Fight Aging!

Myostatin is a circulating inhibitor of muscle growth. It has been an area of research interest for some time, long enough for myostatin loss of function mutants to have been identified or engineered in a range of mammalian species: mice, dogs, cows, and so forth. Complete loss of function in the myostatin gene throughout life is accompanied by exceptional muscle growth and strength, alongside a lesser amount of visceral fat tissue. All told it seems a benefit with little to no downside.

Since muscle mass and strength is lost with advancing age, there have been efforts to develop therapies based on inhibition of myostatin, such as via monoclonal antibodies. The popularity of GLP-1 receptor agonist drugs that produce loss of muscle mass in addition to visceral fat tissue by reducing calorie intake has resulted in an even greater pharmaceutical industry interest in developing ways to avoid this loss of muscle.

There are many possible points of intervention beyond direct inhibition of myostatin expression, circulating levels, or activity. One possibility presently in clinical trials is the inhibition of myostatin receptors. Another example is the upregulation of follistatin, a circulating molecule that acts in opposition to myostatin, and comes with a similar body of work in mouse studies, where genetic engineering or gene therapies have produced heavily muscled mice. A number of therapies claim to improve follistatin levels, and follistatin gene therapies are now used to some degree in the medical tourism industry. Data on human efficacy is thin to non-existent, however.

Meanwhile, research into myostatin continues as the range of possible muscle growth therapies expands. Today's open access paper is a very interesting tour of what can be learned from the very large genetic databases that now exist. Only the one convincing human myostatin mutant with very evident effects is known to the scientific community, but these large databases allow the discovery of other individuals with mutations that produce a weaker loss of function in the myostatin gene. Since genetic data is coupled with a large amount of other health data in the UK Biobank, one can actually map mutation to muscle strength and other characteristics known to be affected by myostatin.

Humans with function-disrupting variants in the myostatin gene (MSTN) have increased skeletal muscle mass and strength, and less adiposity

Myostatin negatively regulates skeletal muscle size in multiple species, and therefore, myostatin blockade has been therapeutically explored to promote muscle growth in humans, including to counter the muscle loss seen in obese humans using GLP1R agonists. In this study, we present results from a large multi-cohort genetic association analysis, using data from 1.1 million individuals to examine the effects of function-disrupting mutations in the myostatin gene (MSTN) on traits relevant to body composition and cardiometabolic health.

Carriers of function-disrupting variants display decreased adiposity, an increase in lean mass, and increased grip strength and creatinine levels. We further characterize the effects of these variants on body composition using whole-body MRI data from UK Biobank, leveraging deep learning models to perform automated image segmentation for 77,572 individuals. Among mutation carriers increased muscle mass is observed across multiple muscle groups, with heterozygote carriers of loss-of-function-like mutations exhibiting increases in excess of 10%.

Our findings demonstrate that lifelong reduction in myostatin function enhances muscle size and strength in humans while decreasing body adiposity, providing insights into the potential benefits and safety of long-term therapeutic blockade of myostatin signaling.

The dominant amyloid cascade hypothesis for Alzheimer's disease broadly states that amyloid-β aggregation occurs early in the progression of the condition, setting the stage for later and much more damaging neuroinflammation and tau aggregation. There remains a great deal of room to debate the details of this progression, how exactly amyloid-β and tau aggregation are linked. Is it as simple as a matter of chronic inflammation generated by amyloid-β aggregation slowly rising to the level of inciting a feedback loop between tau aggregation and further inflammatory signaling? Or some other more direct connection between the biochemistry of amyloid-β aggregation and tau aggregation? Here, researchers advance a novel theory on this topic.

Alzheimer's disease (AD) is defined by cognitive decline in conjunction with accumulation of aggregated amyloid β (Aβ) and tau, yet existing models of AD fail to provide a simple connection between Aβ and tau. However, microtubules provide an intriguing nexus for pathological interactions between the two. Tau binds to microtubules and is critical to maintaining their proper function. We demonstrate that Aβ also binds to microtubules with affinity comparable to that of tau itself.

We hypothesize that displacement of tau by Aβ leads to microtubule dysfunction and facilitates tau phosphorylation and aggregation. Importantly, in this model, aggregation of Aβ is not the primary cause of toxicity, which allows many of the apparent contradictions between Aβ pathology and cognition to be rationalized. This model highlights the importance of both tau and Aβ and enables additional therapeutic and intervention strategies to be considered.

