Fight Aging!

Lipid metabolism is a complex area of study. Any given lipid can be transformed into scores of other molecules with quite different properties, and the scientific community's understanding of what each of these lipid products is doing in our biology is far from complete. Even just looking at cholesterol alone quickly becomes a sizable undertaking; if you were under the impression that researchers know exactly what every modified form of cholesterol or transformed product of cholesterol does in detail, you may be surprised to see just how much is left to catalog, map, and comprehend. Cellular biochemistry is very complicated, and there are only so many researchers and only so much time.

So science tends to proceed by establishing points of focus on specific molecules or specific interactions, and incrementally mapping nearby molecules and interactions. The further away from these points of focus one moves, the less complete the understanding. One of the scientific programs first started in the SENS Research Foundation has led to a growing point of focus on 7-ketocholesterol and its effects. 7-ketocholesterol is a oxidized form of cholesterol known to be toxic and thought to have no useful purpose in metabolism. Evidence points to a role for 7-ketocholesterol in atherosclerosis and a range of other conditions, and thus a company, Cyclarity Therapeutics, was formed to develop therapies to clear 7-ketocholesterol from tissues. That program is currently in its early clinical stages.

The scientific process doesn't stop at "7-ketocholesterol is toxic, and thus we should clear it from tissues to improve health", however. 7-ketocholesterol exists in the sizable space of alterations to cholesterol and products of cholesterol. Many of the transformations that can be applied to cholesterol can also be applied to 7-ketocholesterol. Do researchers have a good idea as to what these further derivatives of 7-ketocholesterol are doing to cells? Not really, but the point of focus established on 7-ketocholesterol will expand slowly to these products and their effects.

Emerging role of 7-Ketocholesterol and hydroxylated 7-Ketocholesterol in the pathophysiology of disease

Cholesterol is a vital lipid molecule essential for cellular structure and function. Oxidation of cholesterol leads to the formation of biologically active oxidized cholesterols known as oxysterols. Among oxysterols, 7-ketocholesterol (7KC) is a key product, primarily formed by oxidation at the C7 position of the cholesterol molecule. 7KC is notably elevated in conditions such as hypercholesterolemia and within atherosclerotic lesions, often at higher concentrations than other oxysterols. Growing research highlights 7KC's significant involvement in the development and progression of a wide array of diseases and aging cells, where it is widely recognized for its cytotoxic, pro-inflammatory, and pro-apoptotic properties, positioning it as a critical factor in pathophysiology.

While 7KC has traditionally been studied as an end-product of cholesterol oxidation, increasing evidence suggests that it also serves as a precursor or co-product in the generation of more structurally complex oxysterols bearing multiple oxidative modifications. Among these, double-substituted oxysterols such as 7-keto-25-hydroxycholesterol (7-keto-25-OHC) and 7-keto-27-hydroxycholesterol (7-keto-27-OHC) represent an underexplored but potentially significant class of downstream metabolites.

The presence of both a C7 ketone and a side-chain hydroxyl group profoundly alters sterol polarity, membrane partitioning, and reactivity. Compared with mono-substituted oxysterols, double-substituted species are expected to exhibit reduced membrane affinity, enhanced aqueous solubility, and increased accessibility to intracellular targets. These physicochemical properties may influence their transport, cellular distribution, and rate of further metabolism or clearance. Moreover, the coexistence of two oxidative modifications may amplify biological activity, either through additive effects or through the emergence of distinct signaling properties not observed with single modifications. These metabolites of 7KC represent the dynamic interplay between oxidative damage and cellular sterol metabolic pathways. Elucidating their biological functions will be essential for a more comprehensive understanding of oxysterol biology in health and disease.

In recent years, researchers have noted that circular RNAs accumulate in cells in old age. It has been unclear as to whether this is only a marker of dysfunction or a change that in and of itself causes further downstream issues. The fastest way to obtain an answer to this sort of question is to repair the problem and see what happens. Researchers here identify that levels of RNASEK, a protein responsible for breaking down circular RNA, decline with age, allowing circular RNA levels to rise. Forcing increased expression of RNASEK slows aging and extends life, which strongly suggests that circular RNAs are harmful in some way. The researchers suggest that harms result from circular RNA aggregation in the cell, but further research is needed on this topic.

Until now, circular RNA has been regarded mainly as an aging marker because of its stability, which allows it to accumulate over time. However, the molecular mechanism for removing this RNA and its direct link to aging had not been clearly identified. Using Caenorhabditis elegans, a short-lived roundworm widely used in aging research, researchers first confirmed that the circular RNA-degrading enzyme RNASEK is essential for longevity. They also discovered that as aging progresses, the amount of RNASEK decreases, resulting in an abnormal accumulation of circular RNA within cells.

Conversely, artificially increasing the levels of RNASEK (overexpression) extended the lifespan and allowed the organisms to survive longer in a healthy state. This implies that the process of appropriately removing cellular circular RNA is critical for maintaining health and longevity.

The research team also found that RNASEK prevents the toxic aggregation of circular RNAs in aged organisms. When RNASEK is deficient and circular RNA accumulates, "stress granules" form abnormally inside the cell, which can impair cellular functions and accelerate aging. RNASEK works alongside the chaperone protein HSP90 (which helps proteins avoid misfolding or clumping) to inhibit the formation of these stress granules and help cells maintain a normal state. Notably, this phenomenon was observed not only in C. elegans but also in human cells. In mammals, RNASEK also functions to directly degrade circular RNA; a deficiency of RNASEK in human cells and mouse models led to premature aging.

Link: https://news.kaist.ac.kr/newsen/html/news/?mode=V&mng_no=59490

The thymus, a small organ near the heart, is important to the function of the adaptive immune system. Thymocytes migrate from bone marrow to the thymus where they mature into T cells. The thymus atrophies with age, and the loss of active thymic tissue reduces the pace at which new T cells are produced. This leads to an adaptive immune system that, lacking sufficient replacements, is ever more populated with senescent, exhausted, and malfunctioning T cells. That this is an important contribution to the loss of immune function that occurs in later life is illustrated by the data presented here, in which researchers correlate degree of thymic atrophy with mortality and incidence of age-related disease in a large human study population.

The thymus is essential for establishing T cell diversity early in life, but undergoes profound involution with age and has therefore traditionally been regarded as largely nonfunctional in adults. Here we propose that preserving thymic functionality is integral to adult health and longevity. We developed a deep learning framework to quantify thymic health from routine radiographic images and evaluated its association with longevity and risk of major age-associated diseases in two large prospective cohorts of asymptomatic adults: the National Lung Screening Trial (n = 25,031) and the Framingham Heart Study (n = 2,581).

In both cohorts, thymic health varied markedly across the population. In the National Lung Screening Trial, higher thymic health was consistently associated with lower all-cause mortality, reduced lung cancer incidence and lower cardiovascular mortality over 12 years of follow-up after adjustment for age, sex, smoking and comorbidities. In the independent Framingham Heart Study cohort, higher thymic health was significantly associated with reduced cardiovascular mortality, independent of age, sex, and smoking. Thymic health was further linked to systemic inflammation and metabolic dysregulation, and associated with modifiable lifestyle factors including smoking, obesity, and physical activity.

Together, these findings reposition the thymus as a central regulator of immune-mediated ageing and disease susceptibility in adulthood, highlighting its potential as a target for preventive and regenerative strategies to promote healthy ageing and longevity.

Link: https://doi.org/10.1038/s41586-026-10242-y

Aging clocks are produced from machine learning strategies applied to databases of biological data, typically omics data of various sorts, obtained from people of various ages. Patterns that change with age can be identified and an algorithm defined to take any other person's data and predict their age based on comparisons to the reference database. Whether the predicted age is higher or lower than chronological age says something about the individual's biological age, the accumulation of damage and dysfunction in tissues and systems.

The biggest challenge in using these clocks is that the method of production tells us nothing about how exactly the data used in the algorithm is connected to particular processes or dysfunctions of aging. Thus it is hard to trust the outcome, particularly if the intent is to use clock measures to assess potential interventions that might slow or reverse aspects of aging. The clock may underestimate outcomes, overestimate outcomes, or just produce completely irrelevant results for any specific individual, and we have no good way of knowing which of these is the case.

This issue is well understood by the research community, and there are a number of different approaches that might be taken to improve the situation. Researchers have, for example, built clocks based on clinical measures such as blood counts and inflammatory cytokine levels rather than omics data. This is still not ideal, as the details of the connection between clinical measures and mechanisms of aging remain somewhat nebulous in most cases, but one can at least theorize on what is going on under the hood to a greater degree. Another, much harder approach is to start over and develop the means of building new omics clocks that are, from the ground up, manufactured with the intent of providing greater insight into underlying mechanisms. That work continues, but research groups are producing incremental progress along the way, such as the interpretable clock reported in today's open access paper.

DeepStrataAge: an interpretable deep-learning clock that reveals stage- and sex-divergent DNA methylation aging dynamics

Aging is the strongest risk factor for chronic diseases such as cardiovascular disease, Alzheimer's, and cancer. DNA methylation (DNAm) clocks offer a promising measure of biological age, but most rely on linear models that miss non-linear dynamics and CpG interactions. To address this, we developed a deep neural network (DNN)-based DNAm clock trained on 29,167 samples profiled on Illumina EPIC v1.0 and v2.0 arrays. Using 12,234 CpGs selected through sex- and age-stratified correlations, our model achieved high accuracy (1.89 years) and outperformed published deep learning and elastic net based epigenetic clocks in a separate validation cohort.

Using Shapley Additive Explanations (SHAP), we further uncovered phase-structured, wave-like dynamics in age-influential CpGs: an early-life module, a midlife transition, and late-life remodeling, with distinct timings by sex. These epigenetic waves cohere with non-linear, multi-omic "aging waves" reported in proteomics and longitudinal omics. SHAP further enabled interpretable CpG attribution, revealing structured, sex-specific aging phases: early-life male clocks involved developmental pathways, while female clocks emphasized cytoskeletal regulation; late-life divergence included immune activation in males and transcriptional remodeling in females. Our framework thus unites accuracy with mechanistic interpretability, revealing sex-specific windows when molecular aging reconfigures most rapidly.

The gut microbiome changes in composition with age in ways that harm tissue function and provoke chronic inflammation. Among the potential causes of this shift in composition is the age-related dysfunction of the immune system, allowing growth in microbial populations that should be kept in check. Researchers here work in fruit flies to identify a regulatory interaction that can be targeted to restore some of that lost immune function. It remains to be seen as to how applicable this is to the analogous situation in the mammalian immune system and gut microbiome, but one can hope.

The maintenance of immune homeostasis is critical for tissue health and longevity, yet the regulatory mechanisms linking immune modulation to aging remain poorly understood. Here we found that the transcription factor cAMP response element-binding protein (CREB), activated by JNK signaling in aging guts, transcriptionally suppresses peptidoglycan recognition protein SC2 (PGRP-SC2) - a homolog of mammalian anti-inflammatory PGLYRP1-4 with amidase activity. 16S rRNA sequencing revealed that CREB modulates not only microbial load but also microbiota composition. Elevated CREB activity decreased the Firmicutes/Bacteroidetes (F/B) ratio - a hallmark of age-associated dysbiosis in animals.

Genetic enhancement of PGRP-SC2 rescues age-related gut hyperplasia, microbiota imbalance, and lifespan shortening induced by overactivation of CREB or its coactivator CRTC. Notably, CREB's regulation of PGRP-SC2 operates independently of canonical immune pathways such as Imd/Relish, revealing a previously unrecognized layer of immune modulation. Our findings establish CREB as a central player in age-associated immune dysregulation and propose targeting the CREB-PGRP-SC2 axis as a potential therapeutic strategy for mitigating gut aging and its systemic consequences.

Link: https://doi.org/10.1038/s41420-026-02955-w

Quality of sleep tends to decline with age for reasons both physical and neurological; sleep apnea is a concern for many older people. A broad body of literature connects sleep issues with risk of neurodegenerative conditions. Thus researchers can plausibly expect to take sleep assessment data from a population of people at various ages, and employ machine learning strategies to develop an aging clock derived from that data. Any sufficiently complex data set that changes with age can be used in this way. Researchers here report on an implementation of this approach to measuring the aging of the brain, and produce an aging clock that can predict dementia risk based on sleep electroencephalography results recorded during a sleep study.

Sleep disturbances are increasingly recognized as early indicators and potential modifiable risk factors for dementia. However, the macrolevel sleep architecture has shown inconsistent associations with cognitive impairment and incident dementia. These broad sleep metrics do not fully capture the complex and multidimensional nature of sleep physiology. In contrast, the microstructure of sleep electroencephalography (EEG) directly reflects the neural processes with explicit functional implications. To capture these complex patterns, we developed a sleep EEG-based brain age using a novel, interpretable machine learning approach that integrates multiple age-dependent EEG microstructures into a single agelike number. The difference between brain age and chronological age is termed the brain age index (BAI).

For this individual participant data meta-analysis, sleep study data from 5 community-based longitudinal cohorts were pooled. These cohorts included the Multi-Ethnic Study of Atherosclerosis (MESA; 2010-2013), the Atherosclerosis Risk in Communities (ARIC) study (1987-1989), the Framingham Heart Study-Offspring Study (FHS-OS; 1995-1998), the Osteoporotic Fractures in Men Study (MrOS; 2003-2005), and the Study of Osteoporotic Fractures (SOF; 2002-2004). This meta-analysis included 7,105 participants.

