Fight Aging!

The National Institute on Aging's Interventions Testing Program (ITP) is the full stop at the end of many a debate over the merits of development of one substance or another as a hoped for treatment to modestly slow aging. The ITP uses a very large number of mice and considerable rigor to assess effects on life span. The program typically focuses on small molecules and supplements that have prior evidence for anti-aging effects, and usually those with a long history in the literature. Given the number of compounds that show no effect on life span in the hands of the ITP, this initiative serves as a reminder that any one study in a hundred mice that demonstrates modest slowing of aging does not in fact carry a great deal of weight. There are many such studies in the history of compounds that the ITP has shown to have no effect on life span.

There is always room to argue about dosing and methodology; there was some of that after the ITP reported that fisetin has no effect on longevity. But one can't argue with the large number of mice used and the efforts to impose rigor on the experimental process. Today's open access paper is the latest ITP publication in which possibly promising ways to modestly slow aging were demonstrated to have no effect once studied more rigorously. Of note, α-ketoglutarate is in the list; this had promising data in mice, considerable interest from a number of research and development groups, and made it all the way to a human clinical trial - which failed. In earlier mouse studies, α-ketoglutarate dosing was lifelong. The ITP tried starting at 18 months of age, which didn't work, and here tried starting at 7 months of aging, which also didn't work. If you'd like to look over the data, it can be found at the Mouse Phenome Database.

At a high level, the ITP results obtained over the years can be taken as support for the idea that attempting to discover bioactive molecules that favorably manipulate metabolism is not a viable path forward. It is very challenging, results vary meaningfully between groups, between species, by dose, by age of onset of treatment, and after all of that the best expected outcome is only a modest slowing of aging. This is not a good approach to the problem of aging. Instead, rational design of therapies that can repair known forms of cell and tissue damage seems far more likely to succeed in producing large enough and robust enough effects to care about.

Astaxanthin, meclizine, mitoglitazone, pioglitazone, alpha-ketoglutarate, mifepristone, methotrexate, and atorvastatin-telmisartan do not increase lifespan in UM-HET3 mice

The Interventions Testing Program (ITP) evaluated eleven compounds in genetically heterogeneous UM-HET3 mice to assess their potential to extend lifespan. These interventions included both novel agents and previously tested compounds administered at novel doses or starting ages. Despite prior evidence suggesting lifespan benefits of these proposed interventions in other models or under different conditions, none of the tested compounds significantly increased lifespan in male or female mice. Notably, astaxanthin, mitoglitazone, and meclizine - previously associated with lifespan extension in the ITP - showed no benefit when administered at different doses or starting at later ages.

In females, astaxanthin, late-start mitoglitazone, and pioglitazone were associated with significantly reduced lifespan when pooling the data from all three sites. However, site-specific analysis revealed unusually long lifespans in control females at The Jackson Laboratory, prompting reanalysis using data from the other two sites and only showed a negative effect for mitoglitazone and pioglitazone. This study underscores the importance of rigorous, multi-site testing and highlights the challenges of translating promising initial findings into consistent lifespan benefits at other doses or with alternate starting ages. These results suggest that timing and dosage are critical variables in aging intervention studies and reinforce the need for cautious interpretation of single-site or single-cohort findings.

One of the major projects within the study of comparative biology is the attempt to understand why adult individuals of some species can fully regenerate lost tissues following injury, while mammals such as our own species cannot. A variety of modest inroads into identifying potentially important differences in cellular biochemistry and activity have been made, such as work focused on senescent cells and macrophages, but it remains an unsolved challenge. Researchers here present more data to add to that already under consideration, focused on the role of oxygen sensing in the initial response to injury. It is unclear as to whether it can lead to dramatic improvements in mammalian regeneration, but the work suggests that regeneration could be improved via manipulation of oxygen sensing in injured tissues.

Some animals can regrow lost body parts. Salamanders and frog tadpoles can rebuild entire limbs after amputation. Mammals cannot. For decades, biologists have tried to understand why. Limb regeneration begins with wound healing. After amputation, cells at the injury site must rapidly seal the wound and switch into regenerative cell types. In amphibians, this process runs smoothly. In mammals, it stalls early. Wound closure is slow and scar formation takes over, blocking regeneration. One key difference lies in the environment. Amphibian larvae develop in water, where oxygen levels are lower than in air. Moreover, many regeneration-competent species live in aquatic environments. Meanwhile, mammalian tissues are typically exposed to higher oxygen levels after injury.

Researchers amputated developing limbs from frog tadpoles and mouse embryos and cultured them outside the body under controlled oxygen conditions. Oxygen levels were lowered to match aquatic environments or raised to levels close to air. They tracked how cells responded by measuring wound closure, cell movement, gene activity, metabolism, and epigenetic states, including changes to DNA packaging. The work focused on HIF1A, a protein that acts as a cellular oxygen sensor. When oxygen is low, HIF1A becomes stable and activates programs that set the stage for wound healing and regeneration.

