Fight Aging!

Calorie restriction mimetic drugs reproduce some (usually small) fraction of the beneficial metabolic changes that take place with a reduced calorie intake. An increase in the efficiency of the cellular maintenance processes of autophagy appears to be the crucial point. Researchers here report on their assessment of the alterations produced by the small number of calorie restriction mimetics with robust evidence to slow aging and extend life in mice. This part of the research field seems quite capable of generating any number of treatments that will likely work in humans, but unfortunately from what we know of the effects of calorie restriction, this class of therapy is unlikely to produce a large increase in life span in our species. Short-lived species exhibit a much greater extension of life in response to these metabolic manipulation strategies than is the case in long-lived species. This makes sense from an evolutionary perspective: if the calorie restriction response exists because it helps individuals to survive a seasonal famine to reproduce in later times of plenty, then short-lived species will evolve a much greater plasticity of life span. A season is a much larger fraction of the life span of a mouse than it is of a human.

The pace of aging can be delayed by mutations, dietary manipulations, and drugs, yet the metabolic mechanisms underlying longevity interventions remain poorly understood. Here we present a multi-tissue metabolomic analysis of male UM-HET3 mice treated from 4 to 12 months of age with five validated longevity interventions: rapamycin, acarbose, 17α-estradiol, canagliflozin, or caloric restriction. Using a feature-stabilized XGBoost pipeline applied to seven tissues, we show that metabolomic profiles can identify treated mice as likely recipients of a lifespan-extending intervention well before survival differences emerge. A leave-one-intervention-out procedure confirmed that models trained on any four interventions successfully classified mice from a fifth, unseen intervention, implying shared metabolic alterations across mechanistically distinct treatments.

The most influential metabolites - defined as the minimum set explaining 50% of cumulative model gain - differed substantially across tissues. Only ergothioneine, a dietary antioxidant, ranked highly in more than two tissues: it was elevated by all five interventions in plasma and brain, and by four of five in muscle. Enrichment analyses further identified coordinated remodeling of lipid classes in plasma, perigonadal fat, and kidney. These findings reveal tissue-specific metabolic reprogramming shared across mechanistically distinct longevity interventions and, pending validation against interventions that do not extend lifespan, suggest a path toward metabolomic screening of candidate anti-aging drugs.

Link: https://doi.org/10.64898/2026.06.24.734388

The major hormones produced by the thyroid gland are broadly influential on metabolism and the function of many organs, and thyroid dysfunction is common enough in later life for this aspect of human biochemistry to be very well studied. A range of different unpleasant outcomes and named diseases arise from various imbalances in the production of thyroid hormones. Here, researchers take a particular type of thyroid behavior known to the medical community as non-thyroidal illness syndrome and reframe it as a part of the evolved response to calorie restriction that acts to slow aging - though as it is usually observed in practice by physicians, during times of acute illness, it may be maladaptive.

Non-thyroidal illness syndrome (NTIS), historically termed euthyroid sick syndrome, is characterized by reduced serum triiodothyronine (T3), variable thyroxine (T4), and typically normal or suppressed thyroid-stimulating hormone (TSH) in the absence of intrinsic thyroid disease. Traditionally viewed as an adaptive response to acute illness that does not require intervention, NTIS is increasingly being recognized within broader contexts of metabolic adaptation, including aging, caloric restriction, and pharmacologically induced weight loss. This narrative review reexamines NTIS as a context-dependent metabolic reprogramming response that may represent an evolutionarily conserved survival and longevity mechanism.

Evidence from critical care endocrinology, mitochondrial biology, aging research, caloric restriction studies, and emerging data on glucagon-like peptide-1 (GLP-1) receptor agonists is synthesized to explore the mechanistic and clinical implications of low T3 states. During acute physiologic stress, including infection, trauma, and starvation, reduced peripheral T4-to-T3 conversion and increased reverse T3 production appear to promote metabolic downshifting through decreased mitochondrial oxygen consumption, reduced anabolic signaling, and the redistribution of energy toward immune defense and cellular repair. These adaptations parallel pathways associated with enhanced metabolic efficiency and longevity. Similar thyroid hormone changes are increasingly observed in individuals undergoing significant weight loss, sustained caloric restriction, or GLP-1 receptor agonist therapy.