Link: https://doi.org/10.1093/pnasnexus/pgag034

There has been a surge of interest in the potentially beneficial effects of late life vaccination in recent years. The challenge in looking at correlations between health and adult vaccination status is that we don't know the degree to which it reflects biological mechanisms, such as trained immunity effects reducing the chronic inflammation of aging, versus selecting for people who generally take better care of their health and thus tend towards better outcomes across the board. Causation is hard to derive from human epidemiological data.

Previous studies suggest that a shingles infection can cause blood clots to form around the brain and heart, raising the risk of events such as heart attacks, strokes, and venous thromboembolism. By preventing the infection, the shingles vaccine is thought to also help prevent the formation of these dangerous clots. For the current study, researchers used TriNetX, a database that includes health records of millions of Americans, to assess rates of serious cardiac events in people age 50 years or older with atherosclerotic disease between 2018-2025. The study included 123,411 people who had received at least one dose of either the Shingrix or Zostavax shingles vaccine and the same number of people who had not received any doses of shingles vaccine. Demographics and other health conditions were similar between the two groups.

When researchers examined cardiac events occurring between one month and one year after shingles vaccination (or the same time period for unvaccinated individuals), they found that vaccination was associated with a lower risk across all outcomes studied. Vaccinated individuals were 46% less likely to suffer any major adverse cardiac event and 66% less likely to die from any cause. They were also 32% less likely to suffer a heart attack, 25% less likely to suffer a stroke and 25% less likely to develop heart failure. These levels of risk reduction are substantial, comparable to what would be expected from quitting smoking.

The study focused only on outcomes during the first year after shingles vaccination, so researchers noted that the lifetime impacts may differ from those observed during this time period. A previous study released in 2025 found getting the shingles vaccine was associated with a 23% lower risk of cardiovascular events in a healthy general population, and the vaccine's cardioprotective effects may last for up to eight years.

Link: https://www.acc.org/About-ACC/Press-Releases/2026/03/16/19/33/Shingles-Vaccine-Drastically-Cuts-Risk-of-Serious-Cardiac-Events

As the treatment of aging as a medical condition became more mainstream, there was a tendency for advocates and researchers to avoid talking about extending life span. They instead talked about pushing back the onset of poor health and even said explicitly that the goal of research and development was not to lengthen overall human life. From the perspective of aging as an accumulation of cell and tissue damage and potential rejuvenation therapies as repair of that damage, this view is incoherent. A priori, we know that repairing damage will extend both the overall life span and the period of good function in machinery, including biology. This is well studied under the heading of reliability theory, modeling how damaged systems fail.

In medicine, however, we observe that about half of the upward trend in life expectancy over the past century or more arises from an extension to health without an extension to life span. How can that be? A common explanation is that some forms of late-life damage are relatively little affected by any advance in public health or medical technology. One possibility is that transthyretin amyloidosis is the mechanism of interest, an accumulation of harmful amyloid that contributes to cardiovascular disease, and is now thought to be much more prevalent than previously assumed. Since that is now a treatable condition, albeit one that is only actually treated in the rare very severe cases, it will be interesting to observe what happens when the therapies become generic and thus potentially widely used.

Healthy life extension: Geroscience's north star

Mikhail Blagosklonny was right to say out loud: the goal of geroscience is life extension. Not "vitality" or a polite euphemism for better late-life care, but life extension. He also insisted on disciplined evidence: if we claim we are modifying aging, we should demand hard outcomes in mammals rather than an endless parade of biomarkers. Where I would extend his argument, as a longevity physician, is: the field must stop treating "lifespan vs. healthspan" as a fork in the road. In medicine, and in the lives our patients actually live, they are not competitors. The only mission that is both scientifically coherent and clinically meaningful is healthy life extension: more years in full health.

The "healthspan, not lifespan" framing makes geroscience sound as though it is not about longevity, when longevity is what emerges from delaying the biology that drives multimorbidity. World Health Organization (WHO) data show that from 2000 to 2019, life expectancy increased more than healthy life expectancy, meaning we added years lived with disease or disability. A cross-national analysis quantified the global "healthspan to lifespan gap" at approximately 9.6 years. Modern systems deliver more years, but not more good years. That is precisely why geroscience must be more ambitious. We should treat healthy life extension as the goal and define success as health-adjusted longevity: extending lifespan while proportionally expanding function, resilience, and independence.

If we agree that the goal is healthy life extension, incrementalism becomes a choice rather than a constraint. Consider the balance sheet: within the National Institute on Aging (NIA) budget, the Division of Aging Biology is funded at roughly $346 million, whereas neuroscience-related research is funded in the billions. We have not resourced basic aging biology in proportion to its theoretical leverage: the possibility of delaying many diseases at once. This is not a call to rob disease programs. It is a call to stop pretending a civilization-scale problem can be solved with niche-scale funding.

