochondrial tubulation and biogenesis, including FZO-1/Mitofusin, UNC-43 protein kinase, and DAF-16/FOXO. Importantly, mutation of each of these factors negated lifespan extension in prx-11-defective animals, indicating that pexophagy inhibition promotes longevity only if mitochondrial health is co-maintained.

We also found that experimental perturbation of mitochondria precipitated faster pexophagy with aging, implying bidirectionality in signaling between these two organelles. Our data support a model in which peroxisomes and mitochondria track together with age and interdependently influence animal lifespan.

Link: https://doi.org/10.18632/aging.206395

That evolution does not optimize for species longevity is illustrated by the large number of small alterations in gene sequence or protein level that extend life in short-lived laboratory species such as nematode worms. Here, researchers note a trade-off between the activity of the unfolded protein response in various parts of the cell. When errors in protein manufacture and folding occur, unfolded and misfolded proteins emerge to cause harm. The unfolded protein response is triggered and acts to remove the problem proteins. Everything a cell does requires effort, and evolution has led to systems that balance that effort versus all of the other things a cell could instead accomplish. Therefore the unfolded protein response tends to operate at a level that is suboptimal for longevity in an organism. Further, it appears that assignment of that unfolded protein response effort across different parts of the cell is also suboptimal for longevity.

Disruption of proteostasis is a hallmark of aging. Given that cellular resources are limited, this necessitates a coordinated orchestration of different proteostatic subsystems. Yet, the principles governing this process, including the potential role of trade-offs, are not well defined. Here, we report a trade-off between the endoplasmic reticulum unfolded protein response (UPRER) and the cytosolic unfolded protein response (UPRcyto) in C. elegans that influences lifespan.

We find that wild-type animals maintain high UPRER activity but low UPRcyto activity, a balance actively enforced by the transcription factor LET-607 (ortholog of mammalian CREBH). Consequently, LET-607 deficiency releases this trade-off, causing a seesaw-like rebalancing: UPRER activity decreases while UPRcyto increases. Strikingly, this rebalancing contributes to longevity: animals lacking LET-607 exhibited extended lifespan in a UPRcyto dependent manner. Mechanistically, LET-607 deficiency downregulates one-carbon cycle, which provides the methyl donor S-adenosylmethionine. This subsequently alleviates H3K9me-mediated repression at the promoters of UPRcyto genes, a process involving the regulators and readers of this histone mark, leading to UPRcyto activation.

Our study reveals a transcriptional mechanism that enforces a proteostatic trade-off and demonstrates that evolutionarily acquired UPR balance in wild-type animals is suboptimal for longevity, supporting the antagonistic pleiotropic theory of aging.

Link: https://doi.org/10.1111/acel.70620

Setting aside a few early attempts, the longevity industry started in earnest in the mid-2010s. It had the feel of a hype cycle, a land rush, in the context of a broader bull market. A lot of those companies no longer exist; there are disadvantages in being first into a space. One of those disadvantages is that the first cohort in any venture has the privilege of mapping the novel pitfalls by falling into them. That is done now, and we're into the next stage, which is, quite honestly, a lot more complex, messy, diverse, and hard to explain. We know how this story ends: at some point there will be no distinct longevity industry, because the goal of slowing or reversing the aging process by addressing the underlying causes of aging directly will merge into the ordinary, day to day cut and thrust of pharmaceutical and biotech development. It will be become unremarkable to attempt to treat aging as a medical condition.

We are not there yet! From the extremely conservative point of view of those who steer large pharmaceutical industry companies, treating aging remains a distinct, unproven proposition. That will continue to be the case until novel anti-aging drugs are approved by the FDA and EMA, used by hundreds of thousands of patients, produce undeniable results, and, most importantly, generate a large amount of revenue. The number of such approved drugs is somewhat less important than the collective revenue generated. You might look at the opinion of the powers that be on weight loss drugs and how that has shifted across the advent of GLP-1 receptor agonists as an example of how this shift in will take place for the first very successful anti-aging drugs.

But back to what the longevity industry looks like now, and how that differs from the early days. Today's open access paper offers an opinion on the topic, backed by some analysis. It is an interesting read, albeit very focused on just a few parts of the mainstream of the field, the most popular topics. For my part, I'd have to say that I think matters would be fairly different if the bull market in biotech and pharma had sustained itself across the 2020s rather than vanishing into geopolitics and doldrums. A new industry struggles to forge itself in an environment where funding is tight all round. Much of the present character is the character of an industry in which it is exceptionally challenging to raise funds for clinical development, no matter the promise of the technology in question. But this too shall change.

From lifespan extension to hallmark-informed gerotherapeutic prioritization: A bibliometric-guided, strategy-oriented review of anti-aging drug research

Aging is increasingly understood as a shared upstream biological process that increases vulnerability across cardiovascular, neurodegenerative, metabolic, musculoskeletal, renal, and neoplastic disorders. This view was crystallised by the original hallmarks framework and reinforced by its expanded update, which organise aging into interconnected molecular and cellular processes rather than isolated organ-specific events. The translational implication is substantial because interventions directed at aging biology could, in principle, delay or modify several age-related conditions rather than treating each disease independently. The interdependence of aging hallmarks also provides a rationale for evaluating secondary cross-hallmark effects.

Over the past decade, geroscience has moved from a conceptual proposition to an intervention-oriented discipline aimed at extending healthspan and disability-free survival. This shift has been driven by growing recognition that aging is biologically malleable and clinically consequential at the population level. Mechanisms such as cellular senescence, deregulated nutrient sensing, mitochondrial dysfunction, chronic inflammation, loss of proteostasis, and impaired stress adaptation are now regarded as potentially tractable pharmacological entry points. Accordingly, gerotherapeutic development increasingly requires alignment between molecular or pharmacological design, an aging-related biological vulnerability, measurable target engagement, an appropriate population, and a clinically meaningful endpoint.

The landscape of anti-aging drug research has shifted markedly from exploratory lifespan-extension studies toward a more structured, mechanism-informed, and translationally aware framework. Bibliometric analysis reveals that the field coalesces around three partially overlapping intervention logics - senescence-directed therapeutics, nutrient-sensing and metabolic modulators, and homeostasis-restoring compounds - each anchored in reproducible biological hallmarks. These axes collectively provide a coherent rationale for prioritizing interventions based not solely on historical visibility but on mechanistic plausibility, preclinical evidence, and early human translational signals.

The composition of the gut microbiome changes with age in ways that negatively impact health. There is enough variance in this process of change that correlations can be observed between specific species and metrics of overall composition on the one hand and risk or status of disease on the other. Researchers are building a growing body of knowledge regarding such correlations, and in many cases have found mechanisms indicating that a poor composition of the gut microbiome is a contributing factor in the development and progression of age-related disease. This is a matter of which metabolites are produced by the gut microbiome and in what amounts; some metabolites are necessary for health, others are harmful or provoke chronic inflammation. This work is the first step towards the development of therapies that can alter the composition of the gut microbiome in specific, tailored ways in order to improve health and slow the progression of aging.

Although commonly used tools, such as the Fried Frailty Phenotype, the Rockwood Frailty Index and the Clinical Frailty Scale, capture specific aspects of frailty, existing indices often fail to encompass its full functional, psychological, and physiological dimensions. The Charlson Comorbidity Index (CCI), while widely adopted for mortality risk stratification, is disease-centric and lacks sensitivity to the broader construct of frailty. To better capture this multidimensional nature, we developed the Frailty Mortality Index (FMI), a composite measure integrating functional and psychosocial aspects in addition to comorbidities. Specifically, the FMI is defined by anthropometrics (age and weight), physical function (walking speed and chair stand), current smoking, mental quality of life (QoL) survey, hospital stay duration, and the CCI.

The gut microbiome is increasingly recognized as a regulator of host physiology and potential contributor to frailty pathophysiology. It influences systemic inflammation, metabolism, musculoskeletal function, and immune and neuroendocrine signaling. While aging alters gut microbiota composition and function, gut microbiome profiles observed in frailty differ from those associated with healthy aging, reflecting not just chronological age but also deterioration of physiological processes.

In this work, we use metagenomic sequencing to investigate species-level features associated with frailty-related phenotypes captured by the FMI in SUPERB, a large Swedish cohort including 2,081 women aged 75-80 years. We demonstrate that the FMI is more strongly associated with frailty-related clinical outcomes, including injurious falls, hip fractures, and mortality, than the CCI. We further show that higher FMI is associated with reduced microbiota diversity, including lower gene richness and Shannon index. At the species level, FMI is associated with different species in Enterocloster, Clostridium, Dysosmobacter and Faecalibacterium in models accounting for the overall decline in microbiome gene richness associated with ageing, thereby distinguishing FMI-associated microbial features from general microbiota decline.

