Fight Aging!

Researchers here describe a novel approach to encourage greater regeneration in heart tissue following the injury and lost function incurred during a heart attack. Their work falls into the growing category of practical gene therapies in which a small amount of easily accessible tissue, such as fat or muscle, is transfected to form a factory that generates and releases a beneficial circulating protein. Only a low dose of gene therapy vector is needed, and all of the present challenges in broader delivery of gene therapy are bypassed. The scope of possible uses is restricted to situations in which benefits can be derived from increased amounts of a specific protein in circulation, but this is still a large enough set of possibilities to support a broad industry.

During the first days of life, many mammals have a short-lived ability to regenerate heart muscle cells. A hormone called atrial natriuretic peptide (ANP) plays a key role by encouraging the growth of new blood vessels, calming inflammation, and reducing the formation of scars. As an individual ages, the amount of ANP in their bodies decreases substantially, and the regenerative capacity observed in newborn hearts largely disappears by adulthood. Researchers have understood the potential of ANP for decades, but it's difficult to use as a conventional drug because it begins breaking down after just a few minutes in the body.

Delivering a drug to the heart in a sustained and minimally invasive way is a significant challenge. Drugs aimed at organs such as the liver, lungs, or spleen can often accumulate naturally because of the unique features of their vascular systems and cellular uptake mechanisms. By contrast, the heart lacks such natural accumulation mechanisms, making efficient cardiac drug delivery more difficult. For researchers the solution was to stop trying to deliver the drug to the heart at all. Instead, they developed a two-phase approach that starts by creating a "prodrug" in skeletal muscle before transforming it into ANP within the heart itself.

The researchers designed RNA-lipid nanoparticles that encode Nppa, causing muscle cells in the thigh or arm to produce a molecule called pro-ANP. This molecule, which is not reactive in the body, circulates through the entire bloodstream. A specific enzyme, called Corin, transforms it into ANP. Corin is roughly 60 times more common in the heart than in other organs. In other words, the drug circulates until it reaches the one organ equipped to activate it. In lab experiments, a single injection significantly reduced scarring and improved heart function in small and large animals.

Link: https://www.engineering.columbia.edu/about/news/new-rna-therapy-could-help-heart-repair-itself

Researchers here review the landscape of immune aging with a particular focus on vulnerability to respiratory infections, such as influenza. As we age the immune system becomes ever less capable, the outcome of impaired manufacture of new immune cells, as well as issues that affect the internal workings of cells throughout the body, such as mitochondrial dysfunction and cellular senescence. At the same time the immune system becomes ever more active and inflammatory, a maladaptive reaction to forms of damage in cells and tissues. This creates a landscape in which infectious pathogens find it easier to overwhelm immune defenses, and in which inflammatory reactions to infection can readily become life-threatening, amplified by a dysfunctional immune system.

Every country around the globe is facing continuous growth in both the size and the proportion of older people; by 2050, the global population aged 60 years and above is projected to double, reaching approximately 2.1 billion people. As the population shifts towards older ages, new challenges are emerging, including increased healthcare demands. Among these challenges is "the destruction and remodelling of immune organ structure as well as innate and adaptive immune dysfunction with ageing", so-called immunosenescence, alongside inflammageing, a characteristic inflammatory state in which high levels of pro-inflammatory molecules are expressed. Both states predispose older adults to dysregulated immune responses and, inadvertently, to increased proportions of adverse outcomes, especially in the context of infections such as respiratory viral infections.

In this review, we examine the molecular and cellular pathophysiological mechanisms of immunosenescence and inflammageing that predispose older adults to increased morbidity and mortality from respiratory viral infections. We also outline the clinical implications of the ageing immune system, along with the most up-to-date evidence on possible biomarkers, preventative measures and treatment options aimed at mitigating the effects of immunosenescence on the vulnerability of older adults in respiratory viral infections.

Link: https://doi.org/10.1183/16000617.0248-2025

Cartilage tissue exhibits a relatively poor capacity for regeneration even in youth, but this capacity for maintenance and repair diminishes with age. There are thus some gains to be made in understanding why this happens and developing means of rejuvenation, but ultimately some form of regenerative medicine above and beyond natural degrees of healing will be needed in order to completely address the very prevalent joint issues that occur in later life and culminate in disabling degrees of cartilage loss and osteoarthritis. While this is widely studied, cartilage has so far proven to be a difficult tissue for the tissue engineering community to reproduce and manipulate. The load-bearing capacity and resilience necessary for its function in the body requires an accurate recreation of the complex extracellular matrix structure and cell behavior; pseudo-tissues of the sort that work well in tissue engineering for many organs are not good enough for cartilage.

