Fight Aging!

Every cell contains hundreds of mitochondria, vital organelles tightly integrated into many core cellular processes, and responsible for producing adenosine triphosphate, a chemical energy store molecule used to power the cell. Unfortunately mitochondria become dysfunctional with age, and this is thought to be an important contribution to degenerative aging. A variety of means to address this issue exist or are under development, some more direct and ambitious than others.

Cells will readily take up whole mitochondria from the surrounding tissue environment and make use of them. Thus it is possible to introduce large numbers of mitochondria harvested from cell cultures into a tissue in order to largely replace the native mitochondria. Provided that age-related mechanisms of damage and dysfunction that degrade the effectiveness of mitochondrial populations act slowly, then introducing young, functional mitochondria into an old individual should produce a lasting benefit.

This approach of mitochondrial transplantation has been assessed in small studies using mice, and shown to be feasible. The primary challenge facing those who seek to bring this form of therapy to human patients lies in scaling up existing ad-hoc manufacturing protocols developed for animal studies in order to allow the robust, reliable manufacture of very large batches of human mitochondria. That is where most of the efforts of companies such as cellvie and Mitrix Bio have focused, on the infrastructure of producing mitochondria for transplantation. This has been underway for a few years now, and it seems Mitrix Bio is at the point of conducting an initial safety trial in human volunteers, to start later this year.

Physicist, 90, joins experimental trial to challenge age limits

A new clinical effort aimed at testing mitochondrial transplantation for age reversal is drawing attention - not only for its scientific ambition, but for the identity of its first participant. John G Cramer, a 90-year-old emeritus professor of physics at the University of Washington, has announced he will undergo a novel therapy that uses bioreactor-grown mitochondria, a technology developed by biotech startup Mitrix Bio. The project will be overseen by a collaborative team of researchers from Stanford, UCLA, Northwell Health New York and Mitrix Bio, and is expected to begin on 1 August. It also opens the door to five additional volunteers over 55 or with chronic disease to join as early participants in this exploratory human intervention.

90-Year-Old Physics Professor Launches First Attempt to Break Human Age Barrier (PDF)

Mitrix, a startup launched in 2020 by prominent Silicon Valley scientists and entrepreneurs, has been testing transplantation of mitochondria not only to cure disease but for a more audacious goal: to reverse human aging. Their bioreactor technology is designed to provide the huge volumes of autologous (self-derived) age-reset mitochondria needed to restore cellular energetics and reverse decades of losses in the elderly body.

Leveraging his experience as an experimental physicist, Dr. Cramer has analyzed the latest life- and health-extension drugs. Most are not potent enough to do the job, but he has zeroed in on two that show promise: epigenetic reprogramming, a technique that Silicon Valley billionaires like Jeff Bezos have poured billions into, and mitochondrial transplantation, another fast-growing contender.

"I've analyzed the longevity treatments, and mitochondrial transplantation is the first that seems potentially safe and powerful enough to get someone past 122 in good health. At the age of 90 I'm the oldest person set to try this technology, so if this works, nobody will be able to catch up. I'll always be the oldest young person in history. The senior-est of senior citizens. And the same treatment, if proven safe and effective, might be used to save thousands of people: children with genetic diseases, injured veterans, stroke victims, people with chronic conditions. The medical potential is huge."

You might recall the development a few years ago of a proteomic aging clock that provided estimates of biological age for various organs in the body, rather than simply one overall measure. It was noted that individuals tended to have a distribution of biological ages across various organs, an individual's organs age to different degrees. Here, researchers apply that clock to a subset of the UK Biobank population, and find that it produces the expected results. A higher predicted biological age for a given organ resulting from the clock algorithm correlates with a higher future risk of age-related disease in that organ, and the more organs exhibiting accelerated biological age, the greater the risk of mortality.

Plasma proteins derived from specific organs can estimate organ age and mortality, but their sensitivity to environmental factors and their robustness in forecasting onset of organ diseases and mortality remain unclear. To address this gap, we estimate the biological age of 11 organs using plasma proteomics data (2,916 proteins) from 44,498 individuals in the UK Biobank.

Organ age estimates were sensitive to lifestyle factors and medications and were associated with future onset (within 17 yearsʼ follow-up) of a range of diseases, including heart failure, chronic obstructive pulmonary disease, type 2 diabetes, and Alzheimer's disease. Notably, having an especially aged brain posed a risk of Alzheimer's disease (hazard ratio, HR = 3.1) that was similar to carrying one copy of APOE4, the strongest genetic risk factor for sporadic Alzheimer's disease, whereas a youthful brain (HR = 0.26) provided protection that was similar to carrying two copies of APOE2, independent of APOE genotype.

Accrual of aged organs progressively increased mortality risk (2-4 aged organs, HR = 2.3; 5-7 aged organs, HR = 4.5; 8+ aged organs, HR = 8.3), whereas youthful brains and immune systems were uniquely associated with longevity (youthful brain, HR = 0.60 for mortality risk; youthful immune system, HR = 0.58; youthful both, HR = 0.44). Altogether, these findings support the use of plasma proteins for monitoring of organ health and point to the brain and immune systems as key targets for longevity interventions.

Link: https://doi.org/10.1038/s41591-025-03798-1

Biological age acceleration is the name given to the state of exhibiting a predicted age from an aging clock that is higher than chronological age. Accelerated age via a clock measure is correlated with an increased risk of age-related disease and mortality. This has been demonstrated in a number of large epidemiological studies, and here researchers make use of the UK Biobank data to once again demonstrate that aging clocks do at least somewhat reflect the age-related risk of disease and mortality. Even so, it remains possible to argue over what exactly the clocks are measuring; calling it biological age is a lazy shortcut and possibly not the reality.

As the global population ages, multimorbidity has become a critical public health issue. We analyzed 332,012 adults from the UK Biobank (2006-2022) to investigate the association between biological age - measured by the Klemera-Doubal method (KDM-BA) and phenotypic age (PhenoAge) - and a new comorbidity model encompassing physical, psychological, and cognitive disorders, with overall mortality outcomes over a median follow-up of 13.6 years. Logistic regression models examined the association between baseline health status and accelerated aging, while Cox proportional hazards models assessed mortality risk and disorder development.

