Fight Aging!

The challenge inherent in present approaches to reduce unwanted inflammation and immune activation, such as by targeting circulating tumor necrosis factor (TNF) with monoclonal antibodies in the context of autoimmune conditions, is that this signaling is also used in the normal, desirable immune response. Suppression thus has side-effects on immune competence. Nonetheless, researchers continue to try to improve the approaches to this class of therapy, as it is certainly better than prior alternatives. Here, researchers turn chimeric antigen receptor technology to the clearance of TNF: engineered T cells equipped with suitable engineered receptors casn live in the body for years while continually clearing excessive TNF in circulation.

Extracellular factors, such as cytokines, are implicated in various diseases. Utilizing biologics to functionally neutralize these extracellular factors is a valid therapeutic approach in the clinic. While biologics have shown effectiveness in disease treatment, they have inherent limitations that require further improvement. Due to their short half-lives, biologics must be administered repeatedly to maintain therapeutic efficacy, leading to increased costs, reduced patient compliance, and decreased quality of life. For example, the widely used anti-tumor necrosis factor (TNF) antibody (adalimumab, Humira) requires bimonthly injections for indications like rheumatoid arthritis.

Chimeric antigen receptor (CAR)-T cells, as an exogenous entity, traditionally target surface antigens on tumor or pathogenic cells rather than soluble factors like TNF. Unlike all existing targeted protein degradation approaches, CAR-T cells do not rely on any component of the host's endogenous protein degradation machinery. Moreover, CARs undergo receptor-mediated endocytosis upon antigen engagement and are continuously replenished by CAR-T cells, enabling iterative and sustained target degradation.

In this study, we exploited these properties to engineer a TNFR1 ectodomain-based CAR-T platform for specific, durable degradation of soluble TNF. To overcome the critical barrier of poor CAR-T expansion in immunocompetent hosts, we further applied CRISPR-mediated Bcor/Zc3h12a double knockout to generate long-lived TNFR1-bearing T cells that persist in vivo without preconditioning. We demonstrate that a single infusion of cells confers durable rheumatoid arthritis remission in mouse models, establishing a host-machinery-independent cellular targeted protein degradation platform and a paradigm shift from chronic repeated drug administration to single-infusion intervention for inflammatory disease.

Link: https://doi.org/10.1016/j.hlife.2026.05.003

Degenerative aging, as one might expect, is largely studied in the old. Aging happens in younger people, but doesn't kill or greatly inconvenience them, and is thus not a high priority for the research community. Thus far less is known of how exactly aging proceeds in younger adults, such as which mechanisms are more important. So it is always interesting to see researchers attempting to make some inroads into what is happening to younger adults as a result of those mechanisms of aging. Here, researchers present evidence for measures aging provided by aging clocks in younger adults to have accelerated since the 1950s; one might immediately think of the rising prevalence of obesity as the first place to look for a cause, but there are any number of other possible candidates.

Researchers analyzed data from more than 154,000 young adults in the UK Biobank, a large biomedical dataset containing biological, health and lifestyle data, and from more than 10,000 individuals in the U.S. participating in the National Institutes of Health's (NIH) All of Us Research Program, an effort to build a comprehensive health dataset on more than 1 million people living in the U.S. To estimate the level of biological aging - or age gap - the researchers examined aging at two levels: across the body as a whole, known as systemic aging, and within individual organs, known as organ-specific aging.

For systemic aging, the researchers used established measures, including clinical biomarker-based measures such as PhenoAge and the Klemera-Doubal Method, as well as a metabolomic age score, which provides a measure of individual metabolism. For organ-specific aging, the researchers used blood proteomic data, which measure levels of multiple proteins linked to specific organ systems, to estimate biological aging in individual organs.

The researchers found that individuals in the UK born between 1965 and 1974 had systemic aging that was 23% of one standard deviation higher compared with those born between 1950 and 1954, after accounting for chronological age. In other words, people in the younger birth cohort showed a modest shift toward older biological profiles than people in the older birth cohort when at the same chronological age. The researchers observed a similar pattern in the U.S cohort. Participants born between 1990 and 1999 had systemic aging that was 92% of one standard deviation higher compared with those born between 1965 and 1969.