Lowering oxygen levels had a clear effect on the limbs of mouse embryos. Under reduced oxygen, mouse cells closed wounds faster and showed signs of entering a regenerative program. Stabilizing HIF1A produced similar effects, even when oxygen levels remained high. Frog tadpoles behaved differently. Their limbs regenerated efficiently across a wide range of oxygen levels, including levels well above those normally found in air. Molecular analysis showed that their cells maintain stable HIF1A activity even when oxygen increases, due to low expression of genes that normally shut this pathway down.

By comparing frogs, axolotls, mice, and human datasets, the team found a consistent pattern. Regeneration-competent amphibians show reduced oxygen-sensing capacity, allowing regenerative programs to be initiated and sustained. Mammals show the opposite pattern. Their cells respond strongly to oxygen and switch regenerative programs off soon after injury. The results suggest that mammalian limbs retain latent regenerative potential at early stages, depending on how cells respond to environmental signals such as oxygen. This means that adjusting oxygen-sensing pathways might one day improve wound healing or regenerative responses in humans.

Link: https://www.tuebingen.mpg.de/280592/news_publication_26212730_transferred

Humans, and most other mammals, exhibit a common set of differences between males and females in the trajectory of aging and age-related disease. Females live longer, but with greater disability, for example. Dive deeper to look at the fine details of specific tissues and biological systems, and the list of differences expands. Researchers here report on their assessment of differences between men and women in the aging of the immune system, for example. While interesting, it isn't clear that differences in the progression of aging will be all that important in a future of effective rejuvenation therapies. It is certainly possible that any given narrow approach to rejuvenation that targets just one mechanism of aging will prove to be more or less effective to some degree in men versus women, but a package of approaches that produces comprehensive rejuvenation, addressing all of the causes of aging, should make the whole question of sex differences in aging moot.

Statistics show clear differences in the population's immune system according to sex: men are more susceptible to infections and cancers, while women have stronger immune responses, which translate, for example, into better responses to vaccines. Even so, with a more reactive immune system, the probability of the body attacking itself also increases, causing 80% of autoimmune disease development to occur in women. A new study has demonstrate that immunological aging follows different dynamics between men and women, identifying the cells and genes responsible for the process, and providing a molecular explanation for the differences that previously were only observed globally in the population.

The results reveal that women present more pronounced changes in the immune system with age, with an increase in inflammatory immune cells. This finding could help explain why autoimmune diseases are mainly developed by women, especially at advanced ages, as well as the worsening of certain inflammatory pathologies after menopause. On the other hand, the changes associated with immune system aging observed in men are globally less extensive, but an increase in certain blood cells presenting pre-leukemia alterations was observed, a fact that could explain why some blood cancers are more frequent in older men.

Finding these patterns was possible thanks to the analysis of blood samples from nearly 1,000 people of different ages covering the entire adult life, combined with a technology capable of analyzing each cell individually, called single-cell RNA sequencing. In total, the researchers analyzed the activity of 20,000 genes in more than one million blood cells, which allowed them to identify how the immune system changes over the years and detect clear differences between sexes.

Link: https://www.bsc.es/news/bsc-news/new-bsc-study-reveals-the-first-time-the-female-immune-system-changes-much-more-men-age

Cells have evolved responses to stress that enhance the chance of survival. Many of these responses converge of increased activity of maintenance processes, more recycling of materials, less protein synthesis, and a number of other common mechanisms. Researchers have found that mild stress of near any sort imposed upon a living organism will provoke a net gain in cell function and resilience, which in turn acts to modestly slow progression of the complicated cascade of accumulating damage and dysfunction that we call aging. The bounds of the possible are illustrated by the response to the nutrient stress, induced by fasting or calorie restriction. Short-lived mammalian species such as mice can live as much as 40% longer in response to a restricted but still sufficient nutrient intake. Longer-lived mammals certainly do not exhibit such a large plasticity of life span, even though calorie restriction and fasting appear to be quite beneficial in the short term.

There is no dramatically powerful rejuvenation therapy hiding in the mechanisms of calorie restriction, heat stress, cold stress, and so forth. Nonetheless, a sizable fraction (and perhaps even the majority) of research programs aimed at treating aging as a medical condition are focused on manipulation of stress responses. Today's open access paper is an example of the type. In this case, the stress takes the form of mild mitochondrial dysfunction, encouraging the cell to take steps to defend itself. The hundreds of mitochondria present in every cell manufacture adenosine triphosphate (ATP), a vital chemical energy store molecule. They also generate stress-inducing reactive oxygen species as a byproduct of this activity. When mitochondrial become dysfunctional, oxidative molecule production increases and ATP production diminishes. Our cells have evolved to treat this as a call to action: they increase efforts to clear out underperforming mitochondria, produce more antioxidants, and increase other maintenance activities. When mitochondrial dysfunction is mild, the result is an overall benefit.

Targeting Mitochondrial Stress Responses: Terbinafine and Miglustat as Novel Lifespan and Healthspan Modulators

Age-related diseases share numerous biological impairments. Among these, mitochondrial dysfunction has emerged as a key driver of aging and disease progression. Mitochondria are essential organelles participating in numerous cellular functions, including energy harvesting, biogenesis, regulation of homeostasis and apoptosis. Changes in mitochondrial integrity not only impact cellular metabolism but also critically influence whole-body metabolism, health, and lifespan. Consequently, mitochondrial-targeted therapies have gained significant attention for treating metabolic and age-related conditions.