The median time to dementia was 4.8 years in the MESA cohort (n = 119 [6.6%]), 16.9 years in the ARIC cohort (n = 354 [19.7%]), 13.1 years in the FHS-OS cohort (n = 59 [9.6%]), 3.6 years in the MrOS cohort (n = 470 [17.8%]), and 4.6 years in the SOF cohort (n = 86 [34.3%]). Across the cohorts, each 10-year increase in BAI was associated with a 39% higher risk of incident dementia (hazard ratio [HR] 1.39) after adjustment for covariates. These associations remained after additional adjustment for comorbidities and apnea-hypopnea index scores (HR 1.31) and apolipoprotein E ε4 (HR 1.22), and they were consistent across sex and age groups.

Link: https://doi.org/10.1001/jamanetworkopen.2026.1521

Researchers have identified many contributing issues leading to the characteristic loss of muscle mass and strength that takes place with age. Arguably the central problems are (a) the disruptions of cell behavior caused by chronic inflammation, (b) damage to neuromuscular junctions, depriving muscle tissue of signals it relies upon for normal maintenance to take place, and (c) loss of muscle stem cell activity, and thus a reduced supply of somatic muscle cells to replace losses. These central problems likely interact with one another, but in principle could be addressed distinctly to produce benefits in patients.

Past studies have shown, rather convincingly, that muscle stem cells in older individuals retain their function when moved from an old environment to a young environment. The problem is not so much damage to these cell populations, but rather their growing lack of activity. Stem cells spend most of their time quiescent, only activating to produce daughter somatic cells when needed. With age, activation of stem cells diminishes for reasons that are only partially explored, and may differ considerably in their details from tissue to tissue. In principle, a greater knowledge and control over stem cell activation could be employed to reduce the age-related loss of muscle tissue, but that requires progress in uncovering specifics of the regulatory systems involved that might be targeted by novel therapeutics.

MG53 in Early Skeletal Muscle Stem Cell Activation: Implications for Aged Muscle Regeneration

Skeletal muscle regeneration declines with age despite the persistence of satellite cells (muscle stem cells, MuSCs), suggesting that regenerative impairment reflects functional dysregulation rather than MuSC depletion. Increasing evidence identifies early MuSC activation during the immediate post-injury period as a stress-sensitive, rate-limiting transition that is particularly vulnerable in aged muscle. Aged MuSCs exhibit elevated stress responses and reduced membrane remodeling capacity, accompanied by weakened activation-associated transcriptional induction. In contrast, proliferative and differentiation programs remain largely intact once activation is successfully initiated.

These findings underscore that impaired coordination during early activation contributes to long-term regenerative decline in aging. Within this framework, MG53 (tripartite motif-containing protein 72, TRIM72), a muscle-enriched TRIM family E3 ubiquitin ligase originally identified as a mediator of sarcolemmal membrane repair, may also function as a stress-responsive regulator that stabilizes the early activation environment. Rather than directly determining cell fate, MG53 is proposed to facilitate activation by mitigating stress-associated membrane disruption and maintaining programmatic coordination under age-related physiological constraints.

However, direct experimental evidence defining the role of MG53 in the early activation of aged MuSCs remains limited. Current data primarily support its functions in membrane stabilization, oxidative stress mitigation, and inflammatory modulation. Whether these stress-buffering properties directly influence the early activation transition in aging muscle has not yet been formally tested. In this review, we suggest that MG53 may contribute to the regulation of early MuSC activation under conditions of elevated cellular stress in aged muscle. Clarifying this potential role represents an important direction for future mechanistic investigation.

It has been fifteen years since the first compelling demonstration of clearance of senescent cells in mice. That study paved the way for the transformation of the research community into one convinced of the relevance of cellular senescence to degenerative aging. It also helped to change the culture of aging research more generally, one of the important contributions to a shift in attitudes that has led to a research and development community that understands the treatment of aging as a medical condition to be a practical, desirable goal. Here, discuss the role of cellular senescence in muscle aging specifically; how it contributes to harm and lost function, and what might be done about it.

Cellular senescence is increasingly recognized as a pivotal mechanism driving skeletal muscle aging and the development of sarcopenia, a condition characterized by the progressive loss of muscle mass, strength, and function. This review synthesizes recent evidence detailing the accumulation of senescent cells in aged skeletal muscle, including muscle stem cells (MuSCs), fibro-adipogenic progenitors (FAPs), immune cells, endothelial cells, and even post-mitotic myofibers. Senescence in these cell types impairs regenerative signaling, disrupts niche homeostasis, and propagates chronic inflammation.

Emerging therapeutic strategies, termed senotherapeutics, aim to counteract these effects through senolytics (which eliminate senescent cells) and senomorphics (which modulate the senescence-associated secretory phenotype), as promising interventions to restore muscle function and delay sarcopenia. We will also discuss the remaining challenges and future directions for studying senescence in skeletal muscle.

Link: https://doi.org/10.3803/EnM.2025.2816

There is a reasonable consensus in the research community on the broad categories of issue that lead to and are associated with the aging of the immune system. One can start by dividing immune aging into immunosenescence, a loss of capacity, versus inflammaging, a continual state of unresolved inflammatory signaling, and look at the various contributions to each state, for example. This paper is chiefly interesting for the attempt to propose classes of intervention to address immune aging based on the categorization of issues provided. This would not have been the case twenty years ago; the paper would have outlined what was known of immune aging and possible causes and then stopped. It is a reminder that we now live in an era in which the treatment of aging as a medical condition is widely accepted as an aspirational goal for the life sciences.

Immune aging is best understood not as a collection of isolated defects, but as a complex, interconnected reconfiguration of immune and tissue networks that alters how the body responds to internal and external stressors. Aging causes coordinated changes in innate and adaptive immunity, metabolic pathways, and inter-organ communication, creating a web of interactions whose emergent properties differ fundamentally from those of younger systems. Therapeutic targeting of immune aging aims to rebalance dysregulated inflammatory networks, restore immune adaptability, and improve tissue repair capacity. Current approaches range from mechanistically targeted pharmacological agents to regenerative, metabolic, lifestyle, and precision strategies. Evidence strength varies considerably, with some interventions supported by early clinical data and others remaining primarily experimental.

Interventions directed at fundamental drivers of immune aging, including chronic inflammatory signaling and cellular senescence, represent the most mechanistically advanced therapeutic class. Modulation of the mechanistic target of rapamycin (mTOR) pathway - through agents such as rapamycin and its analogs - has been shown to recalibrate immune metabolism, attenuate excessive inflammatory signaling, mitigate components of the senescence-associated secretory phenotype (SASP), and enhance antiviral responses in older adults, with early-phase clinical trials providing supportive evidence of immunological benefit. However, potential risks include metabolic dysregulation, impaired wound healing, and dose-dependent immunosuppression, emphasizing the need for intermittent or low-dose regimens.

Targeting intracellular inflammatory signaling represents a complementary strategy to rebalance immune network activity. Inhibitors of p38 mitogen-activated protein kinase (p38 MAPK) can restore macrophage functionality, enhance efferocytosis, and promote pro-resolving phenotypes in aging models. While mechanistically attractive, long-term systemic kinase inhibition may carry risks related to host defense impairment and unintended metabolic effects.

Cellular and regenerative interventions aim to restore immune architecture and adaptive capacity. Mesenchymal stem cells (MSCs)-based therapies exhibit immunomodulatory and tissue-repair properties, with encouraging preclinical and early clinical data suggesting benefits for inflammatory dysregulation and impaired regeneration. However, heterogeneity in cell preparations, uncertain durability of effects, and potential tumor-promoting signals remain key concerns. Reconstitution of adaptive immune output through thymic and hematopoietic rejuvenation represents an emerging but strategically important avenue. Beyond IL-7 supplementation, several molecular regulators are under investigation. Forkhead box N1 (FOXN1)-associated pathways, keratinocyte growth factor (KGF), and fibroblast growth factor (FGF) 21 contribute to thymic epithelial integrity and naive T-cell production, with preclinical evidence indicating delayed thymic involution and improved immune function.

Modulation of the gut microbiome through dietary fiber, prebiotics, probiotics, and microbiome-directed therapies can influence systemic inflammation and immune regulation. Diets rich in fiber and prebiotics, targeted probiotic supplementation, and microbiome-directed interventions can enhance gut barrier integrity, promote beneficial microbial taxa, and reduce translocation-induced inflammaging, thereby influencing systemic immune function and inflammatory set points. Improvements in barrier integrity and microbial metabolite production may reduce translocation-driven inflammatory activation. While mechanistically promising and supported by observational studies, variability between individuals and limited standardized clinical trials currently restrict therapeutic generalization.

Link: https://doi.org/10.3390/cells15050414

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

The gut microbiome changes with age in ways that negatively affect tissue function and health. This is known because we live in an age in which it costs little to accurately measure the composition of the gut microbiome from a stool sample: which microbial species, and the relative abundance of each species. Bacterial species can be distinguished from one another by differing sequences of the 16S rRNA gene, so low-cost and relatively unsophisticated gene sequencing approaches can be used to characterize an individual's gut microbiome. The result is something of a golden age in the identification of new ways to adjust the gut microbiome to improve health.

Today's open access paper stands out as interesting, in that the authors establish a correlation between the prevalence of a single bacterial species, Roseburia inulinivorans, and muscle strength in mice and humans. The Roseburia inulinivorans population diminishes with age. Increasing the Roseburia inulinivorans population size via supplementation with live bacteria enhances muscle strength in mice. The size of that increase in strength was on the order of 30%, more than large enough to expect the emergence of a deluge of Roseburia inulinivorans live probiotic supplements in the years ahead. A trial of those supplements will be needed to determine the size of the effect on human muscle strength, but given the low cost of single species probiotic manufacture, that seems worth the effort.

Roseburia inulinivorans increases muscle strength

Gut bacteria have been implicated in a wide range of health conditions, yet their potential role in preventing and treating muscle-wasting disorders remains largely unexplored. We aimed to investigate whether specific gut microbial species are associated with muscle strength and to explore underlying mechanisms linking the gut microbiota to muscle health. We conducted metagenomic analyses in cohorts of younger and older adults extensively phenotyped for muscle strength. Associations were tested between bacterial taxa and performance measures. Causality was assessed by oral supplementation of candidate species in antibiotic-treated mice. Metabolomic profiling and muscle phenotyping were performed to elucidate mechanisms.

The relative abundance of Roseburia inulinivorans, but not other Roseburia species, was positively associated with multiple strength measures including handgrip, leg press, and bench press in humans. Supplementation of R. inulinivorans in mice significantly enhanced forelimb grip strength, whereas other Roseburia species had no effect. Metabolomic analyses revealed that R. inulinivorans reduced amino acid concentrations in the caecum and plasma, while activating the purine and pentose phosphate pathway in muscle. These changes coincided with increased muscle fibre size and a shift from type I to type II fibres. Accordingly, we observed that the relative abundance of R. inulinivorans is lower in older adults compared with young adults.

R. inulinivorans emerges as a species-specific modulator of muscle strength, linking gut microbiota to muscle metabolism and function. These findings support its potential as a probiotic candidate for nutraceutical interventions targeting age-related muscle-wasting diseases.

The aging of the brain is characterized by the formation of solid aggregates of misfolded amyloid-β peptides. This is a foundation for later loss of cognitive function and the development of the more severe, inflammatory dysfunction of late stage Alzheimer's disease. Researchers here provide data from cell studies to suggest that the innate immune cells known as microglia maladaptively manufacture amyloid-β aggregates in the process of attempting to clear amyloid. Microglia have been the target of increasing interest in the context of the aging of the brain and development of neurodegenerative conditions, though much of that has focused on growing inflammation driven by this cell population. It seems we might have to consider that the normal operation of microglia becomes pathological when faced with protein aggregates, a part of the complex opening stages of Alzheimer's disease and perhaps other neurodegenerative conditions.

A new study shows that immune cells called microglia can actively promote the formation of plaques in Alzheimer's disease, challenging the long-standing view that these cells serve only as defenders against plaque buildup. "Most studies suggest that microglia are there to clean up the brain and remove the amyloid plaques. What we discovered is that actually they're part of the problem. They generate plaques. It was thought that plaques aggregate by themselves. And it seems that the microglia, by trying to deal with the problem, amplify it."

The research team shows that microglia can remodel soluble amyloid-beta (Aβ42) into extracellular fibrils with potent seeding activity. Seeding is a key problem in disease: it is the process by which one aggregate gives rise to multiple new aggregates. These are the same type of structures that accumulate in the brains of patients with Alzheimer's disease. "Our results suggest that many plaques in Alzheimer's brains may arise through cellular processes rather than spontaneous aggregation. We think this highlights a second role for microglia we were previously unaware of. Using seeding assays, we showed that cell-generated amyloid more closely resembles brain-derived amyloid and triggers disease-relevant cellular responses, establishing a model that better reflects what happens in patients."