Link: https://doi.org/10.1038/s41467-026-75176-5

Neurogenesis is the name given to the creation of new neurons in the central nervous system, arising from neural stem cell populations, maturing, and then merging with existing neural networks. Neurogenesis is essential to memory and to the maintenance of brain tissue, the only way to replace neurons lost to damage or dysfunction. The pace of neurogenesis declines with age and in neurodegenerative conditions. Here, researchers investigate the link between inflammatory signaling and lost neurogenesis. The aged brain, like the aged body, is characterized by continual unresolved inflammatory signaling, a maladaptive reaction to forms of cell and tissue damage that changes cell behavior for the worse. It is disruptive to tissue structure and function. Any comprehensive package of rejuvenation therapies will have to include some way to address unwanted chronic inflammatory signaling without sabotaging the normal function of the immune system; so far, this has proven to be a difficult challenge.

Adult hippocampal neurogenesis is essential for learning, memory, and mood regulation, and its disruption is implicated in ageing, neurodegeneration, and mood disorders. However, the mechanisms linking inflammation to adult hippocampal neurogenesis impairment remain unclear. Here, we identify chronic tumour necrosis factor-alpha (TNF-α) signalling as a key driver of neurogenic dysregulation via a previously unrecognised type I interferon autocrine/paracrine loop in human hippocampal progenitor cells.

Using a female-derived human in vitro neurogenesis model, single-cell RNA sequencing, and functional T cell migration assays, we show that tumour necrosis factor-alpha induces a robust type I interferon response in hippocampal progenitor cells, promoting chemokine-mediated and CXC motif chemokine receptor 3 (CXCR3)-dependent T cell recruitment and suppressing neurogenesis. This inflammatory signalling cascade drives a fate switch in hippocampal progenitor cells from a neurogenic trajectory towards an immune-defensive phenotype, with critical implications for infectious and inflammatory disease pathogenesis.

These findings uncover a key inflammatory checkpoint regulating human adult hippocampal neurogenesis and highlight potential therapeutic targets to restore neurogenesis in chronic inflammatory states.

Link: https://doi.org/10.1038/s41467-026-74104-x

Aging clocks can be built from any sufficiently complex set of biological data measured in a sufficiently large number of people across a sufficiently large range of different ages. Machine learning techniques are used to find algorithmic combinations of data points that predict age to some sufficient threshold of accuracy. The algorithm is then applied to people who were not in the original sample populations, and most such clock algorithms do an acceptably good job of hitting the mark when considered over groups of people. Unfortunately they are not all that useful for an individual; in part the variance is a problem, but the main challenge is that it is entirely unclear in most clocks as to what the results actually mean. It is also unclear as to how we should expect any given clock to react to any given intervention used to treat aging.

The best path forward to making aging clocks useful for individuals, and for the assessment of novel therapies to treat aging, is probably to collect as much data as possible and observe the emerging patterns. Classes of therapy will have to be assessed in parallel with clocks. Different populations and different strategies for clock use will have to be assessed against actual outcomes, such as mortality rate and disease incidence years later. This won't be a fast process.

Nonetheless, interesting new findings emerge on a fairly regular basis as the use of clocks spreads. In today's open access paper, for example, research demonstrate that change over time in clock assessments is a useful piece of information, perhaps much more useful than single measures. This is particularly relevant to the use of clocks by an individual rather than in a population study, as many of the unknowns become irrelevant when one person uses the same clock repeatedly over a period of years to measure something that may be closely related to the pace of biological aging.

Longitudinal changes in epigenetic clocks predict survival in the InCHIANTI cohort

Over the past years, several proxy biomarkers of biological aging have been developed and validated, with the most advanced using data from DNA methylation. Broadly termed 'epigenetic clocks,' these methylation-based markers of aging have been shown to predict several adverse health outcomes, including mortality, independently of chronological age.

However, whether longitudinal changes in these phenotypes provide additional information on health outcome prediction over and beyond one single measure has not been demonstrated. Based on cross-sectional studies, we cannot definitively exclude that deviations of DNA methylation age from chronological age are determined early in life and are not modulated by behavioral, environmental exposures or changes in health status. In addition, if biological aging clocks are to be used to track the effectiveness of intervention over time, it is important to demonstrate that deviations of epigenetic clock trajectories reflect meaningful changes in health status.

In this longitudinal study of 699 adults from the InCHIANTI cohort followed for up to 24 years, we evaluated whether temporal acceleration of several epigenetic clocks-including first-, second- and third-generation epigenetic clocks-was associated with mortality. We found that faster increases in several clocks were linked robustly to higher risk of death, independent of baseline epigenetic age and other confounders. These findings suggest that dynamic changes in epigenetic aging reflect evolving health status and may serve as sensitive indicators for interventions aimed at extending healthspan and longevity.

When a cell becomes senescent, it ceases replication, grows in size, and devotes its energies to secreting a potent mix of pro-growth, pro-inflammatory signals. Cellular senescence serves useful purposes in embryonic development, wound healing, and suppression of cancer. It also marks the Hayflick limit on replication of somatic cells; a somatic cell either undergoes programmed cell death or becomes senescent on reaching the Hayflick limit. In those scenarios, the senescent cells are destroyed by the immune system shortly after serving their purpose. Unfortunately, the aging immune system becomes ever less capable of efficiently clearing senescent cells, and senescent cells begin to accumulate. Their signaling becomes harmful when sustained over the long term, disruptive to tissue structure and function. This is an important component of degenerative aging.

Senescence is a highly heterogeneous phenotype, and this heterogeneity arises from several layers of biological diversity. Different cell types may vary in their susceptibility to enter senescence and in the molecular pathways they activate upon entering this state, in addition to the core cell-cycle arrest machinery. This context-dependent variability is pronounced, such that senescent cells do not share a universal molecular signature, necessitating the use of multiple markers for their accurate identification. Microenvironmental conditions, including inflammatory cues, extracellular matrix composition, oxygen levels, and immune context, further shape the senescence response and senescence-associated secretory phenotype (SASP). Moreover, distinct senescence-inducing stimuli may engage overlapping but not identical signaling networks, leading to variation in gene-expression profiles, metabolic changes, and secretory programs. Together, these factors can create a spectrum of senescent cell phenotypes that differ in their impact on tissue physiology.

In this review, we focus on the major inducers of cellular senescence. While well-established inducers such as DNA damage and oxidative stress are central drivers of senescence in aging and disease, we also discuss physiological and context-specific triggers to provide a more comprehensive and integrative perspective on senescence induction. Starting from the first-described form of senescence, replicative senescence associated with prolonged cell culture, we provide a comprehensive overview of the major inducers of cellular senescence, including DNA damage, oxidative and mitochondrial stress, telomere attrition, oncogene activation, cell-cell fusion, senescence-induced senescence and developmental stimuli, and summarize the molecular mechanisms through which they trigger the senescence program. Integrating insights into these distinct stimuli, the signaling pathways they engage, and their functional consequences might help to clarify how distinct populations of senescent cells contribute to aging, cancer, and age-related pathologies, and assist in the development of new therapeutic strategies aimed at modulating senescence and its deleterious consequences without deteriorating its beneficial functions.

Link: https://doi.org/10.18632/aging.206391

An interesting question with regard to the growth in the age-related burden of senescent cells is the degree to which it is altered by lifestyle choice. Or, to put it another way, we know the degree to which better lifestyle choices affect pace of aging and life expectancy: how much of that effect is due to a reduced burden of senescent cells? Can the existing burden be reduced by better lifestyle choices, and by how much? Here, researchers review the evidence for dietary lifestyle choices to influence cellular senescence and find it lacking, as the existing body of clinical trial data is not large enough and consistent enough to support definitive statements. As the researchers note, the data is supportive of the hypothesis that dietary choice has more of an impact on the behavior rather than number of senescent cells. The burden remains.

Cellular senescence is a fundamental mechanism of ageing, characterised by stable cell cycle arrest and the acquisition of a pro-inflammatory secretory phenotype (SASP). Nutritional interventions are widely proposed to modulate ageing biology, but their effects on cellular senescence in humans remain unclear. We systematically synthesised evidence from interventional human studies assessing the impact of nutritional strategies on biomarkers of cellular senescence.

Twenty-nine articles (27 trials; 3,811 participants) were included. Across studies, nutritional interventions modulated multiple senescence biomarkers to varying extents, with calorie restriction producing the most recurrent reductions in circulating inflammatory and secretory factors commonly included in SASP panels as well as senescence-associated transcriptomic signatures. Classical markers of cell cycle arrest (e.g., CDKN2A/p16, CDKN1A/p21) and telomere length were largely unchanged or highly variable. Calorie restriction mimetics, particularly metformin and rapamycin, showed context-dependent effects, most evident under conditions of metabolic or physiological stress. Among dietary supplements, n-3 polyunsaturated fatty acids may modulate selected inflammatory/SASP-related circulating markers, although the evidence for dietary supplements remains limited and heterogeneous.

In humans, available evidence suggests that nutritional interventions may preferentially affect senescence-associated inflammatory and secretory biomarker profiles, particularly SASP-related mediators, rather than markers more directly related to senescent cell abundance. However, because SASP factors and circulating cytokines are heterogeneous and not specific to senescent cells, these findings should be interpreted as evidence for possible modulation of senescence-associated markers rather than definitive effects on senescence burden. These observations support the use of multi-marker and functionally relevant endpoints in future clinical studies targeting biological ageing and cellular senescence.