One promising approach is the pharmacological induction of the mitochondrial stress response (MSR), an adaptive pathway that restores proteostasis and promotes resilience to stress. While severe mitochondrial dysfunction is detrimental, mild mitochondrial stress can extend lifespan and delay age-related decline, a phenomenon known as mitohormesis. MSR-inducing compounds have shown potential in mitigating age-related decline and improving outcomes in various conditions.

A key component of the MSR is the mitochondrial unfolded protein response (UPRmt), which coordinates cellular responses to mitochondrial stress and maintains mitochondrial proteostasis. In C. elegans, the UPRmt is initiated by misfolded proteins, leading to the activation of the transcription factor associated with stress 1 (ATFS-1), which induces chaperones, proteases, and metabolic regulators to re-establish mitochondrial homeostasis. Similar mechanisms are observed in mammals, where ATF4 and ATF5 mediate mitochondrial stress responses. Notably, mild mitochondrial perturbations, including mitochondrial ribosomal protein knockdown or antibiotic treatment, like doxycycline, can activate the UPRmt and extend lifespan in C. elegans and other species.

Despite progress in aging research, few pharmacological agents robustly activate the MSR without adverse effects. While antibiotics like doxycycline robustly induce the UPRmt, their antibacterial activity disrupts the microbiome and contributes to antibiotic resistance, limiting their therapeutic potential. Thus, identifying mitochondrial stress inducers without antibacterial properties is crucial.

Here, we screened 770 FDA-approved drugs to identify novel MSR activators. Using C. elegans, we identified terbinafine and miglustat as mitochondrial stress modulators that extend lifespan and healthspan without antibacterial activity. Mechanistically, both compounds activate the UPRmt and engage DAF-16-dependent insulin/IGF-1 signaling, distinct from its canonical activation, revealing a coordinated stress adaptation program. Importantly, terbinafine and miglustat also induce mitochondrial stress responses in human cells, supporting their translational relevance and highlighting new opportunities to target mitochondrial dysfunction in aging.

IGF-1 signaling is perhaps the most well studied mechanism of aging, with extensive work predating the modern enthusiasm for treating aging as a medical condition. Investigation of IGF-1 signaling in the context of aging was a fellow traveler to investigations of calorie restriction in the context of aging, and while these are roads that lead to a greater understanding of the evolution of aging and how pace of aging adapts to environmental circumstances, and have given rise to classes of drugs that may modestly slow aging, they are not likely to lead to any meaningful class of rejuvenation therapy. From a purely scientific point of view, the incomplete state of understanding of cellular biochemistry means that there is a lot left to learn on the topic of how aging progresses and shifts in response to circumstances, and how different systems and mechanisms interact with one another. Surprises remain to be discovered, though once again it seems unlikely that any of the surprises relating to IGF-1 signaling will be capable of giving rise to meaningful rejuvenation therapies.

One strategy to elucidate the relationships between the hallmarks of aging is to investigate how the disruption of one hallmark affects the trajectory of another. In doing so, it may be possible to assess whether these processes act independently, synergistically, or in opposition of each other as they shape human life span. In addition, this strategy may reveal if a hierarchy exists between aging pathways, which could lead to a more integrated and causally ordered model of the aging process. In this study, we apply this strategy to investigate the relationship between two critical drivers of the aging process, mitochondrial mutagenesis and insulin-like growth factor-1 (IGF-1) signaling.

A large body of evidence supports the idea that instability of the mitochondrial genome (i.e., changes in nucleotide sequence, copy number, and organization due to replication errors and DNA damage) leads to a progressive decline in mitochondrial function, which accelerates the natural aging process and contributes to a wide variety of age-related diseases, including sarcopenia, neurodegeneration, and heart failure. A similar body of work describes the role of IGF-1 signaling in the aging process. IGF-1 regulates the growth and metabolism of human tissues, and reduced IGF-1 signaling can not only extend mammalian life span but also confer resistance against various age-related diseases, including neurodegeneration, metabolic decline, and cardiovascular disease. However, how mitochondrial mutagenesis and IGF-1 signaling interact with each other to shape mammalian life span remains unclear.

Unexpectedly, we found that reduced IGF-1 signaling fails to extend the life span of mitochondrial mutator mice. Most of the longevity pathways that are normally initiated by IGF-1 suppression were either blocked or blunted in the mutator mice. These observations suggest that the prolongevity effects of IGF-1 suppression critically depend on the integrity of the mitochondrial genome, revealing an unexpected hierarchy in the pathways that control mammalian aging. Together, these findings deepen our understanding of the interactions between the hallmarks of aging and underscore the need for interventions that preserve the integrity of the mitochondrial genome.

Link: https://doi.org/10.1126/sciadv.aea4279

It is a struggle to derive evidence for causation from human data. It is well established that physical fitness correlates with a lower risk of age-related disease and mortality in humans, and well established that greater physical fitness causes a lower risk of age-related disease and mortality in animal studies. But as a practical matter one can't run the sort of study that would be needed to obtain direct proof of causation in humans. So researchers turn to approaches such as Mendelian randomization, in which one adds an additional set of genetic correlations in order to try to infer at least some support for causation. There are indeed genetic correlations with a tendency to greater physical fitness, and those do correlate in turn with risk of age-related disease and mortality.