It isn't surprising to find that epigenetic clocks predict mortality more effectively than simple clinical measures such as individual biomarkers of age-related chronic inflammation. Epigenetic clocks are derived from many more data points, and at least some clocks, such as the Dunedin Pace of Aging clock, were constructed with the intent of predicting mortality. Nonetheless, one has to run the numbers. Here, researchers look at the ability of various measures and combinations of measures to predict mortality in a large database of human epidemiological data, and find that the epigenetic clock outperforms other options, but is still better augmented with a few clinical measures.

We used data from the Berlin Aging Study II (BASE-II, 60-80 years of age at baseline, average follow-up 7.4 ± 1.5 years, range 3.9-10.4, n = 1,083) to compare 14 biomarkers of aging recently consented by an expert panel for the use as outcome measures in intervention studies: physiological (insulin-like growth factor 1 (IGF-1), growth-differentiating factor-15 (DNA methylation derived, DNAmGDF15)), inflammatory (high sensitivity C-reactive protein (CRP), interleukin-6 (IL-6)), functional (muscle mass, muscle strength, hand grip strength (HGS), Timed-Up-and-Go (TUG), gait speed, standing balance test, frailty phenotype (FP), cognitive health, blood pressure), and epigenetic (epigenetic clock, DunedinPACE). Cox proportional hazard regression analyses were performed to investigate their role in prediction of all-cause as well as cause-specific mortality. Results were adjusted for age, sex, lifestyle factors, and genetic ancestry.

In adjusted models of all-cause mortality, HGS, IL-6, standing balance, cognitive health, and the epigenetic clock (DunedinPACE) statistically significantly predicted mortality, with the epigenetic clock (DunedinPACE) emerging as the strongest predictor. CRP, gait speed, IGF-1, blood pressure, muscle mass, DNAmGDF15, FP and TUG were not associated with mortality in this study. These results were corroborated in subgroup analyses stratified by cause of death. Feature selection identified a minimal biomarker set consisting of muscle mass, standing balance, and epigenetic clock (DunedinPACE) that predicted mortality with nearly the same discriminative accuracy (C-index = 0.63) as the full model including all biomarkers (C-index = 0.65).

In conclusion, among the fourteen investigated biomarkers of aging, DunedinPACE emerged with the strongest and most consistent association with mortality.

Link: https://doi.org/10.1186/s40364-026-00909-z

Collagen molecules of various sorts are a vital component of the extracellular matrix, a complex supporting structure in tissues that is maintained by the cells that reside within it. Aging produces changes in this maintenance, in addition to a growing burden of alterations and damage to the molecules making up the extracellular matrix. Extracellular matrix aging is not as well studied as the aging of cells; this research exists at the intersection of the two, assessing age-related changes in the production of collagens needed for extracellular matrix maintenance in a short-lived laboratory species.

Collagens, long regarded as structural molecules, also regulate stress responses and longevity. In this study, we analyzed our RNA sequencing data and publicly available gene expression data to define their role in Caenorhabditis elegans aging. Collagen expression broadly declined with age, with 16 collagen genes consistently downregulated across independent studies, establishing collagen downregulation as a genetic hallmark of aging. In contrast, meta-analysis of 66 datasets (128 comparisons between normal and long-lived animals) showed collagen upregulation in 84% of long-lived conditions, identifying collagen induction as a conserved signature of lifespan extension.

Using collagen gene expression data, we applied K-means clustering and identified clusters that captured functional, tissue-associated subsets of collagens. Notably, aging-associated collagens were strongly enriched in Cluster 1, which overlapped with hypodermal collagens, while Cluster 2 significantly intersects with lifespan-extension and intestine-enriched subsets, and Cluster 3 likely represents structural collagens contributing to cuticle and muscle integrity. These results indicate that collagen genes grouped by expression-based clustering are not randomly distributed but instead reflect tissue-specific patterns and functionality.

Together, our findings suggest that collagens are dynamic regulators of aging and longevity in C. elegans. Given the conservation of extracellular matrix biology across species, collagens represent candidate biomarkers and targets for promoting healthy aging in both C. elegans and higher animals.

Link: https://doi.org/10.1016/j.mbplus.2026.100192

If the activities of a cell appear precisely engineered and highly efficient, it is because every layer of cellular activity is monitored by some form of quality control mechanism. A cell is a collection of molecules moving at incredible speeds, where every possible collision happens countless times per second. All of the damaging, unwanted reactions that can occur between molecular structures in the cell do in fact happen constantly. Breakage happens constantly. Manufacture of new structures produces flawed outcomes constantly. But all of these issues are cleaned up as they occur. The processes of quality control and maintenance that undertake this cleanup work are collectively vital to cell health and cell function.