Cross-sectional analysis showed that accelerated aging was linked to higher comorbidity prevalence. Longitudinal follow-up revealed that individuals in the highest quartile (Q4) of aging speed (residual difference between estimated biological age and chronological age) had a 16%-17% higher risk of developing a single disorder, a 41%-44% higher risk of multimorbidity, and a 54% higher overall mortality risk compared with the lowest quartile (Q1). Among those with baseline single disorder, dual comorbidity, and triple morbidity, Q4 mortality risk increased by 89%-116%, 118%-166%, and 119%-156%, respectively. Multistate Markov models confirmed that accelerated aging increased the risk of transitioning to disorder, comorbidity, and death by 12%-37%. Individuals aged 45 with triple comorbidity lost an average of 5.3 years in life expectancy (LE), further reduced by 5.8 to 7.0 years due to accelerated aging.

This study highlights that KDM-BA and PhenoAge robustly predict multimorbidity trajectories, mortality, and shortened LE, supporting their integration into risk stratification frameworks to optimize interventions for high-risk populations.

Link: https://doi.org/10.1111/acel.70142

Cells that become senescent cease to replicate and secrete inflammatory signals that are disruptive to tissue structure and function. This happens constantly throughout life, largely as the result of cells reaching the Hayflick limit on replication, but also as a result of stress, damage, or a toxic local environment. In youth, newly created senescent cells are cleared rapidly by the immune system. With age, this clearance is impaired and the number of senescent cells in every cell population increases, contributing to age-related dysfunction and disease.

In today's open access paper, researchers discuss the biochemistry and role of senescence in osteoblast cells and their contribute to osteoporosis, the age-related loss of bone mass and strength. Bone tissue is constantly remodeled, created by osteoblast cells and destroyed by osteoclast cells. With age, the balance of these activities shifts to favor osteoclasts, and thus a gradual loss of bone density is the result. An increase in senescence in the osteoblast population is one of the contributing causes of this outcome, and so therapies targeting senescent cells may help to slow the onset and progression of osteoporosis.

Addressing osteoblast senescence: Molecular pathways and the frontier of anti-ageing treatments

Studies have shown that osteoporosis is closely related to ageing and the senescence of osteoblasts in the bone microenvironment. Counteracting osteoblast senescence and balancing the differentiation, proliferation, and function of osteoclasts and osteoblasts will remain central to age-related osteoporosis research.

During ageing, osteoblast lineages undergo significant changes that affect their ability to form, maintain and repair bone. Osteoblast precursors, including mesenchymal stem cells, show decreased proliferative capacity and multifunctionality, resulting in impaired osteogenic differentiation potential. The biological behaviours and functions of senescence-related osteoblast lineages are regulated by a variety of signalling pathways associated with ageing, which may influence the cell cycle, oxidative stress response, and cell metabolism. In short, the proliferation ability of senescent osteoblast lineages is weakened, affecting the renewal and repair of bone tissue. Moreover, the mineralised bone formation process is also negatively affected by ageing, resulting in abnormal bone matrix formation and mineralisation. This further leads to an imbalance in bone homeostasis in the body and ultimately accelerates bone loss.

Anti-senescence interventions targeting osteoblasts could potentially revolutionise the treatment and prevention of osteoporosis. For instance, pharmacological agents that inhibit senescence-associated pathways, such as mTOR inhibitors or senolytics, have shown promise in preclinical studies by enhancing osteoblast function and bone formation. Similarly, lifestyle modifications, including CR and regular physical exercise, have been demonstrated to mitigate osteoblast ageing and improve bone health. Moreover, the development of novel biomarkers for osteoblast senescence could facilitate early diagnosis and personalised treatment strategies for osteoporosis.

Here find a tour of some of the more high profile projects aimed at the production of gene therapies to treat aging. A lot more could be done than is being done, in large part because present gene therapy vectors have many limitations on the ability to effectively deliver payloads, despite ongoing improvements. They cannot deliver to the whole body in adults. They cannot deliver well to many specific organs without involving direct injections. Delivery is uneven from cell to cell in a tissue. And so forth. These problems are well understood, and many groups are attempting to produce fixes, but for now gene therapies perform well in only some circumstances. For example: permanently increasing circulating amounts of a given signal protein, since the therapy only has to affect a small number of cells in a fat pad following a subcutaneous injection in order to turn them into a factory for that protein.

Gene therapy technology offers transformative potential by enabling precise genetic modifications and targeted delivery to aged tissues. Advances in gene editing tools have revolutionized the modulation of genetic and epigenetic factors associated with aging. Concurrently, optimized delivery systems, including adeno-associated virus (AAV) and lipid nanoparticles (LNPs), enhance targeting efficiency. These advances offer innovative and robust approaches for targeting and modulating aging-related regulatory pathways, promoting a transformative shift in aging intervention from "symptom relief" to "mechanism addressing", while simultaneously accelerating the research and development process.

The development of gene therapy technologies has provided new avenues for aging intervention, demonstrating unique advantages. Compared to traditional approaches such as drug treatments and lifestyle interventions, gene therapy utilizes delivery vectors to achieve in vivo inhibition or activation of key regulatory genes or pathways involved in aging, offering greater potential for delaying aging and extending healthy lifespan. Here, we systematically elaborate on current research progress in gene therapy for aging intervention from aspects of enhancing genomic and epigenetic stability, maintaining energy metabolism homeostasis, modulating immune functions, and promoting cellular rejuvenation.

Link: https://doi.org/10.1016/j.cellin.2025.100254

Researchers here review what is known of the role of PAI-1 in aging. A small number of humans are known to exhibit loss of function mutations in PAI-1, indicating that the activities of PAI-1 are not vital to life. While the known population is very small, and thus there is a great deal more uncertainty as to whether the existing data is representative of how this would work in a broader population, it appears that these individuals may live 7 years longer than their peers. On some time frame the research community will likely develop therapies to inhibit PAI-1 expression or activity, but is worth remembering that therapies inspired by a beneficial mutation usually provide only a fraction of the benefits of that mutation - because they are only partially inhibiting the gene or protein, because a patient only takes the therapy for a few years rather than a lifetime, and so forth.

Plasminogen activator inhibitor-1 (PAI-1), encoded by the SERPINE1 gene, is a serine protease inhibitor primarily recognized for its role in regulating fibrinolysis by inhibiting plasminogen activators which facilitate the conversion of plasminogen into plasmin. Subsequently, active plasmin breaks down fibrin, which is an integral meshwork of blood clots. Hence, PAI-1 effectively slows down or prevents clot breakdown. Beyond this hemostatic function, PAI-1 has emerged as a culprit in contributing to aging and age-related diseases.