Link: https://medicine.washu.edu/news/faster-aging-in-younger-generations-linked-to-rise-in-early-onset-cancer/

Loss of muscle mass and strength with age is universal, leading both to physical frailty and to a harmful disruption of metabolism more generally. Muscle doesn't just exist to provide motive power, it is also a metabolically active tissue. The signals it provides are important to insulin metabolism, for example, in addition to the systemic benefits that result from exercise. The causes of age-related muscle decline are complex and layered. For example, low-level molecular damage of the sort described in the Strategies for Engineered Negligible Senescence (SENS) and the Hallmarks of Aging disrupt the function of neuromuscular junctions linking the nervous system to muscle fibers, and those nerve signals are necessary for the normal adaptive response of muscle tissue. But completely separately, muscle stem cells become progressively less active with age, and the somatic muscle cells produced by those stem cells are needed for muscle growth and regeneration.

All of this is attended by altered levels of expression of countless genes, some of which are more important than others when it comes to regulating the behavior of muscle cells. In today's open access paper, for example, researchers discuss the role of NOX4 in muscle adaptation to use. In youth, using muscle will grow muscle. In later life this becomes less the case. NOX4 appears to occupy an important position in the regulation of this response to exercise, and its levels decline with age. Energetic use of muscle generates oxidative stress through increased activity of mitochondria, and this increase in the production of oxidative molecules as a side-effect of energy metabolism is the primary signal triggering a cascade of protective and adaptive responses. NOX4 is necessary to that process as a producer of specific forms of oxidative molecule; having less of it doesn't just prevent muscle growth, but paradoxically increases the harms done by oxidative signaling as the protective response is attenuated.

A decline in skeletal muscle NOX4 abrogates exercise-induced adaptive homeostasis and exacerbates biological aging

Adaptations to stressors can increase resilience and allow organisms to manage damaging insults. The ability of organisms to transiently adapt to otherwise harmful stressors is known as adaptive homeostasis. A quintessential example of adaptive homeostasis is the response to oxidants, namely, reactive oxygen species (ROS). ROS are highly reactive chemicals generated in response to stressors and as byproducts of life in an aerobic environment. While evolution has harnessed specific ROS, for example, H2O2 for physiological roles such as cellular signaling, stressors resulting in redox imbalance and excess ROS can damage essential macromolecules including proteins, lipids, and DNA to promote cell death and inflammation and contribute to disease.

A decline in both nuclear factor erythroid 2-related factor 2 (NFE2L2)-orchestrated adaptive homeostasis and consequently greater oxidative distress are thought to be key features of aging. In contracting skeletal muscle, the reactive oxygen species-producing enzyme NADPH oxidase 4 (NOX4) is a potent inducer of NFE2L2 adaptive homeostasis. Here, we report that skeletal muscle NOX4 levels decline in aged mice and humans, resulting in abrogated NFE2L2 adaptive homeostasis, increased protein oxidative damage, and decreased muscle function.

We show that deleting NOX4 in skeletal muscle exacerbates the physiological decline associated with aging, resulting in overt sarcopenia and frailty, characterized by physical inactivity, increased adiposity, systemic inflammation, whole-body insulin resistance, and advanced liver disease in aged chow-fed mice. The systems-wide physiological decline in aged skeletal muscle NOX4-deficient mice could be corrected by restoring NOX4 using viral approaches or activating NFE2L2 downstream with sulforaphane and reinstating adaptive homeostatic responses otherwise induced by exercise. Our findings provide important insights into the basis for the decline in NFE2L2-orchestrated adaptive homeostasis that accompanies physical inactivity with age and identify key mechanisms by which exercise may promote healthy aging.

