Fight Aging!

The platelets found in blood are membrane-wrapped cell fragments generated by a specialized population of megakaryocytes. As such, platelets can contain most of the molecules and structures that are present inside a cell, and exhibit behavior and surface features that reflect their parent cell's state. The primary purpose of platelets is to induce coagulation of blood and formation of a clot, or thrombus, where needed, such as following injury. With age, there is a tendency for clotting to be maladaptively triggered, particularly around areas of damage and dysfunction in blood vessel walls, such as where atherosclerotic plaques have developed. But even without atherosclerosis and other damage to the innner endothelial layer of blood vessels, there are still other changes to platelets themselves that make inappropriate clotting more likely.

This is the background that led to the development of widely used anti-thrombotic drugs that suppress the enhanced tendency towards clotting. Unfortunately, these drugs act on the same regulatory systems that are employed during useful, necessary clotting, such as following injury. Bleeding is a problematic side-effect. This is a common story in attempts to intervene in problems that occur with age, with chronic inflammation providing another example. The obvious paths to suppress unwanted behavior in system run awry turn out to also suppress desired behavior in that system. As biotechnology and the capabilities of the life science community advance, however, we start to see the first signs of improvement, of the ability to begin to manipulate these complex systems more adroitly, finding ways to suppress the unwanted outcomes with lesser effects on the desired outcomes.

Researchers discover a new therapeutic target to prevent thrombi with a lower bleeding risk

Antiplatelet drugs are one of the main tools used to prevent thrombus formation in people who have had a heart attack or stroke or who have cardiovascular diseases with a high thrombotic risk. These treatments work by reducing platelets' ability to aggregate and form clots that can obstruct the arteries. However, their use also increases the risk of bleeding, a common complication that limits their use in certain patients and remains one of the major challenges in cardiology today.

Now, a study dentifies a new protein involved in platelet activation that could help advance toward safer antithrombotic therapies. The work shows for the first time that the LRP5 protein, known for its role in the WNT signaling pathway, is directly involved in platelet aggregation and in arterial thrombus formation. "We have observed that both the genetic deletion of LRP5 and its pharmacological inhibition very significantly reduce platelet activation and thrombus formation in preclinical models, but with a much lower bleeding impact than that of classic antiplatelet agents such as aspirin or clopidogrel."

LRP5, a WNT signalling pathway receptor, and platelet activation

Human platelets, as well as platelets isolated from wild-type (Wt) and Lrp5-deficient (Lrp5-/-) mice, were challenged with ADP, collagen, LRP5-specific inhibitors, and standard platelet inhibitor drugs. Both platelet aggregation and flow-dependent platelet deposition on collagen-coated surfaces were significantly lower in Lrp5-/- than in Wt mice. In vivo carotid artery occlusion time measured by real-time blood flow monitoring was significantly prolonged in Lrp5-/- mice. Human platelets express high levels of LRP5 and flow-mediated human platelet deposition and aggregation was highly reduced by LRP5 inhibition. Under the experimental conditions tested, LRP5 deletion did not significantly affect coagulation nor induce bleeding.

These findings reveal for the first time that LRP5 plays a critical role in platelet adhesion and thrombus formation. Genetic deletion and biochemical inhibition of LRP5 markedly impair platelet aggregation and thrombosis in preclinical models, without major effects on haemostasis. Although further research is needed to evaluate its clinical applicability, LRP5 appears as a novel and actionable target to modulate platelet reactivity and thrombosis.

Researchers here report on a novel a way to improve kidney regeneration following injury, using a technique that was developed as a treatment for an injured heart. It is interesting to consider whether it might work on other tissues as well. Perhaps more relevant is the question of whether the therapy would improve ongoing tissue maintenance in an aged organ in the absence of injury; that rather depends on the fine details of the biochemistry, and could go either way.

A drug developed to help heart tissue repair itself after a heart attack might also help kidney tissue repair and regenerate, researchers have found. The drug, called AD-NP1, which was recently approved by the FDA for a Phase 1 clinical trial in humans, works in heart tissue by blocking a protein that disrupts healing and prevents internal organs from fully recovering. Researchers have now found that blocking this protein in kidney tissue speeds repair after kidney injury in mice.

An injured kidney produces a protein called ENPP1 that initiates a metabolic chain of events, disrupting energy production and function of multiple cells in the injured region, impeding tissue repair. The researchers found that blocking ENPP1 enhanced kidney repair and reduced scar tissue formation, thereby improving kidney function. Researchers previously determined that blocking ENPP1 in heart tissue improved healing.

fed mice a diet toxic to the kidneys and administered drugs that cause kidney damage to normal mice and mice with genes knocked out for producing ENPP1. Blood tests showed that these mice all had significant increases in serum creatinine, BUN, and cystatin C, which are signs of renal dysfunction. But after four weeks, these levels were greatly reduced in mice unable to produce ENPP1 compared with control mice, indicating that their kidneys were healing.