A significant body of literature outlines PAI-1's involvement in cellular senescence, inflammation, and tissue remodeling. Elevated PAI-1 levels are consistently observed in conditions such as cardiovascular disease, metabolic syndrome, cancer, and neurodegeneration, suggesting it plays an active role in the aging process. Studies across species demonstrate that circulating PAI-1 level increases progressively with chronological age, paralleling the accumulation of senescent cells and the onset of age-related pathologies. For instance, longitudinal analyses in human cohorts reveal a steep rise in plasma PAI-1 levels after middle age, correlating with increased cardiovascular risk and frailty. This temporal correlation implies PAI-1 may be an active participant in aging, and not merely a passive marker.

Although previous reviews have extensively covered PAI-1 in the context of cardiovascular disease, cancer, and metabolic dysfunction, this review integrates recent evidence with seminal articles in the literature to provide evidence for the model that PAI-1 is not only involved in age-related conditions but is a central driver of the aging process itself. A rare loss-of-function SERPINE1 mutation in humans extends lifespan, illustrating how lifelong PAI-1 reduction can positively impact the human healthspan. Looking forward, targeting PAI-1 with inhibitors could mitigate senescence, restore stem cell function, improve metabolic profile, enhance physiological health, and promise a longer healthspan.

Link: https://doi.org/10.1016/j.bj.2025.100892

A great many aspects of cellular biochemistry change in the aging brain, a sea of changes within which there are a very large number of harmful changes. Some of those harmful changes cause little further issue, most will in turn cause other changes; it is a complex web of interactions. Neither the web nor the biochemistry itself is fully mapped. None of this is anywhere near fully understood. Inroads have been made, but they are just inroads. Human nature being what it is, most research attention is focused on those areas of brain biochemistry that are at least somewhat mapped and catalogued. That neurodegenerative conditions still exist shows that perhaps more attention should be given to the empty places on the map than is presently the case.

Today's open access paper is an example of mapping the empty places. The focus on lysosomal acid lipase did not emerge fully formed from the waters, of course. Researchers have spent a great deal of time and energy understanding the mechanisms of the inherited condition of lysosomal acid lipase deficiency, in which mutation prevents the expression or correct function of this enzyme. As a result of that work, a recombinant protein therapy to deliver lysosomal acid lipase to patients with this rare condition has existed for a decade or so. Lysosomal acid lipase deficiency is detrimental to lipid metabolism, and it is becoming clear that dysfunctions in lipid metabolism can be important in the development of Alzheimer's disease. The importance of today's research materials is the act of stitching these two worlds together, research into lipid metabolism in neurodegeneration on the one hand versus lysosomal acid lipase deficiency on the other, and making them relevant to one another.

Loss of lysosomal acid lipase contributes to Alzheimer's disease pathology and cognitive decline

Alzheimer's disease (AD) is the most common form of dementia with over 90% of cases being sporadic or late-onset AD (LOAD). Though the etiology of LOAD is often unknown, risk factors such as heavy smoking or alcohol use, diabetes, hypertension, and obesity account for much of the risk. Though these exposures have diverse biological impacts, they converge upon a shared pathological progression - the accumulation of intraneuronal amyloid β (Aβ), extracellular Aβ plaque deposition, and pathological tau species formation with aging.

Intraneuronal Aβ is a feature of LOAD that is associated with early cognitive deficits. Aβ normally transits to neuronal endosomes with lysosomal degradation after internalization from the cell surface or endocytosis. Dysfunction of autophagy or lysosomes has been suggested to promote intraneuronal Aβ accumulation and subsequent plaque formation. However, the molecular drivers of lysosomal dysfunction associated with LOAD remain unknown. Human studies also suggest altered lipid metabolism. For instance, the polymorphisms in lipid efflux proteins increase risk, and the ε4 apolipoprotein polymorphism is a strong genetic LOAD risk factor. Lipid metabolism is governed by coordinated actions of lipogenesis, lipolysis, and lysosomal digestion (i.e., lipophagy). However, mechanisms by which aberrant lipid metabolism promote LOAD are unknown.

To identify underlying drivers of LOAD pathogenesis, we compared the cellular and molecular consequences of two distinct midlife risk factors for LOAD, heavy alcohol use and obesity. Using these two risk exposures to identify shared cellular deficits that underly LOAD pathogenesis, we found that the accumulation of neuronal lysosomal lipid (NLL) contributes to LOAD pathogenesis. This involves the loss of lysosomal acid lipase (LAL) the main lysosomal lipase. A role for LAL extended beyond these risk factors with neuronal LAL loss in normal aging that was greatly enhanced in human LOAD subjects without heavy alcohol use or obesity. Signs of a transcriptional mechanism were found, with altered localization of RNA polymerase II across the LAL gene body in female human LOAD hippocampus. LAL neuronal gene therapy blunted the enhancement Aβ pathology and cognitive deficits caused by midlife alcohol and prevented cognitive decline and affective dysfunction with aging in AD mice. Thus, LAL loss with aging contributes to the emergence of Aβ that can be targeted therapeutically for the prevention or treatment of AD.

The research community is now very interested in the development of means to reduce the various hallmarks of aging, a framework for thinking about how to treat aging as a medical condition. This is quite the change from the state of affairs twenty years ago, a time at which it remained scientific career suicide to make a habit of advocating for the development of therapies to slow or reverse aging. Now that the community has come around to the concept of treating aging, there are any number of published commentaries and reviews similar to the one noted here. One can hope that now we are over the hurdle of convincing people to actually work on the problem, the next few decades will see meaningful progress towards reducing the burden of damage and dysfunction in later life.

Aging is a complex biological process characterized by a gradual decline in cellular and physiological function, increasing vulnerability to chronic diseases and mortality. It involves a set of interconnected mechanisms known as the hallmarks of aging, including genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, and dysregulated nutrient sensing. These processes act at molecular, cellular, and systemic levels, contributing to age-related disorders such as neurodegeneration, cardiovascular disease, and metabolic syndromes.