Link: https://doi.org/10.1016/j.arr.2026.103224

It seems a little early in the development of partial epigenetic reprogramming as a class of therapy to be thinking about which of the other approaches to aging it can best be combined with. Nonetheless, a proposal for therapeutic plasma exchange and partial epigenetic programming to go well together is the topic of today's open access paper. The argument is that these two classes of approach are addressing different layers of the dysfunction of aging, and should this do little to interfere with each other's benefits.

Until such time as someone comes up with a safe, viable small molecule reprogramming therapy, it seems likely that reprogramming will remain quite limited in scope because of the delivery challenges inherent in gene therapy. Very few delivery systems have any potential to deliver a payload well to the whole body (or even most of the body), and none of the established options are capable of this outcome. Even when delivery is good for a given tissue, the many different cell types making up that tissue likely vary widely when it comes to optimal dose and duration of reprogramming agents. It is a challenge.

On the therapeutic plasma exchange front, even the most basic, initial questions around dosing and efficacy remain to be answered. Because there is little profit in this type of therapy, no-one with deep pockets has any incentive to run the extensive trials that would be needed to provide definitive answers. As things stand, it seems likely that forms of therapeutic plasma exchange and plasma dilution will spread throughout the medical tourism space, but no firm data will emerge in the near future. This the case for numerous therapies adopted by clinics outside the US and Europe, but which do not bring in enough revenue for someone to sponsor formal clinical trials.

Systemic recalibration and epigenetic resetting as complementary strategies in ageing biology

Systemic and cellular rejuvenation strategies differ fundamentally in their therapeutic targets and in the biological level at which they intervene. Systemic interventions such as therapeutic plasma exchange or young blood administration primarily modify the extracellular and circulating environment. Through removal of pro-ageing and pro-inflammatory factors, or provision of pro-youthful factors, these approaches may improve intercellular communication and reduce adverse systemic influences such as chronic inflammation. Their principal strength lies in the breadth of action across multiple tissues. Their principal limitation is that they do not directly reverse intracellular age-associated changes. Cells with aged epigenomes, altered transcriptional programmes, and accumulated damage may therefore remain only partially responsive.

Partial reprogramming intervenes at the level of intracellular ageing mechanisms. It directly addresses loss of epigenetic information, which the Information Theory of Ageing proposes as the fundamental cause of mammalian ageing. By resetting elements of the epigenetic landscape, partial reprogramming reverses age-associated states such as mesenchymal drift and metabolic dysfunction at their source. Its principal strength lies in mechanistic depth. Its limitation is contextual dependence, because a persistently aged tissue environment may still impose inflammatory, structural, and extracellular constraints that partial reprogramming alone cannot fully resolve. The most important translational question is not which strategy is generally superior, but which biological constraint dominates in a given disease setting and whether both levels require simultaneous intervention.

The dilution hypothesis is examined together with its limitations and the unresolved complexities of systemic interventions. The challenge of cell-autonomous ageing is also considered, particularly the persistence of cell populations that remain refractory to systemic rejuvenation. A conceptual framework integrating these two axes of ageing is then presented. This framework suggests that combined systemic recalibration and targeted partial reprogramming warrant further investigation as a multimodal approach to ageing intervention. Future research priorities include mechanistic clarification of this systemic-cellular interaction and development of robust biomarkers to evaluate multimodal interventions.

Every mechanism of aging influences all of the other mechanisms of aging. Our biology is a big tangled ball of interactions. As a follow up to a recent post on the connection between mitochondrial dysfunction and senescent cell accumulation in the context of intervertebal disc degeneration, here find a different viewpoint that focuses on the connection between epigenetic aging and senescent cell accumulation. In the nucleus of the cell, epigenetic decoration of nuclear DNA and supporting molecules control its structure; these decorations include DNA methylation and modifications to the histone proteins that DNA is spooled onto. Structure in turn determines which genes are expressed, which proteins manufactured. Patterns of epigenetic control over nuclear DNA structure change with age in characteristic ways, some mix of adaptive and maladaptive reactions to other mechanisms of aging, possibly mixed in with a fundamental disruption to this system of control deriving from the repeated operation of DNA repair.

Intervertebral disc degeneration (IDD) is the leading pathological cause of low back pain, while current clinical treatments are only palliative and cannot reverse the programmed cellular senescence driven by epigenetic dysregulation. This process is characterized by progressive loss of nucleus pulposus (NP) cell identity and establishment of a self-amplifying senescence-associated microenvironment. In this review, we synthesize recent advances elucidating how heterogeneous senescent cell populations and their secretory phenotype (SASP) orchestrate a destructive vicious cycle in IDD.

We further dissect the synergistic interplay among DNA methylation, histone modifications, and non-coding RNAs that constitutes the "epigenetic aging clock" and drives premature cellular aging within the disc. Notably, we evaluate emerging therapeutic strategies aimed at clock reversal, including senolytic clearance of senescent cells, epigenetic remodeling using small-molecule inhibitors or CRISPR-Cas9 editing, and cellular reprogramming approaches ranging from induced pluripotent stem cell (iPSC) differentiation to direct lineage conversion. We propose a synergistic "clear, prime, then seed" roadmap that sequentially combines these interventions for optimal regeneration. This work provides a systematic theoretical framework for the clinical translation of epigenetic-targeted therapy for IDD, and breaks through the cognitive limitation of traditional mechanical wear theory.

Link: https://doi.org/10.3389/fragi.2026.1842955

STING is a master regulator of inflammatory signaling, triggered by a range of different sensor proteins for foreign material or forms of damage within a cell. With age, these sensors become overly active even in the absence of the usual stimuli, such as the presence of infectious agents, and the resulting inflammatory response is maladaptive, spreading harms further rather than helping the situation. Continual, unresolved inflammatory signaling is characteristic of old age, and it is disruptive to tissue structure and function. Here researchers note that inflammatory signaling in the body harms the brain via long-range communication between cells that is mediated via production and uptake of extracellular vesicles. Vesicles are small membrane-wrapped packages of molecules, carrying information from one cell to another. Their contents can change dramatically depending on the state of the originating cell, and this is one of the ways in which harms can spread, particularly in the context of chronic inflammation.

All animals age. However, aging is a heterogeneous process, and individual organisms age differently. Moreover, within the same organism, cells or organs do not age at the same speed. For instance, neurodegeneration, a hallmark of aging, generally manifests later than other peripheral aging signs. The genetic determinants of aging are not completely understood.

Gain-of-function (GoF) mutations in leucine-rich repeat kinase 2 (LRRK2GoF) are major genetic risk factors for Parkinson's disease (PD). By analyzing PD patients and LRRK2GoF mice, we show that PD represents an accelerated aging disorder driven by STING-dependent inflammation. This inflammation begins peripherally, disrupts the blood-brain barrier, and causes dopaminergic neurodegeneration.

Mechanistically, aging or LRRK2GoF causes endolysosomal decline, resulting in cytosolic self-DNA accumulation and the release of DNA-containing extracellular vesicles (EVs) that activate the cGAS-STING pathway within and between cells. Our findings identify LRRK2GoF as a key driver of accelerated aging and systemic inflammaging through DNA-containing EVs, highlighting potential therapeutic targets to counteract inflammaging and neurodegeneration.

Link: https://doi.org/10.1016/j.celrep.2026.117640

Intervertebral disc degeneration is a complex dysfunction in the tissue maintenance and tissue properties of the discs between vertebrae. The discs allow flexibility of the spine, cushion impacts, and hold the spine together. Weakening of disc structures leads to tears and other failures that produce a sizable negative impact on the ability of an individual to function. A large subset of the population shows measurable degeneration of intervertebral discs even before reaching age 40, and after that point it becomes a majority. This is a universal aspect of aging, and the question is only how long it will take before something important breaks under stress.

Interestingly, intervertebral disc degeneration is strongly connected to cellular senescence. There are clear lines to be drawn between the burden of senescent cells and the mechanisms leading to loss of disc structural integrity. Senolytic therapies to selectively clear senescent cells have done well in animal models of degenerative disc disorders. Similarly, mitochondrial dysfunction is also strongly linked to intervertebral disc degeneration. Both loss of mitochondrial function and burden of senescence are correlated - the former tends to increase the pace at which the latter grows. It is interesting to note today's open access study, in which improved mitochondrial function also reduces cellular senescence in the course of restoring some lost function to an aged tissue.

Activation of Sirt3 reprograms mitochondrial function to regenerate intervertebral disc degeneration

Intervertebral disc degeneration is the principal pathological basis of low back pain. Currently, there are limited therapeutic strategies to regenerate intervertebral disc. In this study, we found the expression of SIRT3 is significantly negatively correlated with the degree of disc degeneration in humans. In mice, knockout of Sirt3 resulted in pronounced disc degeneration accompanied by increased expression of inflammatory mediators and senescence-associated factors.

Transcriptomic analyses in mice revealed that Sirt3 deficiency was closely associated with dysregulation of calcium signaling pathways and impaired adenosine triphosphate (ATP) synthesis. Bioinformatics analyses identified Ckm and Atp2a1 as hub genes linking Sirt3 deficiency to calcium homeostasis disruption and ATP metabolic dysfunction.