Messenger RNA is manufactured as the first stage of gene expression. The transcriptional machinery of the cell nucleus assembles messenger RNA molecules based on their genetic blueprints before sending them off to be translated into proteins. Following the remarks above, many flawed messenger RNA molecules result from the constant transcriptional activity in the cell nucleus and must be dealt with by a layer of messenger RNA quality control. As is the case for most of the processes involved in gene expression, this quality control is fairly well understood by the research community, likely becomes meaningfully less effective with advancing age, but measuring specific aspects of this quality control process can be challenging, leading to debate.

The function of mRNA quality control in aging and age-related diseases

Aging is accompanied by a gradual decline in physiological functions and an exponential increase in susceptibility to multiple age-associated diseases. Aging is caused by the impairment of biological systems at multiple levels. At the cellular level, the accumulation of senescent cells, which stably stop proliferation, is considered as a major cause of aging. At the molecular level, genomic instability and reduced proteostasis contribute to accelerating both cellular senescence and organismal aging. Recent studies also suggest important roles of messenger RNA (mRNA) quality control systems in aging. Studies using the nematode Caenorhabditis elegans demonstrated the important function of mRNA quality control and homeostatic regulation of splicing in organismal aging. In addition, age-dependent accumulation of stalled ribosomes, which are closely associated with co-translational mRNA quality control systems, contributes to aging and longevity in the budding yeast Saccharomyces cerevisiae and C. elegans.

Eukaryotic cells are equipped with multiple mRNA surveillance systems that eliminate abnormal transcripts. Nonsense-mediated mRNA decay (NMD), a key RNA surveillance process, targets mRNA transcripts that contain premature termination codons (PTCs). Nonstop decay (NSD) eliminates mRNAs without stop codons that cause ribosome stalling at the poly(A) tail, and conventionally no-go decay (NGD) removes mRNAs with internal stem-loop structures or rare codons that cause internal ribosome stalling. Although poly(A)-mediated ribosome stalling has been classically associated with NSD, recent studies showed that poly(A) stretches can also trigger ribosome collisions and activate NGD, indicating a partial mechanistic overlap between the two pathways. Slow elongation caused by non-optimal or rare codons activates a noncanonical mRNA surveillance pathway, codon-optimality-mediated decay, rather than NGD, and the decay of such mRNAs is mechanistically distinct from NGD.

Impairments of NMD, NSD, and NGD contribute to physiological defects such as premature aging and neurodegeneration, highlighting the importance of proper maintenance of mRNA quality control in organismal health. Here, we discuss the critical roles of these pathways in maintaining mRNA quality and preventing the accumulation of aberrant transcripts, which can contribute to aging and age-related disorders. Specifically, we discuss the function of NMD in aging processes and age-related diseases, including cancer and neurodegenerative disorders. We also review the safeguarding roles of NSD and NGD in preventing the accumulation of faulty mRNAs and proteins associated with various diseases. We explore the potential functions of additional mRNA surveillance and the associated signaling pathways, such as ribosome-associated quality control (RQC), in aging and age-related diseases. Understanding the intricate relationship between mRNA surveillance mechanisms and aging may provide key information for developing potential therapeutics that boost these pathways for delaying aging and treating age-related diseases.

Aging can be split up into specific categories in many different ways; age-related diseases as collections of symptoms, specific forms of cell and tissue damage that accumulate, dysfunctions separated by organ, and so forth. None of these categories exist in isolation from the others, however. All aspects of aging interact with one another. Kidney dysfunction affects the brain. Mitochondrial dysfunction influences the burden of cellular senescence. There are a hundred other interactions one might consider that blur the lines of any attempt at categorization of the progression of aging. Nothing is neat and contained, everything interacts.

Aging is accompanied by conserved hallmarks including genomic instability, epigenetic alterations, loss of proteostasis, and mitochondrial dysfunction, but how these processes emerge and become mechanistically linked remains unclear. Here we leverage a proteome-wide, single-cell, subcellular atlas of protein expression, localization, and aggregation across yeast replicative aging to map hallmark-linked remodeling in its spatial context.

We identify hundreds of previously unappreciated molecular changes that underlie major hallmarks of aging and show that hallmark phenotypes frequently manifest as compartment-specific erosion of spatial confinement, relocalization, and aggregation. 91.6% human orthologs of these hallmark-linked yeast proteins also change during human aging. Integrating these spatial phenotypes reveals many molecular connections linking different hallmarks. Temporal analysis suggests that disorganization of nucleolar ribosome biogenesis, proteostasis decline, and mitochondrial dysfunction precede other hallmarks. Together, our findings substantially deepen the molecular underpinnings of aging hallmarks and provide a framework for linking them into a hierarchical sequence of cellular failures.