Researchers here review the state of stem cell therapies for the treatment of age-related degenerative conditions, with particular attention to more recently emerged areas of the field such as efforts to rejuvenate old patient-derived stem cells before their use in therapy. Partial epigenetic reprogramming is not much mentioned in this context as, unlike the use of senolytics, it has not yet advanced to the point of ease of use for the average stem cell clinic. Treating a stem cell culture with cheap and well-established senolytic compounds is very much more feasible in comparison to the time, expertise, and expense needed to safely and reliably partially reprogram cells in that same culture.

Rejuvenation strategies for ageing stem cells focus on restoring their regenerative capabilities, which decline with age, to improve tissue homeostasis and potentially extend health and lifespan. Various pathways regulate the rejuvenation process in the body, but impairment of these pathways can lead to poor stem cell function. Although the body has various pathways, recent trends have new approaches to managing stem cells via new rejuvenation strategies. The primary methods for rejuvenation strategies for stem cells include (a) preconditioning and senolytics, and (b) biomaterials and engineered niches.

Environmental or chemical preconditioning can help in the regeneration of stem cells by increasing proliferation, differentiation, and stress resistance. Hypoxic culture, growth factor priming, and expansion on youth-mimicking matrices, such as decellularised extracellular matrix, are among the techniques to boost mesenchymal stem cells (MSCs) and other stem cell types for renewal. Senolytic drugs, for example, quercetin, fisetin, and dasatinib, selectively remove the senescent cells, and thus lower senescence-associated secretory phenotype (SASP) levels while restoring stem cell and their lineage potential. The drug quercetin showed the removal of senescent MSCs, leading to the enhancement of their proliferating and osteogenic capability, simultaneously inhibiting adipogenesis, adding other strong evidence to the senolytic approach of stem cell rejuvenation. Additionally, MSC exosomes exhibit immunomodulatory, antioxidant and reparative potential on senescent cells.

Engineered niches like scaffolds, decellularized matrices, and hydrogels, can replicate a juvenile extracellular environment to keep the stem cells viable. MSC-loaded chitosan hydrogels, along with MSC exosomes, enhanced fibroblast function, thereby increasing proliferation and collagen formation while reducing matrix metalloproteinases and SASP factors and rejuvenating skin in older mice. Biomaterial carriers enhance transplanted cell survival by mimicking extracellular matrix signals like adhesion ligands, sequestered growth factors, and mechanical stiffness that ultimately led to better engraftment and regenerative efficiency.

Link: https://doi.org/10.3389/fcell.2026.1830358

Therapies that increase muscle tissue regeneration following injury, and possibly also normal maintenance and growth of muscle tissue, are of great interest at present. The widespread use of GLP-1 receptor agonists to induce calorie restriction causes loss of muscle mass as well as fat mass, and so there is a strong financial incentive for the research and development of means to force the body to build more muscle. There was already a strong financial incentive in the sense that everyone loses muscle with age, and frailty is a prevalent and harmful state of poor health, but for some reason that was never as motivating to the development community. Nonetheless, recent years have seen a number of interesting new discoveries in the regulation of muscle regeneration and growth. We will see whether any of them make it to the clinic in some form.

Muscle regenerative capacity declines with aging and disease, which leads to muscle loss and reduced lifespan. Muscle regenerative failure is related to a disrupted network orchestrated by multiple muscle-harbored cell types; whether and how the interplay between macrophages and myofibers contributes to this process is largely unknown. Herein, we report upregulation of histone methyltransferase G9a in both aged human muscle and mouse muscle after injury. Deletion of G9a in either myeloid cells or myofibers accelerates muscle regeneration.

Mechanistically, G9a down-regulates macrophage-derived interleukin 13 (IL13) and suppresses myofiber-derived myokine musclin, respectively, to inhibit myogenesis and macrophage phenotype transition during muscle regeneration. Either IL13 or musclin, per se, accelerated muscle regeneration, and their combined administration showed synergistic effects with therapeutic potentials for muscle degeneration disorders. Collectively, we highlight a crosstalk between macrophages and myofibers through IL13-Stat6 signaling and musclin, both regulated by G9a, which steers a pro-recovery microenvironment after muscle injury, with therapeutic potentials for muscle degeneration disorders.