AD-NP1 is a monoclonal antibody engineered in the laboratory to mimic the function of natural antibodies produced by our immune system. Just as our immune system can produce specific antibodies to bind and inactivate specific pathogens, the monoclonal antibody AD-NP1 has been engineered to target human ENPP1 and no other human protein.

Link: https://newsroom.ucla.edu/releases/ucla-researchers-damaged-kidneys-drug

The accumulation of senescent cells in aged tissues is harmful because these cells generate a potent mix of inflammatory signals known as the senescence-associated secretory phenotype, disruptive to tissue structure and function when sustained over the long term. Researchers are interested in finding ways to selectively suppress this signaling, which involves better understanding the mechanisms that promote it. Here, researchers find a way in which senescent cells provoke the well studied cGAS-STING inflammatory pathway, a system that reacts to mislocalized or foreign DNA in the cell cytoplasm, via export of R-loop DNA structures from the cell nucleus.

Cellular senescence contributes to inflammaging in part through the senescence-associated secretory phenotype (SASP). R-loops, three-stranded nucleic acid structures, contribute to innate immune response in cancers; however, the role of R-loops in senescence and inflammaging remains largely unknown. Here we show that nuclear-derived cytoplasmic R-loops promote the SASP and inflammaging. We detect an accumulation of nuclear-derived R-loops in the cytoplasm of senescent cells with an enrichment in alpha-satellite repeats. These cytoplasmic R-loops localize into cytoplasmic chromatin fragments (CCFs) and activate the cGAS-STING innate immune pathway to drive the SASP.

We identify the exportin-1 (XPO1)-DEAD-Box helicase 1 (DDX1) complex as essential for the nuclear export of R-loops and their subsequent localization into CCFs. Inhibition of XPO1 with KPT-330 suppresses nuclear R-loop export and its localization into CCFs, attenuates the SASP, mitigates age-associated inflammation and extends healthspan. These findings reveal nuclear export of R-loops as a potential target for suppressing age-associated inflammation.

Link: https://doi.org/10.1038/s43587-026-01147-6

The primary scientific impulse is to accumulate data and extract knowledge from that data. Application of that knowledge to the production new technologies is a distant afterthought. So too in the life sciences specifically. When it comes to cellular senescence as a driving mechanism of aging, the primary focus of the research community is to employ modern omics tools to build as great a body of data as possible regarding the burden of cellular senescence in aged tissues. In particular this includes the ways in which the state of senescence differs between cell types, or even within the same cell type. Senescence appears to be much more a collection of distinct subtypes than initially suspected.

None of this changes the potential utility of early senotherapeutics, such as the low cost senolytic combination of dasatinib and quercetin that selectively pushes senescent cells into programmed cell death. Clearing even a third of lingering senescent cells from aged tissues produces dramatic benefits in aged mice, meaning a clear reversal of many different age-related diseases and dysfunctions. Yet relatively little effort has been made to rigorously assess this and other early senolytic drugs in humans. A few small academic clinical trials at a few doses have been undertaken when it comes to dasatinib and quercertin, too small a sample to say anything other than the results seem promising, and one company has made it as far as phase 2 trials for a poor choice of senolytic strategy before failing. One would think that the quality of the animal data demands a greater effort when it comes to dasatinib and quercetin.

Scientists Develop First Comprehensive Atlas of Human Cellular Senescence in Aging

A massive scientific initiative to decode how aging reshapes the human body reached a major milestone this month. The National Institutes of Health (NIH) Cellular Senescence Network (SenNet) published its first wave of discoveries. Together, they represent the first coordinated effort to map senescent cells - damaged or aged cells that stop dividing but refuse to die - at single-cell and spatial resolution. When cellular senescence occurs, these "zombie cells" accumulate over time. They secrete harmful chemicals that trigger inflammation and damage surrounding tissue. This process drives aging and fuels chronic diseases like arthritis, cancer, and Alzheimer's disease.

Charting human cellular senescence in aging and disease

Cellular senescence was first recognized in long-term in vitro cultures, where cells eventually ceased dividing yet remained metabolically active. Later studies revealed that senescence also occurs in vivo as a distinct cellular state induced by stress, damage, or other stimuli, resulting in permanent cell-cycle arrest alongside widespread alterations in intracellular and extracellular signaling, including the senescence-associated secretory phenotype (SASP). However, in the human body, we still know surprisingly little about which cell types undergo senescence, their abundance, their spatial distribution, and the impact on the microenvironment across different organs and tissues.

Without such a comprehensive "blueprint" of senescent cells in human tissues and organs, it is nearly impossible to address fundamental questions about their roles in maintaining tissue homeostasis, driving age-related physiological decline, or contributing to chronic diseases. Moreover, emerging evidence suggests that senescence is not a single, uniform program but a highly heterogeneous process. It may manifest differently depending on the initiating trigger, its duration, the tissue microenvironment, the cell type affected, and the individual's age or life stage. Yet, this diversity has been documented primarily in cell culture or animal models, with very limited characterization in human tissues.