Link: https://vib.be/en#/news/brain-immune-cells-may-help-build-not-just-clear-alzheimers-plaques

One of the avenues by which regular exercise produces health benefits is through adjustment of the composition of the gut microbiome, favoring the production of metabolites that improve health. A range of metabolites produce by gut-resident microbial species influence important cell types in the body and brain, and are to some degree necessary for normal tissue function. Here, for example, researchers trace the influence of exercise through its effects on the abundance of various bacterial species in the gut to alterations to tryptophan metabolism to effects on memory function and mood in the brain.

Exercise exerts beneficial effects on mood and memory. One emerging pathway through which exercise influences brain health is via the gut microbiota, which produces metabolites that can influence host brain functions. However, it is not yet known which exercise-induced alterations in the gut microbiota are associated with alterations in systemic metabolites that may affect the brain. We investigated the effect of exercise on the gut microbiota and serum metabolomics profile in adult male rats and examined the association of these microbial-mediated changes with brain processes.

Exercise decreased the relative abundance of two tryptophan-metabolizing bacterial genera, Alistipes and Clostridium. Serum metabolomics revealed that exercise enhanced tryptophan metabolism, with a greater abundance of the serotonin catabolite 5-hydroxytryptophol identified. The abundance of genus Clostridium was negatively nominally associated with serum levels of 2-oxindole, an indole derivative. Analysis of the gut-brain modules also revealed that tryptophan metabolism was enhanced by exercise. Furthermore, exercise decreased hippocampal expression of the aryl hydrocarbon receptor, a mediator of the effects of tryptophan-metabolizing gut microbes on neuronal function.

Taken together, results suggest that exercise modulates gut microbes associated with systemic tryptophan metabolism, which may exert beneficial effects on memory and mood via regulation of the aryl hydrocarbon receptor.

Link: https://doi.org/10.61373/bm026r.0009

On the matter of cellular senescence as a contributing cause of degenerative aging, there is a school of thought whose members argue that at least some senescent cells are doing something useful by existing, despite their problematic behavior. Therefore therapeutic approaches should focus on prevention of senescence (senostatics) or reducing the harmful senescence-associated secretory phenotype (SASP) (senomorphics) rather than on outright destruction of senescent cells (senolytics). Within the array of possible ways to reduce the pace at which cells become senescence, sabotaging the ability of senescent cells to encourage their neighbors to also become senescent has been little explored, so it is interesting to note recent work on this topic.

Today's open access paper represents is an early step on the path to finding ways to block bystander senescence. It is likely that the relevant interactions differ by cell type and tissue, making it a more challenging exercise than would otherwise be the case. Here, the focus is on the brain, and the researchers outline potential target interactions that might be blocked to reduce the spread of cellular senescence in an aged brain. As an approach to therapy, this does have the look of an intervention that could increase risk of cancer, however. The ability of the senescent state to spread from cell to cell is one of the ways in which early cancers are suppressed before they can become an issue. But at the end of the day, the only practical way to assess hypothetical benefits versus hypothetical risks is to build a therapy and test it in animal studies.

Characterizing the SASP-Dependent Paracrine Spreading of Senescence Between Human Brain Cell Types

One of the defining phenotypes of a senescent cell is the senescence-associated secretory phenotype (SASP), which can propagate senescence in neighboring cells both in vitro and in vivo. Importantly, this paracrine spreading of senescence can act in a cell non-autonomous manner, influencing neighboring cell populations and contributing to immune cell recruitment. As cellular senescence has recently been linked to both age-related neurodegenerative phenotypes and local inflammation and is more clearly defined across brain cell types in a cell-type-dependent manner, an urgent question remains regarding how a cell-type-specific paracrine spreading of senescence occurs in the brain.

Here, we sought to unravel the relationship between key brain cell types (astrocytes, endothelial cells, microglia, oligodendrocytes, and neurons) in the context of a paracrine spreading of senescence via the SASP. We utilized our previously established in vitro DNA damage-induced human brain cell line senescence model and conditioned media experiments to profile the cell-type-dependent SASP, characterize the directionality of a paracrine spreading of senescence between the relevant cell types, identify key SASP ligands and receptors that mediate the cell-type-specific spread, and target these factors using various inhibitors in an attempt to prevent the paracrine spreading of senescence.

We demonstrate that a cell-type-specific SASP profile of each brain cell type drives differential induction of secondary senescence, where some cell types can induce senescence in themselves as well as in other cell types, while other cell types are only capable of receiving secondary senescence induction, but cannot spread. Importantly, we identified both cell-type-specific and common SASP ligands and receptors, which we successfully targeted to prevent the induction of secondary senescence depending on the cell types communicating with one another. Taken together, this work gives key insights into the mechanisms of paracrine spreading of senescence between brain cell types in vitro and offers potential therapeutic targets to prevent this spreading, which may in turn help to alleviate age-related tissue decline and inflammaging.

Researchers here provide data on the correlations between (a) secreted proteins circulating in blood that are distinct to senescent cells of various types, and (b) a number of different age-related conditions. Some cell types are better than others when it comes to the strength of correlation between the burden of senescence as assessed by circulating proteins and status of given age-related condition. This process of mapping the landscape of senescence and aging sets the stage for the development of better assays that can inform patients as to the risk resulting from the burden of senescence, and later the degree of improvement produced by therapies capable of reducing the burden of senescent cells.

Senescence is characterized in part by proteomic expression changes, including the secretion of pro-inflammatory cytokines and other proteins, which become amplified during sustained senescence and in large part drive its deleterious effect in a chronic, age-related context. These senescence-associated proteins (SAPs) have since proven to be heterogeneous by cell type and senescence-inducing stimulus.

One promising technique in assessing individual senescence burden is through the quantification of SAPs in circulating plasma. The plasma senescence burden has previously demonstrated compelling clinical associations, including with age, frailty, and mortality. In recent years, a group of senescence-targeting compounds collectively known as senotherapeutics has been investigated for their limited and context dependent senescence-attenuating effects. Senotherapeutic drugs have demonstrated an ability to lower circulating SAPs in human trials, and to partially alleviate some aging phenotypes.

A remarkable recent finding is that beyond general clinical traits such as age and mortality, organ-specific proteins can be tracked in circulation and used to model organ age and organ-specific clinical traits. Considering the previously demonstrated clinical relevance of circulating canonical senescence signatures, examining cell type-specific senescence signatures in circulation could similarly shed light on the unique clinical relevance of organ-specific senescence.

In this study, senescence signatures from the Senescence Catalog (SenCat), including 14 human cell types such as peripheral blood mononuclear cells, renal epithelial cells, vascular smooth muscle cells, among others, are examined for their clinical relevance in circulation in two longitudinal studies: 1,275 participants of the Baltimore Longitudinal Study of Aging (BLSA) and 997 participants of the Invecchiare in Chianti (InCHIANTI) study. Notably, pooled senescence proteins outperformed non-senescence proteins in predicting many clinical parameters such as age and hypertension, and in many instances cell type senescence signatures mapped most strongly to their corresponding health domain. Importantly, the immune cell senescence signature is associated with future onset of several diseases such as diabetes.

Link: https://doi.org/10.64898/2026.02.06.26345739

Senescent cells accumulate in tissues with age to promote degenerative aging. Senescent cells cause harm via the signals that they send to other cells, the senescence-associated secretory phenotype (SASP). The SASP is by no means fully understood, and while it clearly contains many pro-inflammatory and pro-growth signals, it probably has many other effects as well. Here, researchers provide evidence for one specific SASP signal molecule to interfere in the benefits of exercise. Clearance of senescent cells should therefore produce an enhanced response to exercise in old individuals, in addition to the other benefits already demonstrated in a sizeable number of animal studies.

Adaptation to physiological stress is fundamental to health but varies widely among individuals. In humans, this heterogeneity is evident in markedly different gains in fitness in response to identical exercise training. The molecular determinants of this variable "trainability" remain poorly understood. Here we identify insulin-like growth factor binding protein-7 (IGFBP7), a senescence-associated secreted protein, as a circulating constraint on exercise adaptation.

Plasma proteomics in older adults enrolled in a randomized exercise trial revealed that IGFBP7 levels inversely predicted fitness gains after one year of high-intensity interval training despite similar baseline fitness. In mice, genetic deletion of IGFBP7 markedly amplified training-induced gains in exercise capacity across distinct training protocols, whereas somatic overexpression abolished this advantage. In the UK Biobank, lower IGFBP7 levels were associated with reduced mortality and multiple incident age-related diseases, mirroring the breadth of ties between fitness and healthspan.

Together, these findings identify circulating IGFBP7 as a molecular brake on physiological plasticity in response to exercise, linking training responsiveness, aging biology, and health outcomes.

Link: https://doi.org/10.64898/2026.02.09.26345899

Startup biotech companies have started to use the publication of preprint scientific papers as a way to enhance their standing with investors; putting out a preprint is considerably faster than formal publication, and requires no review process. Many startups undertake programs of research and development that are novel enough to have little in the way of a foundation of prior scientific literature, and thus this is one area of scientific publication in which more weight than usual should be given to the peer review process. In particular, one should be skeptical regarding claims of very large extension of life span in animal models in preprint papers.

Yes, someone will turn up at some point with a surprising, novel approach to rejuvenation that is impressive in comparison to the past scope of slowed aging and extended life in mice, and perhaps that program will be wrapped in a biotech company, and perhaps they will want the benefits of publishing as soon as possible rather than waiting on review. That future seems inevitable, given the pace of progress in aging research and the trend towards opening and democratizing the peer review process. Nonetheless, extraordinary claims still require extraordinary evidence. The history of claimed extension of life span in mice is littered with failed replication, and particularly so for studies that used small numbers of mice and claimed a large extension of life.

The startup biotech program reported in today's preprint paper is conducted by Sentcell. It is interesting and novel enough for the rest of the world to be skeptical until much more work on the topic is published. The size of the reported extension of life in mice resulting from their novel therapy is very large relative to the best that can be achieved via established approaches; large enough to reduce the credibility of the work, especially given the small numbers of mice used per study group. The researchers claim to have isolated a particular subset of cell communications that induces rejuvenation, which in and of itself is reasonable. Many companies and research groups are indeed exploring how cells might change one another's behavior for the better. Consider that stem cell therapies produce benefits via the signaling of transplanted cells as one example among many. It is the size of gain in mouse life span reported here that calls for a far greater body of supporting evidence in order to be taken at face value, given how very much larger it is than the effects of, e.g. stem cell therapies, exosome therapies, senolytics, and so forth.

CD4+ T cells confer transplantable rejuvenation via Rivers of telomeres

One theory attributes ageing to the accumulation of terminally differentiated or senescent cells in multiple tissues, disrupting homeostasis. A true fountain of youth would need to target senescent cells across organs, be tightly regulated, and transfer youth-promoting activity from a young organism to an old one - as in the original parabiosis studies. One rejuvenation candidate arises from telomere transfer between immune cells. We previously showed that antigen-presenting cells (APCs) donate telomere-containing vesicles to CD4+ T cells during immune synapse formation, extending their telomeres, preventing senescence, and generating long-lived, stem-like memory T cells.

Here we show that, after telomere acquisition, recipient CD4+ T cells undergoing fatty acid oxidation, assemble and release "Rivers" of telomeres into the circulation. These Rivers recycle surplus APC telomeres unused by the T cells and rejuvenate tissues throughout the body, extending lifespan - an unprecedented programme in which CD4+ T cells transmit youth-promoting signals between organisms. While analysing antigen-specific T cell memory responses, we observed that APC telomere transfer was accompanied by abundant extracellular telomeric material. Histology revealed that these extracellular telomeres were not merely tethered to T cells but arranged in vessel-like networks, suggesting release into circulation. The elongated, punctate structures appeared to flow along these networks, evoking miniature streams of genetic material - henceforth referred to as telomere Rivers.

In aged mice, adoptive transfer of young or metabolically reprogrammed CD4+ T cells triggered River production in vivo, and Rivers isolated from these animals could be transplanted into other aged mice to propagate the rejuvenation phenotype independently of T cells. River therapy extended median lifespan by ∼17 months, with several mice surviving to nearly five years. This immune-driven telomere transfer pathway is conserved across kingdoms, including plants, defining the first systemic, transplantable programme of youth.

The chemistry of structural proteins in the lens of the eye changes with age in ways that render the lens less flexible, contributing to vision issues such as presbyopia, and eventually degrade its transparency. Age-related cataracts are the outcome of chemical alterations that cloud the lens and eventually lead to blindness. Better understanding the chemistry involved in this loss of transparency should hopefully lead to ways to replace the problematic molecular structures, or at least help to prevent the early stages of their formation. This is more challenging for the lens of the eye than is the case for most tissues that become damaged with age, as there is at best very limited natural replacement of the structural proteins of the lens. At present, replacement approaches are focused on surgery to replace the lens rather than any sort of nanoscale, chemical intervention that preserves the existing tissue.

The human eye lens plays an essential role in vision by focusing light onto the retina. This transparent tissue consists of densely packed crystallin proteins that exhibit remarkable solubility despite minimal protein turnover. Unlike most proteins, which are continuously recycled, crystallins must remain stable and soluble throughout the human lifespan. Aging causes damage to the lens, primarily via photochemical oxidation. Over time, this causes crystallin aggregation and leads to cataract.