While transient reductions in T3 may reflect adaptive energy conservation, persistent low T3 states in the setting of chronic inflammation, cardiometabolic disease, sarcopenia, or advanced aging may contribute to impaired mitochondrial function, reduced metabolic flexibility, and loss of physiologic resilience. NTIS may therefore represent a spectrum of adaptive and maladaptive responses influenced by physiologic context, duration, and inflammatory burden. A systems-based, longevity-oriented framework may improve the interpretation of low T3 states and help guide future research aimed at distinguishing beneficial metabolic adaptation from pathologic endocrine suppression.

Link: https://doi.org/10.7759/cureus.110397

Anti-aging medicine has long been a small specialty field of practice culturally adjacent to sports medicine, but considerably less rigorous and more derided by the mainstream. The present development of a longevity industry, based on means to slow and reverse aspects of aging conclusively demonstrated in laboratory animals and now slowly making their way towards the clinic, is going to have interesting effects on the field of anti-aging medicine. Over some period of time, anti-aging medicine will become reputable, a field in which physicians manage the delivery of treatments for aging that actually work. The field will swell to become the majority of all medical practice, as the majority of all serious illness and death is age-related.

Initially, this growth and takeover of mainstream medicine will look fairly prosaic, as it will likely occur in advance of the availability of any very impressive therapies. It will be built on lifestyle choice, weight management, and calorie restriction mimetic drugs like rapamycin, and the involvement of governments will be driven primarily by the desire to reduce the burden of ever expanding entitlement spending in an aging population. The really interesting therapies and outcomes will arrive later, finding a system ready and waiting for them. As an example of what this early transition will look like, one might read today's open access position paper on the Italian health system, proposing the changes needed for an effective focus on aging.

Towards integration of healthspan strategies into the Italian National Health Service

Italy currently ranks among the world's oldest nations, with adults aged ≥65 years accounting for 24.1% of the population - the highest proportion in the EU - and a projected median age of 51 years by 2050. While life expectancy at birth reaches 85.4 years for women and 81.4 for men, Healthy Life Years amount to only 69.6 and 68.5, respectively, documenting a substantial lifespan-healthspan divide. The prevalence of multimorbidity and disability exceeds 60% in adults aged ≥75 years; women bear a disproportionate share of this burden, both as patients and as caregivers. Meanwhile, the Italian National Health Service (Servizio Sanitario Nazionale, SSN) remains hospital-centric, regionally fragmented, and predominantly reactive, with prevention accounting for a historically modest share of total expenditure.

Against this background, longevity medicine is an emerging, prevention-oriented discipline that aims to extend healthspan - defined here as the portion of life lived in good health, with preserved physical and cognitive function and without significant disability or multimorbidity. It integrates multi-omic biomarkers, digital monitoring, adaptive trial methodology, and life-course risk stratification within a translational framework. Although most constituent tools remain at an exploratory or surrogate stage, and clinical utility has yet to be established, the emphasis on early intervention and precision prevention offers potential to reduce the accumulation of age-related disease and ease long-term pressure on the SSN.

This position paper analyzes Italy's demographic and epidemiological trajectory, examines the structural constraints of the SSN, and outlines the scientific foundations of longevity medicine. It advocates for multidisciplinary translational research and identifies five strategic investment priorities: (i) clinically validated biomarkers of biological age; (ii) interoperable digital monitoring platforms; (iii) Bayesian adaptive multimodal trials; (iv) explainable-AI risk stratification tools; and (v) longevity-informed curricula in medical training. These proposals should be regarded as a staged agenda for evaluation; their relevance will depend on whether they deliver measurable gains in patient-relevant outcomes, feasibility, and cost-effectiveness within the SSN.

Questions regarding the relative importance of different mechanisms and dysfunctions to the progression of aging and eventual mortality are hard to answer definitively. Even given a straightforward class of therapies to target one specific mechanism of aging in isolation of all others, such as senolytics to clear lingering senescent cells, one still has to look at a lot of different studies, extrapolate from mice to humans, and the answer is fuzzy. The other sort of fuzzy answer comes from statistical techniques applied to large longitudinal human epidemiological data sets: compare humans who exhibited different levels of the mechanism in question, and see what happened to them over time. That is the approach taken here in the matter of the chronic inflammation as a driver of aging and age-related mortality. As you can see, the answer produced is a sizable range, arguably not all that informative.

Global population aging underscores the urgent need for biomarkers quantifying biological aging trajectories. While DNA methylation-derived pace of aging (DunedinPoAm) measures individual differences, its generalizability across diverse populations and mechanistic links to systemic inflammation remain underexplored. This study aimed to systematically examine the longitudinal associations between the DunedinPoAm and all-cause mortality in a multiethnic cohort, and to quantify the extent to which systemic inflammatory biomarkers mediate these associations using causal mediation analysis.