Link: https://doi.org/10.1038/s41419-026-08944-2

Epigenetic control over nuclear DNA structure determines which sequences of DNA are exposed to transcription machinery in the cell nucleus, and thus which genes are expressed. As epigenetic decorations to DNA and its structural helpers are constantly added and removed, structure changes and so does gene expression. Which proteins are produced from their genetic blueprints, and in what amounts, is an important determinant of cell behavior. Epigenetic patterns and the structure of DNA changes with age, and so does gene expression. There are any number of examples of age-related changes in the level of expression of a specific protein that are clearly harmful, as animal studies have shown that health improves when the change is reversed.

If one thinks that aging is essentially epigenetic aging, which many people do judging from the vast funding flowing into the development of partial epigenetic reprogramming therapies intended to reset epigenetic decorations to a youthful pattern, then one should probably be very interested in which other interventions are known to reduce epigenetic age in human trials. People with other opinions on the nature of aging should still find the list interesting. Still, it has to be said that it is far from clear that there is a usefully comprehensive mapping of aging to epigenetic aging, or that even the better epigenetic clocks are actually measuring biological age, or measuring aspects of it in a way that will accurately reflect any given specific change to biochemistry produced by potential treatments for aging. There are clearly mechanisms of aging that cannot be fixed by reprogramming, such as accumulation of metabolic waste that cannot be effectively broken down by even youthful cells, or mutational damage to DNA.

Turning back time: a comprehensive list of interventions that decrease next-generation epigenetic aging clocks in humans

Epigenetic aging clocks estimate age from DNA methylation patterns and have become central tools in longevity research. More recently, next-generation clocks have been developed to better compensate for the known divergence between chronological age and epigenetic age in ways that relate to lifestyle, health, and age-related disease. Although epigenetic clocks represent investigational biomarkers, these newer models are more strongly associated with all-cause mortality risk than first-generation clocks. As such, interventions that modify them are of interest. To test this, we performed a series of systematic searches and identified 41 human studies reporting the effects of interventions on at least one next-generation epigenetic clock.

Our data suggest that a diverse range of pharmaceutical, lifestyle, supplementation, non-pharmaceutical clinical, and psychosocial interventions can decrease epigenetic age, including exercise, a plant-rich diet, the GLP-1 receptor agonist semaglutide, caloric restriction, ketamine, omega-3 fatty acids, a multivitamin-multimineral supplement, umbilical cord plasma, and the cholesterol-lowering drug pitavastatin. Nicotinamide riboside, rapamycin, senolytics, and several other interventions showed no detectable effect, whereas plasmapheresis and other therapeutics accelerated epigenetic aging. We also summarize reported effect sizes and compare next-generation clocks with respect to their frequency of use and responsiveness to intervention.

Mitochondria are power plants, hundreds of them in every cell working to create the chemical energy store molecule adenosine triphosphate (ATP) used to power cellular processes. They are the evolved descendants of ancient bacteria, and still act like bacteria in many ways. They are also very complex, and while a great deal is known of their structure and biochemistry, a complete and detailed answer as to why exactly their function declines with age is lacking. It is well established that exercise improves mitochondrial function, both in the short term and over the long term of maintaining physical fitness. This in turn explains some fraction of the beneficial effects of exercise and fitness when it comes to slowing the pace of degenerative aging.

Brain aging is a complex biological process characterised by progressive neuronal and synaptic decline, in which disruption of mitochondrial quality control plays a central role. This system encompasses multiple synergistic components, including mitochondrial biogenesis, dynamic equilibrium, autophagic clearance, and energy metabolism. Aging induces dysfunction across these processes, precipitating mitochondrial fragmentation, functional decline, and energy crises, ultimately driving cognitive deterioration.

Exercise is a promising non-pharmacological intervention for preserving brain health during aging, and its benefits may be mediated, at least in part, through modulation of mitochondrial quality control. Specifically, exercise has been shown to activate key signaling pathways such as AMPK/SIRT1/PGC-1α, thereby promoting mitochondrial biogenesis and metabolic adaptation. It may also regulate mitochondrial dynamics and mitophagy via pathways including cAMP/PKA/Drp1 and AMPK/mTOR. In addition, emerging evidence indicates that exercise may influence brain mitochondrial function through activity-dependent regulation of mitochondrial gene expression and systemic signaling factors.