Link: https://doi.org/10.64898/2026.02.26.708335

Sarcopenia is the name given to the characteristic age-related loss of muscle mass and strength, once the process enters more severe stages. The loss of strength and resilience is an important contribution to frailty, but muscle is also a metabolically active tissue and loss of muscle negatively affects metabolism as well as physical capacity. Chronic inflammation is a feature of aging, as the immune system reacts to cell and tissue dysfunction in maladaptive ways. That chronic inflammation contributes to all of the common age-related conditions by interfering in the maintenance of tissues; this includes muscle tissue and the development of sarcopenia.

Sarcopenia is a syndrome characterized by an age-related progressive decline in skeletal muscle mass, strength, and function. It represents a significant public health concern because of its adverse impact on the quality of life and prognosis of older adults. Chronic low-grade inflammation contributes to the pathophysiology of sarcopenia through multiple pathways, including cellular senescence, immunosenescence, oxidative stress, mitochondrial dysfunction, hormonal alterations, and gut microbiota dysbiosis. Moreover, obesity, a chronic inflammatory condition, is associated with sarcopenia, leading to sarcopenic obesity, which further exacerbates muscle loss and functional impairment.

In terms of interventions, exercise, nutritional supplementation, and combined approaches have demonstrated efficacy in improving muscle mass and function, as well as conferring demonstrable anti-inflammatory benefits. In addition to conventional hormonal therapies, pharmacological strategies, particularly anti-inflammatory agents and treatments targeting inflammatory pathways, show considerable therapeutic promise.

This review examines the central role of chronic inflammation in the development and progression of sarcopenia, as well as its underlying mechanistic basis. It also elaborates on the roles of key inflammatory cytokines, such as C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), in regulating muscle protein metabolic balance and their potential utility as biomarkers. A deeper understanding of the relationship between inflammation and sarcopenia will not only help elucidate its complex pathogenesis but also offer critical directions for the future development of early diagnostic tools and targeted anti-inflammatory interventions.

Link: https://doi.org/10.3389/fphar.2026.1733798

Senescent cells accumulate with age in tissues throughout the body, the result of a growing imbalance between the pace at which somatic cells enter the senescent state in response to damage, stress, and the Hayflick limit on the one hand and the pace of clearance of senescent cells by the immune system on the other. The growing burden of senescent cells disrupts tissue structure and function via inflammatory signaling. This is thought to produce a significant, important contribution to degenerative aging, and over the past fifteen years cellular senescence has become major focus of life science research and development.

Today the field of senotherapeutics, meaning anti-aging therapies that in some way target senescent cells, is in the strange superimposed state of both existing and yet to emerge. Senostatics slow the rate at which cells become senescent, and the low cost, generic mTOR inhibitor rapamycin appears to be a legitimate senostatic. Senolytics selectively destroy senescent cells, and the senolytic combination of dasatinib and quercetin, the subject of several early stage clinical trials, also costs little. Senomorphics impede the bad behavior of senescent cells, and many existing drugs might qualify as senomorphic to some degree.

The two named options above are readily available via off-label prescription to any older individual willing to try. Yet use is not widespread. The large clinical trials that would provide concrete demonstrations of efficacy (or lack of same) have not been conducted, and do not seem likely to be conducted. Generic drugs cannot command enough revenue to support the regulatory cost of large clinical trials. The research community and longevity industry is instead focused on the development of a wide range of novel senotherapeutics, and progress largely remains at a preclinical stage. Today's open access paper is an opinionated tour, but gives a sense of where things stand, the variety of approaches under consideration.

Emerging strategies in senotherapeutics: from broad-spectrum senolysis to precision reprogramming

Cellular senescence, originally described as a finite proliferative arrest in cultured somatic cells, has since been recognized as a central mechanism underlying aging and the development of age-associated disorders. The progressive accumulation of senescent cells (SnCs) promotes chronic inflammation through the senescence-associated secretory phenotype (SASP) and circumvents immune-mediated clearance by upregulating pro-survival and immune checkpoint pathways. Early "first-generation" senolytics, including navitoclax (ABT-263) and the dasatinib-quercetin (D + Q) combination, provided proof-of-concept that selective removal of SnCs can alleviate certain fibrotic, metabolic, and cardiovascular pathologies in preclinical studies. However, these agents exhibited notable drawbacks, such as dose-dependent thrombocytopenia, variable therapeutic efficacy, and the emergence of resistance mechanisms. Consequently, current research has shifted toward precision senotherapy, though significant translational challenges remain.