Although understanding oxidative damage is critical to understanding cataract formation and how it can be prevented, it is difficult to study in native biological systems. Here, we use genetic code expansion to introduce an oxidation product, 5-hydroxytryptophan (5HTP), in a key site in human γS-crystallin, enabling it to be specifically investigated under controlled conditions. Replacing a critical tryptophan residue with 5HTP leads to reduced stability and increased aggregation.

Link: https://doi.org/10.1016/j.bpr.2026.100251

Take an aging population and a measure of function, and on average that measure will decline over time. That is degenerative aging in a nutshell, a loss of function, eventually including the very important function of staying alive. Within the environment of an average decline, however, it is possible to find individuals who manage to improve function between time points. Consider that it is well demonstrated that even very old people can improve capacity and reduce mortality risk by undertaking programs of structured exercise and strength training, for example. Few of us are exercising to an optimal level.

A widespread assumption exists among scientists, health care providers, and the public that later life is a time of inevitable and universal cognitive and physical decline. This assumption is likely due to considering older persons who improve to be exceptions, and the reliance on aging-health measures that do not allow for improvement. In contrast, we utilized a measure that allowed for an upward trajectory to occur. Our objective was to examine whether a meaningful number of older persons improve with this measure and, if so, to examine whether a promising modifiable culture-based variable, positive age beliefs, contributes to this improvement.

Individuals 65 years and older, who participated in a nationally representative longitudinal study, had their physical health assessed by walking speed and their cognitive health assessed by a global performance measure. We calculated the percentage of the sample that showed improvement in each domain from baseline to the last measurement up to 12 years later. We also examined whether a positive-age-belief measure predicted this improvement in regression models. It was found that 45.15% of persons improved in cognitive and/or physical function over this period, and positive age beliefs predicted these two types of improvement, both with and without adjusting for relevant covariates.

Link: https://doi.org/10.3390/geriatrics11020028

Species capable of exceptional regeneration also tend to have longer life spans and slowed aging relative to similar species with less proficient regenerative capabilities. Various closely related species of spiny mouse have been studied in the context of mammalian regeneration because of their ability to shed a large amount of skin and supporting tissues as a defensive mechanism, and later regrow that tissue without scarring. This exceptional regenerative capacity extends to at least some internal organs as well. Spiny mice have been used in past studies that pointed to differences in the activity of macrophage cells as one of the important determinants of complete regeneration versus scar formation.

Macrophages are innate immune cells that are deeply involved in ongoing tissue maintenance and regeneration from injury. Finding out exactly how differences in macrophage behavior are regulated in species capable of proficient regeneration, and whether those changes can be introduced into humans as a basis for therapy, remains an ongoing project. Today's open access paper extends this line of research to further link altered macrophage and broader immune behavior in spiny mice to a slowed pace of age-related decline. There is clearly a bigger picture here regarding aging, tissue maintenance, regeneration, and the innate immune system that researchers are in the early stages of assembling, step by step. At the end of the day it seems likely that there will be close ties between how the innate immune system regulates inflammation, its efficiency in certain activities, such as clearance of senescent cells, and both aging and regeneration.

Immunometabolic resistors of aging in long-lived golden spiny mice

One of the key manifestations of aging is a loss of biological resilience, including a slowdown in cell and tissue repair processes due to chronic sterile inflammation and metabolic stress. Long-lived wild rodents closely related to laboratory mice on the evolutionary scale may allow identification of dormant pathways that resist aging. Spiny mice (Acomys) are known for their exceptional regenerative capacity, but their resilience to aging is unknown.

Here, we report that aged golden spiny mice (Acomys russatus), reared in a non-pathogen-free environment, resist functional decline, have a greater repair capacity with reduced senescence in immune-metabolic organs compared to their sister species, eastern spiny mice (Acomys dimidiatus). Compared to A. dimidiatus, A. russatus retained high tissue repair capacity, reduced frailty with lower inflammaging, fibrosis, cellular senescence, and youthful transcriptome even beyond 4 years. Given that our A. russatus cohort was outbred and reared under non-SPF conditions, this model could be especially relevant for the identification of biomedically relevant mechanisms of health and longevity that are typically obscured in standard genetically identical laboratory mice.

Aged A. russatus maintains transcriptional integrity akin to young mice, highlighting experimental checkpoints for inflammation and mortality. A finding of immune system adaptation of A. russatus was the maintenance of functional thymic architecture till 4 years of age. Notably, the thymi of A. russatus were protected from lipoatrophy and involution, similar to naked mole-rat and long-lived fibroblast growth factor 21 (FGF21) transgenic mice that maintain naïve T cell repertoire till advanced age. We further identified that elevated levels of clusterin in A. russatus macrophages restrain inflammaging and enhance health span in aged mice. Thus, A. russatus biology reveals therapeutically actionable targets that may enhance or maintain function during aging.

Some of the organs in the body do not have to be in their current location, nor structured in a single mass of tissue, in order to carry out all of their functions. The liver is one of these organs. Many (not all, but many) of the functions of the liver could be carried out by small amounts of liver tissue distributed throughout the body. Thus the existence of companies like Lygenesis, shepherding clinical trials of liver tissue organoid transplantation into lymph nodes to help restore lost function. Here, researchers report on the early stages of development for an alternative approach that is even less like normal liver tissue, essentially just an injection of cells and hydrogel rather than any production of structured tissue for transplantation, but that nonetheless produces a small volume of pseudo-tissue at the injection site that can carry out many of the functions of the liver.

Liver transplantation remains the standard treatment for end-stage liver failure, yet it is limited by donor scarcity, surgical complexity, and poor accessibility. Cell-based therapies offer an alternative, yet their translation has been hindered by low engraftment, poor localization, and a lack of delivery strategies that are both effective and minimally invasive. To address these challenges, we developed injected, self-assembled, image-guided tissue ensembles (INSITE), an injectable platform composed of primary human hepatocytes (PHHs) and hydrogel microspheres that assemble in situ into supportive, vascularizable scaffolds following image-guided delivery.

Ultrasound-guided delivery into an ectopic site enabled precise graft localization, persistent noninvasive imaging, and vascular integration in vivo. Hepatocytes remained confined within these scaffolds and maintained long-term functional activity. Furthermore, tuning material properties allowed control over scaffold remodeling and vascular recruitment to enhance graft function. By integrating image-guided delivery with a modular scaffold, INSITE establishes a clinically compatible strategy for advancing minimally invasive cell therapies.

Link: https://doi.org/10.1016/j.celbio.2026.100378

Researchers here mount an argument for aging to have evolved due to the interaction between (a) limited nutrient availability in the environment and (b) the options a cell has for generating the vital chemical energy store molecule adenosine triphosphate (ATP). Broadly, ATP can be generated via glycolysis in the cytoplasm or oxidative reactions in mitochondria, at least in eukaryotes such as mammals. Mitochondrial ATP production is slower and more energy-efficient, but both avenues decline with age. Loss of ATP production is harmful to cell and tissue function, most prominently in tissues with high energy needs such as muscle and the brain. Why does ATP production decline with age? The argument advanced here is that this decline evolved in part because it helps the survival of offspring by limiting parental consumption of resources, which borders on being a group selection mechanism. Group selection has long fallen out of favor, but a number of theories of aging, particularly those in the programmed aging category, have considered it to one degree or another.

Why do animals not have an eternal lifespan? Animals possess sophisticated systems that, in many species, appear capable of supporting immortality. Second, why do lifespans vary considerably among species despite similarities in genetic makeup, specifically the central dogma linking DNA, RNA, and protein synthesis, which warrants a molecular explanation? For example, elephants live thirty times as long as mice.

Significant differences between ATP production by glycolysis and oxidative phosphorylation include the quantity produced, production speed, and functional roles. Glycolytic ATP production is approximately 100 times faster than oxidative phosphorylation. ATP from glycolysis supplies rapid energy during acute demands, while oxidative phosphorylation supports basal/homeostatic cellular energy needs. Glycolysis plays important role in cell division and DNA repair. Additionally, the glycolysis activator HIF-1α promotes mitochondria repair through mitophagy. These findings suggest that decreased glycolytic ATP production during aging may underline various age-related symptoms. Immortal cells exhibit a metabolic profile characterized by highly active glycolytic ATP production and HIF-1α activation, even in oxygen-rich conditions.

Populations of species cannot grow infinitely, and one of the major limiting factors in natural world is food supply. The shift from glycolysis to aerobic metabolism increases energy efficiency, benefiting individual survival during food shortages, which can be caused by environmental changes or emergence of competitors for the food. This indicates that reduced glycolytic ATP production with aging can benefit the species by enhancing survival of parent generation at starvation conditions and allocating food to offspring generation in natural world where food supply is limited. Only species that happened to have an optimal rate of reduction in glycolytic ATP production over time were selected and survived through generational changes.

The optimal rate of glycolytic ATP decline for survival varies among species and depends on factors such as environment, competition, maturation time, and body size. This concept clarifies the significant differences in aging rates and lifespans across species despite largely conserved biological components. This is exemplified by the naked mole rat, an exceptionally long-lived species that lives underground where there are few environmental changes and predators, and maintains unrestrained glycolytic flux and ATP supply to adapt to underground life with low oxygen levels.

Link: https://doi.org/10.18632/aging.206356

Mitochondria are the power plants of the cell, vital to cell and tissue function. Mitochondria become damaged and dysfunctional with age, unfortunately, and this is thought to be a major contribution to age-related degeneration. That cells will take up mitochondria from the surrounding environment and put them to use has been established for some years. It is the basis for the development of mitochondrial transplantation therapies as a way to improve cell function in old tissues, delivering youthful mitochondria to augment the activities of native mitochondria that have been impaired by mechanisms of aging. Meanwhile, the research community continues to explore how exactly cells achieve uptake of mitochondria, as greater knowledge of the details may lead to ways to significantly improve on the coming first generation of mitochondrial transplantation therapies.

In today's open access paper, researchers report results from their study of how exactly the processes of endocytosis can be used to ingest mitochondria while preserving their structure and function. As a mitochondrion comes into contact with the exterior of the cell membrane, a region of the membrane wraps around the mitochondrion and then breaks off to bring it inside the cell, wrapped in an endosome. At some point the endosome is removed and the mitochondrion is fully internalized, intact and able to contribute to cell metabolism. This is a very high level description; there are a number of functionally distinct forms of endocytosis, and it appears that different types of endocytosis are used interchangeably for mitochondrial uptake, making it a more robust behavior.

Uptake mechanisms and functions of isolated mitochondria in mesenchymal stromal cells

Mitochondrial transplantation holds great promise as a therapeutic strategy; however, the mechanisms by which recipient cells interact with and internalize isolated mitochondria remain unclear. Therefore, in this study, we isolated functional mitochondria from mesenchymal stromal cells (MSCs) and characterized their biological activities and physicochemical properties. Additionally, effects of isolated mitochondria on MSC functions were evaluated.

Treatment with isolated mitochondria promoted cell proliferation, improved cellular viability under stress conditions, and increased the oxygen consumption rate, indicating enhanced bioenergetic capacity. Uptake of isolated mitochondria by MSCs was visualized via fluorescence imaging and quantitatively assessed over time, showing progressive internalization within 24 hours. To investigate the mechanism of mitochondrial uptake, endocytosis was chemically inhibited, which revealed that endocytic pathways contributed to the internalization of the isolated mitochondria.

These findings suggest that MSCs incorporate isolated mitochondria via active uptake mechanisms and that the internalized mitochondria retain their functional activity. Collectively, our results provide critical evidence of mitochondrial internalization in MSCs and offer insights into the potential applications of mitochondrial therapy for various diseases.

A number of existing classes of drug are suspected to be geroprotective to some degree, altering metabolism in ways that either reduce ongoing cell and tissue damage or help to resist some of the consequences of that damage. We should expect effects on life span at established doses to be modest at best, but there is always the question of how large an effect on human life span can remain hidden because no-one was looking all that hard for it. Here, researchers present evidence for a commonly used PPARα agonist to slow aging in various mouse model. It remains a question as to whether effects in humans are meaningful in comparison to, say, the established benefits of regular exercise.

Aging poses a growing global health burden, creating an urgent need for effective interventions. This study reveals that fenofibrate, a clinically approved drug for hyperlipidemia, exerts significant anti-aging effects by targeting fundamental aging processes. We demonstrated that fenofibrate treatment delays systemic aging in D galactose-induced aging mice, 18-month-old mice, and SAMP8 mice and reverses cellular senescence. Mechanistically, fenofibrate ameliorates age-related lipid accumulation, as evidenced by lipidomic profiling and histological analyses in both cellular and animal models.

Notably, we identify carnitine palmitoyl transferase 1 C (CPT1C) as a crucial mediator of fenofibrate's ability to restore mitochondrial function in senescent cells, as validated by comprehensive metabolic analyses. Fenofibrate is a specific peroxisome proliferator activated receptor α (PPARα) agonist. These effects are mediated through PPARα activation, upregulating downstream metabolic regulators CPT1C. Fenofibrate cannot reverse aging in Pparα knockout mice, establishing that its anti-aging effects are strictly PPARα-dependent.