The NIH SenNet consortium aims to build the first comprehensive human reference framework for heterogeneous senescent cell states, defined as "senotypes," providing the resources and tools needed to finally ask and answer the deep and meaningful questions about how senescent cells influence human aging and disease. The SenNet publication collection highlights some of the progress made in generating the human cellular senescence atlas during healthy aging of whole lymph nodes, lung parenchyma, prefrontal cortex tissues of the brain, and 14 other tissues; during disease in the liver and human chronic wounds from aged skin; and during the COVID-19 pandemic. Some of the manuscripts highlight the senolytic therapies identified and tested within the SenNet consortium. We envision that mapping senescent cells across human tissues will enable the development of precise diagnostics and senolytic therapies that selectively target harmful senescence while preserving its beneficial roles, transforming the management of aging and chronic diseases.

Researchers have discovered many correlations between age-related diseases that occur in very different tissues at opposite ends of the body and, at first glance, appear to have little to do with one another. These correlations arise because the many varied outcomes of aging emerge from a much smaller set of underlying mechanisms of damage, such as mitochondrial dysfunction and accumulation of senescent cells. The patterned burden of these these forms of damage, amount and distribution in the body, will tend to favor the emergence of some forms of age-related disease over others. Regardless of how this all progresses, these underlying forms of damage are the real target that should be addressed by potential therapies to treat aging.

Age-related macular degeneration (AMD) is one of the leading causes of irreversible vision loss among the elderly in industrialized countries. Neovascular AMD (nAMD), characterized by choroidal neovascularization, represents the most vision-threatening form of AMD and is uniquely dependent on vascular endothelial growth factor (VEGF)-driven angiogenesis. While the ocular consequences of nAMD are well-established, mounting evidence suggests potential links between AMD and systemic diseases, including cancer. AMD and cancer may share several common risk factors and biological mechanisms, such as advanced age, smoking, oxidative stress, chronic inflammation, and dysregulated angiogenic pathways, notably involving VEGF.

Beyond angiogenesis, nAMD may also reflect broader systemic aging biology. Increasing evidence suggests that nAMD is associated with processes such as chronic low-grade inflammation ("inflammaging"), immune dysregulation, and extracellular matrix remodeling. Cellular senescence, while an important component of aging, has been suggested to play dual roles: tumor-suppressive early via growth arrest, but tumor-promoting later through the senescence-associated secretory phenotype (SASP). In the context of AMD, several studies have demonstrated involvement of senescent retinal pigment epithelial cells and their SASP signatures.

These mechanistic lines of evidence provide a framework in which nAMD might not only share angiogenic pathways with cancer but also intersect with systemic aging processes, potentially helping to explain its selective associations with certain malignancies. Recent genome-wide studies have revealed that both AMD and various cancer types exhibit polygenic susceptibility involving complement activation, lipid metabolism, and extracellular matrix regulation-pathways that are also implicated in tumor microenvironments and cancer progression-raising the possibility that such systemic vulnerability could extend beyond the eye.

Link: https://doi.org/10.18632/aging.206383

Increased FGF21 expression is essential to the life extension produced by the practice of calorie restriction. It is a part of the regulatory system governing the beneficial reaction to low levels of protein intake, an evolved response that helps to increase the odds of individuals surviving long winters and other periods of famine. Here, researchers report on the use of an FGF21 AAV gene therapy in mice to produce the sweeping improvements in health that are characteristic of most calorie restriction mimetic strategies.

The decline of organ function during aging limits healthspan. Despite the potential of lifestyle interventions to improve health, sustained maintenance of healthspan is challenging, and no gerotherapeutic drugs have been approved. Here, we demonstrated that aged and geriatric male and female mice treated with muscle-directed adeno-associated viral (AAV) vector-mediated fibroblast growth factor 21 (FGF21) gene therapy extended healthspan and lifespan with sustained organ benefits. This treatment normalized body weight and adiposity, improved insulin sensitivity and glucose homeostasis, preserved hepatic detoxification capacity, counteracted age-related kidney disease, promoted cardiac health and muscular function, and enhanced cognition.

Transcriptomic and histopathological analyses indicated improved whole-body energy homeostasis and cellular fitness, which were mediated by tissue-specific adaptations, including enhanced mitochondrial function, restored proteostasis, and reversion of inflammation, fibrosis, and amyloidosis. AAV-FGF21 treatment also activated AMPK signaling. These results highlight FGF21 gene therapy as a potential strategy to promote healthspan and delay age-related deterioration.

Link: https://doi.org/10.1016/j.ymthe.2026.05.025

Any sufficiently complex set of biological data assessed in a large population of various ages can be used as a basis to create an aging clock. Machine learning techniques are used to find algorithmic combinations of measurements that map to chronological age or observed mortality risk within the reference population. That algorithm then predicts age or mortality risk when used in people outside the reference population; where a person's predicted age is higher than chronological age this is thought to represent a higher burden of damage and dysfunction, and thus a greater biological age. Aging clocks have been show to work pretty well at a population level, but it remains difficult to establish how the measured parameters are determined by mechanisms of aging, and whether a clock assessment is of any practical use for one individual in the health and medical contexts.