This review synthesizes three next-generation strategies developed to address limitations of early senolytic agents. (1) Immune-based senolysis: This approach applies immuno-oncology principles to counter immune evasion of SnCs. Strategies include blocking immunosuppressive ligands such as GD3 ganglioside, engineering chimeric antigen receptor (CAR) T cells to target senescence-specific surface markers like urokinase-type plasminogen activator receptor (uPAR), and exploiting metabolic vulnerabilities (e.g., glutaminolysis and ferroptosis) to sensitize SnCs to immune-mediated clearance. (2) Tissue-precision proteolysis-targeting chimeras (PROTACs): These agents recruit organ- or tissue-specific E3 ligases (e.g., von Hippel-Lindau (VHL)) to selectively degrade anti-apoptotic proteins such as BCL-xL. Localized activity may reduce systemic toxicity and mitigate dose-limiting effects observed with traditional inhibitors. (3) Microbiome-epigenetic interplay: This strategy modulates the gut-liver axis to enhance senolytic efficacy. Short-chain fatty acids (SCFAs), such as butyrate, epigenetically regulate drug transporter expression and suppress the SASP, while dietary interventions may create a microenvironment favorable to senolysis.

These approaches offer potentially more targeted and personalized therapeutic options but face significant challenges, including immunopathology, manufacturing complexity, off-target effects, and long-term safety concerns. The ongoing shift from broad inhibition to precision reprogramming represents a promising but preliminary step in the treatment of age-related diseases.

An increasing number of cells in aged tissues enter a senescent state, ceasing replication and generating pro-inflammatory signals that are disruptive to tissue structure and function. In the case of innate immune cells, however, there is some question as to whether they are in fact senescent or just adopting features of senescence, and that leads to debate over whether these cells are in fact harmful. Neutrophils, also known as polymorphonuclear leukocytes, are an important cell type in the innate immune system. Here, researchers show that neutrophils in aged individuals exhibit features of cellular senescence, but stop short of calling them senescent cells. They also show that this behavior is harmful, as it impedes the immune response to infection.

Aging drives increased susceptibility to respiratory infections by Streptococcus pneumoniae (pneumococci). Polymorphonuclear leukocytes (PMNs) are among the first responders in the lung following pneumococcal infection and are required for bacterial clearance. However, PMN antimicrobial function declines with age. To identify mechanisms underlying this decline, we performed RNA sequencing on PMNs in the lungs of young and old mice following pulmonary infection with S. pneumoniae. We observed significant transcriptomic differences across host age.

Transcriptional analysis followed by functional validation revealed that in infected mice, PMNs from aged hosts failed to upregulate several effector activities including glycolysis and subsequent mitochondrial reactive oxygen species (ROS) production, which are necessary for bacterial killing by PMNs. Conversely, PMNs in aged mice displayed a higher senescence-associated secretory phenotype (SASP) score and upregulated pathways involved in cellular senescence. Follow-up functional characterization found that in uninfected hosts, PMNs in aged mice expressed higher levels of SASP factors IL-10, TNFα, and ROS, had a lower incidence of apoptosis, and had a higher proportion of cells positive for senescence-associated β-galactosidase, features of a senescent-like phenotype.

Importantly, blocking TNFα, one of the SASP factors, altered the senescent-like phenotype and boosted the antibacterial activity of PMNs from aged hosts and increased host resistance to S. pneumoniae pulmonary infection. In conclusion, host aging is associated with altered PMN phenotype, including a shift toward senescent-like energy-deficient cells, which contribute to impaired host defense and represent potential targets for improved interventions against infection in older adults.

Link: https://doi.org/10.1111/acel.70435

The standard view of the evolution of aging is that aging exists because natural selection operates more strongly on features of young animals than on features of old animals. A faster time to reproductive success will be selected over a slower time to reproductive success. This leads to the evolution of biological systems that are front-loaded for early efficiency, but that decay to become dysfunctional over time. Aging is near universal but not actually universal, however. For example, varieties of hydra are in fact immortal, exhibiting no loss of function over time. How to explain the existence of the few immortal species in the presently dominant view of the evolution of aging? Here, researchers build a model of the evolution of aging in which a runaway feedback loop leading to immortality is a possible outcome.

In recent years, senescence is increasingly understood as a process of damage accumulation that accelerates with age throughout an organism's lifespan. That understanding has rarely been introduced to senescence evolution theory. In classic models, including Mutation accumulation and Antagonistic pleiotropy, the intensity of selection over genes is determined by the timing of their effect on mortality. They conclude senescence evolution occurs because of weak selection on late-acting genes. Despite the success of these classic explanations, several phenomena have not been fully addressed. One is the existence of species exhibiting negligible senescence - mortality rate that remains constant with age.