Our findings demonstrate that fenofibrate delays aging progression of mice and reverses cellular senescence in the PPARα-dependent way. Fenofibrate attenuates lipid accumulation and mitochondrial dysfunction in senescent cells and aged mice by activating the PPARα-CPT1C axis. This research provided the first evidence that pharmacological PPARα activation can directly modulate natural aging through coordinated improvement of lipid metabolism and mitochondrial function. The clinical relevance is underscored by the safety profile and widespread use of fenofibrate, suggesting its immediate potential as a repurposed anti-aging therapeutic. Furthermore, this work establishes PPARα as a master metabolic regulator of aging processes and reveals CPT1C as a novel therapeutic target for age-related metabolic dysfunction.

Link: https://doi.org/10.1016/j.phrs.2026.108154

Periodontitis, the formal name given to inflammatory gum disease, is known to correlate to risk of a range of age-related conditions, including osteoporosis, the loss of bone mass and strength that occurs with age. A number of different mechanisms may be responsible for these correlations, and it remains a matter for debate as to which is most important. In the context of cardiovascular disease, researchers have focused on leakage of oral bacteria and inflammatory metabolites into the circulation via injured gums. Here, in the context of osteoporosis, researchers suggest that the oral bacteria responsible for periodontitis can alter the composition of the gut microbiome in ways that impair bone tissue maintenance, favoring the destruction of bone extracellular matrix by osteoclasts over matrix deposition by osteoblasts.

Epidemiological studies have highlighted an association between periodontitis and osteoporosis. However, the mechanism underlining this association remains unclear. Here, we revealed significant differences in the salivary microbiota between periodontally healthy individuals and periodontitis patients, with periodontitis patients exhibiting increased salivary microbiota diversity and an elevated abundance of pathogenic bacteria.

Using an ovariectomized (OVX) mouse model, we demonstrated that the salivary microbiota from periodontitis patients exacerbated bone destruction by modulating the gut microbiota. Metabolomic analysis revealed that the periodontitis-associated salivary microbiota suppressed tryptophan metabolism. The tryptophan metabolite indole-3-lactic acid (ILA) directly inhibited osteoclast formation and differentiation. In OVX mice treated with periodontitis salivary microbiota, supplementation with ILA effectively suppressed osteoclastogenesis and alleviated the detrimental effects of periodontitis-associated salivary microbiota on systemic bones.

In summary, our data demonstrate that periodontitis can affect systemic bone metabolism via the oral-gut axis and that ILA supplementation serves as a potential therapeutic option to mitigate these adverse effects.

Link: https://doi.org/10.1038/s41368-025-00415-2

Neurogenesis is the creation of new neurons from stem cell populations, followed by the integration of these newly created cells into existing neural networks. Neurogenesis is required for memory and learning to take place in the adult brain, and is thought to provide an important contribution to what limited capacity for regeneration exists in brain tissue. If researchers could induce a greater degree of neurogenesis, this could be a path to greater repair of an injured brain, and restoration of lost function in an aged brain.

This high level view of neurogenesis skates over a great deal of complexity, much of which has yet to be mapped. For example, which cell populations are responsible for generating new neurons? What are their regulating mechanisms? Why does activity decline with age? Neurogenesis does not emerge from one single cell population; it isn't just neural stem cells, and even that label covers a great many distinct varieties and locations of cell within the brain. Some sources of neurons are even found outside the brain - nearby, but not within brain tissue.

Today's open access paper gives a sense of the work needed to pin down just one of the many cell populations that can act as sources of new neurons for the adult brain. Here, the cells are resident in bone marrow of the skull. The authors summarize their findings to present both the distinct subpopulation of mesenchymal stem cells that generates neurons and a way to beneficially manipulate its activity via increased expression of the ANKRD1 gene. A viral gene therapy delivered systemically, but where the ANKRD1 expression is constrained by promoter, increases neurogenesis in aged mice to improve cognitive function.

ANKRD1 sustains a neurogenic BMSC niche and counters cognitive aging

Craniofacial bone marrow mesenchymal stromal cells (BMSCs) derived from neural crest stem cells (NCSCs), which represent a transient embryonic progenitor population endowed with diverse lineages, including peripheral neurons and glia. Emerging evidence suggests adult BMSCs retain traces of their NCSCs heritage, exhibiting latent neurogenic plasticity that could be harnessed for neural repair. Despite progress in characterizing BMSCs multipotency, the transcriptional circuits preserving their neural competence during aging and the mechanisms by which they deteriorate remain unresolved.

In this study, through scRNA-seq of human BMSCs, we discovered a discrete subpopulation exhibiting molecular signatures of neurogenic potential. Gene enrichment analysis identified ANKRD1 as a top-scoring candidate, and subsequent validation studies confirmed its role as a key regulator of this neurogenic phenotype. We propose that ANKRD1 may sustain neurogenic competence in undifferentiated BMSCs, a capacity that is progressively eroded by aging or differentiation-associated transcriptional reprogramming. Mechanistically, protein-DNA interaction profiling revealed that ANKRD1 directly engages with enhancer elements of SOX2 and NESTIN, thereby preserving their expression and reinforcing neural-lineage characteristics.

Critically, neuron-targeted ANKRD1 delivery rescues spatial memory deficits in aged mice. These findings establish ANKRD1 as a therapeutically tractable regulator that sustains neurogenic chromatin reservoirs to support neurocognitive resilience, opening avenues to counter cognitive aging.

Researchers have demonstrated that many forms of mild, repeated stresses can improve cell function and slow aging. Lack of nutrients, lack of oxygen, heat, cold, oxidative damage, and others have been demonstrated to be beneficial in animal studies. Here, researchers discuss what is known of the response to hypoxia specifically, but note that many of the mechanisms involved are the same as those involved in other forms of stress response. The cell increases maintenance activities, for example, such as the processes of autophagy responsible for recycling damaged proteins and structures. This in turn helps to reduce the risk of cells becoming senescent. A fair amount of effort has been devoting to finding ways to trigger increased autophagy and other beneficial responses to mild stress using small molecule drugs, which has given rise to work on mTOR inhibitors and a range of other classes of compound.

Hypoxia is a physiologically relevant microenvironment in both normal and diseased tissues and has emerged as a potent modulator of cellular senescence and organismal longevity. This review synthesizes evidence that hypoxia delays senescence across diverse experimental systems and species, and highlights mechanisms by which hypoxia rewires chromatin states during senescence-associated transitions. We focus on oxygen- and α-ketoglutarate-dependent epigenetic regulators, particularly histone lysine demethylases, whose catalytic activities are limited under hypoxia. Consequently, histone methylation increases and higher-order chromatin organization is stabilized.

Using oncogene-induced senescence as an experimentally tractable framework, we discuss recent findings showing that hypoxia suppresses senescence-associated histone clipping, preserves nuclear lamina integrity, and restrains large-scale heterochromatin reorganization while leaving canonical cell-cycle arrest largely intact. We further consider emerging links among DNA damage, epigenetic instability, and aging phenotypes, and propose that senescence can be viewed as a breakdown of coordinated epigenetic homeostasis. By integrating these concepts, we position hypoxia and hypoxia-mimetic interventions as promising strategies to modulate aging-associated cellular states and to explore therapeutic opportunities in age-related pathologies.

Link: https://doi.org/10.4062/biomolther.2026.014

The study of aging is an ongoing project, as is the study of cellular metabolism. The research community remains some way from a complete understanding, and as such there is a great deal of ongoing empirical discovery. Popular areas of study exist because someone demonstrated that a particular approach to therapy produced a slowing or reversal of measurable aspects of aging. Others then join in to try to understand how it works. None of these existing approaches are yet fully understood, in part because they produce complex changes in complex systems. Layered atop considerations of aging in laboratory mice and humans is the point that the world contains thousands of species that researchers might plausibly study, many of which exhibit quite different patterns of aging or specific aspects of aging biology. There is more complexity than can be engaged with in any reasonable amount of time, but discoveries made in recent decades suggest that there is the potential to find useful new approaches to the treatment of aging by comparing different species. It just won't happen quickly.

Despite still being an emerging field of research, biogerontology has made remarkable progress in identifying molecular principles of cellular aging over the last two decades. The categorization of these principles into "hallmarks of aging" has proven useful, as experimental modulation of these hallmarks in various model organisms can alter aging trajectories. In nature, we encounter remarkable variation in lifespan and demographic aging across individuals, species, populations, and space. Why has this variability evolved? Do the same "hallmarks of aging" identified as important in laboratory animals explain this variation? How do the molecular processes shaping aging vary across species and environmental conditions? What role do developmental processes and conditions play in shaping the onset and rate of aging across species? These fundamental questions remain largely unanswered. Yet, they are critical not only for advancing the biology of aging but also for designing interventions to mitigate age-related decline.

Understanding why particular pathways or hallmarks matter in specific taxa, and how developmental processes interact with environmental constraints to shape aging, requires synthesizing and comparing mechanisms identified in classical model organisms with those discovered in non-model species spanning broad phylogenetic and ecological contexts. Many evolutionary theories of aging were proposed well before the discovery of the molecular mechanisms involved, and they remain largely theoretical. Moreover, the growing number of model organisms and the expanding array of experimental and theoretical approaches used to study aging have often remained compartmentalized. As a result, integrating these diverse insights into a unified framework has become increasingly important. As a step toward this goal, this field perspective outlines general biological mechanisms that help explain the variability in aging patterns and longevity across the animal kingdom.

Link: https://doi.org/10.1038/s44318-026-00725-z

The immune system changes with age, a mix of damage and reactions to that damage. Some of those reactions make things better and some are maladaptive, making things worse. Immune cell populations change in size, and immune cells themselves carry burdens of dysfunction, the usual forms of damage and change one might expect from the Strategies for Engineered Negligible Senescence (SENS) view of cellular aging. Immune cell behaviors change in response to both internal shifts and the altered environment they find themselves in, a change in the signaling produced by all of the other cells in the body. Much of this is a matter of chronic inflammation, a sustained activation of the primary triggers that cause the immune system to react in defense of the body. In old age these triggers become constantly active, a maladaptive response to damage and dysfunction in cells through the body.

The complement system is a major component of the innate immune system, a well-mapped collection of circulating signal molecules and their cell surface receptors that acts to call the immune system to action against forms of infection and damage. But one should also consider that the innate immune system is actively involved in tissue maintenance and function beyond defense, and thus any aspect of the immune system likely affects normal tissue function as well. The complement system is in one sense easy to measure, just assess the levels of the various signals. In another sense it is hard to measure; what do specific alterations in signaling actually mean for system-level functions, or functions in the tissues supported by innate immune cells? This has been fairly well studied, as complement dysfunction is implicated in a range of autoimmune conditions, and in aging itself, but firm answers remain challenging here, just as is the case elsewhere in our biochemistry.

Within this context, the authors of today's open access paper show a distinct pattern of differences in complement signaling between older individuals who do and do not go on to develop Alzheimer's disease. This fits with much of the research into the relationship between the innate immune system, particular its inflammatory behavior, and the development of neurodegenerative conditions. To a large degree, the innate immune system of the central nervous system is not the same innate immune system of the rest of the body; the two sides communicate with one another, but the brain has microglia where the rest of the body has macrophages and other cell types. Microglia are similar to macrophages, but with important additions to their portfolio of duties that relate to the maintenance of connections between neurons. A growing body of work implicates the dysfunction and inflammatory behavior of microglia in the onset and progression of neurodegenerative conditions.

Systemic complement factors in aging, Alzheimer's disease and other dementias: a longitudinal study over 10 years

The complement system, an essential component of innate immunity, contributes to pathogen clearance, removal of apoptotic cells, and elimination of misfolded proteins. Within the central nervous system (CNS), circulating complement factors are actively involved in neuronal development, synaptic remodeling, and immune surveillance. However, aberrant complement activation is increasingly associated with neuroinflammatory pathologies, including Alzheimer's disease (AD).

We conducted a study involving two cohorts: a longitudinal cohort (n = 235; all cognitively normal at baseline) and a cross-sectional cohort (n = 323; including 53 with AD, 54 with vascular dementia, 51 with Parkinson's disease dementia, 56 with behavioral variant frontotemporal dementia, and 52 with dementia with Lewy bodies). Plasma levels of 14 complement factors were assessed every 2 years over a 10-year follow-up period in the longitudinal cohort and once in the cross-sectional cohort.

In this 10-year follow-up study, complement factors C4, C4b, Factor I, Factor D and Properdin showed progressive deviations from normative aging trajectories exclusively in individuals who later converted to AD. These alterations correlated robustly with established cerebrospinal fluid (CSF) biomarkers, indicating that peripheral complement remodeling reflects AD-specific pathophysiology rather than age-related change. Collectively, these findings establish complement dysregulation as a systemic hallmark of Pre-AD and identify a discrete panel of proteins with potential for early detection and treatment.

Bioprinting even small sections of replacement tissue faces a range of challenges relating to recapturing the small-scale structure of natural tissues. The formation of blood vessels is a particularly thorny issue that can be bypassed in some circumstances, such as rebuilding muscle following injury. A sufficient vasculature will be established in newly bioprinted constructs as they integrate with neighboring existing tissue, provided that the constructs are not too large. In muscle, alignment of muscle fibers is another structural challenge. Muscle tissue functions because its myocytes are aligned with one another. Here researchers report on solving this alignment challenge by using an electric field, demonstrating that the resulting bioprinted muscle can restore function in injured rats.