Nonetheless, researchers are creating new clocks at a fair pace. Most omics based clocks use immune cells from a blood sample, and there has been some discussion over the years as to how relevant this is to aging in other tissues. Another point of interest has been how to separate variations in immune function that arise from stress, infection, and other transient causes from those arising from mechanisms of aging. With this background context in mind, today's open access paper reports on the use of a single cell assessment of chromatin accessibility in many different immune cell subtypes. Chromatin is structured nuclear DNA, with different sections either spooled and compact to prevent gene expression, or unspooled and accessible for gene expression. This structure is controlled by epigenetic decorations, and determines the behavior of the cell by determining which proteins are manufactured.

sc-ChromAging: A Single-Cell Chromatin Accessibility-based Clock Decodes Cell-Type-Specific Epigenetic Aging Trajectories

The aging process in humans constitutes a complex progression that exerts widespread effects across various organ systems, with the immune system displaying particularly significant dysregulation. This deterioration of immune integrity, often termed immunosenescence, is intrinsically linked to an attenuated capacity for tissue regeneration, a heightened vulnerability to infectious diseases, and the disruption of systemic homeostasis, all of which facilitate the pathogenesis of age-associated morbidities. While chronological age serves as a rough proxy for these changes, it often fails to capture the substantial heterogeneity in health trajectories among individuals. Consequently, the quantification of biological age through molecular biomarkers has emerged as a pivotal strategy to assess aging status and predict health outcomes. Among the hallmarks of aging, epigenetic remodeling is considered a primary driver of the aging process.

The concept of an epigenetic clock was pioneered using DNA methylation data. However, the majority of existing DNA methylation clocks rely on bulk tissue profiles, which makes it difficult to discern whether observed changes arise from alterations within specific cells. Chromatin accessibility, measured by single-cell assay for transposase-accessible chromatin-sequencing (scATAC-seq), reflects the regulatory potential of the genome. As an upstream layer, chromatin state provides unique mechanistic insights into how the aging process rewires the regulatory network of immune cells, yet high-resolution clocks based on scATAC-seq remain unexplored.

To decode the epigenetic heterogeneity of immune aging, the cell-type-specific chromatin accessibility aging clock sc-ChromAging were constructed using a high-quality scATAC-seq dataset derived from the Chinese Immune Multi-Omics Atlas (CIMA) cohort. The predictive performance of sc-ChromAging was evaluated across five major immune cell types. Significant heterogeneity in predictive performance was observed, and the CD4+ T cells exhibited the highest predictive accuracy. To further investigate the epigenetic signatures of aging at higher granularity, the analysis was extended to 25 immune cell subtypes. Consistent with the lineage-level findings, subtypes within the T cells displayed higher predictive accuracy. Notably, CD4+ naïve T cells showed the highest accuracy among subtypes.

The relatively high predictive accuracy observed in CD4+ naïve T cells suggested that their chromatin landscape may effectively reflect the biological aging process. Mechanistically, this high precision may be related to the intrinsic program of thymic involution. Unlike memory or effector subsets whose epigenomes are mainly remodeled by antigen exposure, naïve T cells may maintain a relatively quiescent state where chromatin accessibility changes are driven primarily by the intrinsic aging program. Notably, although CD8+ naïve T cells also showed relatively good predictive performance, their accuracy remained lower than that of CD4+ naïve T cells. This distinction suggests that a quiescent phenotype alone does not necessarily confer the same degree of age predictability across naïve T-cell compartments. One possible explanation is that the chromatin state of CD8+ naïve T cells may be more susceptible to extrinsic regulatory influences associated with their survival and maintenance, including cytokine-dependent homeostatic signals and other environmental stimuli.

Alongside calorie restriction, exercise represents the gold standard of proof for an intervention to slow degenerative aging. Sadly the research community has demonstrated all too few approaches that can robustly improve on exercise and physical fitness in the matter of aging, and none of those yet have compelling human data to support the extensive animal studies. Rapamycin and senolytics spring to mind as those with the greatest amount of data. Partial epigenetic reprogramming is also interesting but still too new to have gathered a very large body of animal work, despite the vast funding devoted to it in recent years. Thus pharmacological mimicry of the response to exercise continues to interest researchers, and programs in this part of the field continue to emerge.

Global declines in physical activity have contributed to an acceleration in immune aging, characterized by systemic inflammation (inflammaging) and impaired immune regulation (immunosenescence). This narrative review provides an overview of the evidence in both preclinical and clinical models supporting exercise as a critical intervention to counteract immune aging and its related diseases.