Importantly, the administration of Sirt3 activator 2-APQC in a D-galactose-induced aging mouse model significantly ameliorated intervertebral disc degeneration-associated pathological changes, evidenced by restored mitochondrial function, reduced inflammation and cellular senescence, and rescued expression of hub genes Ckm and Atp2a1.

Studies tend to show that even a late life adjustment of lifestyle can meaningfully improve health and reduce mortality risk. It is never too late to gain some benefit from a better diet, more physical activity, greater physical fitness, and loss of excess visceral fat tissue. As an illustration of this point, researchers here show that older people who improve their lifestyle choices exhibit a sizable reduction in the risk of cognitive impairment versus those who retain a poor set of lifestyle choices.

This study included 6,765 older adults from the Chinese Longitudinal Healthy Longevity Survey. Data on lifestyle, including dietary habits, sleep quality, physical, cognitive, and social activity were self-reported from 2008 to 2014. Cognitive function was measured using the Mini-Mental State Examination from 2014 to 2018. Over a mean follow-up period of 5.9 years, 1,659 participants (24.5%) developed cognitive impairment. Three distinct lifestyle behavior trajectory classes were identified: "Low-Declining" (n = 4,342, 64.2%), "Moderate-Improving" (n = 1,777, 26.3%), and "High-Declining" (n = 646, 9.5%).

Compared with the Low-Declining group, the Moderate-Improving group was associated with a lower risk of cognitive impairment (hazard ratio, HR = 0.368), a longer time to cognitive impairment onset (mean = 6.433 years) and a slower rate of annual cognitive decline (0.806 points per year). Similarly, the High-Declining group showed a reduced risk (HR = 0.629, delayed onset (mean = 4.969 years) and a slower decline rate (0.543 points per year) compared with the Low-Declining group. Thus an upward trajectory of moderate lifestyle engagement, as well as a high but declining class, was associated with better cognitive outcomes compared with persistently low or declining engagement.

Link: https://doi.org/10.1186/s13690-026-02007-w

How far can one go, practically speaking, and in the relatively near future, to develop therapies to treat aging based on replacement of worn parts? Some forms of replacement therapy have existed for decades, and have arrived at a fairly sophisticated level of development. These approaches include organ transplantation and replacement of damaged bone with non-biological materials. These therapeutic options have their limitations and drawbacks, the largest of which is the need for major surgery. One view of the present era in biotechnology is that it represents an effort to move from approaches requiring major surgery to approaches that regrow and replace tissues in situ without major surgery, based on either cell therapies or manipulation of native cell populations. This transition is a slow one, clearly.

Recent discoveries and therapeutic developments in longevity science have made it increasingly clear that a vast amount of age-related damage and systemic changes at the level of molecules, organelles, cells, tissues, organs, and organisms must be reversed to yield durable and multi-tissue rejuvenation as well as further extensions in healthy lifespan. Advanced biological and synthetic replacement, maintenance, and multi-targeted damage-removal strategies for cells, tissues, and organ systems represent some of the most promising longevity interventions, with the potential to reverse an unprecedented fraction of age-related changes, and to prevent, slow, or even reverse age-related diseases and dysfunction.

We define replacement-based ageing interventions as strategies that replace cells, tissues, organs, physiological systems, or cellular components (e.g., mitochondria or genes) with biological or synthetic alternatives. Biological replacements include transplantation of stem cells, organs, and bioprinted tissues (e.g., progressive brain replacement using cells and biomaterials), bioengineered cell therapies (e.g., CAR-T and synthetic cells), and therapeutic plasma exchange. Synthetic replacements include prostheses, external medical devices (e.g., dialysis machines), and brain-machine interface systems (e.g., cortical implants).

Replacement-based approaches are predicted to act synergistically with emerging regeneration and synthetic damage-removal technologies capable of targeting and exporting hundreds of molecular and organellar damage types from cells without relying solely on inherently limited and declining endogenous repair, clearance, and export processes.

Link: https://doi.org/10.1111/acel.70516

Age-related impairment of drainage of cerebrospinal fluid from the brain is a topic of increasing interest. This was pioneered by the work of Leucadia Therapeutics, specifically focused on the drainage path for the olfactory bulb leading through the cribriform plate, but most present work is focused instead on the glymphatic system drainage that parallels the vasculature supplying the brain. The two pathways decline in capacity with age, but for very different reasons, and will need different forms of therapy. Thin channels for fluid flow through the cribriform plate ossify shut with age. The glymphatic system suffers from a failure of regulation of peristaltic flow through vessels, however.

Cerebrospinal fluid drainage is a way to remove metabolic waste from the brain. Declining flow means that this waste will build up. This includes the protein aggregates associated with neurodegenerative conditions, and probably a great many other forms of metabolic waste that individually have more subtle effects, but collectively act to provoke cell dysfunction when present at high levels. One of the more important consequences is thought to be a maladaptive inflammatory reaction in glial cells in the brain, which in turn drives the onset and progression of neurodegenerative conditions.

In today's open access paper, researchers assess measures indicative of loss of cerebrospinal fluid drainage in patients with isolated rapid eye movement (REM) sleep behaviour disorder (iRBD), which is a failure of the normal suppression of muscle activity during REM sleep. iRBD is now recognized as a very early symptom of synucleinopathies such as Parkinson's disease. Synucleinopathies are characterized by the aggregation and spread of misfolded α-synuclein through the central nervous system, and associated neuroinflammation. A failure of cerebrospinal fluid drainage can only make this worse, closing off one way to remove aggregated proteins, and increasing inflammation as a consequence.

CSF turnover dysfunction: a hidden early biomarker in iRBD?

Evidence in Alzheimer's disease and other dementias shows that changes in cerebrospinal fluid (CSF) turnover and perivascular spaces (PVS) volume are associated with disease progression through impairment of waste-clearance glymphatic pathways. Volume of CSF, PVS, and drainage structures such as venous sinus are mostly excluded in current MRI studies of premanifest synucleinopathy.

Here, we used MRI to investigate whether modifications in CSF, PVS, and venous sinus volumes occur in 18 prodromal synucleinopathy patients (namely isolated rapid-eye-movement sleep behavior disorder, iRBD) compared to 20 healthy young and 18 elderly controls. Our results demonstrated increased CSF and PVS volumes in iRBD without a matching increase in drainage venous structures, as observed in elderly controls. This suggests increased CSF and PVS fluid stasis, possibly due to impaired CSF filtration, a mechanism that could reduce glymphatic function and exacerbate the neurodegenerative process in iRBD.

Vaccinations can produce a lasting effect known as trained immunity, altering the behavior of the innate immune system and resulting in both a reduction in the chronic inflammation of aging and a more effective immune response to unrelated infectious agents. Arguably the largest body of research into trained immunity involves the BCG vaccine for tuberculosis, widely used outside the United States. A lesser body of work examines the trained immunity effects of a small number of other vaccines that are more commonly provided to adults rather than children. For most vaccines, there is no human data, and trained immunity itself is well documented, but not well understood in detail. Here, researchers report on a small trial to assess the effects of BCG vaccination on older people with and without Alzheimer's disease, to see whether the changes produced by trained immunity are sizable enough to justify further trials and widespread use.

Immune aging may contribute to Alzheimer's disease. Bacillus Calmette-Guérin (BCG), a vaccine known to induce trained immunity, has been linked to reduced Alzheimer's risk in prior studies. However, whether trained immunity can be observed in the human central nervous system remains unclear. We conducted two related one-year, open-label clinical trials in adults aged 55 years or older (n = 12 without Alzheimer's-related pathology; n = 11 with Alzheimer's-related pathology) recruited at a single center. Participants received two intradermal BCG vaccinations one month apart.

We show that BCG induces persistent, trained immunity-like changes in immune cells in cerebrospinal fluid, including enhanced innate responsiveness and associated transcriptional programs. These responses differ from blood, suggesting compartment-specific immune imprinting. In participants without Alzheimer's-related changes, these immune shifts are accompanied by decreased amyloid-β levels in cerebrospinal fluid and increased levels in blood. BCG was well tolerated, with no unexpected safety signals observed. This approach may represent an early neurodegenerative intervention strategy, although larger controlled studies are needed to confirm these observations.

Link: https://doi.org/10.1038/s43856-026-01691-7

Senescent cells are involved in tissue regeneration. Cells enter a senescent state following injury, and in the usual course of events assist in the intricate coordination between immune cells, stem cells, and other cell types that is required to regrow tissue. These senescent cells are then cleared by the immune system. With age, in poorly regenerative tissues, or in severe or persistent injuries, the presence of senescent cells following injury can become excessive and maladaptive. The signaling produced by senescent cells lasts too long, the cells are not cleared, and it causes further harm. As researchers here note, this is what happens following a heart attack, suggesting that there is likely some timing for the delivery of senolytic therapies to selectively destroy the cells become senescent immediately following the ischemic injury of a heart attack that could improve patient outcomes.