We investigated potentially causal associations between genetically predicted aerobic fitness and multiple health phenotypes using a two-stage phenome-wide Mendelian randomization (MR) study. We screened 712 health-related phenotypes as outcomes using publicly available European-ancestry genome-wide association study (GWAS) summary statistics from OpenGWAS (Discovery GWAS n > 5,000), prioritizing non-UK Biobank/non-FinnGen datasets for Discovery when available and selecting an independent GWAS for Validation.

We identified 108 Discovery associations, of which 34 remained valid and statistically significant after Validation. Higher genetically determined aerobic fitness was associated with lower lacunar stroke risk, lower arterial stiffness, higher heart rate variability, lower diastolic blood pressure, more favorable anthropometric measures, lower use of antidiabetic drugs, lower asthma risk, lower C-reactive protein, higher bone mineral density, favorable liver function biomarkers, favorable platelet-related traits, multiple blood-count-derived hematological cell indices and counts, as well as higher years of schooling. Adverse associations were confined to atrial fibrillation, valvular heart disease, and systolic blood pressure.

Genetically determined aerobic fitness is linked to a broad pattern of favorable cardiometabolic, inflammatory, musculoskeletal, respiratory, hepatic, and hematological phenotypes, alongside a narrow set of potential cardiovascular hazards.

Link: https://doi.org/10.1249/MSS.0000000000003975

The tau protein is involved in maintaining stability of microtubule structures in the axons that connect neurons. It isn't the only protein that undertakes this task, and loss of functional tau doesn't produce immediate issues. Tau is important in some functions of memory, however, and mice lacking tau exhibit a range of cognitive defects that grow with age. Tau is well studied not for these aspects of its function, but because it is one of the few proteins that can be altered in a way that allows it to form solid aggregates that are disruptive to cell function. Tau aggregation to form the structures known as neurofibrillary tangles is a feature of late stage Alzheimer's disease. The consensus view of this stage of the condition is that tau aggregation and chronic inflammation form a feedback loop that accelerates dysfunction into widespread cell death in the brain.

The progression of Alzheimer's disease provides the appearance of a spread of tau aggregation from region to region in the brain. Study of the brain is challenging, however, and while there is a consensus on this point - that altered forms of tau can seed more dysfunction in a prion-like way and spread from cell to cell via synapses - there are other potential explanations for the observed outcomes. For example tau aggregation could be universal in the brain, but some regions are more vulnerable to the aggregation processes than others, and therefore exhibit a greater burden of neurofibrillary tangles earlier in the progression of the condition. Today's open access paper is an example of the way in which researchers must strive to circumvent the inability to directly access a large number of living human brains at various stages of Alzheimer's disease. Instead, the researchers synthesize a number of indirect approaches - models, genetics, postmortem tissues, and imaging data - to produce supporting evidence for the consensus view of a synaptic spread of tau aggregation.

Tau seeds induce neurofibrillary tangle formation across brain regions via individual-specific connectivity

Tau protein promotes assembly and stabilization of microtubules. In normal aging and Alzheimer's disease (AD), tau can become hyperphosphorylated, which reduces its affinity for microtubules and drives its mislocalization from axons to the body of the neuron and dendrites. Aberrant tau accumulation in the form of neurofibrillary tangles (NFTs) is a strong pathological correlate of cognitive decline. Based on postmortem human brain studies, the spatiotemporal progression of NFTs begins in layers II and III of the entorhinal cortex (EC), extends to the hippocampus and temporal cortex, entering the limbic system before reaching broader neocortical regions, which subsequent tau positron emission tomography (PET) studies confirmed in vivo. When tau is confined to the medial temporal lobe, patients typically experience memory problems, but once tau enters the neocortex, broader cognitive impairment often emerges.

The mechanisms underlying tau spread are unclear, but may rely on a process, referred to as tau seeding, in which abnormal forms of tau protein induce misfolding and aggregation of normal tau proteins in a template-dependent manner. Prior studies using cell cultures, mouse models, and human neuroimaging have each explored certain facets of tau pathology progression. However, whether endogenous tau seeds are the entities that induce NFTs across the aging human brain via naturally occurring connectivity remains to be confirmed. An alternative hypothesis that accounts for the observed NFT distribution is a gradient in region vulnerability, which does not involve tau seeds spreading from early-affected regions.

To investigate this question, we measured tau seed bioactivity data in synaptosomes from postmortem inferior temporal gyrus (ITG) and superior frontal gyrus (SFG) tissues of 128 individuals and combined this data with genotype and antemortem fMRI measurements from the same individuals. Via multimodal integration of these data, we provided supporting evidence that tau seeds from an early-affected brain region induce local NFTs as well as drive tau seeds and NFTs in a late-affected, far-removed region. Also, extending past tau-PET studies that demonstrated spatial correspondence between tau deposition and connectivity patterns, we further showed that individual-specific intrinsic connectivity modulates tau seed-NFT relationships. Our results thus support the hypothesis that tau seeds use synaptic connections to spread tau across connected regions in the human brain.