Bioprinting provides an unparalleled tool for engineering living tissue constructs that mimic the structural organization of native skeletal muscles. However, it remains a challenge for existing bioprinting strategies to recapitulate the highly aligned cellular architectures inside skeletal muscles, primarily due to low printing resolution and limited capability for in situ microenvironmental regulation. Here, we propose to employ the electrical force during the electrohydrodynamic (EHD) bioprinting process to induce the in situ orientation of cell-laden fibrin-alginate hydrogel, which provides nanostructural guidance to the encapsulated cells for the formation of highly aligned skeletal muscle constructs.

It was observed that the randomly distributed fibrin protofibril aggregates gradually elongated into uniformly aligned nanofibers at the Taylor cone stage as the applied voltage increased to 3 kV. The oriented fibrin nanofibers further direct in situ cellular alignment along the EHD bioprinting trajectory, facilitating the freeform fabrication of parallelly or circumferentially aligned muscle tissue constructs in vitro. The addition of conductive polymers into the fibrin-alginate hydrogel endows the EHD-bioprinted living constructs with muscle-specific conductivity and cellular organization, which promote myotube differentiation and maturation.

The resultant aligned and conductive muscle constructs promoted in situ muscle regeneration in a rat injury model and restored lost muscle functions at the defect regions. The presented EHD bioprinting strategy for fibrin-alginate hydrogel provides a versatile and simple platform to freely fabricate conductive, living tissue constructs with designer cellular alignments.

Link: https://doi.org/10.1088/2631-7990/ae3923

Perhaps the most useful way to think of atherosclerosis, the ultimately fatal growth of fatty plaques in blood vessel walls, is as a condition driven by macrophage dysfunction. Macrophages are innate immune cells responsible for repair and maintenance in blood vessel walls. Where blood vessels are damaged, native macrophages are joined by monocytes from the circulation that transform into macrophages. These cells attempt repair of outright damage but also ingest any harmful excess of lipids (such as cholesterol) in the blood vessel wall, returning those lipids to the circulation for delivery to the liver. When macrophages efficiently carry out this work, atherosclerosis is prevented or even reversed. Atherosclerosis progresses when macrophages become dysfunctional, which can be caused by excess lipids, systemic inflammation, the molecular damage of aging, or other environmental factors. All of the contributing factors and risk profiles associated with atherosclerosis can be viewed through the lens of how they impair macrophage function in the regions of the blood vessel walls that are most affected by damage and excess lipid accumulation.

Atherosclerosis is a chronic inflammatory disease driven by pathological processes such as macrophage foam cell formation. Semaphorin 7A (SEMA7A) is an immunoregulatory signaling molecule known to modulate immune responses and cellular adhesion. However, the contribution of macrophage-derived SEMA7A to atherogenesis has yet to be fully elucidated. In this study, we analyzed gene expression profiles of human mononuclear cells from the Gene Expression Omnibus (GEO) database and revealed highly expressed SEMA7A and its receptor integrin β1 in macrophages. The upregulation of SEMA7A and integrin β1 was also observed during the differentiation of THP-1 monocytes into macrophages.

Mice with macrophage-specific deletion of Sema7a showed a 57.2% reduction in atherosclerotic lesion size and improved plaque stability in atherosclerosis mouse model compared to control mice. Mechanistically, macrophage SEMA7A promoted the expression of macrophage scavenger receptor 1 (MSR1) and lipid uptake mediated by integrin β1 and downstream JNK signaling pathway in macrophages. Notably, pharmacological inhibition of integrin β1 with integrin receptor antagonist GLPG0187 effectively suppressed atherosclerosis progression. These findings identify macrophage-derived SEMA7A as a key driver of atherosclerosis through a novel integrin β1/JNK/MSR1 axis, providing potential targets for the prevention and treatment of atherosclerosis.

Link: https://journal.hep.com.cn/fmd/EN/10.1007/s11684-025-1181-z

The human body hosts countless viruses in addition to the other forms of microbe such as bacteria and fungi. Most of these viruses are commensal species, most likely harmless throughout much or all of the life span, playing their parts in the microbial ecosystems that exist within and around the body. At the present time there is considerable enthusiasm for the study of the gut microbiome, and this is one avenue of research in which viruses are being cataloged and their activities considered by researchers. Another avenue is the study of persistent infectious viruses, primarily herpesviruses, and their effects of health over the course of aging. Persistent viruses may contribute meaningfully to age-related immune dysfunction and various age-related diseases. Consider what is known of the effects of cytomegalovirus on the immune system, or the evidence for other herpesvirus species to contribute to the onset and progression of Alzheimer's disease.

In today's open access paper, researchers review what is known of the human virome and its impact on health and aging. At the high level, the theme is that much is yet to be mapped and discovered. Despite considerable progress in gathering data, particularly in recent years, the research community's understanding of the role of viruses in human aging still contains large dark areas and many unknowns. We might think that this is in part the case because we lack a good way to clear viral infections. Given tools that can selectively destroy specific viruses, such as the DRACO system still somewhere in the development process, it would become much easier to determine the activities of various species and their effects on health.

The gut and circulating virome: emerging players in aging and longevity

A growing body of evidence indicates that the human virome, comprising both the gut and circulating viral communities, plays a critical role in shaping host physiology across the lifespan. In the context of aging, this complex viral ecosystem is increasingly recognized as a key modulator of immune function, inflammation, and metabolic balance, with direct implications for healthspan and longevity. While much attention has traditionally focused on bacterial components of the microbiota, recent advances in metagenomics have uncovered age-related shifts in the composition and function of the virome, including expansion of specific bacteriophage families, reactivation of latent viruses, and the persistence of commensal viral pathobionts.

These changes are tightly linked to immunosenescence, chronic inflammation, and neurodegeneration, hallmarks of unhealthy aging. Notably, centenarians appear to harbor a unique virome signature marked by increased viral diversity, enhanced lytic activity, and the enrichment of phage-encoded metabolic functions, suggesting a potential protective role in extreme longevity. Despite these insights, significant challenges remain in virome profiling, including technical biases, database limitations, and the vast proportion of taxonomically unassigned sequences known as "viral dark matter". This review highlights emerging data on the aging virome, underscores its relevance within the Geroscience framework, and discusses current barriers and future directions for translating virome research into clinical aging studies.

Research into the biochemistry of longevity does not proceed at a rapid pace, even now that the field has become popular. Much of this research takes the form of first discovering longevity-enhancing mutations in short-lived species and then painstakingly tracing chains of cause and effect from protein to protein and interaction to interaction. Since cellular metabolism is by no means fully understood, even in the extremely well studied nematode worm C. elegans, this takes a long time. For example, we can see that is has taken thirty years or so to move from the first C. elegans longevity-enhancing mutation to the discovery of many more, and now here finding that some of these mutations converge on the activity of the FMO-2 gene. This slow pace of increased understanding is one of the reasons why manipulating the operation of cellular metabolism to slow the pace of aging seems a poor choice of primary goal for research and development, versus the alternative approach of finding specific forms of damage and attempting to repair them.

A mild impairment of mitochondrial function activates the hypoxia inducible factor (HIF-1)-mediated hypoxia stress response pathway leading to a HIF-1-dependent increase in lifespan. Lifespan extension resulting from HIF-1 stabilization is dependent on activation of flavin-containing monooxygenase-2 (FMO-2). In this work, we explored the role of fmo-2 in the long lifespan of genetic mitochondrial mutants in C. elegans. We found that fmo-2, but not other fmo genes, are specifically upregulated in the long-lived mitochondrial mutants clk-1, isp-1, and nuo-6. Disruption of fmo-2 through RNA interference or genetic mutation shortens the lifespan of these mitochondrial mutants indicating that fmo-2 is required for lifespan extension in these worms.

Moreover, signaling molecules that have been shown to be involved in upregulation of fmo-2 are also required for the long life of clk-1, isp-1, and nuo-6 mutants including HLH-30, NHR-49, and MDT-15. Finally, we examined the effect of multiple lifespan-promoting pathways in clk-1 mutants on the expression of fmo-2. We found that in all cases, genes required for clk-1 longevity are also required for the upregulation of fmo-2 in clk-1 worms. These genes included DAF-16, PMK-1, SKN-1, CEH-23, AAK-2, HIF-1 and ELT-2. Combined, this work advances our understanding of the molecular mechanisms contributing to longevity in the long-lived mitochondrial mutants and identifies FMO-2 as a common downstream effector of multiple pathways that modulate longevity.

Link: https://doi.org/10.64898/2026.02.10.705198

That new neurons are generated in the adult brain and integrate into existing neural networks was first established in mice in the 1990s, but considerable debate has taken place since then as to whether this adult neurogenesis also occurs in humans. Working with human brain tissue has always been logistically difficult, and this combined with methological challenges in the quantification of neurogenesis allowed uncertainty to continue. At this point, the balance of evidence and scientific consensus is that adult neurogenesis does occur in our species, and further is necessary to the operation of memory and learning. Here, in addition to providing further confirming data for human adult neurogenesis, researchers suggest that differences in neurogenesis could contribute to sustained cognitive function in older individuals who exhibit relatively little cognitive aging.

The existence of human hippocampal neurogenesis has long been disputed and its relevance in cognition remains unknown. Recent studies have established the presence of proliferating progenitors and immature neurons and a reduction in the latter in Alzheimer's disease (AD). However, their origin and the molecular networks that regulate neurogenesis and function are poorly understood. Here we studied human post-mortem hippocampi obtained from different cohorts: young adults with intact memory, aged adults with no cognitive impairments, aged adults with extraordinary memory capacity (SuperAgers), adults with preclinical intermediate pathology or adults with AD.

Using multiomic single-cell sequencing (single-nucleus RNA sequencing and single-nuclei assay for transposase-accessible chromatin with sequencing), we analysed the profiles of 355,997 nuclei isolated from the hippocampus samples and identified neural stem cells, neuroblasts and immature granule neurons.

Dysregulated neurogenesis was largely associated with changes in chromatin accessibility. Analyses of transcription factors and target gene signatures that distinguished each of the groups revealed early alterations in chromatin accessibility of neurogenic cells from individuals with preclinical AD, and such changes were even more evident in samples from individuals with AD. We identified a distinct profile of neurogenesis in SuperAgers that may reflect a 'resilience signature'. Finally, alterations in the profile of astrocytes and CA1 neurons govern cognitive function in the ageing hippocampus. Together, our study points to a multiomic molecular signature of the hippocampus that distinguishes cognitive resilience and deterioration with ageing.

Link: https://doi.org/10.1038/s41586-026-10169-4

The composition of the gut microbiome changes with age. Microbial species capable of provoking inflammation, by infiltrating tissues or via production of harmful metabolites, grow in number. This occurs at the expense of populations that produce beneficial metabolites, such as butyrate, known to promote function in a number of different tissues. The reasons for this shift of composition are not fully understood, especially since meaningful change starts to occur relatively early in adult life. Immune dysfunction likely plays a significant role, however, as the immune system is responsible for gardening the gut microbiome, keeping harmful species to a minimum.

Rejuvenation of the aged gut microbiome via fecal microbiota transplantation from a young donor has been shown to improve health and extend life in animal studies. To what degree are these benefits a restoration of youthful microbial metabolite production versus a removal of inflammatory species, however? Today's open access paper provides evidence to suggest that it is mostly a matter of reducing the production of harmful metabolites. The researchers did not rejuvenate the aged microbiome in old mice, but instead used high dose antibiotic treatment to greatly reduce all microbial populations in the gut. This allowed the assessment of health and physiology in an environment in which the production of harmful microbial metabolites was also greatly reduced.

The result reported in the paper is a significant improvement in aspects of brain health. Removing the gut microbiome in this way is not a viable approach to therapy for the population at large, but the results reported here suggest that benefits will arise from any approach that successfully reverses the increase in numbers of harmful microbes that is characteristic of the aged gut microbiome. Restoring the youthful population sizes of helpful microbes is good, but likely less important to the benefits demonstrated in animal studies of gut microbiome rejuvenation via fecal microbiota transplantation.

Microbiome depletion rejuvenates the aging brain

Aging is associated with cognitive decline and increased vulnerability to neurodegeneration driven by an array of molecular and cellular changes like impaired vascular integrity, demyelination, reduced neurogenesis, and chronic inflammation. Recent studies implicate the gut microbiome as a modulator of brain aging, but the underlying mechanisms remain elusive. Here, we show that depleting the gut microbiome by administering antibiotics to aged mice induces widespread molecular and structural rejuvenation in the brain.

Our transcriptomic analyses by single-nucleus RNA sequencing revealed pronounced transcriptional shifts across multiple brain cell types. We confirmed that antibiotic treatment improves vascular density, promotes myelination, enhances neurogenesis, and reduces microglial reactivity. Functionally, microbiome-depleted mice showed improved hippocampal memory performance. Analyses of brain and plasma cytokine levels showed a decrease in several pro-inflammatory factors post-treatment and identified candidate factors, including the chemokine eotaxin-1. Inhibiting eotaxin-1 alone can reverse several aspects of brain aging.