Link: https://doi.org/10.3390/biology15110854

Members of the life insurance industry have typically been far ahead of the rest of the general public outside the life sciences when it comes to an appreciation of progress towards therapies to treat aging as a medical condition. It is a very large industry, and thus has significant funding to direct towards analysis and prediction of trends in medicine. The prospect of increasing healthy human longevity, of a change in the way in which aging is addressed by medical research and development, is both an existential threat and opportunity for the life insurance industry. Those who predict correctly will thrive, and those who do not will suffer.

Thus it is always interesting to see how insurance industry researchers and analysts react to developments in the medical life science space. Here, the focus is on aging clocks, ways to combine biological data that predict mortality risk across populations. If biological age could be measured accurately for an individual via any specific variety of aging clock, and thus a good estimate of intrinsic mortality risk derived that individual, one would imagine that the life insurers would adopt this technology very rapidly. They have every motivation to do so. The reasons why they have not so far done are the same reasons as to why clocks are not yet the gold standard for assessing the quality of potential rejuvenation therapies: the clocks are not accurate for individuals, and their underlying connections to biological age are not fully understood.

Biological Clocks: Ready for Prime Time?

John Smith is a 50-year-old male applying for a life insurance policy. His medical history is unremarkable, and his recent medical visits record good health. He exercises regularly and is an enthusiastic member of several wellness programs. A recent test from a longevity company reports a biological age of 46, and records that he is aging at 0.7 years per year. Both the company and Mr. Smith are excited that his life expectancy is well above normal. Are they right? And if they are, should life insurers be excited too?

Chronological age is the widely accepted starting point of mortality assessment. It is also time-honored, having first appeared in insurance life tables in the 17th century. Yet it is a blunt metric: two 50-year-olds may have quite different health statuses and life expectancies. Biological age is a term that is widely used in the aging literature. But curiously, it has no accepted definition. This reflects both the complexity of aging and the lack of any gold-standard metric. It reflects how old the body has become, functionally and biologically. It incorporates dimensions of health, such as current physiological state, and the cumulative molecular and cellular damage that has accrued over time. Thus, at face value, biological age would seem to provide more useful underwriting information than chronological age. If one of our 50-year-olds had a biological age of 46 and the other 54, mortality projections would be quite different, and premiums could reflect these.

So, where did John Smith's biological age determination come from? It was likely provided by an "epigenetic clock." which is an algorithm that estimates chronological age from patterns of cellular DNA methylation. Epigenetic clocks are statistical models, trained on methylation status of selected subsets of CpG sites - typically ranging from a few hundred to a few thousand - chosen to optimize predictive performance.

What are the rubs against epigenetic clocks? There are quite a few. Epigenetic clocks are not trained to provide reliable predictions at the individual level. Rather, they are statistical models designed to minimize error across thousands of samples. Consequently, when applied to a single person, their estimates are biologically noisy. Epigenetic age is not a traditional biomarker, such as BMI or serum glucose, which can generate reliable individual-level information. Thus, to equate a younger predicted epigenetic age with a younger biological age, even though this is common practice, is an overextension. Epigenetic clocks are highly dependent on the training data and the populations from which they are derived. If a clock is applied to different populations - such as the very fit (Mr. Smith) or self-selected individuals (those likely to buy a commercial test) - the predictions may be inaccurate.

Are epigenetic clocks of value to life insurers? Not at present. While biological age, to the extent it is equated with epigenetic age, does predict mortality, it does not outperform traditional mortality risk predictors such as age, sex, smoking, blood pressure, BMI, and medical history. Similarly, pace-of-aging, although an outwardly attractive metric, does not outperform traditional measures of current health status. One exception might be the young or apparently healthy, where traditional risk factors are absent, and early deterioration might be captured. Another might be the small number of older individuals where all traditional risk markers are negative; epigenetic clocks may provide better insight into current health. But both scenarios would require longitudinal analyses to prove clock utility.