Dysfunction in the cells making up the inner lining of blood vessels, the vascular endothelium, is thought to be an important first step in the aging of the vasculature more generally, setting the stage for the development of atherosclerotic lesions, a declining capacity of smooth muscle to contract and dilate vessels in order to control blood pressure, and leakage of the blood-brain barrier, among other issues. Researchers here review the contribution of two important aspects of cellular aging to the aging of the vascular endothelium; firstly the growing number of senescent cells, and secondly the decline in mitochondrial function. These are connected, as mitochondrial dysfunction is considered to contribute to an increased pace at which cells become senescent.

The vascular endothelium performs numerous regulatory functions that impact inflammatory responses, thrombosis, vascular tone, and angiogenesis. Endothelial dysfunction is a key contributor to the pathogenesis of various human diseases, either as a primary trigger or as a consequence of organ damage. This review examines how ageing reshapes endothelial cell metabolism and mitochondrial function, progressively undermining endothelial homeostasis and resilience.

Age-related endothelial alterations, including reduced nitric oxide bioavailability, heightened oxidative stress, impaired vasodilatory capacity and pro-inflammatory activation, arise from coordinated shifts in energy production, substrate utilization and redox signaling. In this context, cellular senescence, a stable arrest of the cell cycle accompanied by distinct metabolic, secretory, and inflammatory changes, appears to be an important response to cumulative metabolic and mitochondrial stress. Senescent endothelial cells not only reflect this stress burden but also actively propagate dysfunction through sustained pro-inflammatory and pro-oxidant signalling, thereby accelerating vascular ageing. We highlight the central role of mitochondria in these events. Age-associated mitochondrial dysfunction disrupts bioenergetics, enhances reactive oxygen species generation, and fuels chronic low-grade inflammation, amplifying endothelial decline.

By bringing together current evidence-based knowledge on endothelial cell bioenergetics, mitochondrial impairment, and metabolic reprogramming, this review identifies mitochondria-driven metabolic deterioration as a key mechanism underlying endothelial ageing and underscores mitochondrial metabolism as a promising, yet underexploited, therapeutic target in age-related vascular dysfunction.

Link: https://doi.org/10.1016/j.arr.2026.103119

The extremely high cost of obtaining clinical approval for a new drug incentivizes the research and development communities to focus on finding new uses for existing drugs in place of the rational design of new drugs. This likely contributes to a reduced quality of therapies; we live in a world in which the creation of marginally effective drugs is favored over the search for better drugs because it is cheaper to find marginally effective drugs. One of the few drug repurposing exercises that is producing interesting results is the search for senotherapeutic therapies among drugs approved for the treatment of various cancers, as many of these drugs have positive effects on cancer precisely because they selectively destroy or otherwise suppress the inflammatory signaling of senescent cells, but were developed prior to an understanding of the importance of this mechanism.

The accumulation of senescent cells in white adipose tissue (WAT) is closely associated with the functional decline of WAT and plays a causal role in the pathogenesis of metabolic diseases. Therefore, the elimination of senescent cells in WAT holds promise for the treatment and prevention of age-related metabolic diseases. Using a drug-repositioning strategy for 2,150 clinically applied compounds, we discover that homoharringtonine (HHT), an FDA-approved anti-leukemic drug, manifests senotherapeutic activity in vitro in multiple cell types including human preadipocytes, while inflicting minimal cytotoxicity to non-senescent cells.

HHT treatment prevents diet- or age-induced metabolic abnormalities in male mice targeting senescent adipocytes and preadipocytes to improve WAT function and reduce WAT inflammation. Moreover, HHT treatment attenuates age-associated phenotypes of human adipose tissue. Mechanistically, the senotherapeutic effects of HHT are mediated through the direct interaction of HHT with heat shock protein family A member 5 (HSPA5). Importantly, we found that HHT treatment delays aging and extends the lifespan in progeroid and aged mice. Our study demonstrates the novel senotherapeutic potential of HHT to mitigate age- and obesity-related metabolic dysfunction and extend longevity in mice.

Link: https://doi.org/10.1038/s41467-026-70475-3

Control over the structure of nuclear DNA is critical to both gene expression and interactions between DNA damage and DNA repair systems. Most of us are by now at least passingly familiar with the concept of the chromosomes of nuclear DNA existing as a mix of (a) spooled and tightly packaged regions known as heterochromatin, where gene sequences are hidden from transcriptional machinery and genes are thus not expressed, versus (b) unspooled regions where transcription can take place, the gene sequences read to allow assembly of corresponding RNA molecules. Epigenetic decorations to DNA and supporting molecules drive a constant shift between spooled and unspooled structures. This necessary regulation of structure and function all changes for the worse with advancing age for reasons that are incompletely understood.