Our findings demonstrate that age-associated microbial inflammation contributes to brain aging and that its attenuation can restore youthful features at the molecular, cellular, and functional levels. Targeting the gut microbiome or its circulating mediators may therefore represent a non-invasive approach to promote brain health and cognitive resilience in aging.

Some gene sequences can give rise to circular RNAs when transcribed. As a class, circular RNAs are not as well studied as other classes of molecule in the cell, but it is becoming apparent that, as for just about everything one might find in a cell, some circular RNAs become relevant in the context of aging. Here, researchers discuss findings relating to circular RNAs generated from mitochondrial genes. In particular circular RNAs for MT-RNR2 appear to meaningfully affect mitochondrial function, and lower levels of MT-RNR2 in older individuals may be involved in the age-related decline of mitochondrial function. The best way forward to a greater understanding is to manipulate MT-RNR2 expression and see what happens as a result. In general, improved mitochondrial function should be a good path to the production of therapies that improve health, but the question is always how great an improvement can be achieved, and that remains to be seen in this case.

During mammalian aging, there are changes in abundance of noncoding RNAs including microRNAs, long noncoding RNAs, and circular RNAs. Although global profiles of the human transcriptome and epitranscriptome during the aging process are available, the existence and function of mitochondrial circular RNAs originating from the mitochondrial genome are poorly studied. Here, we report profiles of circular RNAs annotated to the mitochondrial chromosome in young and old cohorts.

The most abundant circular RNA junctions are found in MT-RNR2, whose level is depleted in old cohorts and senescent fibroblasts. The mitochondria-localized RNA-binding protein GRSF1 binds various mitochondrial transcripts, including linear and circular MT-RNR2, with a distinct RNA motif. Linear and circular MT-RNR2 bind a subset of TCA cycle enzymes, suggesting their possible function in regulating glucose metabolism in mitochondria to preserve proliferating status in young cohorts. In human fibroblasts, depletion of GRSF1 reduced levels of circMT-RNR2 and fumarate/succinate, concomitantly accelerating cellular senescence and mitochondrial dysfunction.

Taken together, our findings demonstrate the existence and possible function of circular MT-RNR2 during human aging and senescence, implicating its role in promoting the TCA cycle. Future mechanistic studies will reveal how these mitochondrial circular RNAs are produced by trans-splicing, possibly, and how the circular RNAs accelerate the TCA cycle to preserve the proliferation status and suppress senescence as well as aging.

Link: https://doi.org/10.18632/aging.206354

The brain requires a great deal of energy to function. That energy is provided by mitochondria, hundreds of these organelles in every cell producing the chemical energy store molecule adenosine triphosphate (ATP), that activity reliant on the nutrients and oxygen delivered via the vascular system. The brain operates at the limit of its metabolic capacity even in youth, as demonstrated by the fact that exercise and the consequent increased supply of blood to the brain transiently increases cognitive function. Mitochondrial function declines with age, and this has consequences. But as researchers show here, improving the capacity of mitochondria to provide the cell with energy can enhance cognitive function at any age.

Expensive energy usage in neurons must be limited to avoid unnecessary overconsumption of fuels in the brain that could otherwise be useful for survival. During neuronal activity, synapses synthesize the exact levels of energy that are consumed during each firing event, without underproducing or overproducing ATP. While the work of several laboratories has identified how mitochondrial metabolism is upregulated on demand in activated neurons to preserve the metabolic integrity of synapses, the importance and the molecular identity of mechanisms slowing down mitochondrial metabolism after firing have remained elusive.

From insects to mammals, essential brain functions, such as forming long-term memories (LTMs), increase metabolic activity in stimulated neurons to meet the energetic demand associated with brain activation. However, while impairing neuronal metabolism limits brain performance, whether expanding the metabolic capacity of neurons boosts brain function remains poorly understood. Here, we show that LTM formation of flies and mice can be enhanced by increasing mitochondrial metabolism in central memory circuits.

By knocking down the mitochondrial Ca2+ exporter Letm1, we favour Ca2+ retention in the mitochondrial matrix of neurons due to reduction of mitochondrial H+/Ca2+ exchange. The resulting increase in mitochondrial Ca2+ over-activates mitochondrial metabolism in neurons of central memory circuits, leading to improved LTM storage in training paradigms in which wild-type counterparts of both species fail to remember. Our findings unveil an evolutionarily conserved mechanism that controls mitochondrial metabolism in neurons and indicate its involvement in shaping higher brain functions, such as LTM.

Link: https://doi.org/10.1038/s42255-026-01451-w

The longevity industry will at some point diffuse into the broader pharmaceutical and biotech industries. It will cease to be so distinct in culture, technology, and regulation as to merit the drawing of firm lines. Treating aging as a medical condition is no longer looked upon as strange by the powers that be, even though the public at large has yet to catch up entirely to this new viewpoint. This relatively new environment of approval means that sizable funding is available, and indeed deployed in large amounts to advance the cause, both by private and public sources.

One of the US government programs in which program managers have become very sympathetic to the cause of treating aging is ARPA-H, portions of which one might think of as spiritual successors to the attitudes and aims of DARPA, except that the focus is progress in medical technology specifically. That clinical trials are so enormously expensive to prepare for and run is the fault of government regulatory bodies, a mess created over decades. Now another arm of government will feed public funds into that process to enable more groups to make progress in passing the financial hurdle that regulators created. As is usually the case, however, it is largely the already well funded, high-profile initiatives that receive that assistance; if one is connected enough to have a large chance of obtaining major government funding, one is connected enough to be able to raise just as much from private sources, and have probably already done so.

Regardless, medicine is a highly regulated industry, and this is how the game is played in any industry in which government appointees exert such a large degree of control over what does and does not happen. In these years in which the first therapies that might slow aging (or in a few cases selectively reverse aging) are making their way into clinical trials, most groups are indeed trying to play the game as it exists, with all of its flaws, as in the bigger picture it is vital to demonstrate to the world at large that the treatment of aging can be real. An increasing number of companies are looking for alternative paths, however, such as those setting up their initial clinical trials in much less costly locations, and intending to initially prove their worth and provide access via medical tourism. From a very high level perspective, the most important outcome for the next decade or two is that therapies for aging, as many different approaches as possible, are meaningfully tested in humans - however that outcome is achieved. Even a few successes will give rise to a massively larger industry, with enough weight behind it to meaningfully change the way in which medical development takes place.

ARPA-H pours millions into healthspan-focused human trials

The US Government, via its Advanced Research Projects Agency for Health (ARPA-H) initiative, is putting up to $144 million into multiple projects aimed at extending healthspan - the years people live in good health. Through its PROSPR program, ARPA-H is funding seven research teams working to treat aging as a tractable biological process, and proving, in humans, that intervening earlier can help people stay healthier for longer.

Short for "Proactive Solutions for Prolonging Resilience," PROSPR's goal is to overcome one of the key challenges that has limited clinical development in geroscience: aging is slow, and its associated diseases and conditions can take years or decades to emerge, making conventional trials unwieldy and expensive. The initiative aims to use longitudinal human data to identify early, actionable biomarkers that respond before late-stage outcomes appear. Those biomarkers are intended to serve as surrogate endpoints that can show, within one to three years, whether an intervention is plausibly shifting an individual's trajectory toward better function, resilience, and quality of life.

Longevity biotech Cambrian has been awarded up to $30.8 million to support human trials of a daily, oral, next-generation rapamycin analog intended to selectively inhibit mTORC1. The company views dysregulated mTORC1 signaling as a key driver of the metabolic decline that accumulates with age, and it is tying its program to "intrinsic capacity," a composite measure of physical and metabolic resilience that declines over time.

Linnaeus has been awarded up to $22 million to advance a drug targeting the G protein-coupled estrogen receptor (GPER) into human trials for healthspan preservation. Interestingly, the company is building on its work in oncology, where more than 100 cancer patients have been treated with its drug (LNS8801) in early human trials and signals observed in those patients suggested potential translation into aging-related benefits.

TDP-43 is a protein only relatively recently discovered to undergo pathological modification and aggregation in the aging brain. Much like amyloid-β, α-synuclein, and tau, this aggregation is thought important in the progression of specific neurodegenerative conditions. Here, researchers present evidence for TDP-43 aggregation to contribute to lost function in vascular dementia. Vascular dementia arises from a reduced blood supply to the brain, or other issues in the vasculature supplying brain tissue with the oxygen and nutrients it needs. The brain operates at the edge of metabolic capacity at the best of times, and as that supply diminishes with age, function suffers. Can some of the consequent damage done to the brain be prevented? Obviously it would be ideal to maintain a healthy vasculature instead of trying to compensate for vascular aging, but the research community does spend a lot of time looking at possible compensatory approaches, ways to sabotage at least some of the maladaptive reactions to the damage and dysfunction of aging.

Vascular dementia (VaD) ranks as the second most common cause of dementia worldwide and is linked to the highest mortality rate among dementia subtypes. A key driver of VaD pathogenesis is chronic cerebral hypoperfusion (CCH), a state of persistently reduced blood flow to the brain stemming from cerebrovascular compromise. A hallmark of VaD, CCH can diminish cerebral blood flow by as much as 40%, triggering hypoxia-induced cellular stress. This includes oxidative damage, mitochondrial failure, and heightened neuroinflammation, which collectively impair blood-brain barrier integrity and promote white matter lesion (WML) formation.

Recent evidence points to Tar DNA-binding protein 43 (TDP-43) as a potential mediator in this cascade. While TDP-43′s pathological role is well-established in amyotrophic lateral sclerosis (ALS), frontotemporal dementia, and Alzheimer's disease (AD), its involvement in VaD is poorly understood. In healthy neurons, TDP-43 is crucial for synaptic function and stress response. Under pathological conditions, however, it undergoes detrimental modifications, including hyperphosphorylation, nuclear-to-cytoplasmic mislocalization, and aggregation that are common processes across neurodegenerative diseases. These aberrant forms of TDP-43 lose their normal function and can acquire toxic properties, potentially exacerbating neuroinflammation. While TDP-43 pathology is a well-established feature of several neurodegenerative diseases, its potential role in the context of cerebrovascular injury remains largely unexplored.

This study demonstrates that CCH, a key feature of VaD, triggers pathological TDP-43 changes, namely cytoplasmic mislocalisation and hyperphosphorylation, in both in vivo and in vitro models. In a mouse model of VaD, time-dependent cytoplasmic accumulation of TDP-43 and pTDP-43 was observed in cortical and hippocampal neurons, with elevated pTDP-43 despite stable total TDP-43 levels, implicating phosphorylation in its aberrant redistribution. These results mirror hallmark features of TDP-43 proteinopathies in neurodegenerative diseases, such as ALS and AD, and suggest that similar mechanisms may be triggered by vascular insults.

Link: https://doi.org/10.1002/alz.71196

Researchers here report an association between late life survival and levels of specific piwi-interacting RNAs. This subcategory of non-coding RNAs, meaning RNA molecules that are not translated into proteins, has attracted more interest of late in the context of aging and age-related changes to the regulation of gene expression. The understanding of the role of non-coding RNAs in metabolism lags behind the still incomplete understanding of proteins. The life science community is slowly filling in an enormous map of interactions, a map that will contain many large dark areas for a long time yet. There are only so many researchers, and developing a reasonably complete understanding of how even a single protein or RNA contributes to cell metabolism requires years of work in the best of circumstances.

To investigate the relevance of small RNAs to human longevity, we pursued three goals: (a) to validate epigenetic (small RNA) factors underlying survival of older adults, (b) to develop and validate prediction models of survival for potential clinical application, and (c) to identify plausible druggable targets prolonging longevity. We evaluated 828 small non-coding RNAs - 687 microRNAs (miRNAs) and 141 piwi-interacting RNAs (piRNAs) - in baseline plasma from 1271 community-dwelling older adults (≥ 71 years) in the EPESE study. Our predictive model incorporating small RNAs, clinical variables (demographics, lifestyle, mood, physical function, standard clinical laboratory tests, NMR-derived lipids and metabolites, and medical conditions) and age achieved strong performance, with cross-validated area under the curve (AUC) values of 0.92 for 2-year survival in Discovery and 0.87 in external Validation.

Nine piRNAs, all reduced in longer-lived individuals, were identified as potential therapeutic targets. Under the assumption of causal sufficiency, these data provide causal evidence linking circulating small RNAs with survival outcomes in humans. While such inference does not replace experimental validation, it complements mechanistic studies by identifying candidate molecular drivers most relevant to human longevity. Supporting biological plausibility, reduced piRNA biogenesis has been shown to double lifespan in C elegans. Together, our findings identify circulating piRNAs and miRNAs as promising biomarkers and potential therapeutic targets to advance human longevity.

Link: https://doi.org/10.1111/acel.70403

The shape and packaging of nuclear DNA is actively controlled by the cell via decoration of the DNA and supporting structures with additional molecular motifs, such as methyl groups. At any given time much of the genome is tightly spooled into regions known as heterochromatin that are inaccessible to the machinery of gene expression that surrounds nuclear DNA, constantly interacting with it. The structure of nuclear DNA determines gene expression, which regions are unspooled and accessible to translation machinery for the production of RNA from gene sequences versus which regions are spooled and the genes there silenced.