Emerging therapeutic strategies aim to delay or reverse aging by targeting specific hallmarks. These include senolytics to eliminate senescent cells, NAD+ boosters, and mitophagy inducers to improve mitochondrial health, epigenetic reprogramming, and caloric restriction mimetics such as metformin and rapamycin to modulate nutrient-sensing pathways. Advances in regenerative medicine, gene editing, and organ cross-talk modulation are also contributing to the development of personalized, multi-targeted anti-aging therapies. Integration of omics technologies and biomarker research is expected to enhance our ability to monitor biological aging and optimize interventions for healthy longevity. This review highlights the current understanding of the hallmarks of aging and explores potential treatment strategies in light of our recent findings.

Link: https://doi.org/10.3389/fcvm.2025.1631578

One of the things that can be done with an aging clock based on transcriptomics is to screen compound libraries for drug candidates that reduce age-related changes in gene expression in specific cell populations. Here, researchers run an in vitro screen for compounds capable of achieving this goal in various brain cell types. It is likely that this sort of work will over time greatly expand the present list of compounds known to at modestly slow aging, but it seems unlikely to make more more of a difference than that. Based on past results, any sort of unbiased screening will uncover novel calorie restriction mimetics and senotherapeutics with modest effect sizes. There doesn't appear to be much else under this stone; researchers announce rejuvenation, but one always has to look at the effect sizes, which are usually small. More impressive interventions in aging seem likely to only emerge from the deliberative design of more advanced forms of drug capable of achieving specific goals related to the damage and dysfunction of aging.

The increase in life expectancy has caused a rise in age-related brain disorders. Although brain rejuvenation is a promising strategy to counteract brain functional decline, systematic discovery methods for efficient interventions are lacking. A computational platform based on a transcriptional brain aging clock capable of detecting age- and neurodegeneration-related changes is developed. Applied to neurodegeneration-positive samples, it reveals that neurodegenerative disease presence and severity significantly increase predicted age.

By screening 43,840 transcriptional profiles of chemical and genetic perturbations, it identifies 453 unique rejuvenating interventions, several of which are known to extend lifespan in animal models. Additionally, the identified interventions include drugs already used to treat neurological disorders, Alzheimer's disease among them. A combination of compounds predicted by the platform reduced anxiety, improved memory, and rejuvenated the brain cortex transcriptome in aged mice. These results demonstrate the platform's ability to identify brain-rejuvenating interventions, offering potential treatments for neurodegenerative diseases.

Link: https://doi.org/10.1002/advs.202503344

Aging negatively impacts muscle regeneration for reasons that remain incompletely understood. This incomplete understanding exists in part because muscle regeneration involves a complex set of interactions between different cell types that shifts over time as the response to injury progresses. It requires a great deal of effort to build a clear picture at the level of cell biochemistry. Nonetheless, it is evidently the case that aging impairs the activity of muscle stem cells, it impairs the niches in which those cells reside, it alters the behavior of immune cells for the worse, and so forth. There are starting points.

Similarly, one can point to the chronic inflammation of aging and its ability to impairs regeneration, interfering in the normal short-term inflammatory signaling that follows injury. One can point to all of the known causes of aging and suggest that addressing them will improve the situation. That said, most research groups take the challenge to be the identification of specific regulatory mechanisms that drive maladaptive reactions on the part of cells in injured aged muscle. The next step is then the development of therapies that sabotage those mechanisms. This sort of approach doesn't fix underlying damage, but can dampen the response to that damage.

Today's open access paper is an example of this sort of research. The authors report on a mechanism by which macrophages in aged muscle are impaired in ways that reduce the capacity for regeneration. There is an age-related reduction in levels of selenoprotein P in these macrophages. Experimental approaches to inhibit and boost selenoprotein P levels are shown to reduce and increase regenerative capacity respectively. The role of selenoprotein P in cellular biochemistry is not well understood, however. It is thought to be an antioxidant molecule, but may well have other functions yet to be identified. So it is a little unclear as to what exactly is going on under the hood.

Immune aging impairs muscle regeneration via macrophage-derived anti-oxidant selenoprotein P

Adult skeletal muscle is a plastic tissue and can regenerate after trauma- or exercise-induced myofiber damage via muscle stem cells (MuSCs), that exit quiescence, expand, differentiate, and eventually fuse to form new functional myofibers. Although MuSCs are absolutely required for skeletal muscle regeneration, their surrounding non-myogenic counterparts in the local niche coordinate inflammatory signals and tissue remodeling to sustain adult myogenesis. However, this process is altered in a variety of conditions, including muscle diseases, some metabolic conditions such as diabetes, and aging.

Failure of mounting an efficient skeletal muscle regeneration in aged organisms has been attributed to both intrinsic alterations of MuSCs and modified environmental cues. Since they are the support of muscle regeneration, a variety of intrinsic alterations have been identified in the old MuSCs, including changes in epigenetics and signaling, as well as alterations in metabolism and proteostasis. Extrinsic alterations have also been described including alterations in the number or in the nature of immune cells, in some properties of fibro-adipogenic precursors (FAPs), and in extracellular matrix (ECM) composition, as well as systemic factors. However, if cell-cell interactions are well-described in the adult regenerating muscle, the impact of aging on the molecular regulation of cell components of the MuSC niche and on cell-cell interactions during regeneration is still poorly known.

Here, we compared and analyzed the time course of the various cell types constituting the MuSC niche during muscle generation in young and old mice. Aging alters the expansion of all niche cells, with prominent phenotypes in macrophages that show impaired resolution of inflammation. RNA sequencing uncovers specific profiles and kinetics of genes and molecular pathways in old versus young muscle cells, indicating that each cell type responds to aging in a specific manner. Moreover, we show that macrophages have an altered expression of Selenoprotein P (Sepp1). Macrophage-specific deletion of Sepp1 is sufficient to impair the acquisition of their restorative profile and causes inefficient skeletal muscle regeneration. When transplanted in aged mice, bone marrow from young wild type mice, but not Sepp1 knockout mice, restores muscle regeneration. This work provides a unique resource to study MuSC niche aging, reveals that niche cell aging is asynchronous and establishes the antioxidant Selenoprotein P as a driver of age-related decline of muscle regeneration.

Cells respond to a broad range of various stresses in quite similar ways. Cold, heat, lack of nutrients, lack of oxygen, presence of toxins, irradiation, and so forth, may all have different sensors and initial responses, but these responses converge on an increase in maintenance and repair processes - such as autophagy. When stress and consequent damage and dysfunction is mild, this increased maintenance and repair produces a net benefit. Repeated or constant mild stresses can thus modestly slow aging by making cells more resilient to the forms of damage and dysfunction that arise in later life.