Returning to the question of why cartilage tissue becomes less regenerative with age, in today's open access paper the authors turn their attention to macrophages. Macrophages of the innate immune system are present in large numbers in tissues throughout the body, and are deeply involved in the intricate processes that accompany tissue regeneration and tissue maintenance. Researchers have discovered a regulatory gene for macrophage behavior in cartilage that biases these cells towards pro-regenerative, anti-inflammatory patterns of behavior. Expression declines with age, however, and thus macrophages become increasingly inflammatory, leading to a reduced capacity for cartilage tissue maintenance and regeneration. Given the expression of this gene as a target, therapies can now be designed and tested to improve cartilage maintenance in older individuals.

Single-cell omics reveals arg-1 as a key regulator of age-dependent macrophage-mediated cartilage repair

Aging is a significant factor influencing the recovery capacity following cartilage injury, with notable differences observed between older and younger animals. Studies indicate that younger animals exhibit enhanced regenerative potential, including better cartilage repair and reduced inflammatory responses, compared to their older counterparts. This disparity may be attributed to age-related declines in stem cell activity, extracellular matrix synthesis, and immune function.

Macrophages play a multifaceted and context-dependent role in the pathogenesis of cartilage injury, contributing to both inflammatory progression and tissue repair. In the synovial microenvironment, macrophages exhibit remarkable plasticity, dynamically shifting between pro-inflammatory (M1-like) and anti-inflammatory (M2-like) phenotypes in response to local signals. While M1-polarized macrophages drive joint inflammation through the production of cytokines such as tumor necrosis factor-α (TNF-α), Interleukin-1β (IL-1β), and Interleukin-6 (IL-6), M2-like macrophages promote resolution of inflammation and tissue remodeling. However, this dichotomy is oversimplified, as single-cell studies reveal a spectrum of macrophage activation states in cartilage injury, with distinct subsets associated with disease severity and treatment response. Furthermore, synovial macrophages interact with fibroblasts, T cells, and osteoclasts, forming a complex cellular network that perpetuates joint destruction.

Our study employed single-cell RNA sequencing (scRNA-seq) to investigate the differential recovery capacity between young and aged animals following cartilage injury, explicitly addressing the inherent heterogeneity of immune cells within the joint. Through comprehensive profiling of joint tissues before and after injury, we aimed to identify age-dependent molecular mechanisms that govern post-injury recovery. Our analysis revealed that young animals exhibit a significantly higher proportion of anti-inflammatory macrophage subsets compared to aged counterparts, suggesting a link between specific immune cell states and enhanced tissue repair potential.

Further network analysis pinpointed Arg-1 (Arginase-1) as a central regulator within anti-inflammatory macrophages. Functional validation through in vivo and in vitro experiments demonstrated that Arg-1 overexpression inhibited inflammation and reactive oxygen species release in aged animals, partially rescuing their impaired recovery phenotype. These results not only elucidate the mechanistic basis for age-related disparities in cartilage injury recovery but also highlight Arg-1 as a novel therapeutic target to improve joint repair in elderly individuals. By integrating single-cell omics with mechanistic validation, this study provides critical insights into anti-inflammation macrophage in cartilage injury and offers a potential strategy to mitigate age-associated decline in tissue regeneration.

As the understanding of more recently discovered modes of programmed cell death are fleshed out, they receive greater attention from various groups focused on specific aspects of aging. In this review the programmed cell death mechanism is PANoptosis and the area of focus is the aging of the heart. Some means of preventing overly aggressive, maladaptive programmed cell death in the context of aging have performed fairly well in animal studies, but the details matter and progress towards useful therapies is ever slow and uncertain.

As the vital power organ of the human body, the health of the heart directly determines an individual's quality of life and longevity. With the accelerating global aging population, cardiac aging-related diseases have become a major public health threat. Although existing interventions (e.g., senolytics) can delay cardiac aging to some extent, their efficacy remains limited, necessitating the exploration of novel mechanisms to develop more effective therapeutic strategies.

lytic cell death modality, integrates core molecular mechanisms of pyroptosis, apoptosis, and necroptosis into a dynamically regulated "death signaling network". As a unique programmed cell death paradigm, it transcends classical boundaries of these pathways by forming the PANoptosome complex, which orchestrates caspase family members. It may contribute to cardiac functional decline by accelerating cardiomyocyte loss, fibrosis, and chronic inflammation.

Targeting PANoptosis-based intervention strategies (e.g., gene editing, RNAi, combination therapy, and novel delivery systems) has demonstrated significant therapeutic potential, offering new preclinical avenues to delay or alleviate cardiac aging. This review summarizes the molecular mechanisms and roles of PANoptosis in cardiac aging, including its regulatory networks, key evidence driving cardiac aging, and targeted intervention strategies, thereby providing a theoretical foundation for developing PANoptosis-targeted therapies against cardiac aging.