For this cohort study, information on a nationally representative cohort of 21,004 U.S. adults was extracted from the National Health and Nutrition Examination Survey (NHANES) conducted from 1999 to 2002. Data were analyzed from 2,532 participants, with a mean follow-up duration of 18.5 ± 1.29 years. Higher DunedinPoAm quartiles exhibited graded mortality risks (Q4 vs. Q1: hazard ratio, HR = 2.50), which persisted after multivariable adjustment. Restricted cubic splines revealed a non-linear association, indicating the presence of threshold effects. Systemic inflammation mediated 2.33% to 23.5% of the mortality risk associated with DunedinPoAm, driven by CD4+ T cells, B cells, CRP and comprehensive inflammatory indices. A significant interaction with diabetes underscored metabolic dysregulation as a vulnerability factor.

Link: https://doi.org/10.1186/s13148-026-02206-w

The heart regenerates poorly in comparison to other tissues, and the maladaptive inflammation that occurs following a heart attack does not help the situation. Fibrosis and scarring occurs in inflamed heart tissue, causing loss of function and heart failure. Stem cell therapies and the use of exosomes derived from stem cells are well demonstrated to reduce unwanted inflammation in animal studies, and are fairly widely used in the medical tourism industry. Here researchers report on the assessment of the ability of an exosome therapy to reduce heart failure following an induced heart attack in pigs, showing that it reduces the formation of scar tissue and helps to maintain heart function.

Myocardial ischemia-reperfusion (MIR) injury drives adverse remodeling and heart failure after ST-elevation myocardial infarction (STEMI), yet no therapy directly targets the fibrotic response. Here, we developed a good manufacturing practice-compatible extracellular vesicle (EV)-enriched secretome from bone marrow mesenchymal stromal cells and identified a laminin-521-based production strategy suitable for clinical translation.

The EV-enriched secretome exhibited in vitro immunomodulatory activity, and in murine MIR-injury models, treatment preserved left ventricular ejection fraction, reduced platelet-derived growth factor receptor beta (PDGFRβ)-associated myofibroblast activation quantified by positron emission tomography (PET) imaging, attenuated fibrosis, and promoted reparative macrophage polarization.

In a clinically relevant porcine ischemia-reperfusion model, intracoronary administration was cardioprotective. We further developed a clinically approved PDGFRβ-targeted PET-imaging platform for longitudinal assessment of fibrotic activity in STEMI patients, where preliminary observations suggest that myofibroblast activation persists for up to 2 months after STEMI in selected patients. Together, these findings establish a translational therapeutic-diagnostic framework for individualized management of MIR injury.

Link: https://doi.org/10.1016/j.stem.2026.07.003

Cells become senescent throughout life, because of stress or damage or reaching the Hayflick limit on replication, but senescent cells only begin to accumulate with age. When a cell becomes senescent, it grows in size, ceases to replicate, and turns its energies to creating signals promoting inflammation and growth. The immune system is responsible for destroying senescent cells after they have served their purpose, which is usually to attract the attention of immune cells to locations where they are needed to prevent or repair issues. While clearance of senescent cells is efficient in young people, it becomes much less efficient with age, allowing a population of lingering senescent cells to grow over time in tissues throughout the body. The pro-growth, pro-inflammatory signals that are helpful in the short term become harmful when sustained over the long term, disruptive to tissue structure and function and helping to promote the damaging state of chronic inflammation that is characteristic of later life.

Senolytic therapies to selectively destroy senescent cells exist, such as the dasatinib and quercetin combination, but are not widely used, conclusive clinical trial data has not yet been generated, because these are low cost drugs and supplements. No-one can make enough money from them to justify investment in large clinical trials. Meanwhile many companies are working to develop novel, patent-protected senolytic therapies that will be able attract sufficient funding for conclusive clinical trials, and those will be the (much more expensive) drugs that make their way into widespread use. This is the way that modern regulated medicine works.

Meanwhile, another faction of the research community is more interested in finding ways to suppress the inflammatory signaling of senescent cells rather than destroy them. This approach also has its low cost drugs, such as rapamycin, that are unlikely to be the subject of very large clinical trials for their ability to suppress the bad behavior of senescent cells any time soon. Nowhere near as many companies are actively working on novel drugs to alter senescent cell behavior, but the academic research community is identifying new possibilities at a fair pace. Today's open access paper, for example, describes a novel way in which mitochondria support the generation of inflammatory signaling by senescent cells, which opens up a few possible targets for careful sabotage.