There is a lot more to DNA structure than just this, however. For example, the intricate regulation of nuclear DNA structure incorporates the presence of double-strand breaks known as DNA gaps, distinct from the harmful DNA double strand breaks that occur as a form of damage. These DNA gaps are thought to reduce potentially damage-inducing stress forces, but this may or may not be their primary function. Researchers have observed that the number of these DNA gaps declines with age, and have speculated that this change may produce harm. In today's open access paper, researchers provide fairly direct evidence for this proposition via use of a gene therapy that directly induces DNA gap formation in aged non-human primates. The researchers observe a range of improvements in biomarkers of health following treatment, suggesting that more DNA gaps leads to improved cell and tissue function; all in all, quite an interesting outcome.

Box A of HMGB1 plasmid reverses the age-related changes in the plasma proteomic profile of perimenopausal monkeys

A characteristic feature of aging is the accumulation of DNA damage, which plays a significant role in the deterioration of cellular function. The sustained destruction of DNA and the subsequent activation or failure of the DNA-damage response (DDR) are pivotal in the aging process, often leading to detrimental cellular outcomes such as senescence, apoptosis, and telomere shortening. Maintaining DNA integrity is crucial for cell viability. One mechanism employed by cells to ensure this integrity involves the dynamic regulation of DNA structures, often observed as DNA gaps, known as youth-DNA-gaps. These gaps are believed to minimize mechanical stress and torsion forces within the DNA structure, thereby protecting it from damage. Interestingly, the number of these physiological DNA gaps typically is reduced in yeast, rats, and human cells as they age, as well as in chemically-induced senescent cells.

High Mobility Group Box 1 (HMGB1) protein has emerged as a key molecule involved in various biological processes highly relevant to aging, including inflammation, DNA repair, and cell senescence. The Box A domain of HMGB1 is a highly conserved DNA-binding domain crucial for modulating HMGB1's biological functions. Box A is known to bind DNA and interact with other proteins, acting as a molecular regulator that influences the formation of DNA gaps to enhance DNA integrity and protection. Growing evidence suggests that Box A-induced DNA gaps may reverse aging characteristics in vivo and in vitro, having been shown to inhibit liver fibrosis and improve aging brain functions in aged rat models. Furthermore, Box A can enhance stemness, suggesting a role in improving stem cell activity compromised by illness and aging.

This study investigates the potential role of the Box A domain HMGB1 in modulating age-related changes. We utilized a label-free quantitative proteomic technique to analyze the plasma proteome of three female adult and eight female perimenopausal cynomolgus macaques (Macaca fascicularis), with the perimenopausal group receiving an intravenous administration of the Box A plasmid. Proteomic analysis revealed differential expressions in proteins primarily associated with stress response, immune regulation, lipid transport, and cellular homeostasis following Box A plasmid intervention. Notably, the expression levels of key proteins, such as apolipoprotein E (APOE) and sex hormone-binding globulin (SHBG), showed a reversal effect, restoring levels closer to those observed in the younger, adult monkeys. These findings highlight the potential of the Box A of HMGB1 plasmid as a therapeutic candidate to mitigate age-related proteomic alterations, offering a novel avenue for targeted interventions in aging and associated diseases.

The burden of lingering senescent cells grows with age in tissues throughout the body. Cells enter the senescent state constantly, but the pace of clearance of senescent cells by the immune system falters with advancing age. Senescent cells secrete a mix of pro-inflammatory, pro-growth signals that are disruptive to tissue structure and function when sustained for the long term. Analysis of circulating molecules in a blood sample can in principle be used to measure the body-wide burden of senescent cells, though no strong consensus approach has emerged yet from the various methods demonstrated in recent years. Here, find another contender for that consensus approach, where researchers use proteomic assessment of blood samples to build a score based on the strength of senescent cell signaling, and find that this score correlates with mortality risk.

The accumulation of senescent cells is a recognized hallmark of biological aging and is associated with the onset of multiple chronic medical conditions. Senescent cells exhibit a distinct secretory profile, known as the senescence-associated secretory phenotype (SASP), which can propagate cellular senescence to neighboring and distant tissues. Measuring SASP factors in blood serves as a practical proxy for cellular senescence burden and may help track disease states and intervention outcomes.

We developed and validated a composite SASP Score by integrating large-scale population proteomics data with a semi-supervised deep learning framework. The analytical workflow included: (1) selection of biologically curated SASP proteins; (2) development of a Guided autoencoder with Transformer (GAET) model using data from the UK Biobank Pharma Proteomics Project (UKB-PPP); (3) internal evaluation and association analyses within the UK Biobank; and (4) external validation and longitudinal assessment in an independent randomized clinical trial cohort.

The deep learning-based SASP Score was a strong, independent predictor of mortality risk and incident serious, chronic medical conditions (e.g., dementia, COPD, myocardial infarction, stroke). In an independent cohort, multimodal exercise significantly changed the SASP Score trajectory over 18 months.

Link: https://doi.org/10.64898/2026.03.20.26348913

Excessive, constant inflammation in response to aspects of one's own cellular biochemistry is a feature of both autoimmune disease and aging. While transient inflammation is necessary for effective regeneration and defense against pathogens, constant unresolved inflammatory signaling is destructive to tissue structure and function. It is a major component of the pathology of common age-related conditions. The challenge in addressing this is that unwanted inflammation and desirable inflammation both involve the same molecular signals and points of control. To date, therapies that reduce chronic inflammation do so via crude blockade of signals or mechanisms, with the side effect of reduced immune capability, a reduction in the normal immune response when it is needed. The research community is slowly making progress towards finding points of distinction, however, approaches to intervention that have greater effects on unwanted inflammation than they do on the normal immune response. One such line of work is noted here, focused on autoimmunity.