Regular physical activity modulates systemic inflammation, reduces neutrophil extracellular trap (NET) formation, and promotes favorable shifts in immune cell populations, including T cell and natural killer (NK) cell subsets. Exercise interventions have been associated not only with maintaining immune health but also in mitigating autoimmune disease progression, improving metabolic regulation, enhancing tumor immune surveillance, and reducing neuroinflammation. Emerging studies highlight the role of exercise in promoting vascular normalization within the tumor microenvironment, alleviating tumor hypoxia and acidosis, and restoring T and NK cell function.

In the elderly, appropriately prescribed multimodal exercise regimens may lower infection risk without clear evidence of immunodepression, supporting exercise as a potentially safe and effective strategy for immune rejuvenation. Furthermore, novel mechanistic insights, including the modulation of NET burden, IGF-1 signaling, kynurenine metabolism, and microbiome composition, suggest that exercise influences key biological pathways underlying age-related immune decline. While exercise offers broad clinical benefits, future research should prioritize mechanistic studies to optimize exercise prescriptions and inform the development of exercise-mimetic therapeutics.

Link: https://doi.org/10.3389/fragi.2026.1832962

The functional connectome is a map of connections between brain regions, produced via MRI imaging. Features tend to be fairly distinct from individual to individual, and change over time. Researchers here show that the functional connectome can be used to predict handgrip strength in patients exhibiting age-related frailty, which is quite interesting. One tends to think of loss of hand strength as emerging from degeneration of local musculature and local neuromuscular junctions. The results suggests that there is a component of physical frailty localized in the brain, though it is also possible that this reflects downstream issues resulting from the underlying mechanisms of aging occurring distinctly in both locations.

Physical frailty, which refers to a decline in physical strength and energy, is prevalent in older adults and has been attributed to impaired cognitive function and adverse health outcomes. The strength of a contraction on a handgrip, known as isometric handgrip strength, has been used as a marker of physical frailty. While handgrip strength can partially be explained by muscle properties (e.g., cross-sectional area and architecture), it may also be influenced by neural adaptations, such as intermuscular and intramuscular coordination.

There is a growing use of imaging-derived data from different modalities to predict clinical phenotypes and disease risk. In this context, handgrip strength has been attributed to resting-state functional connectivity within motor and salience networks. For example, within healthy older adults, researchers found that higher functional connectivity of the motor cortex to putamen, insula, and cerebellum was associated with higher handgrip strength. Another study investigated whole-brain functional connectivity (i.e., connectome) and observed that higher handgrip strength was associated with greater functional segregation of the salience ventral attention network in older adults at rest.

Because the connectome is unique for each person, akin to a "brain fingerprint", it may also serve as a personalized marker that can be used to predict their individual behavioral measures. A predictive model can be developed using connectomes from tasks involving motor components. Such tasks shift the brain into a more alert, motor-relevant state, offering greater sensitivity to motor-related conditions like frailty compared to resting-state connectivity. In this study, we focused on healthy older adults and had them perform two perceptual discrimination tasks on two different functional MRI sessions, both of which involved a non-dominant handgrip manipulation. We aimed to test the identifiability of the task-based connectomes across the sessions and identify the key functional connections (FCs).

We measured participants' maximum isometric voluntary contraction (MVIC) of their non-dominant hand as an indicator of frailty and neuromuscular health. We identified FCs predictive of MVIC, which may partly explain motor-related impairments in frail older adults. Finding such brain-based biomarkers for grip strength could identify potential target sites for motor rehabilitation programs.

Link: https://doi.org/10.3389/fnins.2025.1697908

Klotho is one of the few robustly longevity-associated genes. The effects of increased klotho expression on life span in mice that are arguably large enough to be interesting even if one prefers more of a focus on damage repair in the treatment of aging. A number of companies are developing therapies based on either the delivery of klotho fragments shown to improve function in aged animals, or using gene therapies to promote klotho expression and secretion. While klotho is important in the aging kidney, it is the ability of circulating klotho to promote function in the aging brain that has attracted greater interest, perhaps in large part because the biochemistry of its influence on the brain is less well understood.

Brain aging is accompanied by progressive disturbances in calcium signaling, mitochondrial function, redox balance, neuroimmune regulation, and barrier-fluid homeostasis, collectively increasing susceptibility to neurodegenerative diseases. Therefore, identifying physiological regulators that stabilize these interconnected processes is central to understanding brain aging. Klotho, an antiaging protein initially characterized by its systemic roles in mineral metabolism and lifespan regulation, has emerged as a key modulator of cellular and tissue homeostasis across multiple organs, including the central nervous system.

In the brain, Klotho is predominantly expressed in the choroid plexus and selectively in neuronal and oligodendroglial populations, positioning it at the interface of barrier physiology and neural function. Experimental studies have indicated that Klotho contributes to cerebrospinal fluid homeostasis, synaptic plasticity, neurogenesis, myelination, and resistance to metabolic and oxidative stress. Rather than acting through disease-specific pathways, Klotho stabilizes the core physiological axes that govern neuronal resilience, including Ca2+ signaling, mitochondrial-redox homeostasis, neuroimmune balance, growth factor signaling, and barrier integrity. Consistent with these physiological roles, reduced Klotho availability is associated with cognitive decline and multiple neurodegenerative disorders.