Mitochondrial metabolism and epigenetic crosstalk drive SASP

Senescent cells promote tissue dysfunction in part through the senescence-associated secretory phenotype (SASP). Cytosolic mitochondrial nucleic acids activate innate immune signalling to initiate this inflammatory programme. Here we show that mitochondrial metabolism provides a second layer of control that enables execution of the inflammatory programme. In senescent cells, the mitochondrial pyruvate-citrate-acetyl-CoA axis is upregulated, increasing the availability of acetyl-CoA to support histone acetylation at SASP genes. Whereas mitochondrial DNA-driven signalling activates inflammatory transcription factors, acetyl-CoA availability is required for robust transcription of SASP genes.

Accordingly, enhancing acetyl-CoA levels promotes SASP gene expression, whereas inhibition of SLC25A1, the mitochondrial citrate exporter, reduces histone acetylation at SASP loci, limiting activity of this programme. In vivo, inhibition of SLC25A1 reduces chromatin accessibility at SASP loci, dampens inflammation, and improves healthspan in aged mice. Together, these findings identify a mitochondrial metabolic checkpoint that enables the epigenetic execution of innate immune signalling, revealing a mechanism that selectively controls the inflammatory output of senescent cells.

Researchers here restricted old mice to eating only during the 12 hours of the day in which they are usually inactive or asleep, for three days every week, and continued this restriction for a period of 8 weeks. The mice placed on time restricted feeding exhibited improved muscle function versus those who could eat at all times of the day. Studies of reduced or time restricted food intake tend to converge on the concept that benefits derive from spending some amount of time in a state of hunger, however that is achieved. Low nutrient availability triggers a range of adaptive processes in cell behavior, including increased cell maintenance activities. The result is improved cell function, improved tissue function, and a slowing of the pace of aging. While short-term effects are quite similar across species, the effect on pace of aging over the longer term is far larger in short-lived species than in long-lived species.

Sarcopenia, defined as the age-related decline in skeletal muscle mass and function, markedly reduces physical performance, threatens functional independence, and diminishes quality of life in older adults. Although the clinical manifestations of sarcopenia typically emerge later in life, underlying molecular alterations, particularly within the mitochondrial network, occur well before symptom onset. Growing evidence indicates that dietary interventions, including caloric restriction as well as changes in meal timing, composition, and overall intake, play a critical role in attenuating age-associated pathologies. Time-restricted feeding (TRF) is a dietary regimen in which all caloric intake is confined to a defined daily time window and has emerged as a feasible and widely adopted variant of caloric restriction.

This study investigates the effects of inactive phase TRF on skeletal muscle health in a middle-aged murine model, with a particular focus on its potential to delay or attenuate the decrease of physical performance only by modifying daily feeding schedules. Our findings demonstrate that inactive phase TRF allows to dissect the impact of mistimed nutrient intake and confers beneficial effects on skeletal muscle, including improved muscle strength and maintenance of basal glycemia during early aging. These effects were accompanied by a tendency to increase succinate dehydrogenase expression and significantly reduced lipid droplet accumulation. These effects correlate with muscle type-specific adaptations of the mitochondrial network and sarcoplasmic reticulum-mitochondria interaction in response to TRF.

Collectively, these findings support the potential of inactive phase TRF as an easy-to-follow therapeutic intervention during middle age to maintain physical performance in early aging.

Link: https://doi.org/10.1038/s41598-026-60902-2

Aging clocks of many varieties have been produced in recent years by applying machine learning techniques to a wide range of biological data that changes with age. This approach yields a tool that is disconnected from our understanding of the mechanisms of aging; links between the forms of cell and tissue damage and dysfunction that drive aging and the measures making up the clocks have yet to be determined. This makes it hard to interpret results, and hard to make practical use of a clock to assess the quality of any given approach to slowing or reversing aging. We have no idea in advance as to whether a given clock will perform well for a given intervention, and finding out is a slow process. The primary approach to this challenge taken by the research community is to produce new clocks at a fair pace, and gather as much data as possible on how the clocks behave, in search of patterns of clock behavior.

The outcome most often used to develop aging biomarkers is age itself, i.e. years lived since birth. However, in humans, relying on years lived as an outcome introduces a range of biases, most prominently confounding of aging with survival; humans in their 70s and beyond are, by definition, successful agers, having outlived most of their peers. The results of machine learning analysis differentiating older from younger people could therefore reflect not only aging-related biological damage, but also resilience.