Link: https://doi.org/10.3389/fcvm.2026.1759908

Does the correlation between late life vaccination and reduced risk of neurodegenerative conditions such as Alzheimer's disease exist because vaccination produces benefits such as reduced chronic inflammation via trained immunity, or because people who undergo vaccination tend to be more diligence in all matters relating to health? Mechanistic or behavioral, or both? And if both, how much of the overall observed effect size arises from each side? Researchers here find a way to obtain more insight into this correlation, as they show that different vaccine doses correlate with different degrees of reduced dementia risk. We should not expect this to be the case unless the outcome is driven by biological mechanisms resulting from vaccination.

Previous studies, including large cohort analyses comparing vaccinated and unvaccinated adults, suggest that routine immunizations such as inactivated influenza vaccines (IIVs) may reduce Alzheimer dementia (AD) risk. Whether AD risk differs after high-dose IIV (H-IIV) vs standard-dose IIV (S-IIV) remains unexamined. We hypothesized that AD risk would be lower among adults ≥65 years after H-IIV compared with S-IIV.

This retrospective cohort study analyzed data spanning 2014-2019 from IQVIA PharMetrics Plus for Academics, a US health care claims database. Eligible participants were ≥65 years with ≥2 years of continuous medical and pharmaceutical coverage and no previous diagnostic or pharmacotherapeutic indicators of cognitive impairment. Vaccinations were identified by name and Current Procedural Terminology codes. Participants were followed for up to 3 years postvaccination. Incident AD was defined using International Classification of Diseases codes and AD medication dispenses (cholinesterase inhibitors, memantine).

The H-IIV group included 120,775 unique participants (185,183 person-trials; mean age 74.4 ± 5.5 years; 57.3% female), and the S-IIV group included 44,022 participants (53,918 person-trials; mean age 73.0 ± 6.1; 56.4% female). H-IIV was associated with significantly lower AD risk during months 1-25 postvaccination. Further research is needed to clarify whether the observed difference reflects protection against influenza infection or non-infection-related mechanisms.

Link: https://doi.org/10.1212/WNL.0000000000214782

Transthyretin is one of a small number of proteins that can misfold and aggregate to cause pathology in tissues, primarily the cardiovascular system, but other organs as well once aggregation becomes very severe. Despite being a universal mechanism that operates in all older individuals, transthyretin amyloidosis is presently treated as a rare condition by the medical, development, and regulatory communities, because only the most severe cases exhibit evident symptoms that are easily diagnosed. Of those patients diagnosed, some have mutations that drive misfolding and aggregation of transthyretin, while some are simply the most severe examples of what is actually a prevalent issue in later later. Evidence from studies involving post-mortem examinations of tissues suggest that many very old people exhibit a degree of transthyretin amyloidosis that is in principle life-threatening, capable of contributing to cardiovascular mortality.

In recent years a number of drugs have been developed that act to reduce transthyretin misfolding and aggregation to a large enough degree to allow natural clearance mechanisms to catch up. As drugs go, they are fairly effective at achieving this outcome and have reasonable safety profiles. They are only used in the most severe, readily diagnosed patients, and thus regulated and priced as though transthyretin amyloidosis is a rare disease, however. Treatment is enormously expensive, as is usual for rare diseases, and will likely remain so until patent protection runs out and the drugs become generic. Before that point arrives there is all too little incentive for the drug owners to branch out and offer greater availability at a lower price point, regardless of the accumulating evidence for transthyretin amyloidosis to be a prevalent late life issue with meaningful effects on cardiovascular disease and mortality.

Nonetheless, it is worth keeping an eye on this part of the field as data accumulates from the long-term use of these transthyretin amyloidosis drugs. It provides an assessment of their value for a future of broadened generic use in the older population, once the market catches up with the science regarding implementation of that broader use. Today's open access paper is of interest in this regard, providing data on long-term use of acoramidis. Transthyretin exists in a dynamic equilibrium between monomer and tetramer forms, and only the monomer form contributes to amyloidosis. The better of the existing drugs, like acoramidis, act by stabilizing the tetramer form and thereby greatly reducing the size of the monomer pool. Clearly this works to reduce both amyloid and pathology.

Long-Term Durability of Acoramidis Efficacy in Transthyretin Amyloid Cardiomyopathy

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive disorder caused by destabilization of serum transthyretin (sTTR). Acoramidis, an approved therapy that achieves near-complete (≥90%) sTTR stabilization, demonstrated clinical benefit through month 30 in ATTRibute-CM, which was incremental through month 42 in the open-label extension (OLE); however, the longer-term durability of outcomes has not been reported.