A coordinated response to stress is crucial for promoting the short-term and long-term health of an organism. The perception of stress, frequently through the nervous system, can lead to physiological changes that are fundamental to maintaining homeostasis. Activating the response to low oxygen, or hypoxia, extends healthspan and lifespan in the nematode worm C. elegans. However, despite some positive impacts, negative effects of the hypoxic response in specific tissues prevent translation of their benefits in mammals. Thus, it is imperative to identify which components of this response promote longevity.

Here, we interrogate the cell-nonautonomous hypoxic response signaling pathway. We find that HIF-1-mediated signaling in ADF serotonergic neurons is both necessary and sufficient for lifespan extension. Signaling through the serotonin receptor SER-7 in the GABAergic RIS interneurons is necessary in this process. Our findings also highlight the involvement of additional neural signaling molecules, including the neurotransmitters tyramine and GABA, and the neuropeptide NLP-17, in mediating longevity effects. Finally, we demonstrate that oxygen- and carbon-dioxide-sensing neurons act downstream of HIF-1 in this circuit.

Together, these insights develop a circuit for how the hypoxic response cell-nonautonomously modulates aging and suggests valuable targets for modulating aging in mammals.

Link: https://doi.org/10.1101/2025.05.04.652087

Circadian rhythms become disrupted with age. The maintenance of circadian rhythm is complex, and thus runs awry in complicated ways. For example, researchers have demonstrated an age-related mismatch between the activities of different circadian regulatory systems, leading to a growing contribution to age-related dysfunction in tissues. Researchers here review the evidence for disruption of circadian rhythm to specifically contribute to the progression of Parkinson's disease. In fact, there appears to be a bidirectional relationship between disrupted circadian rhythm and the pathology of Parkinson's disease.

Emerging evidence suggests that the circadian clock, the body's intrinsic timekeeping system, may play a critical role in the pathophysiology of Parkinson's disease (PD). Circadian rhythms (CR), which regulate a wide array of physiological processes, including sleep-wake cycles, hormone release, and metabolic functions, are disrupted in PD patients. This disruption not only exacerbates the motor and nonmotor symptoms of PD but may also influence the progression of neurodegeneration. Understanding the link between circadian rhythms and PD could reveal therapeutic strategies that align treatment with the body's natural rhythms, potentially improving outcomes and quality of life for patients.

Given the pervasive influence of circadian clocks on biological functions, optimizing the timing of pharmacological interventions, physical therapy, and lifestyle modifications in accordance with circadian rhythms could enhance treatment efficacy and mitigate side effects. In this review, we cover a wide range of potential medical-related applications of CR-spanning from its use as a biomarker, diagnostic or therapeutic approach while combining insights across cellular or animal models, and humans, with a particular focus on the PD field.

Molecular evidence also strongly links circadian clock dysfunction to neurodegeneration, particularly through disruptions in core clock genes (e.g., BMAL1 and PER2), and clock-controlled genes, which play critical roles in cellular homeostasis, mitochondrial function, and neuroinflammation. Furthermore, interventions to revert circadian changes, including bright light therapy or melatonin supplements, have shown promising benefits in improving both motor and nonmotor symptoms. Thus, if circadian disruption were purely a consequence of PD, the observed benefits of circadian-based interventions would be less likely, suggesting a bidirectional relationship where circadian dysfunction may, in addition, accelerate disease onset and or progression, as well as symptoms.

Link: https://doi.org/10.1038/s41531-025-01009-9

One of the reasons why the immune system declines with age is that hematopoietic stem cell populations that are resident in the bone marrow and responsible for creating immune cells become progressively more damaged and dysfunctional over time. It isn't just the stem cells, however. Stem cells reside within structures of supporting cells known as niches. The niche itself becomes damaged and dysfunction, contributing to the problems exhibited by stem cell populations.

One of the most direct approaches to stem cell aging is to introduce into the body a replacement population of undamaged, rejuvenated stem cells, such as those that can be generated via the creation of induced pluripotent stem cells from a patient tissue sample. Some preparation and finessing is needed for hematopoietic stem cell transplants to ensure the transplanted cells survive, but this is already accomplished as a form of treatment for severe disease. The preparation is stressful on the patient at the present time, but it should be possible to develop less stressful approaches if the potential for a much broader use of hematopoietic stem cell transplantation emerges.

Unfortunately, and as noted in today's open access paper, the age-damaged state of the stem cell niche ensures that one cannot just transplant youthful hematopoietic stem cells and expect it to reliably improve function. Young cells are impeded by the damaged niche, and coerced into adopting a state that is closer to that of old cells. This is a universal issue across stem cell populations, and a solution is much needed.

Differential effects of young and old hematopoietic stem cell niches on bone marrow-derived dendritic cells

Aging is linked to various dysfunctions of the immune system, including the decline of its primary developmental source: the hematopoietic stem cell (HSC) niche. This decline leads to chronic inflammation, increased vulnerability to infections, cancer, autoimmune diseases, and reduced vaccine efficacy. As individuals age, the HSC niche undergoes significant changes, including greater adipocyte accumulation and alterations in the molecular microenvironment, which may influence the development and function of immune cells. Among these cells, the impact of the aging HSC niche on dendritic cell (DC) function is less understood.

Heterochronic autologous HSC transplantation is a promising intervention to prevent age-related disorders, contributing to the extension of healthspan and longevity, however, several murine experiments failed to produce the expected results, which led us to presume that the problem lies within the old HSC niche. Therefore, we created in vitro models of young and old HSC niches and examined how these microenvironments affect the differentiation and maturation and functionality of BM-derived DCs (BMDCs).

An analysis of the conditioned media from young and aged HSC niches revealed that the environment of aged niches exhibited an increased presence of adiponectin. This media was subsequently utilized in BMDC differentiation and maturation protocols, with their effects closely monitored. Our results indicate that the old HSC niche microenvironment promotes premature BMDC activation, characterized by elevated MHC class II expression and enhanced allostimulatory capacity of BMDCs at their immature stage.

Additionally, lipopolysaccharide stimulation of BMDCs, used to induce DC maturation, significantly increased CD86 expression on BMDCs from the aged niche. However, these cells did not show superior allostimulatory capacity compared to their counterparts from the young niche environment. By analyzing the BMDC cytokine profile, we observed that when cultured in aged niche-conditioned media, the BMDCs secreted significantly higher levels of IL-6, indicating a heightened proinflammatory activation state. Collectively, our findings suggest that aging-related changes within the HSC niche can considerably alter DC functionality by disrupting their normal development from BM precursors.