An alternative approach that may overcome this limitation is to apply machine learning to an outcome that represents something closer to what many interventions aim to modify: the current rate of aging-related biological deterioration. We developed such a measure, Pace of Aging, by modeling changes over 20 years of follow-up in a panel of organ-function measurements among participants in the Dunedin Longitudinal Study. Critically, it also proved sensitive to the effects of calorie restriction, the intervention best established to slow aging in a range of laboratory models.

If using Pace of Aging in machine learning analysis to develop aging biomarkers can yield more sensitive endpoints for clinical trials, this would be consequential for the field. However, there are alternative explanations for the calorie restriction trial result. The participants in the trial (CALERIE) were healthy midlife adults, similar to the Dunedin Study members whose data were used to develop DunedinPACE. In contrast, the leading survival-time biomarker, the GrimAge epigenetic clock, was developed using data from older adults, many of whom had prevalent chronic disease. The critical factor could therefore be similarities between the participants whose data were used to develop the biomarker and the participants in the clinical trial.

To adjudicate between these competing hypotheses, biomarker design vs. demographic similarity, we developed a novel Pace of Aging biomarker in the same older-adult cohort used to develop GrimAge and tested its response to intervention in the CALERIE trial. We obtained data from the Framingham Heart Study Offspring Cohort. We adapted our Pace of Aging method for mixed-age cohorts with variable follow-up of organ-function measures and applied it to develop a novel DNA methylation biomarker of Pace of Aging in data from the Framingham Heart Study Offspring Cohort. When applied in independent cohorts, this novel biomarker (1) demonstrated exceptional technical reliability; (2) revealed a pattern of accelerating Pace of Aging with advancing age, replicating a finding first observed for our original Pace of Aging biomarkers developed in the Dunedin Study. In analysis of a randomized controlled trial of calorie restriction in healthy, non-obese humans (CALERIE), our novel Pace of Aging biomarker was slowed by calorie restriction, parallel to our original Pace of Aging biomarker.

Link: https://doi.org/10.64898/2026.07.07.26357388

A broad variety of aging clocks have been created in recent years. Such a clock is produced via machine learning techniques applied to any sufficiently complex set of biological data that tends to change with age. Everything from imaging to blood chemistry to omics data sets can and has been used for this purpose. A reference data set is processed to derive combinations of measurements that predict chronological age, or mortality risk, or some other output. A good clock then produces similar results in other data sets. A potentially useful clock also has the characteristic that a predicted clock age higher than chronological age correlates with a greater risk of mortality and age-related disease.

It is proposed that aging clocks are a measurement of biological age. If starting out with the very simple concept that biological aging is an increase in the risk of mortality due to intrinsic causes, then clocks that show correlation between clock age and mortality risk can reasonably be considered a first step in that direction. At any more detailed level of inquiry, however, it becomes a great deal less clear as to whether any given clock is actually decent measure of biological age. It is also difficult to gain consensus on how exactly to define biological age in any more detailed way. This is in part because aging is very complex. Any given clock is probably only sampling the consequences of some of the mechanisms involved. Can we trust that any given clock will correctly predict the outcome of a therapy that only affects one mechanism of aging, such as a senolytic drug that clears senescent cells from aged tissues? Not without actually running a lengthy study to find out.

Thus researchers are at present accumulating as much data as they can on the way in which various mainstream aging clocks behave in response to interventions and circumstances. In today's open access paper, for example, researchers look at how clock age correlates with mortality risk following surgery in older people. It is well known that surgery is an increasingly hazardous choice at older ages, but really the hazard scales with damage and dysfunction, not age. The level of accumulated damage and dysfunction varies from person to person of a given age, and thus perhaps clocks can help to better assess the risk attending some of the hard medical choices that have to be made in later life.

Biological aging increases risk of postoperative morbidity and mortality: an international, multi-cohort study

Surgery is very common and risky for older adults. Though surgical procedures on aging patients occur commonly, the outcomes are mixed. After major surgery, the risk of poor functional recovery, long-term disability, institutionalization, and 1-year mortality is significant. Surgery contributes to significant physiologic stress, and resilience to and recovery from physiological stress impacts postoperative outcomes. Chronological age (time since birth) is an insufficient proxy for surgical resilience, and restricting surgical care by chronological age is imprecise and potentially harmful. Instead, biological estimates of aging, termed biological age, provide a quantitative metric of aging for people across the entire age spectrum, and may better reflect vulnerability to surgical stress.