This review positions Klotho as a central determinant of cognitive reserve and neuro-resilience, providing a unifying physiological framework that links systemic homeostasis to brain aging and explains how disruption of Klotho signaling amplifies vulnerability to neurodegenerative disease, whereas its preservation supports lifelong brain integrity.

Link: https://doi.org/10.4196/kjpp.26.015

Senescent cells accumulate with age, a situation that appears more a result of the aging immune system failing to achieve timely clearance of newly senescent cells rather than a significant increase in the pace at which cells become senescent. Senescence occurs in response to cellular damage and stress, but also when somatic cells reach the Hayflick limit on replication. A senescent cell becomes larger, ceases replication, and devotes its energies to the secretion of pro-growth, pro-inflammatory signals. In the short term and in youth this is usually beneficial, helping to coordinate tissue maintenance, regeneration, and suppression of potentially cancerous cells. When sustained for the long term, the signaling of senescent cells is disruptive to tissue structure and function, however, contributing to the damaging chronic inflammation of aging.

In principle, clearing out lingering senescent cells should improve the ability of other classes of rejuvenation therapy to produce benefits. This is particularly thought to be case for stem cell and exosome therapies that rely upon generating favorable signals to improve the behavior of a patient's cells, thereby dampening chronic inflammation and hopefully enhancing regeneration and tissue maintenance. Senescent cells and signaling therapies stand in opposition, and it makes sense that a reduced burden of senescent cells should improve outcomes for signaling therapies.

This has to be tested, of course. Today's open access paper reports on the results from one example of this sort of study. Unfortunately the researchers involved chose to employ accelerated aging mouse models rather than naturally aged mice, so one can't take the results entirely at face value. Still, it is supportive of the consensus view on the opposition between senescent cells and signaling therapies. Interestingly, the researchers used a senolytic vaccine rather than a small molecule; you might recall an earlier study that employed this specific vaccine to slow cancer progression in mice.

Synergistic senolytic-regenerative therapy significantly extends healthspan and lifespan

Regenerative medicine, particularly through stem cell-based therapies, holds immense potential for treating chronic diseases and mitigating the effects of aging by restoring tissue function and homeostasis. Mesenchymal stem cells (MSCs), have been extensively investigated for their paracrine effects, immunomodulatory properties, and capacity to promote tissue repair via secretion of growth factors. Personalized MSC (pMSC) are a type of autologous stem cells developed by Immorta Bio which can be produced in an "age-specific" manner by controlling the extent of differentiation during generation from pluripotent stem cells. MSC are attractive from an anti-aging perspective because of the studies showing young MSC can suppress and in some cases even inhibit characteristics of aging.

Despite promising preclinical outcomes, and one FDA approval for an orphan disease, clinical translation of MSC therapeutics remains limited, with many trials demonstrating modest efficacy in conditions characterized by fibrosis, inflammation, and organ failure. A key barrier to successful regeneration is the accumulation of senescent cells, a hallmark of aging and chronic pathology that actively impedes stem cell function. Senescent cells, induced by stressors such as oxidative damage, telomere attrition, or chemotherapeutic agents, enter a state of irreversible cell cycle arrest and secrete a constellation of pro-inflammatory cytokines, chemokines, and matrix-degrading proteins collectively known as the senescence-associated secretory phenotype (SASP). SASP components not only perpetuate local inflammation but also directly antagonize regenerative processes by inhibiting stem cell proliferation, differentiation, and survival.

Experimental models of organ failure and accelerated aging, including carbon tetrachloride (CCl4)-induced hepatotoxicity and doxorubicin chemotherapy, reliably recapitulate this senescent environment, manifesting as increased aging markers and impaired physical capacity alongside biochemical evidence of tissue damage. Here, we investigate the hypothesis that senescent cells and their SASP directly impair pMSC-mediated regeneration in models of liver failure and accelerated aging. Using SenoVax, a novel senolytic immunotherapy, in combination with pMSCs, we evaluate synergistic effects on biochemical markers of liver function, aging and regenerative biomarkers, survival, and physical fitness attributes of aging. Combined senolytic and pMSC therapy outperformed monotherapies and produced clear synergistic benefits, including significant biochemical improvement of liver failure parameters, reversal of accelerated aging features, and restoration of regenerative signaling pathways. These findings support the concept that clearance of senescent cells can act as a critical adjuvant to regenerative therapies for chronic disease and aging.

Producing new aging clocks is easier than overcoming the hurdles to the practical use of existing aging clocks, so the research community is generating new clocks at a fair pace while failing to make much concrete progress on the challenging problem of how to use clocks to assess novel potential rejuvenation therapies. An aging clock measures some combination of parameters that at least appears to reflect biological age. Given that clocks are reverse engineered from epidemiological data via machine learning techniques and the research community has not established clear links between biological age and any of the specific parameters used in a clock, it is entirely unclear as to whether any given clock will accurately reflect the outcome of an actual rejuvenation therapy. Will it understate or overstate the effects of repairing some form of cell and tissue damage? Will its predictions regarding mortality risk turn out to be correct? They only way to find out at present is qualify a specific clock for a specific intervention via the slow and expensive life span studies that everyone wants to avoid. Some way to fix this present situation is needed, and building more clocks seems unlikely to achieve that goal.