Currently, the primary causes of death following myocardial infarction include sudden cardiac death, malignant arrhythmias, and acute heart failure, all resulting from myocardial necrosis caused by coronary artery occlusion. Cellular senescence refers to the permanent arrest of cell proliferation in response to stress stimuli; it serves as a crucial tumor defense mechanism and is closely associated with tissue aging and chronic inflammation. The senescence-associated secretory phenotype (SASP) is one of the most characteristic features of senescent cells. Cardiac cells develop a SASP and secrete SASP factors in response to stimuli such as oxidative stress, DNA damage, and hypoxia, playing a key role in immune regulation and tissue repair following myocardial infarction.

The SASP exhibits marked spatiotemporal heterogeneity following myocardial infarction: during the acute phase, it contributes to inflammatory amplification and immune cell recruitment; during the subacute phase, it is involved in inflammation resolution, matrix remodeling, and scar formation; and during the chronic phase, it promotes chronic inflammation, paracrine senescence, pathological fibrosis, and cardiac dysfunction. Spatially, the SASP influences scar stabilization in the infarct zone, inflammation-electrophysiological coupling in the border zone, and compensatory remodeling in the distal region. The sustained expression of the SASP is a major driver of adverse ventricular remodeling and excessive fibrosis following myocardial infarction.

Therefore, targeting senescent cells and persistent, pathological SASP represents a highly promising therapeutic strategy in the field of cardiovascular regenerative medicine. This review will discuss senescence in different cell types following myocardial infarction, the spatiotemporal heterogeneity of the immune response mediated by the SASP after myocardial infarction, and the immune cells regulated by the SASP.

Link: https://doi.org/10.3389/fimmu.2026.1850084

There is a large body of evidence in animal studies to show that treatment with dasatinib and quercetin clears a fraction of the lingering senescent cells present in tissues throughout the body to restore more youthful function to many different organs and systems. Today's open access paper, focused on kidney rejuvenation via removal of senescent cells, is yet another to add to the scores of existing studies. Dasatinib is a generic chemotherapeutic drug, while quercetin is a plant flavonol; both cost little. Dasatinib can be readily obtained these days via anti-aging clinical practices, offshore pharmacies, and the other usual approaches to access low cost prescription drugs. Quercetin can be found in any supplement store.

Sadly, exactly because dasatinib and quercetin are cheap compounds, there is very little incentive for anyone to fund the sizable expense of running large clinical trials to first establish optimal dosing, and secondly confirm that this treatment is as good for aged humans as it is for aged mice. Those trials that have taken place were funded by academic institutions, were small, exploratory, and the results were promising. Only larger trials can move from promising to "yes, this works," however. Meanwhile, any older person willing to put in the effort can run their own study of one, and see how a range of biomarkers look before and after treatment. The human trials suggest that side-effects for a short course of treatment are minimal compared to potential benefits.

Multi-omics profiling reveals systemic rejuvenation of the aged kidney through senolytic therapy

Cellular senescence is a key driver of kidney aging, leading to functional decline and increased susceptibility to chronic kidney disease. While the senolytic combination of dasatinib and quercetin (D + Q) has shown promise in mitigating age-related pathologies, its long-term effects and underlying multi-level systemic mechanisms in the aging kidney remain poorly defined. Here, we systematically evaluated the long-term effects of D + Q in naturally aged mice using multi-omics approaches. Beginning at 12 months of age, mice assigned to the treatment arm received biweekly oral gavage of the D + Q cocktail for a total duration of 8 months.

We show that D + Q treatment reduces senescence markers (p16, p21, SA-β-gal), restores the anti-aging protein Klotho, and attenuates renal fibrosis and inflammation. Proteomic profiling reveals that D + Q enhances apoptotic clearance of senescent cells and promotes proliferative and regenerative pathways. Moreover, D + Q reactivates PPARα signaling, improves fatty acid oxidation, and reduces lipid accumulation in aged kidneys. Single-cell transcriptomics further demonstrates that D + Q reverses transcriptional aging signatures across multiple renal cell types and remodels cell-type-specific pathways associated with metabolism, inflammation, and fibrosis. Cell-cell communication analysis reveals that D + Q normalizes the hyperconnected intercellular network in aged kidneys, particularly by modulating inflammation-related signaling.

Our findings offer a comprehensive, systems-level understanding of how senolytic therapy restores renal homeostasis, emphasizing its potential as a multifaceted intervention to combat kidney aging.

Animal studies suggest that the composition of the gut microbiome is at least as important as diet and exercise when it comes to influencing the pace and progression of aging. Both diet and exercise influence the gut microbiome as well - nothing in the body acts in isolation. The composition of the gut microbiome changes with age, and in animal studies approaches that restore a more youthful balance of microbial populations to aged animals improve health and extend life span. Here, researchers review what is known of the links between the metabolites produced by the gut microbiome and the health of aged tissues in the body, with a particular focus on muscle and the brain.

Cognitive frailty, characterized by the coexistence of physical frailty and cognitive impairment, has emerged as a major challenge in aging populations and is closely linked to sarcopenia, neurodegeneration, and chronic inflammation. Increasing evidence suggests that the gut microbiota acts as a central regulator of neuromuscular and neurocognitive aging through the integrated gut-brain-muscle axis.

This review highlights how microbial dysbiosis, reduced short-chain fatty acid (SCFA) production, systemic endotoxemia, and altered microbial metabolites contribute to mitochondrial dysfunction, neuroinflammation, anabolic resistance, and impaired neuroplasticity. Key signaling mediators, including SCFAs, bile acids, tryptophan-derived metabolites, cytokines, and myokines such as irisin, brain-derived neurotrophic factor (BDNF), and cathepsin B, orchestrate bidirectional communication among the gut, skeletal muscle, and brain.

We further discuss the role of exercise-induced microbiota remodeling and muscle endocrine signaling in promoting mitochondrial biogenesis and cognitive resilience. In addition, emerging translational strategies including probiotics, prebiotics, postbiotics, polyphenol-rich functional foods, marine bioactives, and precision nutrition are explored as potential interventions targeting this axis. Collectively, the gut-brain-muscle axis provides a novel systems biology framework for understanding cognitive frailty and developing integrated therapeutic strategies for healthy longevity.

Link: https://doi.org/10.3390/microorganisms14061366

Researchers here describe an approach to encouraging regrowth of small vessels in heart tissue, involving transplantation of organoids composed of the various cell types needed to form new vessels. Like other cell therapy strategies for an injured or aged heart, delivery involves making a patch of pseudo-tissue that is layered onto the surface of the heart. The patch mimics enough of the function of a natural extracellular matrix to increase survival of transplanted cells. More generally, we might consider whether this sort of strategy would work for other tissues; loss of capillary density is a feature of aging throughout the body, and ways to restore a more youthful extent of capillary networks could be meaningfully beneficial.

Ischemic heart disease (IHD), also known as coronary artery disease, is a leading cause of death and morbidity. IHD arises when blood vessels of the heart become clogged, blunting oxygen and nutrient supply to heart muscle cells, which eventually die off, leading to heart attack or heart failure. Although larger blood vessels can be replaced surgically to restore blood flow, there is currently no treatment targeting smaller blood vessels, so-called microvessels, which are essential for the uniform blood circulation within the heart muscle.

Researchers made vascular organoids, which are small aggregates of cells capable of forming new blood vessels, from endothelial progenitor cells (EPCs) isolated from human blood and mesenchymal stem cell-derived smooth muscle cells (SMCs) from human bone marrow. The team then placed patches of vascular organoids onto the outer heart surface of pigs with IHD and followed them for four weeks. Encouragingly, heart function in pigs receiving organoid patches was improved compared to untreated animals, and progression of IHD towards heart failure was mitigated. The organoid patches survived for several weeks and individual cells from the surface patches were found in deeper layers of the pig hearts suggesting they are migrating into the heart.

Link: https://www.eurekalert.org/news-releases/1133607

The point of studying the biochemistry of very long-lived humans is to try to better understand which of the many underlying mechanisms of damage and dysfunction that drive degenerative aging are the most important and thus should be prioritized for the development of therapies. One can look at the differences in the sequences of proteins, expression of proteins, and the operation of metabolism and try to infer why those differences tend to exist more often in long-lived individuals, try to make a link to a known form of damage. The point is not to to try to emulate the specific biochemistry of long-lived individuals: all that will happen as a result of that is a modest decrease in pace of aging, while one will still wind up frail, greatly impacted by degeneration, and with a very high mortality rate. It is a small gain. We would like to engineer larger gains.

In today's open access paper, researchers find that SIRT6 variants that are more common in centenarians are protective because they reduce the burden of senescent cells in aged tissues. The response to that finding should be to ramp up development of more and better senotherapeutic research programs with the goal of selectively removing senescent cells from the aging body on an ongoing basis, or at the very least halting the harmful signaling that is the primary mechanism by which lingering senescent cells are disruptive to structure and function in surrounding tissues. The response should not be to deliver better versions of SIRT6 into patients via gene therapy, as this will be far less beneficial.