Here we explore, consistent with recent evidence, an alternative model: where genes affect mortality throughout an organism's lifespan, and the shape of this effect determines selection. We expanded Hamilton's classic model of senescence evolution using these notions. Our model takes into account evolutionary dynamics between external mortality risk, potential mortality risk from internal damage, reproduction start age, and reproduction rate. The analysis of the model suggests biological limitations on reducing the potential mortality risk from internal damage can lead to a positive feedback loop in senescence evolution where genes that slow senescence can increase selection for further senescence retardation. Our model sheds light on several phenomena, not fully explained by classic theory, including Peto's paradox, Strehler-Mildvan correlation, and negligible senescence.

Link: https://doi.org/10.1002/ece3.72988

Most programs aiming to produce therapies that treat aging involve some form of manipulation of cellular metabolism, usually via small molecules initially derived from screens that showed effects on function or survival in lower animals. Effect sizes are usually modest, and decrease relative to species life span as species life span increases; large increases in function and life span in a nematode worm translate to modest gains in a mouse. Where we have the ability to compare mice and humans, in the matter of growth hormone metabolism and calorie restriction, we know that sizable gains in mice do not translate to sizable gains in humans.

Researchers, particularly Brian Kennedy's team, have shown that most combinations of this sort of intervention fail to be useful. Any two marginally positive age-slowing changes to metabolism are far more likely to interfere with one another than they are to combine for a greater effect. Yet aging is a combination of forms of cell and tissue damage, and thus multiple treatments will be needed to address aging. To combine therapies is a desirable end goal, but it must be pursued rationally, using combinations made up of therapies that specifically address different forms of age-related damage. In principle, such combinations should be far less likely to interfere in one another's operation, and the outcome for health and longevity more likely to be additive and greater than any one therapy alone.

This view of combined therapies as the end goal was always implicit in the Strategies for Engineered Negligible Senescence (SENS) view of aging and how to go about the construction of rejuvenation therapies. One must repair the damage, and thus one must combine different repair strategies that address different forms of damage. This is the central point that the Longevity Escape Velocity (LEV) Foundation is attempting to demonstrate in their large, long-running mouse studies. The goal is to pick sensible combinations of therapies based on a damage repair philosophy, and show that these combinations can be additive. Nothing is ever straightforward, and there are clearly things to be learned along the way, but so far the LEV Foundation seems to be proving their point, a useful counterbalance to the work of Brian Kennedy.

Robust Mouse Rejuvenation: Breaking the Ceiling of Longevity Research

For decades, the field of biogerontology has largely focused on a single strategy: manipulating metabolism to slow down the rate at which we age. While approaches like caloric restriction have produced fascinating results in short-lived organisms like worms and flies, they have shown clear limits in mammals. At LEV Foundation, we are pursuing a distinct alternative: maintenance through damage repair. All age-related damage can be classified into a manageable number of categories. Since there are different types of damage, a single therapeutic intervention is insufficient. To achieve meaningful rejuvenation, we must move from isolation to synergy.

This necessity is the foundation of the Robust Mouse Rejuvenation (RMR) programme. We define RMR as a specific engineering benchmark: a multi-component intervention that increases both mean and maximum lifespan in mice by at least 12 months. This must be achieved in a mouse strain with a well-documented mean lifespan of at least 30 months, with treatment initiating only at the advanced age of 18 months. To hit this target, the RMR programme consists of large-scale studies designed to determine how leading-edge interventions behave when deployed together.

The RMR1 study served as a first test, operating at an unprecedented scale with 1000 middle-aged mice divided into 10 subgroups per sex. This granular design allowed us to map the complex web of interactions. We selected four interventions that had individually shown promise in extending mouse lifespan: rapamycin, senolytics, telomerase gene therapy, and hematopoietic stem cell transplantation. By administering these simultaneously, we sought to establish whether their combined impact could finally break through the lifespan ceiling that no single intervention has ever managed to overcome.

The overarching conclusion following the completion of RMR1 is a qualified win for synergy. RMR1 successfully demonstrated that combining damage-repair interventions with metabolic modulation (rapamycin) yields additive benefits. Specifically, we observed a distinct rectangularisation of the survival curve. This means that we significantly increased mean lifespan by ensuring more mice survived into late life. However, we must be clear about the limits of this result. We did not observe a radical extension of maximum lifespan (the age of the oldest survivors). While the all-four combination group outperformed both the naive and mock controls, the "robust" goal of shifting the entire mortality window remains the target for future iterations.