Accurate quantification of biological age is essential for early risk stratification and intervention of chronic diseases. Here, we present StackAge, an ensemble-based biological aging clock that integrates large-scale plasma proteomic and metabolomic profiles from 30,376 participants in the UK Biobank. StackAge demonstrated high accuracy in age prediction (Pearson r ≈ 0.93 with chronological age) and substantially enhanced risk prediction for 12 chronic diseases, achieving area under the curve (AUC) exceeding 0.90 for type 2 diabetes, Alzheimer's disease, and chronic kidney disease. Notably, the incorporation of estimated aging rates consistently improved disease prediction beyond conventional omics and demographic features.

Feature interpretation and pathway enrichment analyses revealed that aging-associated biomarkers were enriched in inflammation, metabolic stress, and extracellular matrix remodeling pathways. Mediation analysis further indicated that modifiable lifestyle factors may accelerate biological aging, thereby increasing susceptibility to cardiovascular, neurological, immune, and musculoskeletal disorders. Together, these findings establish a robust multi-omics framework for quantifying individual aging trajectories and highlight biological age as a clinically actionable indicator for precision prevention and health management of age-related diseases.

Link: https://doi.org/10.1093/bib/bbag271

Adjusting the operation of metabolism to modestly slow aging has long formed the bulk of fundamental research into intervention in aging. All living organisms exhibit some plasticity of life span when subject to mild stresses, such as lack of nutrients, heat, cold, and so forth. Unfortunately this strategy seems unlikely to lead to therapies that greatly improve upon the effects of exercise and lifestyle choice, particularly given the evidence for metabolic adjustment to produce ever smaller gains in longevity as species life span increases. Nonetheless, this form of research persists, driven by the scientific urge to obtain complete understanding of the way in which aging progresses in detail. Here, for example, researchers provide evidence for there to be multiple options for the adjustment of metabolism to slow aging, not just one path.

While aging is the greatest risk factor for the development of neurodegenerative disease, the role of aging in these diseases is poorly understood. Our previous work has shown that targeting aging pathways can be neuroprotective in animal models of neurodegenerative disease. Based on these findings, we believe that by gaining insight into the aging process, that knowledge can be applied to identify novel therapeutic targets for neurodegenerative disease. To advance our understanding of aging, we used a genomics approach to identify genes regulated by multiple lifespan-extending pathways. We performed RNA sequencing on nine long-lived C. elegans mutants representing seven longevity pathways: insulin/IGF-1 signaling, dietary restriction, germline deficiency, impaired chemosensation, reduced translation, elevated mitochondrial reactive oxygen species (ROS), and mild mitochondrial impairment.

We found that most pairs of long-lived mutants exhibited a significant overlap in differentially expressed genes. Comparing gene expression across the entire panel of long-lived mutants revealed three distinct longevity groups that could be clearly distinguished by gene expression. Interestingly, two of these groups showed modulation of specific genetic pathways in opposite directions, suggesting that there are multiple alternative strategies to achieving long life. Filtering for genes similarly modulated in at least six mutants identified 196 upregulated and 62 downregulated aging genes. Upregulated genes were enriched in immunity, defense, and metabolism, while many downregulated genes impacted translation and gene expression. To assess the ability of these genes to enhance longevity individually, we knocked down the commonly upregulated genes in long-lived mutants and evaluated the resulting effect on lifespan. Using this approach, we identified several genes that affect lifespan individually. Upregulation of at least some of these genes was sufficient to enhance stress resistance and extend lifespan in wild-type worms.

Overall, the shared longevity genes identified in this work offer potential targets to promote healthy aging and decrease age-onset disease.

Link: https://doi.org/10.64898/2025.12.29.696944

Macrophages are innate immune cells found throughout the body, important not just for their ability to defend against infectious pathogens, but also deeply involved in tissue maintenance and regeneration. Macrophages can adopt different packages of behaviors - known as polarizations - in response to circumstances. The simple model, which likely glosses over many lesser differences that are important in some contexts, divides the macrophage population into M1 and M2 polarizations, distinguished by surface features as well as by behaviors. M1 macrophages generate inflammation and aggressively hunt down pathogens. M2 macrophages resolve inflammation and engage in tissue maintenance activities, such as ingesting cellular debris and waste products. Both polarizations are necessary, but aging brings imbalance, often characterized as too many M1 macrophages where M2 macrophages are what is needed.