Here researchers examine immune cells from centenarian blood samples and note a distinct pattern of structure in their DNA. Further investigation points to one specific transcription factor, ERG, that appears to reduce cellular senescence, and thus might be theorized to improve immune function in the aged tissue environment. There are no doubt many other specific differences in activity that might be investigated more deeply, however. Transcription factors alter DNA structure and other aspects of gene expression for many genes, thousands in some cases. They are thus interesting points of potential intervention in the behavior of the cell, a greater centralization of regulatory control over function than most genes.

ERG phase separation attenuates cellular senescence

Our study defines a distinct chromatin accessibility signature in perihipheral blood mononuclear cells of centenarians, characterized by a global increase in chromatin openness across multiple immune subsets. Notably, this increase does not reflect accelerated senescence as aging usually along with increase chromatin accessibility, but rather suggests a unique chromatin configuration associated with exceptional longevity. In particular, B cells from centenarians display enhanced accessibility at promoter and enhancer regions that typically close with age, while closing peaks are enriched in quiescent loci that generally open during aging. These findings highlight that centenarians maintain an atypical epigenetic state, potentially supporting immune resilience and genomic stability in extreme old age.

Integrative analysis highlighted the E-26 transformation-specific (ETS)-related transcription factor ERG as a longevity-associated regulator. Functional studies in human cells showed that ERG forms nuclear condensates through liquid-liquid phase separation, a property associated with altered chromatin organization and reduced expression of cellular senescence-related genes, including CDKN2A. Consistent with these effects, ERG condensation was associated with attenuation of cellular senescence phenotypes. Together, these findings connect epigenomic features observed in centenarians with transcription factor biophysical properties and cellular aging control, highlighting phase separation as a regulatory layer that may contribute to cellular resilience during aging.

Cells have evolved to detect molecular markers of invading pathogens, such as out of place DNA sequences, and react with inflammatory signaling. One such system is the interaction between the DNA sensor cGAS and the regulatory of inflammation STING. Researchers have focused on this system in recent years, as it becomes maladaptively triggered with advancing age. Age-related dysfunctions in the cell lead to fragments of mitochondrial DNA and nuclear DNA escaping into the cytoplasm, where they are detected by cGAS, which then triggers STING. The result is an environment of inflammatory signaling that is disruptive to tissue structure and function, a further contribution to degenerative aging. Interfering in this process presents the same challenges as interfering in any aspect of inflammation, in that the cGAS-STING interaction serves a necessary purpose in addition to becoming problematic with age. It cannot be straightforwardly suppressed without producing harmful side effects.

The past few years have seen an explosion of interest in and knowledge about the cGAS-STING pathway in aging and neurodegenerative disease. Although this pathway is indispensable for host defense and is tightly regulated under physiological conditions, its aberrant activation emerges as a potent driver of the neuroinflammatory cascade and neuronal dysfunction during aging. The accumulation of both exogenous and endogenous DNA serves as a persistent trigger for cGAS, culminating in a vicious cycle of STING-dependent IFN-I and pro-inflammatory cytokine production. This chronic, low-grade inflammation is a hallmark of aged brain tissue and a key contributor to the progression of conditions like Alzheimer's disease, Parkinson's disease, and ALS. The promising results from preclinical studies utilizing cGAS or STING inhibitors, which have demonstrated efficacy in ameliorating cognitive decline and neuropathology in various models, underscore the therapeutic potential of targeting this pathway.

However, several pivotal questions and challenges must be addressed to translate these foundational discoveries into effective clinical interventions. For example, the characteristics of the DNA that activate the cGAS-STING pathway are crucial. The origins, oxidation extent, amount, manner, and rate of DNA release (e.g., during different forms of cell death) significantly influence the intensity of the downstream immune response. The relative contribution of mitochondrial DNA versus nuclear DNA and viral DNA remains hotly debated.

In conclusion, the cGAS-STING pathway serves as a master regulator of age- related neuroinflammation and a compelling therapeutic target for a range of neurodegenerative conditions. Importantly, the pathological outcome is determined not merely by whether the pathway is activated, but more profoundly by the strength of the signal, the cellular context of activation, and the source and properties of the stimulating DNA, such as whether it is exogenous or endogenous, oxidized, or otherwise modified. Given this complexity, a precise understanding of the cGAS-STING pathway is essential to understanding neuroinflammatory damage. Looking ahead, we should aim to design therapeutic strategies that precisely modulate the cGAS-STING pathway - both in degree of activity and cell-type specificity - to safely unlock its potential for clinical benefit.

Link: https://doi.org/10.1186/s40364-026-00906-2

Aging clocks derived from a database of age-related changes in specific biological data must be validated for any specific use. The construction of the clock grants no insight into how its component measures relate to any specific aspect of aging, or to any specific age-related condition. Even conceptually similar clocks might exhibit quite different relationships with a given age-related condition, a point that is illustrated by the results of this study: some epigenetic clocks show very poor correlation with dementia risk, while others do correlate well enough to provide some insight.

Aging is the strongest risk factor for dementia; however, few studies have examined the association of biological aging with incident dementia. We analyzed 6,069 cognitively unimpaired women (mean age = 70.0 ± 3.8 years) in the Women's Health Initiative Memory Study to examine the association of accelerated biological aging, measured with second and third-generation epigenetic clocks (AgeAccelPheno and AgeAccelGrim2, and DunedinPACE, respectively) with incident mild cognitive impairment (MCI) and probable dementia.

Multivariable Cox proportional hazards models were adjusted for age, education, race, ethnicity, smoking, hormone therapy regimen, physical activity, body mass index, and estimated white blood cell counts. For comparison, we also examined first-generation epigenetic clocks (AgeAccelHorvath; AgeAccelHannum). We evaluated effect modification by age, race/ethnicity, hormone therapy regimen, menopause type (natural vs. surgical), and APOE ε4 carriage.

There were 1,307 incident MCI or probable dementia events over a median follow-up of 9.3 years. The adjusted hazard ratios for incident MCI/probable dementia per one-standard deviation increment were 1.07 for DunedinPACE, 1.11 for AgeAccelGrim2, and 1.01 for AgeAccelPheno. Only AgeAccelGrim2 remained significant under the Bonferroni-corrected threshold for significance. Other epigenetic clocks were not associated with incident MCI/probable dementia. There was no effect modification in most subgroup analyses.

Link: https://doi.org/10.1111/acel.70424

Somatic mosaicism in tissues occurs as a result of random mutational events in stem cell populations. Stem cells accumulate mutations randomly over time, a small fraction of the continual damage to nuclear DNA that slips past the highly efficient DNA repair machinery. Those mutations spread out into tissue via the daughter somatic cells generated by the stem cells. A tissue made up of somatic cells thus exhibits an ever more complex mosaic pattern of overlapping mutations over time. Somatic mosaicism in the immune system is known as clonal hematopoiesis. This is arguably the most studied form of somatic mosaicism, as the immune cells produced by hematopoietic stem cells are readily accessible via a blood sample.

Somatic mosacism sets the stage for cancer by spreading mutations that raise the odds of any specific cancerous combination of mutations occurring in any one somatic cell. But does somatic mosaicism contribute more generally to degenerative aging and loss of function, and is this contribution large enough for us to care about? There is some evidence to suggest that this is the case, but an important role for somatic mosaicism in aspects of aging other than cancer risk is far from conclusively demonstrated at this point in time. Clonal hematopoiesis seems likely to be where that is initially proven, if it is going to be.

Ageing Through the Looking-Glass: The Different Flavours of Clonal Haematopoiesis

Clonal haematopoiesis (CH) is the presence of acquired mutations in blood cells and is a consequence of ageing that is linked to malignancy, cardiovascular disease and other diseases of ageing. CH is a reflection of genomic instability with ageing; however, there is evidence that CH may exacerbate features of normal ageing, including inflammageing and immunosenescence, and more directly contribute to disease causation. CH can manifest as mosaic loss of X or Y chromosomes, autosomal mosaic chromosomal rearrangements, or point mutations or small insertions or deletions. However, differences in CH definitions, detection methods and cohort characteristics have contributed to heterogeneous and sometimes discordant findings across studies.

It has been hypothesised that the different forms of CH may all arise from a 'common soil' of genomic instability, that is, that shared heritable and environmental factors may promote the acquisition and subsequent expansion of mutations. However, it remains largely unknown whether associations between CH and diseases of ageing reflect correlation or whether CH may directly cause disease. Here, we review the relationship between ageing and CH, including how CH develops, and how it interacts with other features of ageing including inflammageing, immunosenescence, epigenetic ageing and telomere shortening. We also review what is known about the overlap between different forms of CH and whether they make independent contributions to risk of disease.

The different forms of CH share common germline and environmental risk factors and have overlapping prevalence and disease associations, suggesting they reflect common underlying processes of ageing. CH is also associated with other biomarkers of ageing, namely accelerated epigenetic age and shorter telomere length. The presence of CH may reflect a biologically older haematopoietic system and exacerbate features of normal ageing, including inflammageing and immunosenescence, which may be important causal mechanisms explaining the association between CH and a variety of diseases of ageing. Additionally, inflammation likely also promotes further expansion of CH. Different forms of CH may work together to promote clonal expansion and synergistically promote disease including through promoting inflammation. CH may also synergise with, or be influenced by, other sources of inflammation outside the haematopoietic system, potentially including somatic mutations in other tissues or epigenetic changes. There is some evidence that different forms of CH may make independent contributions to disease risk.

The balance of microbial species making up the gut microbiome changes with age in ways that promote inflammation and other harms. Researchers can accurately map the composition of the gut microbiome using sequencing approaches, and are steadily identifying specific microbial species and mechanisms that contribute to the dysfunctions of age. A number of approaches exist to restore a more youthful gut microbiome composition, such as fecal microbiota transplantation from a young donor or flagellin immunization, but none are yet very widely used in the context of attempting to improve late life health.

Physiological and pathological changes associated with aging contribute to deteriorating disease prognosis in sepsis. However, the mechanisms by which these disturbances exacerbate inflammation remain underexplored. In this study, fecal samples were collected from aged and young septic patients and mice and subsequently transplanted into young pseudo-germ-free mice via fecal microbiota transplantation. Fecal, colon tissue, and blood samples were collected to be used 16S rDNA sequencing to characterize the gut microbiota, histopathological examination, enzyme-linked immunosorbent assay and FITC-dextran intestinal permeability assay to assess gut injury and gut barrier function.

Additionally, nontargeted and targeted metabolomics were used to identify differential metabolites in the feces of aged and young septic mice. To further validate the roles of specific bacterial strains and their metabolites in sepsis, genetically engineered bacteria were used in both in vivo and in vitro experiments.

The results showed an increased abundance of Klebsiella aerogenes (K. aero) in aged hosts, which led to elevated histamine (HA) production and exacerbated intestinal barrier dysfunction. Importantly, K. aero strains carrying a histidine decarboxylase gene variant were identified as major HA producers. Mechanistically, HA was shown to drive intestinal barrier dysfunction by inhibiting Nlrp6 expression and its subsequent binding to LC3, thereby impairing autophagy. Treatments that modulated HA levels or overexpressed Nlrp6 ameliorated inflammation in septic mice. These findings suggest that targeting the HA-Nlrp6-LC3 axis could offer a novel therapeutic approach for managing sepsis, particularly in aged populations.

Link: https://doi.org/10.1080/19490976.2026.2630475

Atherosclerosis involves the growth of fatty plaques in blood vessel walls that weaken and obstruct those blood vessels. It is a universal condition; all older individuals exhibit some degree of plaque formation. A heart attack or stroke occurs when an unstable, fatty atherosclerotic plaque ruptures and the debris blocks a vessel somewhere downstream. Interestingly, atherosclerosis is quite different in character between the sexes. Until menopause, atherosclerosis proceeds more slowly in women, and as noted here women tend to exhibit lesser degrees of plaque in later life. That does not, unfortunately, translate into a lesser degree of risk of plaque rupture.

This study evaluated health data for more than 4,200 adults (more than half of whom were women) to compare how quantity of plaque influenced the risk of major heart conditions. The study included people with stable chest pain and no prior history of coronary artery disease. Participants were randomized to undergo diagnostic evaluation via coronary computed tomography angiography (X-ray images of the heart and blood vessels) and followed for about two years.

Fewer women had plaque in their coronary arteries than men (55% of women vs. 75% of men). Women also had a lower volume of artery plaque than men (a median of 78 mm^3 among women vs. 156 mm^3 in men). Despite less plaque, women were just as likely as men to die from any cause, have a non-fatal heart attack or be hospitalized for chest pain (2.3% of women vs. 3.4% of men). In addition, women faced increased heart risk at lower levels of plaque compared to men. For total plaque burden, women's risk began to rise at 20% plaque burden, while men's risk started at 28%. With increasing plaque levels, risk rose more sharply for women than for men.

"Because women have smaller coronary arteries, a small amount of plaque can have a bigger impact. Moderate increases in plaque burden appear to have disproportionate risk in women, suggesting that standard definitions of high risk may underestimate risk in women."

Link: https://newsroom.heart.org/news/women-may-face-heart-attack-risk-with-a-lower-plaque-level-than-men