Current autoimmune disease treatments like hydroxychloroquine work by broadly blocking endosomes, the compartments inside cells where incoming materials are sorted and processed, including molecules that trigger immune responses. While effective, this approach can lead to significant side effects - including gastrointestinal problems and, less commonly, vision damage-causing a significant number of patients to stop treatment.

Researchers focused on two proteins, Munc13-4 and syntaxin 7, that must bind together for immune sensors called Toll-like receptors (TLRs) to activate inside endosomes. This "molecular handshake" plays a key role in detecting the foreign DNA and RNA from invaders like viruses and bacteria. However, in autoimmune diseases, TLRs become overactive, detecting self-nucleic acids, for example, from neutrophil-extracellular traps, and trigger chronic, damaging inflammation even without a real threat.

The team screened roughly 32,000 compounds and identified molecules that specifically block the Munc13-4-syntaxin 7 interaction without disrupting other cellular functions. Because Munc13-4 is found mainly in immune cells, the compounds offer a targeted way to calm inflammation. "Most treatments for autoimmune diseases manage symptoms; they don't change the underlying course of the disease. What's exciting about this approach is its potential to be disease-modifying: targeting the specific molecular machinery that drives inflammation, rather than broadly suppressing the immune system."

The most potent compound, ENDO12, reduced inflammation in animal models that were also given a TLR-activating molecule. Blood levels of inflammatory markers - including immune system activators IL-6 and IFN-γ, and the enzyme myeloperoxidase - dropped significantly in those that were treated. Crucially, ENDO12 did not impair the animal models' ability to fight a real viral infection: they showed a normal antiviral immune response when exposed to a virus. This selectivity addresses a major concern with immunosuppressive drugs: that dampening inflammation might leave patients vulnerable to infections.

Link: https://www.scripps.edu/news-and-events/press-room/2026/20260406-catz-endotollins.html

A sizable body of evidence indicates that transposons contribute to degenerative aging. Transposons of various categories are DNA sequences that code for molecular machinery capable of writing copies of the original DNA into other locations in the genome. They are largely the remnants of ancient retroviral infections, altered and degraded over evolutionary time, while likely remaining an important mechanism of mutational change for future evolution. Transposons are suppressed in youth, the nuclear DNA sequences spooled and hidden from transcriptional machinery, but one of the noteworthy aspects of aging is a loss of epigenetic control over nuclear DNA structure and thus over gene expression. Stretches of DNA containing transposons unspool and become accessible to transcriptional machinery. Transposon expression produces molecules that are sufficiently virus-like for evolved defenses to react with inflammatory signaling, while the haphazard insertion of transposon sequences is a form of DNA damage, breaking genes.

Just like retroviruses, retrotransposons require reverse transcription to function. That part of the research and development community focused on HIV, human immunodeficiency virus, has spent decades developing ever better means of sabotaging reverse transcription. In today's open access paper, researchers report on their investigation of the effects of such antiretroviral drugs on measures of biological age. The researchers made use of data and samples originating from pharmacokinetic clinical studies of combinations of antiretroviral drugs in healthy volunteers. One combination of drugs did reduce measures of biological age, while the other did not. This suggests that there is indeed something interesting here, but that the fine details matter when it comes to the implementation of transposon suppression.

An FDA-Approved Tenofovir Alafenamide-Based Antiretroviral Therapy Reduces Biological Age in Healthy Adults: First Human Proof-of-Concept for Retrotransposon-Targeted Gerotherapeutics

Nearly half of the human genome (∼45%) is composed of transposable elements (TEs). Aging is accompanied by a progressive erosion of epigenetic silencing that permits the transcriptional reactivation of these TEs, particularly retrotransposons such as LINE-1 and endogenous retroviruses. In young somatic cells, these elements are maintained in a transcriptionally inert state by DNA methylation, heterochromatin, and KRAB-ZFP/KAP1 surveillance. However, with age the fidelity of these mechanisms declines, and retrotransposon-derived transcripts and cytoplasmic DNA accumulate. This age-dependent retroelement reactivation is now recognized as a proximal driver of biological aging hallmarks including a senescence-associated secretory phenotype (SASP) and age-related tissue dysfunction.

The dependence of retroelements on reverse transcription has made nucleoside reverse transcriptase inhibitors (NRTIs), which were developed and licensed for HIV treatment and prevention, attractive candidate gerotherapeutics. For instance, a retrospective analysis of longitudinal aging intervention studies identified antiretroviral therapy as one of the most consistent interventions associated with reductions across 16 epigenetic clocks. Early mechanistic work showed that multiple NRTIs including 3TC (lamivudine), tenofovir disoproxil fumarate (TDF), stavudine, and zidovudine can directly suppress human LINE-1 retrotransposition in cell-based reporter systems. Consistent with this, 3TC (lamivudine) blunted LINE-1 cDNA-triggered type I interferon signaling and components of the SASP in senescent human cells and reduced age-associated inflammatory signatures across multiple tissues in aged mice.