Centenarian SIRT6 variants elevate SIRT6 protein and enhance cellular senescence resistance

Centenarians represent a natural model of delayed human aging, offering a unique opportunity to uncover genetic mechanisms that promote longevity. However, the functional consequences of the genetics variants carried by these long-lived individuals remain poorly characterized in physiologically relevant systems. Here, we introduced two linked missense variants in SIRT6 enriched in Ashkenazi Jewish centenarians into the endogenous SIRT6 locus of human embryonic stem cells and differentiated them into somatic lineages to define their effects in a native genomic context.

We revealed that centenarian variants elevated endogenous SIRT6 protein abundance through weakened interaction with vimentin, and altered endogenous SIRT6 enzymatic activities, including enhanced mono-ADP-ribosyltransferase activity and reduced deacetylase activity. Functionally, these variants delayed replicative senescence and conferred resistance to progerin-induced stress, accompanied by preservation of DNA repair gene expression programs and suppression of transposable element derepression. Guided by these findings, we evaluated the translational potential of both genetic and pharmacological interventions, demonstrating that adeno-associated virus (AAV)-mediated delivery of centenarian SIRT6 or pharmacological activation of SIRT6 using fucoidan from Fucus vesiculosus (Fucoidan-FV) partially attenuated aging-associated molecular defects, including genome instability and LINE1 derepression, in progeria fibroblasts.

Together, these findings demonstrate that centenarian variants exert multifaceted effects on SIRT6 function to enhance cellular stress resistance, and providing a framework for translating genetic discoveries from long-lived individuals into mechanistic insight and potential gerotherapeutic strategies for healthy aging.

The more severe later stages of Alzheimer's disease are characterized by altered forms of tau protein aggregating inside neurons to cause dysfunction, inflammation, and cell death. Researchers here show that tau can spread between neurons via extracellular vesicles, and identify the protein arc as necessary to this process. Once a mechanism involved in the spread of pathological proteins is developed, it is potentially a target for future therapies that might slow the progression of disease.

Neurodegenerative diseases are characterized by protein aggregation in specific brain regions that spread across the brain as the disease progresses. A major histopathological hallmark of Alzheimer's disease (AD) and tauopathies, such as frontotemporal dementia (FTD) and chronic traumatic encephalopathy, is intracellular neurofibrillary tangles that consist of misfolded tau protein. During aging, tau becomes hyperphosphorylated, resulting in misfolding and a decreased affinity for microtubules. Tau pathology is transmitted cell to cell, and the spread and levels of pathological tau strongly correlate with the degree of cognitive decline in AD patients.

We find that the neuronal gene Arc is critical for the release of tau in neuronal extracellular vesicles (EVs) via a direct protein-protein interaction. Brain extracellular vesicles (EVs) purified from transgenic rTg4510 mutant tau mice (rTgWT) crossed with Arc knockout mice (rTgArc KO) contain less tau and reduced tau seeding potential. Both Arc and tau are co-packaged in mouse and human brain-derived EVs. Moreover, Arc levels in brain-derived EVs isolated from human Alzheimer's disease (AD) brains show a strong positive correlation with phosphorylated EV-tau levels. rTgArc KO mice have increased accumulation of intracellular tau and a modest increase in cell toxicity early in disease progression. Strikingly, intercellular tau transmission is almost absent in Arc KO mice. These results show that Arc is critical for the packaging of tau in EVs, which plays a significant role in intercellular tau transmission.

Link: https://doi.org/10.1016/j.cell.2026.06.008

The gut microbiome generates a vast range of metabolites, some beneficial or even necessary to health, and some actively harmful, provoking chronic inflammation or other dysfunction. With age the balance of microbial populations making up the gut microbiome changes for the worse. Researchers have observed declines in the generation of some beneficial metabolites and increases in the generation of some harmful metabolites. Among the harmful metabolites, the neurotoxic imidazole propionate has been shown to accelerate atherosclerosis, and evidence suggests a contribution to a range of other age-related conditions. Here, researchers report on evidence in mice and humans for imidazole propionate to accelerate the pace of neurodegeneration leading to Alzheimer's disease.

The gut microbiome modulates metabolic and neurovascular processes implicated in Alzheimer's disease and related dementias (ADRD), but the underlying mechanisms remain unclear. Here, we identify the bacterial metabolite imidazole propionate (ImP) as a modifier of ADRD pathology.

In a cohort of 1,196 cognitively unimpaired adults, higher plasma ImP levels were associated with lower preclinical cognitive scores and biomarkers of ADRD, both cross-sectionally and longitudinally. Fecal metagenomic analysis linked putative ImP producers to ADRD phenotypes. Genome-wide integrative analysis revealed a locus on chromosome 12 associated with both plasma ImP levels and AD risk in humans, supporting a host genetic contribution to ImP regulation and a causal role of this metabolite in AD.

In mice, chronic ImP administration exacerbated AD-like pathology. ImP impaired brain endothelial barrier and promoted tau hyperphosphorylation in primary neurons, an effect blocked by glycogen synthase kinase-3β inhibition. Together, this study links ImP to hallmarks of neurodegeneration and suggests that targeting ImP may represent a potential strategy to modify ADRD risk.

Link: https://doi.org/10.1038/s41467-026-74744-z

The retina is considered a part of the central nervous system. As is the case for the brain, a barrier of specialized cells surrounding the blood vessels supplying retinal tissue controls the passage of molecules between blood and tissues. This barrier becomes dysfunctional with age and age-related conditions, and leaks inappropriate molecules into retinal tissue to cause further damage and dysfunction. Again, this is very analogous to barrier dysfunction in the brain, and is thought to be a major contributing factor in age-related neurodegeneration and consequent degenerative conditions.

One of the approaches under development for the treatment of damaged retinal tissue, such as in the context of macular degeneration or diabetic retinopathy, is to produce new cells that can replace dead or dysfunctional cells, or otherwise help to improve function via a health profile of secretions. In today's open access paper, researchers report on generation of endothelial cells of the retinal barrier from induced pluripotent stem cells. When introduced into a damaged mouse retina, these cells help to repair tissue and restore a functional vasculature.

Derivation of functional retinal endothelial cells from human pluripotent stem cells for therapeutics and modelling

Retinal tissue has the highest energy and oxygen usage in the body due to the retina's intense and continuous neuronal activity. This demand leads to a crucial reliance on the inner blood-retina barrier (iBRB) to maintain ocular homeostasis. The iBRB is a specialized anatomical unit composing the vasculature located within the internal retinal layers of the central nervous system. Retinal endothelial cells (RECs) in the iBRB are continuous endothelial cells (ECs) that form tight junctions to regulate the diffusion of small molecules, such as ions and water, across their cell-cell interface.

Dysfunction and vascular leakage of the iBRB have been identified as a hallmark of numerous retinal microvascular diseases, including diabetic retinopathy (DR), the leading cause of blindness and a common pathology found in patients with diabetes mellitus. The breakdown of the iBRB occurs due to prolonged hyperglycaemia exposure, leading to increased permeability of the endothelial barrier and reduced oxygen delivery to the retina, causing ischaemia. As DR progresses, it can eventually lead to bleeding, retinal detachment and irreversible blindness.

In this study we harnessed Wnt-β-catenin signalling to derive RECs from human induced pluripotent stem cells (iRECs) that can generate a continuous endothelial barrier with a characteristic retinal phenotype and genotype as well as iBRB functionality. We established the therapeutic potential of the iRECs for the ischaemic eye using an oxygen-induced retinopathy (OIR) mouse model. When injected into oxygen-induced retinopathy mice, iRECs integrated into the host vascular network and revascularized the ischaemic eye, rescuing the tissue.

The growth in number of senescent cells with age is an important mechanism of degenerative aging. Many studies in mice have demonstrated rapid rejuvenation and reversal of many different aspects of aging and age-related conditions via selective destruction of senescent cells in aged tissues. Here, researchers review what is known of the way in which the age-related expansion of the senescent state in cell populations impedes stem cell function in older individuals. Stem cells support tissues by generating a supply of daughter somatic cells to replace losses, as well as via signaling that is important to regenerative capacity. As stem cell activity declines so too does tissue function and health.

Several cellular settings have been identified where senescence induction seems to exclude stem cell activity, thereby suggesting a functional competition between the two processes. One such example are mesenchymal stem cells (MSCs) used in therapy. Many of the potentially beneficial MSC properties are attributed to their ability to grow as high-density monolayers known as MSC sheets, which however can rapidly acquire senescence features under sustained high-density conditions. Another case of functional competition between senescence and stemness relates to bone marrow mesenchymal stem cells (BMSCs) which constitute a lifelong reservoir for somatic cell generation, and are shown to be significantly useful in bone regenerative medicine. It has, however, been observed that BMSC osteogenic differentiation is inhibited by senescence, thereby limiting the BMSC regenerative potential.

A considerable body of evidence where documented antagonism between senescence and stemness is pivotal for physiological homeostasis refers to muscle tissue. Muscle tissue regeneration relies heavily on satellite cells, a quiescent adult stem cell population whose regenerative capacity declines upon aging. Stellite cells from geriatric populations fail to retain their quiescent state under normal conditions, which extensively impacts their self-renewal and regenerative properties. Resting satellite cells in geriatric mice switch to a pre-senescence state thereby losing quiescence, a process driven by p16INK4A derepression. Thus maintenance of quiescence in adults, in fact, relies on repression of senescence.

