Fight Aging!

Human life expectancy has increased steadily over time since the 1800s, but much of the analysis is focused on life expectancy at birth, where the dominant effects involve improvements in early life survival. More interesting are the measures of remaining life expectancy at some adult age. These measures also increase over time, but more slowly. In recent decades, the increase in life expectancy at age 65 has increased at a pace that is on the order of one year in every ten. Since this happened over a span of time in which little to no meaningful progress was made in deliberately treating aging as a medical condition, it is reasonable to ask how it happened. As is usual in matters of human epidemiology, firm answers are hard to come by. Correlations are easy to generate, but it is challenging to prove causation, or determine the relative importance of different contributions to an observed outcome.

Nonetheless, researchers have generated insight from the statistics of human mortality. For example work from fifteen years ago shows an equal split between (a) reduced premature mortality, compressing mortality to a smaller range of later ages, and (b) a reduction in mortality in those later ages. It is an open question as to whether these are both manifestations of the same underlying mechanisms, resulting from improvements in public health, reduced exposure to severe infection, general advances in medicine, and so forth. If we accumulate less damage along the way, do we also tend to live longer? Reliability theory suggests this is the case, building on what is known of the statistics of the failure of complex arrays of redundant parts.

In one sense a reduced mortality due to intrinsic causes and age-related disease is equivalent to a slower pace of aging, as aging is defined by its effects on mortality. In another sense, whether aging has been slowed depends on how one defines aging - at the level of mechanisms, capacity, and cellular biology rather than at the level of epidemiology and mortality, that is. Today's open access paper is a consideration of whether we can or should say that increased life expectancy means that aging is slowed versus postponed, and that is a distinction that really does force one to engage with how exactly aging is defined. What, mechanistically, is aging, exactly, if the pace of aging does not change, but the age of onset of aging can vary? This is a very different view to that provided by reliability theory.

The rhythm of aging: Stability and drift in the individual rate of senescence

Human aging is marked by a steady rise in the risk of dying with age - a process demographers call senescence. Over the past century, life expectancy has risen dramatically, but is this because we are aging slower, or simply starting it later? This has been framed as a testable hypothesis: the rate at which the risk of dying increases with age for humans may be a basic biological constant that is very similar and perhaps invariant across individuals and over time. From this perspective, gains in life expectancy would reflect delayed aging, not a change in the underlying process of senescence. But if the rate of aging is truly changing, it would suggest that the biological processes underlying senescence are more responsive to environmental, behavioral, or historical conditions than previously assumed.

We focus on actuarial senescence - the age-related rise in mortality risk - which, in most adult populations, shows an exponential increase in mortality with age, well described by the Gompertz law. The Gompertz slope measures how quickly risk accelerates as deterioration accumulates. Though not a direct biological measure, is widely used as a proxy for the rate of aging. Empirical tests of this hypothesis have yielded mixed findings. This may suggest that the variations in could be historically driven. Period events - such as wars, pandemics, and economic crises - strike multiple cohorts at once, just at different ages, and their lasting consequences can subtly distort the mortality patterns within each exposed cohort through cumulative shifts. As a consequence, when we estimate cohort by cohort, we may be tracing not a pure signal of the aging process, but the lasting effects of these shared historical events. As these shocks accumulate over time, they can produce variations that mimic a change in the slope of mortality, even if the underlying biological rate is constant.

We ask whether cohort-to-cohort variation in the Gompertz slope reflects a shift in the pace of aging or the effects of period shocks. We test this idea using a framework that decomposes the pace of senescence into three components: a biological baseline, a long-term trend, and the cumulative impact of period shocks. Applying this to cohort mortality data above age 80 from 12 countries, we find that once period shocks are accounted for, there is no statistical evidence of a long-term trend, consistent with the hypothesis. Analyses using lower starting ages yield the same qualitative conclusion. Rather than indicating a change in the process that drives senescence, these variations are consistent with echoes of shared historical events. Together, these findings indicate no evidence of a persistent directional change in the individual rate of aging.