This OLE of the ATTRibute-CM randomized clinical trial is an international, multicenter, ongoing OLE study. Data accumulated between October 2021 and April 2025 through month 24 of the OLE (month 54) are reported. Participants (aged 18-90 years) who completed ATTRibute-CM and met the OLE eligibility criteria were invited to enroll in the OLE. Data were analyzed from May 2025 through November 2025. All OLE participants received open-label oral acoramidis, 800 mg, twice daily. Acoramidis recipients from ATTRibute-CM continued therapy (continuous acoramidis) and placebo recipients switched to acoramidis (placebo to acoramidis).

The primary outcome was time to event for all-cause mortality (ACM), cardiovascular-related mortality (CVM), and first cardiovascular hospitalization (CVH), which was assessed for both groups. Biomarkers of disease progression (N-terminal pro-B-type natriuretic peptide [NT-proBNP]), sTTR, functional capacity (6-minute walk distance [6MWD]), and heart failure-related health status (Kansas City Cardiomyopathy Questionnaire-Overall Summary [KCCQ-OS] score) were analyzed.

In ATTRibute-CM, 632 participants were randomized to receive acoramidis (n = 421) or placebo (n = 211); mean (SD) age was 77.3 (6.6) years, and 62 participants (9.8%) were female. Overall, 389 participants enrolled in the OLE (263 in the continuous acoramidis group; 126 in the placebo-to-acoramidis group). Continuous acoramidis treatment reduced risks of ACM (hazard ratio [HR] 0.55) and CVM (HR 0.51) through month 54, with consistent efficacy across all prespecified subgroups. Continuous acoramidis reduced time to first CVH (HR 0.53) through month 54. Through month 54, continuous acoramidis stabilized increases in NT-proBNP, sustained higher sTTR levels, and stabilized KCCQ-OS score and 6MWD. Switching from placebo to acoramidis at month 30 was associated with stabilization of NT-proBNP and KCCQ-OS score and improvements in sTTR and 6MWD through month 54. No new long-term safety concerns were identified.

The capacity for neurons to regrow the axons that connect them is relatively limited. The tissue of large nerves, largely made up of axons, does not readily regenerate; the closer to the central nervous system one comes, the less the capacity for regrowth following injury. This is not the case for all species, and thus - in principle at least - there must be regulatory controls in cellular biochemistry that can be adjusted to encourage lesser degrees of obstructive scarring and greater regrowth of axons. Here, researchers report on one recently discovered way to enhance axon regrowth that works in both peripheral nerves and the spinal cord.

Axon regeneration is limited in the mammalian central nervous system. Neurons must balance stress responses with regenerative demands after axonal injury, but the mechanisms remain unclear. Here we identify aryl hydrocarbon receptor (AhR), a ligand-activated basic helix-loop-helix/PER-ARNT-SIM transcription factor, as a key regulator of this stress-growth switch. We show that ligand-mediated AhR signalling restrains axon growth, whereas neuronal deletion or pharmacological inhibition of AhR promotes axonal regeneration and functional recovery in both peripheral nerve and spinal cord injury models.

Mechanistic studies reveal that nerve injury induced AhR activation in dorsal root ganglion neurons enforces proteostasis and stress-response programs to preserve tissue integrity. By contrast, AhR ablation redirects the neuronal response towards elevated de novo translation and pro-growth signalling, enabling axon regeneration. This growth-promoting effect requires HIF1α, with shared transcriptional targets enriched for metabolic and regenerative pathways. Single-cell and epigenomic analyses further revealed that the AhR regulon engages the integrated stress response and DNA hydroxymethylation to rewire neuronal injury-response programs.

Together, our findings establish AhR as a neuronal brake on axon regeneration, integrating environmental sensing, protein homeostasis, and metabolic signalling to control the balance between stress adaptation and axonal repair.

Link: https://doi.org/10.1038/s41586-026-10295-z

New senolytic drugs to clear the accumulation of senescent cells in aged tissues are working their way into clinical trials at the usual slow pace for medical development, slowed even further by the poor biotech investment market of the past three years. Rubedo Life Science's first drug to target GPX4 mechanisms has now made it through a phase 1 trial; the company took the safer path of a topical application in skin conditions where cellular senescence is thought to be an important driver of pathology. That strategy looks promising based on the initial data. The largest challenge for biotech and pharmaceutical companies lies in convincing people to fund the first clinical trials in the first indication for their approach to drug development; given success, matters become easier after that point. So companies tend to initially pursue safer, more certain paths rather than those that may offer greater rewards in terms of addressing the burden of disease in the population.

Rubedo Life Sciences, focused on discovering and rapidly developing selective cellular rejuvenation medicines targeting aging cells, today announced preliminary results from a single-center, ascending-dose, randomized, double-blind, vehicle-controlled trial in patients with plaque psoriasis, atopic dermatitis, and skin aging (photo-aged skin). The recently completed Phase 1 clinical trial, conducted in the European Union, was designed to assess the safety, tolerability, clinical effects, plasma bioavailability, and pharmacodynamics of topical RLS-1496 - the first-ever GPX4 (selective glutathione peroxidase 4) modulator to be studied in human trials, and the first specifically targeting cellular rejuvenation, an area of great interest to the scientific community as a new therapeutic pathway. The study met its primary endpoint, with RLS-1496 also demonstrating early signs of efficacy.