Given that senescence is intrinsically characterized by proliferation arrest, while stemness refers to an inherent self-renewal capacity and production of differentiated progeny, the two cellular states are often perceived as mutually exclusive. Indeed, in this review we present an accumulation of evidence where the establishment of senescence may impose a barrier to stemness during natural processes such as aging, and upon reversing this functional competition (e.g. via genetic or pharmacological interventions) cell fate may change, as shown in multiple cell types and tissues such as MSCs, muscle satellite cells, dental pulp stem cells, or pancreatic β-cells.

Interestingly extensive functional synergy between the two states is widely observed in cancer, because the "dark side of senescence" may promote tumorigenic traits through senescent cell paracrine activity or even escape from the senescent state itself. Such activity was found to occur at least in B-cell lymphomas, liver, colon, and lung cancer.

Link: https://doi.org/10.18632/aging.206387

Accelerated aging conditions are not really accelerated aging conditions; each is a dysfunction in which one specific mechanism runs amok, generating damage and dysfunction that superficially resembles the damage and dysfunction of aging. Most of the known accelerated aging conditions are strongly connected to malfunctions in DNA repair, and dysfunction arises at least in part due to an accumulation of mutational damage in critical cell populations. Here, researchers describe an accelerated aging condition in which the underlying dysfunction is an increase in DNA methylation, distorting the epigenetic regulation of nuclear DNA structure and gene expression, again in ways that are superficially similar to the epigenetic changes of aging. Just as DNA repair disorders provide some insight into normal aging, with caveats, so too we might expect an epigenetic disorder to shed some light. The fine details still matter, however. Dysfunction is not equivalent to accelerated aging, even if it has the appearance of accelerated aging.

Declining tissue function and regenerative capacity underlie many chronic diseases. Experimentally establishing the mechanistic basis for such tissue aging presents substantial challenges, given decades-long timescales and multifactorial origins. Epigenetic alterations have been proposed to have a key etiological role, but whether they are correlative or causal remains a key unanswered question, as does their contribution to specific age-related pathologies.

Here we describe an epigenetically driven accelerated aging syndrome. We demonstrate that DNMT3A gain-of-function mutations in Heyn-Sproul-Jackson syndrome recapitulate age-related gains in DNA methylation (DNAme), cause multilineage stem cell dysfunction, and phenocopy aspects of aging in humans and mice. We also show that region-specific DNA hypermethylation at lineage-specific genes can explain reduced stem cell output and lineage skewing. Hence, starting from a Mendelian disorder, we implicate DNAme-mediated stem cell dysfunction in the etiology of medically important age-related hematological, bone and metabolic pathologies, which might be targetable by future therapies.

Link: https://doi.org/10.1038/s41588-026-02633-8

In recent years, researchers have noted that one variant of the BPIFB4 gene is associated with human longevity. This was discovered in the usual way, by noting that older populations tend to have a higher proportion of individuals carrying the variant than is the case for younger populations. In other words, individuals without the protective variant have an incrementally higher mortality rate. The longevity-associated variant of BPIFB4 appears to reduce cardiovascular dysfunction and mortality, and also reduces the chronic inflammatory signaling characteristic of aging. That slowed cardiovascular aging may or may not be entirely a consequence of the reduced inflammation; that remains to be determined.

Studies in mice have shown similar outcomes, and, interestingly, the BPIFB4 protein is robust enough to deliver orally and still produce benefits. Meanwhile, investigations of the underlying biochemistry of BPIFB4 and its role in the body continues, seeking a better understanding of how exactly it works.

Today's open access paper reports on new findings regarding the way in which BPIFB4 interacts with the immune system, which appears to be mediated via the activities of platelets. Platelets are cell fragments manufactured by megakaryocyte cells; they might be thought of as mini-cells that exhibit the surface features and some of the contents of their megakaryocyte progenitors. The primary purpose of platelets is to produce clotting when needed, but even when that is not happening, platelets are active participants in the complex dance of interactions between cells. Researchers suggest that effects hinge on the degree to which CD47 appears on platelet surface membranes, which offers a possible path to developing a drug to mimic BPIFB4 benefits.

The LAV-BPIFB4-Platelet-CD47 Axis: A Novel Mechanism Associated With Immune Resilience in Longevity

Long-living individuals (LLIs) possess remarkable genetic resilience, characterized by protective variants that confer immune robustness and resistance to age-related diseases. The longevity-associated variant of BPIFB4 (LAV-BPIFB4), enriched in centenarians, demonstrated pleiotropic benefits including reduced inflammation, cardiovascular protection, and immune system rejuvenation. However, the molecular mechanisms underlying these protective effects remain incompletely understood.

Here, we revealed that LAV-BPIFB4 fundamentally reshaped the immune features of platelets to establish enhanced immunomodulatory capacity through CD47 upregulation. Of note, centenarians displayed an elevated percentage of circulating CD47+ reticulated platelets (RPs), a condition mimicked by LAV-BPIFB4 carriers which exhibited significantly elevated CD47 levels both on RPs and mature platelets' surface. In agreement with an early acquirement of CD47 overexpression, MEG-01 megakaryoblastic cells overexpressing LAV-BPIFB4 produced CD47-high platelet-sized particles.

Functionally, platelets from LAV carriers suppressed monocyte activation and inflammatory cytokine production through CD47-dependent mechanisms, selectively reducing p38 MAPK activation while leaving NF-κB signaling largely unaffected in response to lipopolysaccharide. Recombinant LAV-BPIFB4 administration in vivo increased CD47 on murine platelets and reduced, ex vivo, LPS-induced monocyte activation, validating cross-species therapeutic potential. Critically, recombinant LAV-BPIFB4 protein phenocopies genetic effects, rapidly increasing CD47 expression on wild-type platelets through cytoskeleton-dependent trafficking mechanisms and conferring enhanced anti-inflammatory capacity. This might represent a translatable strategy to replicate some of the biological features associated with a longevity-associated variant beyond genetic carriers.

The nature of medical regulation makes it extremely expensive to develop a new drug, and considerably less expensive to find a new use for an existing approved drug. Thus repurposing drugs receives more attention than it perhaps should, and the typical outcome is a new marginal use rather than something impressive. This will happen for treatments for aging as well, no doubt. People will find that many existing approved drugs have some small effect on aging and life span in animal studies, and some of those will be marketed and used, and none of that will make any great difference to the world. What are the odds of discovering that an existing drug has an effect size similar to that of rapamycin? Which is to say ~20% life extension in mice and maybe a few years in humans, though that remains to be seen. That is an interesting question; it may be possible for effects on the order of a few additional years of life expectancy to hide in the existing human data because no-one looked that hard. Much more than that seems unlikely, though.

Despite the thousands of genes implicated in age-related phenotypes, effective interventions for aging remain elusive, due to the multifactorial nature of longevity and the interconnectedness of molecular components involved. Here we introduce a network medicine framework to map 2,358 longevity-associated genes onto the human interactome to identify drug-repurposing candidates capable of modulating specific hallmarks of aging. We find that genes associated with each hallmark form a connected subgraph, or hallmark module, allowing us to measure the network proximity of 6,442 compounds to each hallmark.

We then introduce a transcription-based metric, pAGE, which evaluates whether drug-induced expression shifts reinforce or counteract known age-related expression changes within each hallmark module. By integrating network proximity and pAGE, we identify drug-repurposing candidates targeting specific hallmarks and provide a falsifiable framework to leverage genomic discoveries for accelerating drug repurposing in longevity. Our findings are interpretable, revealing molecular mechanisms through which drugs modulate hallmarks.

Link: https://doi.org/10.1038/s43587-026-01161-8

Aging clocks cannot be trusted to produce useful data for any novel intervention in aging. They are produced via machine learning approaches applied to biological data from a large study population, and there is very little understanding of how underlying mechanisms of aging connect to the data used to build the clock. Thus effects on aging produced by way to change mitochondrial function or clear senescent cells may or may not be accurately reflected by any given clock - the only way to find out is to run a lengthy, expensive life span study, which defeats the point of having a quick and simple measure. The only practical way forward to make clocks more trustworthy in the near term, or at least to understand which clocks are most consistent, is to gather as much data as possible on their responses to interventions known to at least modestly impact aspects of aging, and that is exactly what is happening.

Aging-related chronic diseases are driven by multiple mechanisms, motivating efforts to develop feasible interventions that can attenuate biological aging. DNA methylation-based epigenetic clocks, particularly measures of the pace of aging such as DunedinPACE, are sensitive to relatively short-term changes in aging processes. However, evidence from randomized controlled trials remains limited. We conducted a randomized controlled trial to test a 12-week multimodal lifestyle intervention comprising exercise and dietary guidance involving daily consumption of yogurt containing Bifidobacterium longum BB536 on DNA methylation-based aging measures in overweight men aged ≥50 years.