This stability does not imply that aging is fixed in all aspects. Over the past century, survival has shifted toward older ages and life expectancy has increased substantially. These improvements may primarily reflect declines in baseline and background mortality rather than persistent changes in the rate at which mortality rises with age. In demographic terms, the onset of senescence may be postponed even if its tempo remains stable.

The aging and longevity of flies is very dependent on intestinal function. The noted longevity-associated gene INDY acts on intestinal function, for example. Here, researchers report on their investigation of the role of the gut microbiome in INDY-related longevity in flies. As might be expected given the present state of knowledge of the role of the gut microbe in long-term health and aging, there are signs of a contribution. These results are only a first step, however; the gut microbiome is a complex array of different microbial species, and there is a great deal more that might be catalogued in terms of its relationship to genetic associations with longevity in this species.

Reduction in the Indy (I'm not dead yet) gene, a plasma membrane citrate transporter, in Drosophila and its homolog in worms extends lifespan by promoting metabolic homeostasis. Indy reduction delays the onset of aging-associated pathology in the fly midgut, including preservation of intestinal barrier integrity and intestinal stem cell homeostasis. Gut microbiota has broad impacts on host metabolism, health, and aging. Age-related dysbiosis impairs intestinal barrier function and drives mortality. However, the underlying mechanisms that link increased microbial load to frailty and negative effects on health remain mostly unclear.

Here we show that Indy heterozygote flies have significantly lower bacterial load and increased diversity during aging compared to controls. However, the presence of the microbiome was not required for Indy lifespan extension, though removal of microbes did enhance the effects of Indy reduction on longevity, suggesting potential interactions between the microbiome and Indy. Indy down-regulation was linked to reduced expression of the JAK/STAT signaling ligands Upd3 and Upd2 in the midgut of young flies, which likely contributes to preserved intestinal stem cell homeostasis. Altogether, our results suggest that Indy reduction impacts microbiome load and composition, which preserves gut homeostasis and extends lifespan through impacts on JAK/STAT signaling pathway.

Link: https://doi.org/10.64898/2026.03.25.714291

PEPITEM is a circulating peptide involved in resolution of inflammation and reduction of chronic inflammation. Levels of PEPITEM decline with age, which is one of the reasons why inflammatory athritis becomes worse with age, in that this inhibitory mechanism declines in effectiveness. Studies in animal models have shown that injection of synthetic PEPITEM can improve symptoms; an example of this sort of work is noted here.

Inflammatory arthritis is a group of diseases, including rheumatoid arthritis (RA) and psoriatic arthritis (PsA), where the immune system attacks the joints, causing severe joint damage, pain, and disability. Under normal conditions, adiponectin in the bloodstream stimulates white blood cells to produce PEPITEM, which in turn reduces white blood cell migration in the tissues, preventing an unregulated inflammatory response. However, in inflammatory arthritis, white blood cells fail to respond to adiponectin, and secrete less PEPITEM in the joint. The natural 'break' that prevents white cell migration into the joint cavity is lost, and the inflammatory response becomes unregulated.

The initial study of peripheral blood mononuclear cells (PBMCs, white blood cells) harvested from treatment-naïve human donors with suspected inflammatory arthritis showed a reduced capacity to respond to adiponectin, which could be restored by the addition of PEPITEM. Further examination of whole blood indicated a lower bioavailability of PEPITEM in patients with early RA, leading the researchers to hypothesise that supplementation with PEPITEM could restore immune regulation and reduce the inflammatory changes seen in early-stage disease.