In psoriasis patients an overall reduction in senescent cells seen with RLS-1496 in the mid- and high-dose cohorts. Some subjects treated with RLS-1496 had a reduction of senescent cells, which was associated with a reduction of inflammatory cytokines such as IL-19 and S100A7; this reduction was not seen in the vehicle cohort. An average 20% reduction in epidermal thickness was observed on histology in subjects treated with RLS-1496 for one month. A statistically significant relationship was seen between target engagement and improvement in clinical psoriasis severity.

In atopic dermatitis patients, even higher levels of target engagement and substantial clinical improvement were seen in atopic dermatitis subjects on RLS-1496. After one month of treatment, 25% of subjects on RLS-1496 had a ≥4-point change in pruritus (or itching) on the numeric rating scale (NRS); no vehicle subjects had a 4-point or more change on the NRS.

Early photo-aging data show a dose-dependent target engagement in non-lesional photo-aged skin. Histology, proteomics, and spatial transcriptomics indicate that collagen gene and protein expression increase with treatments over time, in particular, spatial transcriptomics shows an effect in dermal fibroblasts. Spatial transcriptomics show indication that senescence-associated secretory phenotype and inflammatory biomarkers decrease with treatments over time in keratinocytes.

Link: https://www.businesswire.com/news/home/20260326810310/en/Rubedo-Life-Sciences-Announces-Positive-Preliminary-Phase-1-Clinical-Trial-Results-for-Lead-Drug-Candidate-RLS-1496-in-Patients-with-Plaque-Psoriasis-Atopic-Dermatitis-and-Skin-Aging

Many capabilities in biotechnology are assuredly possible, just not possible today. The tools are too crude, the knowledge of cellular biochemistry still incomplete. The goal at the end of the day is as complete a control as possible over cell and tissue behavior. This naturally implies the ability to grow new organs, even new bodies, for use in medicine to support the aged and the diseased. There is no reason to think it is actually impossible just because it is presently impossible.

Research proceeds incrementally. We can look at the well-funded, very mainstream efforts to produce new organs for transplantation, a goal that remains impossible as a practical concern at the present time, and see the various stages of evolution of the process. At each stage, there must be some product that can sustain commercial efforts and attract further funding for research and development. So on the road to tissue engineering of new organs, we can see the first steps as the production of organoids: finding recipes that allow the self-assembly of pseudo-tissues that recapture some of the features of the real thing. Organoids exist for many tissue types, across a spectrum spanning cells in a dish to actual tissue with a fully developed extracellular matrix, are the basis for potential regenerative therapies via transplantation to support a failing organ, and are widely used in research.

We can look at the far less advanced efforts that could ultimately lead to the generation of new bodies, such as the work of R3 Bio and Kind Biotechnology, and see that this part of the field has similar early stage goals. In this case, it is the production of pseudo-embryos lacking brains and other features, collections of organs working together much as they do in a real embryo, and which can be used in research and development, or to grow small amounts of tissues for transplantation. They represent a step beyond organoids in terms of recreating something more relevant to a real tissue, can potentially replace some animal studies, and presumably will find a market that can support further evolution of the technology. As is the case for organoids, this first step isn't a simple matter; a great deal of work and discovery is required to obtain a useful result.

The production of pseudo-embryos lacking brains and other features is unlike other human organoid work in that it will likely rouse some degree of reflexive opposition. Thus working with human materials will probably remain off the table until the world at large has had a chance to digest the existence and use of mouse and non-human primate pseudo-embryos. A sizable reduction in the number and scope of animal studies is a noble goal, but the collective laity is not rational about the progression of medicine and biotechnology. The spirit that drove historical popular opposition to autopsies remains alive and well, as demonstrated by the relatively recent opposition to embryonic stem cell research; it will no doubt rouse itself again for the use of human pseudo-embryos in research, once awareness spreads, spurred on by a journalistic profession that has become a cog in an outrage machine, no matter how many animals are spared.

Cellular senescence has been increasingly implicated in the development of pulmonary fibrosis, a largely irreversible condition with a poor prognosis under the current standard of care. An early clinical trial of first generation senolytic drugs to clear senescent cells showed promising results, but the condition remains a low priority among companies developing various forms of novel senolytics. Here, researchers discuss one of the primary mechanisms targeted by early senolytics, the BCL-2 protein known to be involved in preventing apoptosis in senescent cells, in the context of pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease that develops in response to chronic epithelial injury. Unlike injury-induced homeostatic lung repair during which fibroblasts undergo apoptosis and clearance, the lungs of IPF patients continue to accumulate apoptosis-resistant, pro-fibrotic, extracellular matrix-producing fibroblasts.