We evaluated PhenoAge, a validated biological age metric, in an international multi-cohort study comprising over 430,000 surgical patients across the UK, USA, and South Korea. In the UK Biobank (N = 291,845), PhenoAge was a robust, independent predictor of 1-year mortality (odds ratio, OR = 1.043), major adverse cardiovascular events (OR = 1.041), and 30-day readmission (OR = 1.02), even after adjusting for chronological age, Fried Frailty Index, Charlson comorbidity score, American Society of Anesthesiologists (ASA) physical status, surgical complexity, and other common surgical risk factors. "Fast Agers" faced a 49% higher risk of mortality than "Normal Agers". The main findings were replicated across three independent international cohorts (MOVER, OR = 1.03; Weill Cornell, OR = 1.036; INSPIRE, OR = 1.05), and validated prospectively at a large academic medical center, where PhenoAge predicted acute 3-day complications (OR 1.20).

Navitoclax (or ABT-263) was one of the earliest chemotherapeutics assessed for its ability to selectively clear senescent cells as a senolytic drug. The side effects on platelet function are pronounced, which is probably why it has received less attention than the dasatinib and quercetin combination discovered around the same time. Here, researchers report on a senolytic combination that allows for navitoclax to be used at much lower doses. It is possible that this might make it interesting again, though that ship may have sailed. There are so very many lines of research and development into novel and better senolytics these days, and any attempt to produce widespread use of low cost known senolytics is probably going to remain centered around dasatinib and quercetin, or possibly the use of fisetin if human clinical trial data ever emerges on its efficacy.

Eliminating both senescent and cancer cells through pharmacological intervention presents a powerful therapeutic strategy against aging and tumor progression. Navitoclax has emerged as a promising candidate with both senolytic and antitumor activity, but its clinical application remains limited due to dose-dependent thrombocytopenia and tumor-specific resistance. To overcome these limitations, we combined dichloroacetate and metformin with a 10-fold reduced dose of Navitoclax (ABT-263) and show that this pharmacology, termed, DMA, selectively targets the metabolic vulnerabilities underlying senescent and malignant cells.

We demonstrate that DMA effectively ablates different types of senescent and cancer cells in vitro by exacerbating their defects in ATP production. Notably, the treatment is well tolerated by healthy human cells and in mice in vivo, and in fact improves the functional performance of aged mice after acute administration and extends lifespan after prolonged dosing. While the in vivo effects of DMA are yet to be fully explored, our findings suggest that it might represent a new, clinically viable way to combat cancer and senescence without toxicity to healthy cells and tissues.

Link: https://doi.org/10.18632/aging.206399

The ability to accurately determine the composition of the gut microbiome via 16S rRNA sequencing is resulting a great deal of very interesting data on differences in the gut microbiome that are characteristic of aging, age-related diseases, and long-lived individuals. Here, researchers report that centenarians tend to have more Clostridium scindens in their gut microbiome, and demonstrate in aged mice that a metabolite produced by this bacterial species reduces intestinal barrier dysfunction. That the intestinal barrier becomes more leaky with age is an important contributing cause of chronic inflammation and other forms of dysfunction caused by the presence of unwanted bacteria, metabolites, and other molecules in the circulatory system and tissues throughout the body.

Microbial networks and keystone taxa play pivotal roles in maintaining gut microecological stability and host homeostasis, irrespective of their abundance. However, most previous studies of aging-associated gut microbiota have relied on abundance-based analyses, largely overlooking microbial networks and microbe-host interactions. Here, we employed a co-occurrence network approach to identify keystone taxa during aging in humans and mice. We found that centenarians harbor distinctive keystone taxa dominated by members of Clostridium, of which Clostridium scindens (C. scindens) can significantly enhance microbial network stability, probably contributing to longevity and reduced susceptibility to age-related diseases.

Mechanistically, C. scindens produces indole-3-acetic acid (IAA) from tryptophan via the enzymes amidase (AMIE) and aldehyde dehydrogenase (ALDH). Oral administration of either C. scindens or IAA effectively mitigates intestinal aging by restoring gut barrier dysfunction in aged mice. Further analysis revealed that C. scindens-derived IAA restores intestinal dysfunction through activation of aryl hydrocarbon receptor (AHR) signaling, leading to upregulation of intestinal CLDN10, a key tight junction protein. Structurally, IAA enhances Claudin-10 transcription by promoting AHR binding to its promoter region.

Our findings provide new insights into the characterization of microbial networks in centenarians and highlight that C. scindens and IAA may contribute to healthy longevity by promoting gut microecological stability and host homeostasis.