Their work in mouse models of inflammatory arthritis and gouty arthritis showed that injection of synthetic PEPITEM could prevent the onset of inflammatory arthritis, with significant reductions in disease incidence. In addition, joint swelling was reduced by PEPITEM when compared with infliximab - the current standard of care. Tissue studies confirmed that these changes were mirrored in synovial tissue (tissue inside the joints), with significantly less joint inflammation, cartilage damage, and bone erosion observed in PEPITEM treated mice, and significantly fewer white blood cells infiltrating the joints. Molecular studies showed significant down regulation of inflammatory mediators (NF-kB and COX2 protein) within the synovial tissue in PEPITEM-treated mice compared to controls, and a significant increase in the foxp3 transcript, which is crucial for the development of a type of white blood cell that suppresses the immune response, to prevent excessive inflammation and autoimmune disease.

Link: https://www.birmingham.ac.uk/news/2026/pepitem-replacement-therapy-shows-potential-for-early-stage-inflammatory-arthritis

The World Health Organization (WHO) launched intrinsic capacity into the space of ideas relating to the study of aging a decade ago; it is defined as "the composite of all the physical and mental capacities that an individual can draw on." At a more detailed level, intrinsic capacity is envisaged as the sum of motor capacity, sensory capacity, general vitality, psychological wellness, and cognition capacity. What the WHO authors did not specify is how to measure any of this, specifically and in detail.

Putting a fuzzy definition in front of the scientific community is like dangling catnip in front of a bunch of cats, and so now there exist a fair number of proposed approaches for measuring intrinsic capacity that are accompanied by published epidemiological data, but there is little to no consensus as to which of these approaches is the one to move ahead with, and no great ability to compare the data produced via one scientist's intrinsic capacity to data produced via another scientist's intrinsic capacity.

This hasn't stopped a continued flow of new publications in which researchers compare someone's definition of intrinsic capacity to other health data, such as epigenetic age. This may all settle into a consensus at some point, but postponing anything to await that outcome seems unwise. Free-form debates of this nature can last decades. Today's open access paper is another that seeks to build upon the concept of intrinsic capacity and efforts to define it precisely, this time in the direction of animal models of aging. Given that no-one can agree on how intrinsic capacity should be measured in human patients, why not expand that discussion to the animal models that inform the development of new therapies with the potential to slow or reverse aspects of aging?

Could animal models be used to longitudinally track intrinsic capacity during aging?

The World Health Organization (WHO) recently highlighted the importance of promoting healthy aging worldwide, a process characterized by the maximization of functional ability, enabling well-being in older adulthood. This concept inspired the development of the Integrated Care for Older People (ICOPE) program and the Intrinsic Capacity (IC) construct, with the latter serving as core element of ICOPE for clinical use. IC represents the composite of all mental and physical internal attributes of an individual. It is often operationalized through five key domains: cognition, locomotion, vitality, sensory function, and psychological capacity.

Research on IC during aging in humans is growing, being marked by high IC variability. Longitudinal monitoring must be prioritized to capture aging trajectories and identify modifiable risk factors. However, the need for a long-time window spanning decades of human life poses a significant challenge to investigating IC decline over time. In contrast, animal models offer a strategic alternative due to their shorter lifespans compared to humans. For example, the typical lifespan of a mouse is 2-3 years, whereas specific fish models (e.g., killifish) may live only 4-6 months. Thus, leveraging these models for longitudinal IC tracking offers a viable pathway that may expedite the elucidation of IC dynamics and mechanisms during aging.

Preserved functional ability can be objectively assessed through behavioral paradigms in animal studies. By using these measurements in observational or experimental settings, animal models can recapitulate the longitudinal trajectories of IC during aging. To facilitate crosstalk with humans and accurately capture age-related changes in IC, assessment tools should meet specific criteria: they should target the corresponding IC domains in humans, show a decline over time with aging, and exhibit sufficient amplitude to distinguish meaningful functional loss. Here, we discuss how longitudinal IC investigations in mice and fish may advance human research and care during aging. Particular attention will be given to assessing, in experimental models, all IC domains longitudinally, interactions across IC domains, and the definition of a set of potentially informative IC assessments in both mice and fish.