Here, we show that prevention of PDGFRα+ fibroblast apoptosis by conditional BCL-2 expression leads to the emergence and persistence of senescent, pro-fibrotic fibroblasts along with enduring, pathologic fibrotic lung remodeling. Additionally, spatial transcriptomic studies of human IPF lungs confirmed the presence of senescent, BCL-2 expressing α-smooth muscle actin+ myofibroblasts in fibrotic regions.

Of translational significance, selective BCL-2 inhibition with ABT-199 in fibrotic mice re-engaged the apoptotic pathway in fibroblasts, reduced senescence, and promoted fibrosis resolution and lung regeneration. Our findings suggest that sustained BCL-2 expression in fibroblasts prevents homeostatic lung repair, drives persistent fibrosis and is a therapeutically relevant target to reverse persistent pulmonary fibrosis.

Link: https://doi.org/10.1038/s41467-026-69865-4

uPAR is expressed as a surface marker on senescent cells, and researchers have published the results of targeting chimeric antigen receptor (CAR) T cell therapies to uPAR in the context of clearing senescent cells from aged tissues. Absent an enormous reduction in cost, it is unlikely that CAR T therapies will see much use in this context, but they continue to be used in cancer therapy. Here, researchers show that targeting uPAR-expressing cells in and around solid tumors enables CAR T therapy to work in this context. CAR T therapy was developed for leukemia and has so far struggled to make the jump to the more complex environment of solid tumors; different approaches are needed, and this one seems to be producing positive results so far.

The urokinase plasminogen activator receptor - or uPAR - is a protein found on the outside of cells. In healthy tissue, very few cells have uPAR on their surface; it's primarily found on myeloid immune cells, and helps with processes associated with wound healing. But in cancer, which co-opts the body's normal wound healing programs, both tumor cells and cells in the fibrous "niche" that support the tumor produce a lot more uPAR. By focusing on uPAR, the new approach allows researchers to target cells in a particular state rather than a specific type of cell.

The CAR T cells that target CD19 in leukemia and lymphoma, for example, primarily target B cells - including cancer cells that develop from B cells. uPAR, on the other hand, tends to show up on the most dangerous, identity-shifting cancer cells - as well as on nearby support cells that are stuck in a constant wound-healing mode, building scar tissue and suppressing the immune response. In the study, researchers found uPAR was elevated in 12 of the 14 human cancer types they analyzed, with especially high levels in some types of ovarian, pancreatic, colon, lung, and brain cancers.

In preclinical experiments, uPAR-targeted CAR T cells were effective at killing cancer cells across multiple cancer models. And their effect could be further enhanced by combining them with senescence-inducing treatments such as the chemotherapy agent cisplatin, which raised uPAR levels and made tumor cells easier for the engineered T cells to attack. In a mouse model of ovarian cancer, for example, uPAR-targeting CAR T cells were able to wipe out metastases, leading to durable remissions. And mice whose tumors had been eliminated also resisted developing new tumors when researchers tried to introduce cancer again later, indicating the CAR T cells remained active.

Link: https://www.mskcc.org/news/cell-surface-protein-upar-may-hold-key-to-targeting-solid-tumors-with-car-cell-therapy

Rapamycin is increasingly prescribed off-label by anti-aging physicians based on animal studies and very limited human data (even including the relatively recent crowdfunded PEARL trial) for it to improve late-life metabolism. Rapamycin and other mTOR inhibitors are calorie restriction mimetics, provoking a greater level of autophagy to improve cell maintenance. In mice, rapamycin results in a ~20-25% increase in life span, a sizable fraction of the ~40% that is possible via calorie restriction. We know that human calorie restriction is beneficial to health in many ways, but doesn't add more than a few years to life span - while no actual assessment has been carried out, it would be hard for an effect of more than five years or so to remain hidden from interested epidemiologists and scientists across the course of history.

Rapamcyin can be prescribed off-label because it has long been used as an immunosuppressant drug at much higher doses than the anti-aging use, and the safety profile for that use is well mapped. The drug has existed for long enough that it is now generic, outlasted its patent protection. Generic drugs tend to see little further formal clinical trial activity because they cannot produce enough income to sustain the high costs imposed by regulatory authorities. That doesn't stop academics from sometimes managing to obtain enough funding to explore unanswered questions, however.