Studies of physical activity in older people have long demonstrated that, at the lower end of the dose-response curve, even small increases in the amount of activity produce meaningful benefits. While human studies can only show correlations between exercise and health, animal studies fill in the gap to show causation. Being sedentary is bad for your health, but being even a little less than sedentary is meaningfully less bad for your health. Small increases in physical activity are not irrelevant when the overall level of physical activity is low. The study noted here reinforces this point.

Walking cadence has been suggested as a measure of activity intensity; however, it remains uncertain if prefrail and frail older adults can increase their walking cadence and if doing so leads to improvements in functional capacity. We aimed to determine if cadence can be increased and if this leads to improvement in functional capacity in prefrail and frail older adults. We performed a secondary data analysis of a walking intervention in prefrail and frail older adults living in retirement communities. Patients were randomized to Casual Speed Walking (CSW) and High-Intensity Walking (HIW) groups. Our primary outcome was improvement in 6-minute walk test distance above the minimally clinical important difference.

102 participants were included in the final analysis with 56 in the CSW group and 46 in the HIW group. Participants in the HIW group increased their walking cadence as compared to the CSW group during the intervention (HIW averaged 100 steps/min vs. CSW averaged 77 steps/min). Participants that increased their walking cadence demonstrated an increased odds of improvement in their 6-minute walk test minimum clinically important difference (odds ratio: 0.11). Older adults can increase their walking cadence and walking cadence can serve as a surrogate measure of activity intensity during walking interventions. An increase of 14 steps/minute from their comfortable walking cadence increased the odds of improvement in 6-minute walk test.

Link: https://doi.org/10.1371/journal.pone.0323759

The debate over whether aging should be formally declared a disease is entirely driven by the structure of medical regulation. The flow of funding through the medical system is shaped by lists of defined and allowed medical conditions derived from the International Statistical Classification of Diseases and Related Health Problems, and everything not explicitly allowed by regulators is either outright forbidden or a great deal more challenging to bring to the clinic than would otherwise be the case. The people who want aging to be defined as a disease are demanding a less costly, more rapid path of development for therapies to treat aging. It is as simple as that. Here, it is argued that perhaps advocating more directly for that goal of a faster, cheaper development process would be a better idea than focusing on definitions of aging.

Is aging a disease? Debate continues, with both good and flawed arguments, but progress is needed, so here are three ways to move discussions forward. First, this is the wrong question. The right question is what regulatory framework optimizes long term health. Second, aging isn't one thing, but multiple distinct pathological processes. Third, there were analogous debates on obesity - it wasn't a disease but now is. A new proposal to distinguish clinical obesity could be copied.

Advocates rightly see disease status as a path towards clinical trials for aging interventions using aging itself as primary endpoint instead of an individual chronic disease. Opponents rightly worry that labeling everyone past a certain age as 'diseased' loses a meaningful distinction versus current clinical illness thresholds. The real question is whether aging should be a clinical indication for trials. All aged adults are meaningfully biologically less robust when compared with young adults; age is by far the top risk factor for all age-related diseases, and intervening to mitigate this difference is a valid medical goal.

Obesity went through analogous debates for years. Like aging, obesity is a risk factor for and plays a direct causal role in many diseases. Over many years, more and more important organizations classified obesity as a disease - but this remains controversial. The history of arguments on both sides are worth reading and mirror much of the aging-as-disease debate. Recently, the Lancet Commission published a consensus proposal to distinguish more severely pathological obesity, labeled clinical obesity, from less significant pre-clinical obesity. They propose that clinical obesity is a disease, and while they admit obesity and its consequent increased disease risk exist on a continuum, they consider illness to be a meaningful binary state.

Aging is analogous, both overall and its subpathologies. There's a clear continuum with a severe region that even without clinically diagnosable chronic diseases is clinically significant enough based on dysfunction of organs or tissues or functional decline to warrant treatment, before progression to outright age-related diseases. An analogous esteemed commission of aging experts should define criteria for this.

Link: https://longevity.technology/news/is-aging-a-disease/

Aging is an accumulation of specific forms of cell and tissue damage, coupled with the dysfunctions produced by that damage. While the damage of aging would occur regardless of the surrounding environment, many environmental exposures also produce cell and tissue damage. This additional burden of damage can result in what appears to be accelerated aging, even if the damage is somewhat dissimilar in character to that produced during aging by the body itself. Sometimes the damage is in fact similar. Photoaging of skin resulting from ultraviolet light exposure is a good example; like any radiation exposure, this causes a greater burden of some of the forms of damage and dysfunction known to occur with age, such as DNA damage and an increased burden of senescent cells.

One way to reduce the impact of aging is to increase the activity of cellular maintenance processes. Many of the interventions show to slow aging in animal studies involve upregulation of autophagy, for example, a way for cells to remove damaged components in order to better resist damage-induced dysfunction. When most of the cells in the body are more aggressively maintained, age-related declines in tissue function are slowed. In today's open access paper, researchers show that this sort of approach also reduces the impact of photoaging. One of the targets of autophagy is damaged mitochondria in the cell, and this specific form of autophagy is called mitophagy. Since there are hundreds of mitochondria in every cell, and only some of them are at any given time rendered damaged and dysfunctional by radiation exposure, more aggressive clearance of those damaged mitochondria via mitophagy helps to reduce consequent impairment of tissue function.

Human adipose-derived stem cell exosomes reduce mitochondrial DNA common deletion through PINK1/Parkin-mediated mitophagy to improve skin photoaging

Various factors contribute to skin aging, which can be categorized into internal and external factors. External factors include air pollution, ultraviolet (UV) radiation, lack of sleep, and smoking. UV radiation, in particular, causes photoaging. Repeated exposure to UV, especially UVB radiation, generates reactive oxygen species (ROS), which accelerate the breakdown of collagen and elastin by upregulating matrix metalloproteinases (MMPs), leading to photoaging symptoms such as wrinkles, dryness, loss of elasticity, and pigmentation.