The intervention group exhibited a significant deceleration in DunedinPACE, corresponding to an estimated 2.2% slower pace of aging, whereas no meaningful change was observed in the control group. Exploratory analyses further identified a significant reduction in DNAmCystatinC, a renal-related GrimAge surrogate marker, while no clock within the biological age remained significant after false discovery rate correction. These findings suggest that a feasible, multimodal lifestyle intervention-including exercise and dietary guidance with daily consumption of yogurt containing Bifidobacterium longum BB536-may be associated with short-term changes in selected DNA methylation-based aging measures. Larger and longer-term studies are warranted to confirm the durability and clinical relevance.

Link: https://doi.org/10.18632/aging.206386

Ethicists seem a little stuck on the idea that treatments to slow and potentially reverse aspects of aging are only available to the wealthy, or will only be available to the wealthy. Today's open access complaint about making the world a better place at least manages to also touch on what I think is the more pertinent issue, which is knowledge. One can't try interventions that seem plausibly likely to produce benefits in the matter of degenerative aging without knowing that the option is there. One can't make an assessment of the odds of benefit versus harm without knowing a fair amount about biology, mechanisms of action, and the state of the field. One can't accumulate that knowledge without understanding which of the many sources of information are lying through their teeth in order to make money. One can't substitute wealth for knowledge and pay middlemen to point in the right direction without knowing which of those middlemen are corrupt and selling a bill of goods. It's a knowledge problem all the way down.

The most plausible, well-studied initial approaches to treat aging are also readily available at generic drug prices. Rapamycin. Senolytic compounds like the dasatinib and quercetin combination. Or they are free if we're also counting exercise and calorie restriction. The next step up, exosome therapies and stem cell therapies, can be obtained for a few thousand dollars per treatment given a lot of legwork and cost comparison on the part of the patient. The futuristic approaches like partial epigenetic reprogramming? At some point there will be versions that cost little. Just wait.

I suspect that ethicists and journalists and others who like to grind axes on the activities of the wealthy are deceiving themselves. They look at a few exceptional and vocal wealthy people who are spending a great deal on personal health as a hobby and see that as broader reality, rather than a tiny minority engaged in doing unusual things with their time and funding. The reality is that most wealthy people do little that is out of the ordinary when it comes to their health, and have little to no knowledge regarding potential advances in the treatment of aging. Meanwhile, a relatively small number of interested non-wealthy people quietly put in the time to learn the bounds of the possible and undertake self-experiments by trying rapamyin or senolytics, or saving up for exosome treatments. The mainstream pays very little attention to that contingent, and perhaps justifiably so - as for the vocal wealthy self-experimenters, they are a tiny minority of the population.

Meanwhile, most people have no idea. Medicine and biology are not in their wheelhouse, why would they have any idea as to what is in process and speculative and potentially useful? The knowledge problem is the hard problem here, not the finance. Given something that may be useful, and costs little, how does one cut through the background noise of nonsense and self-interest to produce and present clinical proof and induce widespread use? It is a collective action puzzle, and our species does not have a good track record when it comes to solving those.

The Ethics of Extending Life: Longevity Medicine and Health Inequity

In one survey, nearly 80% of 1000 US respondents said they'd like to live to be 120 years old, but only if they remained mentally and physically healthy. Without that hypothetical guarantee, far fewer people wished to live such a long life. We not only want to live longer, we want to live longer and better. From stem cell therapy to biomarker tracking, from genomics to AI algorithms that support early disease detection, medicine has entered a new era in which some view aging as a condition that can be managed and mitigated, provided the right tools are used.

Due to limited accessibility and high costs, those in economically and socially privileged positions have been the first to benefit from these advancements. As life-lengthening medical interventions continue to develop, health span extension may become stratified along socioeconomic lines, concentrating its benefits among the already privileged. Without intentional policy and ethical frameworks, these innovations may deepen population health inequities.

There is another, more subtle accessibility challenge facing longevity medicine: "Even if you made every longevity medicine intervention free, you still need to interpret all that information." That requires the consumer to possess a high degree of health literacy, which is typically higher in well-educated, high-income individuals. "Wealthy patients walking into longevity clinics aren't just buying the intervention, they're buying someone to do that cognitive work and navigation for them, to be the quarterback of their health, or the CEO of their health, which is a service that's almost completely absent from primary care for most other people." Without someone to provide context and guidance, the large amount of data that longevity medicine testing reveals may simply be disregarded, or worse, widen disparities.

Longevity medicine offers fantastic potential for increasing health span - a hope that many of us dream of - but the future of longevity medicine will be defined by not just how long we can live, but by who gets the opportunity to do so.

Pulmonary fibrosis is an age-related condition. Good evidence connects it to the burden of senescent cells in the aging lung, but its causes are otherwise relatively poorly understood. Therapeutic options remain poor, and the prognosis for patients is quite ugly. Fibrosis is nanoscale scarring, an inappropriate buildup of excess extracellular matrix that is disruptive to tissue function. Researchers here explore a loss of the capacity of fibroblast cells to degrade extracellular matrix structures in aged tissue, and identify a regulatory gene that can be overexpressed to produce a greater defense against fibrosis in aged mice.

Idiopathic pulmonary fibrosis (IPF) is a progressive and often fatal interstitial lung disease whose incidence and severity increase markedly with age, indicating that aging is a primary risk factor for IPF. A study in murine models demonstrated that while bleomycin-induced pulmonary fibrosis (PF) can resolve spontaneously in young mice, this reparative capacity is significantly impaired in older animals, potentially causing persistent fibrosis.

A key mechanism underlying extracellular matrix (ECM) degradation involves the phagocytosis of collagen fibrils by fibroblasts and macrophages and their subsequent lysosomal degradation. Aging has been shown to impair the capacity of lung fibroblasts to degrade collagen independently of matrix metalloproteinase activity. Therefore, we hypothesized that an age-associated decline in collagen phagocytosis by fibroblasts is linked to lysosomal dysfunction. However, the upstream regulators governing this process remain poorly defined.

In vivo, aged mice showed impaired fibrosis resolution and reduced lung fPRDM16 levels. Fibroblasts from aged mice exhibited reduced collagen I phagocytosis, elevated lysosomal pH, and increased mitochondrial reactive oxygen species (mitoROS). Enhancing lysosomal function with rapamycin or scavenging mitoROS with mitoquinone restored phagocytosis. fPRDM16 expression was downregulated with age and upon transforming growth factor-β (TGF-β) stimulation. Its overexpression rescued phagocytic defects, improved lysosomal acidification, and reduced mitoROS, thereby disrupting a pathogenic mitochondria-lysosome feedback loop.

We conclude that fPRDM16 downregulation in aging impairs fibroblast-mediated collagen clearance via a mitochondria-lysosome dysfunction loop. Targeting fPRDM16 may represent a novel therapeutic strategy to promote fibrosis resolution.

Link: https://doi.org/10.1016/j.cmp.2026.02.002

If used sensibly, models of aging can offer some insight into the bounds of the possible with regard to which classes of biological mechanism are more or less important in determining pace of aging, onset of disease, and life span. Researchers here use a specific type of model, the saturating removal model of damage accumulation, and tinker with the parameters to see which of the processes represented by those parameters best predict the observed range of life spans across species. Perhaps the most interesting outcome is that mice and humans end up in different broad buckets in terms of categorizing how mechanisms of aging interact; this is far from the only study to suggest that this is the case.

The saturating removal (SR) model was defined and calibrated based on longitudinal damage measurements in mice (senescent cells) and Escherichia coli (membrane damage). The model is based on the simplifying hypothesis that the damage that causes aging can be summarized by a scalar x and that life cannot persist above a certain level of x. The biochemical nature of x can be different in each species. The SR model describes the dynamics of damage by a stochastic differential equation that includes production, removal, and noise. Production rises linearly with age, whereas removal saturates at high damage. Death occurs when damage exceeds a threshold. The SR model explains many quantitative patterns of aging including Gompertz and Weibull hazard curves, distributions of human frailty index, disease incidence curves, and heritability of lifespan.

Different species age in similar ways but their lifespans differ by orders of magnitude. It is not clear how these similarities and differences arise from the accumulation of damage that underlies aging. Does long lifespan arise from reduced damage production, increased removal, or enhanced robustness to damage? Here we apply the saturating removal model and fit it to survival data from well-studied species. Several parameters have near-universal values including ratios of removal rate, noise amplitude, and death threshold. The model parameter that best predicts lifespan is the damage production rate, which spans seven orders of magnitude.

We identify two distinct aging regimes: ballistic aging where damage production outpaces removal, characterizing yeast, nematodes, flies, and mice, and quasi-steady-state aging, where damage tracks a moving set point of balanced production and removal, characterizing humans, dogs, guinea pigs, and cats. These results provide a mechanistic model-based basis of comparative aging that awaits experimental validation.

Link: https://doi.org/10.1038/s43587-026-01138-7

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

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

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

Intermittent hypoxia induces reversible epigenetic age acceleration in old mice

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Gene therapy for aging and longevity

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

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

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

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

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

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

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

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

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

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

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

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

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