Link: https://doi.org/10.1002/imt2.70134

Senescent cells accumulate with age and contribute to degenerative aging via their pro-growth, pro-inflammatory signaling. Even when less than 1% of all cells are senescent in a tissue, the signaling generated by those senescent cells alters the behavior of other cells for the worse, and is disruptive to tissue structure and function. When it comes to what to do about the burden of senescent cells in aged tissues, much of the focus is on the development of senolytic drugs that can selectively destroy these errant cells to some degree. The most popular alternative path is the development of senomorphic drugs that can suppress senescent cell signaling to some degree, but unlike the senolytic development community this cannot yet boast the large number of companies dedicated to producing novel drugs.

Just as there are a great many senolytic compounds in the small molecule libraries and even among presently approved small molecule drugs, there are also a great many senomorphic compounds. Quality varies widely, and, sadly, all too few outperform the effects of lifestyle choices on the burden and behavior of senescent cells. Those that do are relatively neglected by the medical and development communities because they are cheap and out of patent protection; there is not enough profit to be made to support the high costs of clinical trials. So even relative well-known senomorphics like rapamycin are far less widely used than they might be, and it is left to the very slow pace of the academic community to scrape up sufficient funds to conduct large-enough clinical trials to convince more physicians to prescribe for their patients.

Senomorphics are drugs that have to be used continuously, and are unlikely to suppress all problem signaling. Senolytics are drugs that can be used intermittently, and are unlikely to kill all senescent cells. There are clearly trade-offs of cost and convenience in addition to the debates over the potential side-effects of continuously altered senescent cell behavior versus destruction of cells that may be generating harm, but may also be propping up a tissue's structure. For example, what happens when destroying senescent cells broadly in an individual with severe atherosclerotic plaques in which a sizable fraction of cells are senescent? These debates are so far largely conducted in the absence of firm data, and that will likely continue to be the case until both approaches are more widely used in humans.

Senomorphic agents: Multi-target strategies to tame the senescence-associated secretory phenotype for healthy ageing

Cellular senescence serves as a pivotal driver of organismal ageing and its associated pathologies. This detrimental effect is primarily mediated through the secretion of a complex mixture of inflammatory factors, proteases, and other bioactive molecules, collectively termed the senescence-associated secretory phenotype (SASP), which promotes the onset and progression of multiple age-related diseases. Targeting this pathological process, the field of senotherapeutics has recently evolved two principal strategies: senolytics and senomorphic agents.

Senomorphic agents have emerged as a complementary or alternative strategy with distinct advantages. The core principle of this approach is to modulate, rather than eliminate, the function of senescent cells. By inhibiting key signaling pathways such as NF-κB, mTOR, and JAK/STAT, senomorphic agents directly curb the production of the deleterious SASP. This strategy may attenuate inflammation and tissue damage while potentially preserving certain physiological functions of senescent cells. However, the optimal balance between senolytic "clearance" and senomorphic "modulation" remains undefined, and the translational path for both strategies is fraught with challenges that have not been systematically addressed in the literature.

The present review offers three distinctive perspectives. First, we conceptualize the SASP-regulatory network as a hierarchical architecture - from upstream stress sensors to downstream epigenetic effectors - providing a systematic framework for understanding where and how senomorphic agents intervene. This framework is novel in that no prior review has explicitly organized the SASP-regulatory pathways into functional layers. Second, we critically analyze the translational barriers that have received insufficient attention in the existing literature, including the limitations of animal models, the lack of gerodiagnostic biomarkers, and the challenges of tissue-specific delivery. Third, we propose a disease-stage-adapted strategy that integrates senomorphic modulation with senolytic clearance, moving beyond the "either-or" debate toward a synergistic, precision-based paradigm. By bridging mechanistic insights with translational realities, this review aims not only to summarize the current state of the field but also to chart a roadmap for future clinical development of senomorphic therapies.

A number of prevalent age-related conditions are notably different in timing and progression between the sexes. No doubt the list of differences by sex will grow as the research community explores the first therapies that target important mechanisms of aging. Here, researchers report on an attempt to treat intervertebral disc degeneration in mice using a senolytic drug that selectively destroys the BCL-2 and BCL-xL proteins that a senescent cell needs in order to resist programmed cell death. There is a reasonable weight of evidence to point to senescent cell accumulation as an important contribution to intervertebral disc degeneration, but the outcomes here are somewhat less than hoped. Male mice suffer a greater level of pathology from the condition in this model, but also benefit to a greater degree from the senolytic therapy. BCL-2 and BCL-xL may not be the best targets for removal of senescent cells in this condition, or alternatively, the burden of senescence in this condition may be different in character or degree by sex.