RMR1 demonstrated that a single dose of damage repair has a limited window of efficacy. The damage re-accumulates. Future protocols must likely incorporate repeated dosing for interventions like senolytics and gene therapy. However, the male data revealed that combinatorial treatments extend this window significantly when supported by metabolic stability. We have used these critical lessons to design RMR2. The new study replaces the single-dose approach with cyclic treatments using mesenchymal stem cells and an expanded panel of eight interventions. With the blueprint for this next phase complete, funding is the only remaining bottleneck.

Autophagy is the name given to a collection of cellular processes responsible for recycling damaged or otherwise unwanted proteins and structures. The materials to be recycled are conveyed to a lysosome where they are broken down into raw materials that can be reused for further protein synthesis. Many of the most well studied approaches to slowing aging in laboratory species involve increased autophagy. Greater autophagy improves cell function and is demonstrated to reduce the pace at which cells in aged tissues enter the harmful senescent state. Nothing in biology is simple, however. Here, researchers discuss the role of excessive autophagy in sustaining the inflammatory, disruptive signaling that is generated by lingering senescent cells in aged tissues.

Autophagy and cellular senescence are fundamental stress-response programs that critically shape aging and disease progression, yet their functional relationship has remained paradoxical. Autophagy is traditionally viewed as a cytoprotective process that preserves cellular homeostasis and delays senescence. In contrast, emerging evidence demonstrates that autophagy is also indispensable for the survival and pathological activity of established senescent cells. In this review, we propose a "threshold model" to reconcile these opposing roles and to provide a unified framework linking signal transduction, organelle quality control, and therapeutic intervention.

According to the threshold model, autophagy exerts stage-dependent functions governed by stress intensity and disease progression. Below a critical damage threshold, robust autophagic flux suppresses senescence initiation by maintaining mitochondrial integrity, limiting oxidative stress, and preserving proteostasis. Once this threshold is exceeded, autophagy is functionally reprogrammed to sustain the metabolic and biosynthetic demands of senescent cells, including production of the senescence-associated secretory phenotype (SASP).

We highlight key signaling nodes that regulate this transition, including mTORC1, AMPK, p53, and p62, as well as spatial and organelle-specific mechanisms such as the TOR-autophagy spatial coupling compartment (TASCC), mitophagy failure, lipophagy blockade, and aberrant nucleophagy. These processes converge on innate immune pathways, notably cGAS-STING and NF-κB signaling, to drive chronic inflammation and tissue dysfunction. Importantly, we extend this mechanistic framework to clinical translation, synthesizing evidence from ongoing trials in cancer, neurodegeneration, metabolic liver disease, and fibrosis. We argue that effective targeting of the autophagy-senescence axis requires precision gerontology, integrating dynamic biomarkers to guide stage-specific interventions-autophagy activation for prevention and autophagy inhibition or senolysis for established disease.

Link: https://doi.org/10.1016/j.redox.2026.104079

As researchers continue to map the changing composition of the gut microbiome in aging and disease, in ever more detail, they increasingly uncover the problematic activities of specific microbial species and specific mechanisms by which the aging of the gut microbiome can contribute to age-related loss of function throughout the body. This opens the door to the development of means of targeted adjustment of the gut microbiome's composition, and also to the development of therapies that interfere in specific interactions between the microbiome and tissues that cause issues.

Ageing is accompanied by declining memory function, with extremely heterogeneous manifestation in the human population. Brain-extrinsic factors influencing cognitive decline, such as gastrointestinal signals, have emerged as attractive targets for peripheral interventions, but the underlying mechanisms remain largely unclear. Here, by charting a high-resolution map of microbiome ageing and its functional consequences throughout the lifespan of mice, we identify a mechanism by which inhibition of gut-brain signalling during ageing results in impaired neuronal activation in the hippocampus and loss of memory encoding.

Specifically, accumulation of gut bacteria that produce medium-chain fatty acids, such as Parabacteroides goldsteinii, can drive peripheral myeloid cell inflammation through GPR84 signalling. As a result, the function of vagal afferent neurons is impaired, the interoceptive signal received by the brain is weakened and hippocampal function declines. We leverage this pathway to define interventions that enhance memory in aged mice, such as phage targeting of Parabacteroides, GPR84 inhibition and restoration of vagal activity. These findings indicate a key role for interoceptive dysfunction in brain ageing and suggest that interoceptomimetics that stimulate gut-brain communication may counteract age-associated cognitive decline.

Link: https://doi.org/10.1038/s41586-026-10191-6