Current treatments for skin photoaging include photodynamic therapy, oral and topical drugs, and stem cell therapies. Human adipose-derived stem cells (hADSCs) are a type of mesenchymal stem cell with self-renewal and multidifferentiation abilities, as well as immunomodulatory effects. Exosomes are extracellular vesicles, ranging from 30 to 200 nm, formed through endocytosis, fusion, and exocytosis. These vesicles are rich in nucleic acids, proteins, cytokines, and other bioactive compounds. As a promising alternative to stem cells, exosomes eliminate the risk of immune rejection associated with stem cell transplants, offering an effective, non-invasive option for anti-aging therapies. This has led to increasing interest in their potential for skin rejuvenation.

Research has shown that photoaged skin exhibits a tenfold increase in mitochondrial DNA (mtDNA) common deletion compared to sun-protected skin in the same individual. Preserving mtDNA integrity is critical for mitochondrial function. Accumulation of mutations can impair mitochondrial subunits, increasing ROS production and perpetuating oxidative damage within mitochondria. However, mtDNA has limited repair capacity, making the clearance of damaged mtDNA via mitophagy essential for reducing oxidative stress in cells. Mitophagy is a crucial process that regulates mitochondrial quality and quantity in eukaryotic cells, selectively eliminating damaged or dysfunctional mitochondria. The PINK1/Parkin pathway is a well-established mediator of mitophagy.

This study aimed to explore the role and mechanism of hADSC-derived exosomes (hADSC-Exos) in addressing skin photoaging. hADSC-Exos were isolated, and their surface markers were identified. Human dermal fibroblasts (HDFs) and nude mice were exposed to UVB irradiation, and treated with hADSC-Exos. Oxidative stress, senescent cell burden, and photoaging were assessed. In UVB-exposed HDFs and nude mice, the number of SA-β-gal-positive cells, along with levels of p21, ROS, and mtDNA deletion, were significantly increased, but these effects were reduced by hADSC-Exos. Moreover, hADSC-Exos treatment significantly elevated PINK1 and Parkin levels. In conclusion, hADSC-Exos can mitigate skin photoaging by promoting PINK1/Parkin-mediated mitophagy, thereby reducing mtDNA deletion and oxidative stress.

Sarcopenia is the name given to the later, more severe stages of the age-related loss of muscle mass and strength that afflicts all older individuals. Over the past few decades, researchers have increasingly focused on establishing clinical definitions of sarcopenia and and exploring the mechanisms of sarcopenia. Here, researchers take the present standards for diagnosis and use them to build an aging clock for muscle loss, an attempt to provide a more definite measure of risk and progression of sarcopenia, particularly in its earlier stages.

Sarcopenia is a progressive, generalised skeletal muscle disease linked to negative health changes that accumulate across the lifespan. From a pathophysiological standpoint, endocrine and metabolic abnormalities interact with the low-grade chronic inflammation (i.e., "inflammageing"), that is observed in advanced agers, leading to a reduction of protein-synthesis and regeneration, and a parallel pattern of muscle wasting due to increased apoptosis and protein-lysis.

Among the number of initiatives launched to advance knowledge on sarcopenia and prompt preventive/therapeutic approaches, the European Working Group on Sarcopenia in Older People (EWGSOP) has emerged as the most influential in raising awareness and moving the field forward. EWGSOP consensus firstly introduced a broad clinical definition for sarcopenia not limited to muscle loss. This was eventually developed more recently (EWGSOP2) to move muscle weakness and reduced performance to the forefront as primary indicators of sarcopenia. EWGSOP2's recommendations also developed an algorithm for case-finding, diagnosis, and severity determination for a consistent identification of people with sarcopenia or its risk, and simple, specific cut-off points for measures that identify and characterise sarcopenia.

While EWSGOP2's algorithm for sarcopenia screening has undeniably increased awareness of this condition, its categorical nature does not allow to automatically obtain an outcome that quantifies the degree of sarcopenia. Conversely, a scalar, quantitative measure would help identify individuals who do not qualify as sarcopenic despite displaying subclinical alterations that potentially deserve preventive strategies. Such marker would also allow to determine whether interventions aimed at mitigating sarcopenia are truly effective.

This cross-sectional study was planned to develop, in healthy middle-aged and older adults, a novel predictor of sarcopenia based on the motor-functional and anthropometric tests derived from EWGSOP2, which were the primary outcome measures. Participants were tested for body composition, physical performance, blood biomarkers, and risk scores for major healthy issues. Muscle Age Acceleration (MAA) was modelled with Elastic Net regression to extract EWGSOP test mostly contributing to the musculoskeletal ageing trajectory. According to MAA, three trajectories were identified: accelerated agers displayed higher risk for sarcopenia (19%), as compared to normal (9%) and decelerated (2%), paralleled by significant subclinical alterations of blood chemistry markers in accelerated agers.

Link: https://doi.org/10.18632/aging.206269

Age-related deafness is the consequence of some mix of (a) a loss of sensory hair cells of the inner ear, and (b) a loss of connections between these cells and the brain. One approach to treating this problem is to introduce new cells, either via transplantation or via inducing the generation of replacement cells in situ. Both approaches have their challenges, and both would benefit from a greater detail-level understanding of how exactly hair cells develop and become dysfunction. Thus researchers are working towards the production of hair cells on demand. While the initial application of this capability will involve running in vitro studies in research facilities, ultimately it may lead to cell therapies in which patient-matched hair cells are introduced into the inner ear to replace those that are damaged or lost.

Hearing loss affects hundreds of millions of people worldwide and often results from the loss of sensory hair cells in the inner ear - specialised cells that convert sound vibrations into electrical signals for the brain. These hair cells can be damaged by exposure to loud noise, certain medications or infections, and aging. In humans, once these hair cells die, they do not regenerate, meaning hearing loss is often irreversible. Research into how this could be countered has been limited by the inaccessibility of real human hair cells and the inefficiency of lab-based models.

In earlier work, the authors showed that mouse cells can be reprogrammed into those that are more like hair cells using four transcription factors: Six1, Atoh1, Pou4f3, and Gfi1, collectively referred to as SAPG. However, this method relies on viral delivery, which poses challenges for consistency and scalability. Instead, researchers engineered a stable human stem-cell line carrying a doxycycline-inducible version of the SAPG transcription factors. By adding the antibiotic doxycycline to the culture, this method allowed precise control of the reprogramming process. To track when the cells began to take on hair cell characteristics, they included a fluorescent reporter gene that switched on as reprogramming progressed.