Researchers have for some years been casting a very broad net in terms of trying to understand how centenarians, people who survive to age 100 and beyond, are different from those who die at earlier ages. There is plenty of evidence for a fairly distinct biochemistry, such as better immune function and lesser degrees of chronic inflammation. Centenarians are still greatly impacted by the processes of aging, are frail, and exhibit a high mortality rate, so it is not a state to emulate, but it is hoped that this sort of research could help to better understand which aspects of aging are the most important in terms of driving declining function and rising mortality, and thus merit greater attention from the research community.

Centenarians exhibit remarkable longevity and compression of morbidity making them an ideal population for uncovering proteins associated with successful aging. Using proteomics, we characterized the immune and cardiometabolic profiles of centenarians' plasma from the SWISS100 cohort. We identified 583 differentially expressed proteins (DEPs) by centenarians when compared with hospitalized geriatric patients (age 80-90 years) and younger healthy participants (age 30-60 years). We replicated the association of 23 proteins with a standard set of aging proteins (APs) developed by the Targeting Aging with Metformin (TAME) consortium.

By comparing the centenarian signature to an independent centenarian proteomics study, we identified 135 DEPs in both studies with identical aging directions, establishing a robust set of APs in centenarians. Applying fractional polynomial regressions, we uncovered proteins with linear and non-linear profiles associated with age and identified a subgroup of 37 proteins with a younger signature in centenarians. Protein-protein interaction and pathway enrichment analyses of 37 proteins point to programmed cell death, metabolic enzyme pathways, regulation of extracellular matrix stability, immune and inflammatory responses, and neurotrophic signaling pathways. This novel approach to aging research has uncovered new proteins and pathways, which may present promising targets to understand processes associated with longevity and healthy aging.

Link: https://doi.org/10.1111/acel.70409

I expressed some skepticism on the approach of Sentcell. The claim is that under defined circumstances CD4+ T cells will secrete structured extracellular telomere fragments (named "telomere rivers") that produce broadly beneficial effects to extend life span in mice. The very large size of reported extension of life and the small number of mice in the published study were red flags - we've seen this sort of thing before and it doesn't tend to replicate. To the team's credit, it appears that they are moving towards an academic phase 1 trial of this technology to commence this year, so someone is sufficiently convinced to fund this exercise.

A first-in-human clinical trial of an immune rejuvenation therapy developed by biotech company Sentcell and designed to restore the function of worn-out T cells is expected to begin later this year, building on research into the mechanisms of immune ageing. The Phase 1 trial will focus on exhausted or senescent T cells, which accumulate with age and in chronic disease and become less effective at coordinating immune protection. The treatment is administered by intramuscular injection, similar to many commonly used vaccines. Once delivered, it is designed to reprogramme key pathways that drive immune dysfunction, helping immune cells regain characteristics of younger, healthier cells.

The trial builds on research suggesting that some dysfunctional T cells - a type of white blood cell that helps coordinate the body's immune response - can be restored to a more youthful, functional state. Researchers are focusing on CD4+ T cells, often described as the "conductors" of the immune system because they help direct other immune cells to respond to infection, cancer, and disease. Previous laboratory studies suggest that rejuvenated CD4+ T cells may be able to release telomere-containing structures into the bloodstream. Researchers have termed these structures "telomere rivers" and are investigating whether they could help explain how rejuvenated immune cells influence the health and function of other tissues throughout the body. This idea remains under active investigation and has not yet been demonstrated in humans.

Researchers are preparing for Phase 1 of the trial, which will carefully select adult participants and is expected to focus initially on people with evidence of immune dysfunction, including immune ageing and chronic viral infection. Participants will undergo detailed immune profiling before and after treatment. Investigators will look at whether the therapy can restore features of healthy immune function. As an early-stage trial, the primary goals are safety and biological activity rather than demonstrating clinical benefit.

Link: https://www.eurekalert.org/news-releases/1132420

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