Here we evaluated DNA methylation-based measures of biological aging in healthy people without HIV (aged 18-50) using samples from two separate randomized, directly observed dosing pharmacokinetic studies of FDA-approved NRTI regimens containing emtricitabine / tenofovir-alafenamide (FTC/TAF; 200 mg/25 mg) or FTC / tenofovir-disoproxil fumarate (FTC/TDF; 200 mg/300 mg) for 12 weeks.

In the FTC/TAF study (N=36), epigenetic aging measures based on DNA methylation (DNAm) profiling decreased over follow-up, including DunedinPACE (-0.061) and PhenoAge (-6.33), with concordant reductions across additional systems-specific epigenetic clocks including those estimating brain aging. DNAm-based proxies of inflammatory biomarkers also declined, with significant reductions in epigenetic IL-6 (-0.058) and a trend toward reduced C-reactive protein (-0.231). In contrast, the FTC/TDF study (N=43) showed no significant changes across epigenetic clocks and proxies. These findings are consistent with TAF's more favorable cellular pharmacology compared with TDF and support gerotherapeutic effects of FTC/TAF.

Prospective placebo-controlled studies are warranted that integrate clinical pharmacology, direct transposable element readouts, and prespecified geroscience and DNA methylation-based aging endpoints.

There are apparently a great many people who at least intermittently use psilocybin. Interestingly, regular dosing with psilocybin has been shown to modestly extend life in mice, but it is likely that only a subset of human users approach the frequency of dosing used in the mouse studies. Finding those humans is ever the challenge, particularly if one wants to study long-term effects on aging. Here, a researcher takes an initial stab at comparing the longevity of psilocybin users with non-users based on publicly available information, but the sample size is so small that it isn't surprising to see a lack of useful results. The study is more interesting as a way to provoke (a) awareness of the evidence for psilocybin to interact with mechanisms of aging, and (b) some thought on what sort of study design would be both practical and useful.

Researchers have reported that psilocybin promotes resilience and extends lifespan in aged mice. This work garnered considerable media attention, with claims that psychedelics might also extend human lifespan. Psychedelics influence longevity-related pathways in rodents such as glucocorticoid receptor signaling and mitochondrial stress tolerance. In light of these findings and in search of some evidence that psychedelics can indeed extend human lifespan, we examined historical mortality patterns of psychedelic personalities (researchers and advocates who had documented, mostly self-claimed, psychedelic use) and compared this group to biomedical researchers (cancer and aging).

Using publicly available records, we identified individuals who died between 2010 and 2025: (i) psychedelic personalities with documented personal use (n = 11), (ii) cancer researchers (n = 12), and (iii) aging researchers (n = 5). Deaths before age 60 were excluded. Conditional life expectancy at age 40 for their birth cohorts (≈73-76 years, US/UK data) was used as a baseline. All three groups lived well beyond population averages, consistent with the survival advantage of highly educated professionals. Crucially, the psychedelic personalities did not outlive their biomedical peers.

Thus, while researchers have provided compelling mechanistic data in mice, translation to humans requires dose-specific and longitudinal studies to identify whether psychedelics such as psilocybin do indeed have some role in extending lifespan.

Link: https://doi.org/10.1038/s41514-026-00380-y

It is well established that females and males in mammalian (and many other) species exhibit meaningfully different trajectories of health and mortality in later life. It is also well established, at least in mice, that many of the interventions demonstrated to modestly slow aging have meaningfully different outcomes in males versus females. The question of why these differences exist has no satisfactory answer at the present time, however. There are a great many theories and potential contributions, but no data that concretely establishes the important mechanisms and relative sizes of these contributions to the overall effect.

The burden of aging is not shared equally between the sexes, as lifespan and healthspan differ between males and females. Lifespan, the length of time in which an organism is alive, is related to but distinct from healthspan, which is the length of time an organism is free of disease and disability. Women live longer than men in most countries, but women also experience more disease and disability than men.

While scientists seek interventions to increase both healthspan and lifespan, considering sex as a biological variable is imperative to ensure treatments will work optimally in both men and women, or to develop sex-specific interventions. Here, we review dietary, genetic, environmental, behavioral, and pharmacological interventions that increase lifespan in a sexually dimorphic manner in laboratory rodents, including the mouse which is the is most widely used mammalian model system in the aging field.

While sex differences in life history traits have long been of interest to evolutionary biologists, a cellular and molecular understanding of how these traits influence lifespan remains understudied. Starting from fertilization, differences in chromosome complement and hormone levels drive further morphological and behavioral differences. Crucial aspects of female biology, including the role of X chromosome regulation, the role of gonadal hormones, and the role of ovarian health, remain understudied in the context of aging interventions. Whether differences in response to interventions is due sex-specific differences in baseline lifespan, or differences in sexually dimorphic characteristics such as body size, adiposity, metabolism, or even gonadal hormone or chromosome status remains unknown.

Link: https://doi.org/10.1016/j.arr.2026.103123