While enough people are presently using rapamycin off-label at anti-aging doses for a recent study to find more than 300 individuals who were willing to provide information on their rapamycin use, in general this sort of use generates next to no actually useful, robust data. To obtain that data clinical trials of some sort, at the very least run by a reputable organization, remain needed. At present, there is no great consensus that any of the present range of anti-aging doses used in the community are in fact the optimal dose for humans. There are also remaining questions as to the dose at which undesirable immunosuppressive or hyperglycemic effects begin to emerge, and how prevalent they are. So it is good to see that an academic group has found the funds needed to run an initial set of trials aimed at answering these questions.

Large rapamycin clinical trial launches

Researchers are launching a multi-phase clinical study to better understand the biological effects of rapamycin in older adults. The study reflects a shift toward evidence-based dosing, safety, and long-term outcomes rather than off-label and speculative use of rapamycin. "Rapamycin is widely discussed in popular culture as a longevity drug. But there's a difference between something that is biologically plausible and something that has been rigorously tested in people."

The current study is structured as a series of interconnected sub-studies, each designed to answer a specific question. The translational pipeline will move from biological benchmarks to long-term clinical observation. The first sub-study establishes a reference point by examining immune and metabolic markers in younger adults. These measurements help define what "optimal" function looks like before aging-related changes begin.

The second sub-study will determine the optimal rapamycin dosage for older adults that will safely bring them back to the optimal functioning seen in the younger population. The dosage used for transplant patients may be too high for safe use in generally healthy older adults, so the scientists are testing different dosing schedules to determine how much rapamycin is needed to reach biological targets without negative side effects. "This phase is about precision. We're asking how much drug it actually takes to achieve a desired biological effect, not more than that."

The third sub-study is the largest cohort and will run the longest. It is a randomized, placebo-controlled clinical trial involving approximately 84 older adults who will receive either daily rapamycin, intermittent dosing, or a placebo. Participants will be treated for six months and followed for an additional six months to assess both short-term effects and sustained effects after treatment ends.

Muscle tissue is metabolically active to a degree perhaps not fully appreciated in past years. An only partially explored class of signals known as exerkines are generated by muscle tissue in response to physical activity and produce beneficial outcomes to cell behavior and tissue function throughout the body. Much of the signaling that passes between cells is carried by extracellular vesicles, membrane-wrapped packages of molecules of various sorts. As we enter an era in which extracellular vesicles are harvested from donors and cell cultures to be used as a basis for therapies, in much the same way as stem cells have been used, there is an increasing interest in muscle cells as a source of potentially therapeutic extracellular vesicles.

In recent years, a paradigm shift has occurred in the understanding of intercellular communication, moving beyond soluble factors (e.g., myokines) to embrace the critical role of extracellular vesicles (EVs). Among these, exosomes, small lipid-bilayer vesicles (30-150 nm) derived from the endosomal pathway, have emerged as powerful mediators of both localized and long-distance cellular crosstalk. These nanovesicles, which contain a diverse and specific cargo of proteins, lipids, and nucleic acids, are increasingly recognized as "fingerprints" of their originating cells, reflecting their metabolic and physiological state. The confluence of these fields - exercise physiology, exosome biology, and muscle pathology - has given rise to the "exerkine" hypothesis, which posits that the systemic benefits of exercise are, in part, mediated by the modulation of exosomal cargo.

This review will integrates the current evidence supporting this hypothesis, exploring the mechanisms by which exercise-induced exosomes influence muscle health, detailing their role in inter-tissue communication, and critically evaluating their potential as therapeutic tools and biomarkers. Importantly, the circulating EV pool induced by exercise is heterogeneous and originates from multiple tissues and cell types (e.g., skeletal muscle, adipose tissue, endothelium, immune cells, platelets), each contributing distinct cargo signatures and biological effects. Moreover, the physiological impact of a given exosome is not determined solely by its source cargo, but also by the recipient tissue's state (e.g., aging, inflammation, insulin resistance), which shapes uptake, signaling competence, and downstream transcriptional responses.

In this review we detail how exosomal cargo, including non-coding RNAs and proteins, regulates muscle stem cell activation and differentiation, counteracts age-related decline (sarcopenia) by modulating protein homeostasis and inflammation, and facilitates systemic metabolic crosstalk with distant tissues such as adipose tissue. We also critically discuss the burgeoning therapeutic potential of engineered exosomes for musculoskeletal health, while highlighting significant and interconnected challenges in the field, including the lack of standardized methodologies and regulatory frameworks.

Link: https://doi.org/10.3389/fcell.2026.1706977

Epidemiological studies consistently show a sizable difference in mortality rates between those who exercise regularly and those who do not. Clearly at some point aging forces a reduction in activity, and those more impacted by aging will tend to have a greater mortality risk. But animal studies show that exercise does in fact slow aging; it doesn't have much of an effect on maximum life span in mice, but it does reduce mortality and postpone frailty and mortality to lengthen median life span. How much of the observed correlation in humans is due to causation in one direction versus the other is up for debate, but the consensus is that physical activity is beneficial.