The senolytic PROTAC (753b) eliminates senescent cells (SnCs) by targeting ubiquitin-mediated destruction of the anti-apoptotic BCL-2/BCL-xL proteins. Here, systemic treatment with 753b was tested for reduction of age-related intervertebral disc degeneration (IDD) in mice. Five aging male and female mice were intraperitoneally injected with 753b or vehicle between 16 and 22 months of age. Among vehicle controls, intervertebral disc (IVD) histology using Safranin-O/Fast Green staining of paraffin embedded transverse sections revealed significantly greater IDD in 22 month old males than age-matched females.

In 22-month-old males, 753b treatment significantly reduced matrix metalloproteinase (MMP)-mediated aggrecan proteolysis as shown by Western blots, loss of disc matrix aggrecan by immunohistochemistry, age-related histomorphologic features of IDD, and serum protein levels of IL-6 and TNFα protein in treated male mice. While expression of IVD cellular senescence markers IL-6, IL-8, TNFα and p16INK4a assessed by RT-PCR of IVD tissue increased with age in both 22 month old female and male mice, expression of these markers was not reduced by 753b treatment.

These results demonstrate that 753b treatment of aging mice reduced IDD in males but not females, which suggests sex-based differences in the role of senescence in IDD and may have an impact on the potential for females to benefit from anti-senescent therapies for IDD. The observed therapeutic effects of 753b on IVDs of the male mice suggest a global reduction of cellular senescence burden through systemic, non-cell autonomous processes.

Link: https://doi.org/10.18632/aging.206394

Cerebrospinal fluid drainage from the brain into the body is necessary to remove metabolic waste from the brain. The flow declines with age, and evidence strongly suggests that this is an important contribution to the build up of protein aggregates and other waste that drive the onset and development of neurodegenerative conditions. Much of the focus is on the glymphatic system of vessels at the base of the brain, but because Alzheimer's disease starts in the olfactory bulb region of the brain, a few researchers have focused on drainage through openings in the cribriform plate stucture located behind the nose. Restoring passage of cerebrospinal fluid through the cribriform plate via surgical intervention is the task undertaken by Leucadia Therapeutics, for example. Here, researchers further explore that drainage path to find other potential blockages that occur between the olfactory bulb and cribriform plate, and that may also need to be dealt with.

Researchers discovered microscopic openings in the arachnoid membrane, which they named "arachnoid fenestrations", that allow cerebrospinal fluid to pass directly into meningeal lymphatic vessels. The findings reveal the most detailed pathway yet for brain waste clearance and identify a drainage route that progressively deteriorates during aging but can be functionally restored in aged mice. The researchers identified a specialized lymphatic network located between the olfactory bulbs and the cribriform plate, the perforated bone separating the brain from the nasal cavity. Unlike other regions of the arachnoid membrane, this area contained numerous microscopic openings measuring approximately 2 to 12 micrometers in diameter.

Fluorescent tracers injected into the cerebrospinal fluid accumulated around these openings, crossed the arachnoid barrier, entered meningeal lymphatic vessels, traversed the cribriform plate, and continued through lymphatic vessels in the nasal mucosa before draining into cervical lymph nodes. Similar arachnoid fenestrations were also identified in cynomolgus monkeys, suggesting that this specialized drainage structure is conserved beyond mice. To determine whether these openings were essential for CSF drainage, the researchers physically blocked them using microspheres too large to pass through the fenestrations. This dramatically reduced cerebrospinal fluid drainage to cervical lymph nodes, providing direct functional evidence that the fenestrations serve as critical exit portals for CSF.

Instead of delivering treatment by penetrating the meninges, the membrane that cover the brain, the team administered an adeno-associated viral vector expressing vascular endothelial growth factor-C (VEGF-C) through the nasal cavity. VEGF-C is a signaling molecule that promotes lymphatic vessel growth. This less invasive intranasal approach selectively expanded lymphatic vessels surrounding the olfactory bulbs and within the nasal mucosa. Although it did not restore the age-related loss of arachnoid fenestrations or enlargement of the cribriform plate openings, the expanded lymphatic network restored cerebrospinal fluid drainage in aged mice to levels comparable to those observed in young animals.

Link: https://www.eurekalert.org/news-releases/1137060

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

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

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

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

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

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

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