In the search for ways to slow the age-related loss of muscle mass that afflicts every older person, researchers here find that ATF5 is a point of control that regulates a trade-off between muscle mass and muscle quality. Mice lacking functional ATF5 retain muscle mass with age, but muscle quality declines to a greater degree instead. This rules it out as a target for therapy. It is always possible that further investigation of the interactions surrounding ATF5 will lead to insight into how to decouple mass versus quality, but that sort of investigation of biochemical pathways tends to take a very long time.

In skeletal muscle, the mitochondrial network is highly regulated by quality control (MQC) processes including the Integrated Stress Response (ISR) and the mitochondrial Unfolded Protein Response (UPRmt), controlled in part by the transcription factor, Activating Transcription Factor 5 (ATF5). With age, mitochondrial health and function become altered in muscle, but the role of ATF5 in regulating these processes has not yet been evaluated. This study therefore aimed to evaluate the role of ATF5 in mediating mitochondrial quality control and function during aging.

To investigate this, we utilized young (4-6 months) and middle-aged (14-16 months; denoted as aged) ATF5 whole-body knockout (KO) and wild-type (WT) male mice. The normal age-related decline in muscle mass was prevented in the absence of ATF5. This was accompanied by an attenuated rise in important protein degradation regulators, indicating that ATF5 regulates muscle protein turnover with age. Aged ATF5 KO muscle exhibited greater muscle fatiguability than WT counterparts, accompanied by accelerated mitochondrial reactive oxygen species production. The expression of the co-regulatory ISR/UPRmt transcription factors, CHOP and ATF4, was attenuated in response to acute contractile activity in the absence of ATF5. The lack of ATF5 led to a reduction in the levels of mitochondrial protease LonP and was accompanied by an increase in mitochondrial:nuclear derived protein imbalance.

Collectively, these results suggest that ATF5 functions to maintain mitochondrial quality control and muscle endurance at the expense of muscle mass, and its absence attenuates the normal compensatory stress response to contractile activity with age.

Link: https://doi.org/10.18632/aging.206365

Enormous costs are imposed by regulators in the US and Europe on the process of manufacturing a candidate drug to Good Manufacturing Practice (GMP) standards and then running a first clinical trial. Combine this with three years of a bad market for biotech, in which investors have pulled back from investing in preclinical companies, and one sees a much greater pressure than usual to expand alternative paths to obtaining initial human data in a responsible way. Right to Try initiatives within the US are underway, and ever more groups within the medical tourism industry are attempting to position themselves as service providers for an alternative to a first clinical trial in the US or Europe. Próspera in Honduras is the most visible of a fair number of entities. At the end of the day, much of the cost and requirements imposed by the FDA and other bodies are not necessary for responsible safety. When regulators make the task of conducting manufacture and a safety trial in humans cost $20M, but it can actually be accomplished responsibly for $5M, as is the case for many classes of therapy, something must change - and change is coming.

Mitrix Bio has reported preliminary Phase 1 safety results for what it describes as large infusions of transplanted mitochondria in humans, while simultaneously launching a small network of clinics offering the experimental intervention under Right to Try frameworks. Taken together, the announcements mark a transition from laboratory concept to early clinical deployment - albeit on a limited scale.

The initial safety work was conducted at a clinic in Dallas, Texas, involving two older participants who received escalating doses of transplanted mitochondria, with monitoring of blood chemistry and physical condition throughout. According to the company, no obvious adverse effects were observed during the study period. Alongside this, new Mitochondrial Transplant Institute clinics have opened in Newport Beach, Dallas and Palm Beach, where treatments will be offered on an individualized basis by physicians, targeting a wide range of chronic and degenerative conditions.

Mitrix's approach involves the use of bioreactors to grow mitochondria derived from an individual's own cells, with the aim of enabling larger-scale infusions. In the recent safety study, doses were increased incrementally, allowing investigators to assess tolerability before proceeding further. The absence of immediate adverse effects supports continued investigation, and though efficacy data has not yet been released, the company is aiming for full efficacy data by the end of this year.

Link: https://longevity.technology/news/mitrix-moves-mitochondria-into-the-clinic/

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