Long-term causal evidence comparing different physical activity patterns and mortality outcomes is needed. Using observational data to emulate a randomized controlled trial, this study compared different physical activity patterns over 15 years in relation to mortality from all causes, cardiovascular disease (CVD) and cancer in 11,169 mid-aged women in the Australian Longitudinal Study on Women's Health.

Two emulated interventions were compared against consistent non-adherence (control) to World Health Organization moderate-to-vigorous physical activity (MVPA) recommendations during the 15-year 'exposure period': (1) consistent adherence to recommendations (at least 150 min/week) over 15 years (2001-2016; women were 50-55-65-70 years); and (2) starting to meet the recommendations at age 55, 60, or 65 years.

Mortality outcomes that occurred between surveys (women were 53-58 at the first survey and 68-73 years at the last survey), were ascertained from Australian death registries. Comparing consistent adherence to MVPA recommendations with consistent non-adherence, there was evidence (Bayes factor [BF] = 5.71) for a protective effect for all-cause mortality (risk ratio [RR]: 0.50; risk difference [RD]: -5.2%). Findings for cardiovascular disease (BF = 2.05; RR: 0.50; RD: -2.1%) and cancer mortality (BF = 2.26; RR: 0.35; RD: -3.3%) were more uncertain and less conclusive, as were those for an effect of starting to meet MVPA recommendations in the mid-fifties on mortality outcomes.

Link: https://doi.org/10.1371/journal.pmed.1004976

Cells in aged tissues suffer a range of biochemical dysfunctions; broken proteins, altered structures, leakage of materials from one compartment to another. Many of these issues provoke the cell into inflammatory reactions. A range of sensors operate in every cell, triggered by different forms of damage and stress characteristic of aging, and converging on the activation of regulators of inflammatory signaling. One example is the interaction between cGAS and STING. cGAS acts to detect the presence of DNA in the cell cytosol, an evolved defense against infectious pathogens. Unfortunately it is maladaptively triggered by leakage of fragments of DNA from the cell nucleus or mitochondria, a feature of cells in aged tissues. cGAS then interacts with STING to produce inflammatory signaling.

Today's open access paper is interesting for the discussion of what exactly might be done about unwanted cGAS-STING interactions in aging tissues. The focus is the aging of the ovary, but this is a problem that occurs throughout the body. The primary challenge in attempting to suppress unwanted inflammation is that control of unwanted inflammation runs through the same pathways as control over desirable inflammation. Known approaches to interfere in the regulation of inflammation and inflammatory signaling shut down both excessive and necessary inflammation, resulting in undesirable side effects. But perhaps there can be better ways forward, the ability to better distinguish between these modes of activation. As yet there are only hints in early stage research that this can be possible, however.

The inflammatory clock: how cGAS-STING ticks in the aging ovary

Premature ovarian insufficiency (POI) is more than a fertility issue; it's a silent epidemic of accelerated systemic aging in young women, with current treatments failing to address its root cause. For too long, the relentless decline of ovarian function has been viewed as an inevitable mystery. But what if the ovary holds an internal "inflammatory clock," ticking away with each cellular insult and dictating the pace of its own decline? Here, we spotlight a surprising culprit: the cGAS-STING signaling pathway. Far beyond its day job in antiviral defense, this pathway emerges as a master integrator of ovarian aging.

We reveal how stresses like DNA damage and mitochondrial dysfunction leak genetic material into the cell's interior, where cGAS-STING sounds a relentless alarm. This alarm does not just trigger inflammation; it initiates a vicious, self-amplifying cycle of cellular senescence, tissue fibrosis, and follicle destruction - a cycle that may explain why ovarian aging often feels like a one-way street.

Therapeutically, we move beyond mere symptom management to explore strategies for resetting this inflammatory clock. We dissect both direct "brakes" - novel small molecules that silence cGAS or STING - and upstream "shields" that protect mitochondria and genome integrity. Most provocatively, we introduce the concept of "signal reprogramming": not just shutting down the pathway, but cleverly rewiring its output to favor repair over destruction. By repositioning cGAS-STING from a simple sensor to the central processor of ovarian aging, this review charts a course for a new class of therapeutics aimed at preserving ovarian function, not just managing its loss.

In oncology models, persistent STING activation has been shown in certain settings to promote an immunosuppressive microenvironment; notably, co-administration of a TLR2 agonist was reported to "reprogram" STING downstream signaling by enhancing NF-κB activity while attenuating IRF3-dependent interferon responses, thereby overcoming therapeutic resistance. This oncology-informed framework provides a conceptual basis for cautiously exploring whether selective downstream signaling modulation, rather than global pathway inhibition, could theoretically attenuate chronic inflammation while permitting adaptive tissue responses in ovarian aging models.