Thus the research community is interested in developing the means to adjust macrophage polarization for therapeutic benefit. At the outset, this involves better understand the regulation of polarization, and the many distinct influences that contribute to a macrophage adopting one state or another. Today's research materials focus on an aspect of the regulation of circadian rhythm that is known to influence macrophage behavior, and the authors report on their efforts to dig more deeply into how this actually works. This sort of fundamental research is necessary to identify possible points of intervention for the later development of therapies.

Body clock found to control inflammatory responses in macrophages

When our body encounters an injury or infection, the immune system sends out cells known as macrophages to initiate an inflammatory response that begins the healing process. These macrophages can exist in two different states: a pro-inflammatory (M1) state, which promotes inflammation, and an anti-inflammatory (M2) state, which helps resolve inflammation and repairs the tissue. The balance between these two states is important, as disruptions can lead to uncontrolled inflammation, which in turn can give rise to chronic inflammation-associated diseases, including cancer, liver disease, diabetes, and autoimmune disorders.

Previous studies have revealed that macrophage activity is closely linked to the circadian clock, with BMAL1 playing a central role in regulating this process. Researchers have now found that BMAL1 drives macrophages toward a pro-inflammatory M1 state by activating inflammatory signaling pathways in the cell nucleus. Researchers observed that normal mice showed a marked increase in pro-inflammatory M1 macrophages along with elevated inflammatory signals after exposure to a chemical carcinogen. In contrast, mice lacking BMAL1 in their macrophages showed significantly reduced inflammation and suppressed liver tumor development.

Experiments revealed that BMAL1 binds to multi-functional protein 2 (MFP2), a fatty acid-oxidation enzyme normally found in cellular compartments called peroxisomes, and transports it into the cell nucleus. Notably, nuclear MFP2 levels fluctuate according to the time of day in a BMAL1-dependent manner. Once inside the nucleus, MFP2 increases acetyl-CoA levels, which drives acetylation of key proteins including p65, a component of the transcription factor NF-κB, a key regulator of inflammatory genes. This activates NF-κB, which functions as a switch for inflammatory genes, thereby driving macrophages into the pro-inflammatory M1 state. These findings suggest that targeting or blocking nuclear MFP2 and administering drugs at an optimal time of the day could become a new therapeutic strategy for chronic inflammatory diseases and enhance treatment efficacy while minimizing side effects.

The circadian clock component BMAL1 enhances macrophage inflammation by nuclear translocation of peroxisomal β-oxidation enzyme MFP2

The circadian clock regulates diverse immune functions, yet the role of clock components in macrophage inflammation remains controversial, with both pro- and anti-inflammatory effects reported. Here, we identify a previously unrecognized mechanism by which the core circadian clock component BMAL1 enhances the inflammatory response of macrophages through the nuclear translocation of the peroxisomal β-oxidation enzyme multi-functional protein 2 (MFP2). BMAL1 drives MFP2 accumulation in the nucleus, where MFP2 contributes to acetyl-CoA production and acetylation of the NF-κB subunit p65, thereby facilitating M1 polarization and inflammatory chemokine expression. Nuclear MFP2 levels oscillate in a diurnal manner in the liver, but this rhythmicity is abolished in Bmal1-deficient mice. Macrophage-specific deletion of BMAL1 alleviates diethylnitrosamine-induced hepatic inflammation and tumorigenesis, concomitant with reduced inflammatory gene expression. These findings uncover a BMAL1-dependent nuclear metabolic pathway that links circadian regulation of macrophage inflammation and suggest that targeting nuclear MFP2 may offer a therapeutic approach for inflammatory diseases and tumorigenesis.

Researchers here report on an interesting in vitro exercise in the comparative biology of aging. They took fibroblast cells from ten difference mammalian species with widely divergent life spans and chemically induced DNA damage in the cells. Modern DNA sequencing approaches allow an accurate measure of the amount of mutational damage produced by this chemical treatment, which in turn allows a comparison of the degree to which cells from different species can resist such damage via the operation of DNA repair systems. Long-lived species have more efficient DNA repair mechanisms, as determined by this approach.

We test the hypothesis that excess mutations induced in primary fibroblasts by a low dose of N-ethyl-N-nitrosourea (ENU) are inversely correlated with species-specific maximum life span. To measure excess mutations induced by ENU we treated primary cells of 10 mammalian species, greatly differing in life span. We treated all cells with a low dose, non-toxic dose of ENU (20 ug/ml). We then extracted DNA from all treated and untreated cells and quantified somatic mutation burden by single-molecule sequencing. We measured excessive mutations by calculating the increase in single nucleotide variants (ΔSNVs) and we analyzed this across species with linear regression.

The average values for ΔSNV were found to range from 0.773 in mice to 0.367 in whale, resulting in a modest inverse correlation with species-specific maximum life span (R^2 = 0.2067). We conclude that DNA repair accuracy, the main determinant of genome sequence integrity, modestly correlates with life span suggesting that longer lived species have better repair capacities compared to shorter-lived species, which is in keeping with genome instability being a primary hallmark of aging and highlights its important role for longevity.

Link: https://doi.org/10.70401/Geromedicine.2026.0023