When doxycycline was added, the team observed the first signs of reprogramming within three days. By day seven, around 35-40% of the cells expressed key hair cell gene markers such as MYO7A, MYO6, and POU4F3. This represented a more than 19-fold increase in efficiency compared to their previous virus-based approach, in half the time.

Link: https://elifesciences.org/for-the-press/c7eb8bb4/researchers-develop-new-approach-for-generating-inner-ear-hair-cells

Most people who arrive an a hospital in the wake of a first heart attack or stroke due to rupture of an unstable atherosclerotic plaque in the arteries do not have elevated LDL cholesterol. This is cholesterol attached to LDL particles, coming from the liver for delivery to the rest of the body. While high LDL cholesterol is recognized as, on balance across a population, contributing to the pace at which plaque grows, it is not the whole story. It is probably not the most important part of the story either, given than the well-established therapies to lower LDL cholesterol do not reliably regress plaque, and only slow its growth somewhat.

Researchers have in recent years searched for and uncovered a broad range of other mechanisms that contribute to plaque growth in animal models of atherosclerosis. This has led to various markers, such as circulating Lp(a), that correlate with atherosclerotic plaque and consequent cardiovascular disease in human study populations. A number of biotech and pharmaceutical companies are working on the development of therapies to target these mechanisms, near all of which only produce a slowing of plaque growth when tested in animal models.

In today's open access paper, researchers propose a novel way in which the gut microbiome can contribute to the creation and growth of atherosclerotic plaque in blood vessel walls. They point to a metabolite generated by microbes in the gut, imidazole propionate, and demonstrate that it can be used to promote plaque growth in animal models of atherosclerosis. Like all mechanisms promoting plaque growth, this appears to negatively affect the macrophage cells that are drawn to a plaque and attempt to repair the damage, ensuring that more of these cells are incapacitated and killed by the toxic plaque environment.

Imidazole propionate is a driver and therapeutic target in atherosclerosis

Atherosclerosis is the main underlying cause of cardiovascular diseases. Its prevention is based on the detection and treatment of traditional cardiovascular risk factors. However, individuals at risk for early vascular disease often remain unidentified. Recent research has identified new molecules in the pathophysiology of atherosclerosis, highlighting the need for alternative disease biomarkers and therapeutic targets to improve early diagnosis and therapy efficacy.

Here, we observed that imidazole propionate (ImP), produced by microorganisms, is associated with the extent of atherosclerosis in mice and in two independent human cohorts. Furthermore, ImP administration to atherosclerosis-prone mice fed with chow diet was sufficient to induce atherosclerosis without altering the lipid profile, and was linked to activation of both systemic and local innate and adaptive immunity and inflammation.

Specifically, we found that ImP caused atherosclerosis through the imidazoline-1 receptor (I1R, also known as nischarin) in myeloid cells. Blocking this ImP-I1R axis inhibited the development of atherosclerosis induced by ImP or high-cholesterol diet in mice. Identification of the strong association of ImP with active atherosclerosis and the contribution of the ImP-I1R axis to disease progression opens new avenues for improving the early diagnosis and personalized therapy of atherosclerosis.

The practice of calorie restriction, eating as much as 40% fewer calories while still obtaining sufficient micronutrients, is well demonstrated to slow aging in many species, though to a greater degree in short-lived species than in long-lived species. Human studies have demonstrated improved long-term health and measures of aging to result from even mild calorie restriction, closer to 10% fewer calories consumed. Calorie restriction alters near everything in cellular biochemistry throughout the body, making it an unending project for researchers to map and catalog its effects. The consensus is that calorie restriction largely produces its benefits via improved operation of autophagy, but there is so much biochemistry to wade through that it is reasonable to think that more of significance is waiting there to be discovered.

Aging induces functional declines in the mammalian brain, increasing its vulnerability to cognitive impairments and neurodegenerative disorders. Among various interventions to slow the aging process, caloric restriction (CR) has consistently demonstrated the ability to extend lifespan and enhance brain function across different species. Yet the precise molecular and cellular mechanisms by which CR benefits the aging brain remain elusive, especially at region-specific and cell type-specific resolution.

In this study, we performed spatiotemporal profiling of mouse brains to elucidate the detailed mechanisms driving the anti-aging effects of CR. Utilizing highly scalable single-nucleus genomics and spatial transcriptomics platforms, we profiled over 500,000 cells from 36 mouse brains across three age groups and conducted spatial transcriptomic analysis on twelve brain sections from aged mice under CR and control conditions. This comprehensive approach allowed us to explore the impact of CR on over 300 cellular states and assess region-specific molecular alterations.

Our findings reveal that CR effectively modulates key aging-associated changes, notably by delaying the expansion of inflammatory cell populations and preserving cells critical to the neurovascular system and myelination pathways. Moreover, CR significantly reduced the expression of aging-associated genes involved in oxidative stress, unfolded protein stress, and DNA damage stress across various cell types and regions. A notable reduction in senescence-associated genes and restoration of circadian rhythm genes were observed, particularly in ventricles and white matter. Furthermore, CR exhibited region-specific restoration in genes linked to cognitive function and myelin maintenance, underscoring its targeted effects on brain aging.

In summary, the integration of single-nucleus and spatial genomics provides a novel framework for understanding the complex effects of anti-aging interventions at the cellular and molecular levels, offering potential therapeutic targets for aging and neurodegenerative diseases.

Link: https://doi.org/10.1101/2025.05.04.652093

Chimeric antigen receptors are artificial structures added to immune cells such as T cells in order to direct the cells to aggressively attack a cancer. Such CAR-T therapies have proven effective against leukemia, and researchers are working on making them effective for solid tumors as well. At present delivering such a therapy is a slow and onerous process, requiring cells to be harvested from a patient, engineered, expanded in culture, and then injected. This is very expensive. A potentially cheaper approach is to use gene therapy tools to engineer some fraction of circulating T cells in situ in the patient. Researchers have been working on this for a while now, and here find a proof of principle demonstration carried out in mice.

CAR-T cells are made in the laboratory by tinkering with the genetic instructions in immune cells called T cells that are removed from a patient. In particular, the T cells are tweaked to recognize and bind to a protein called CD19 that is abundant on other immune cells called B cells. Many blood cell cancers, including some types of lymphomas and leukemias, develop due to uncontrolled B cell growth.

In this study, researchers used tiny, fat-soluble bubbles called lipid nanoparticles to package messenger RNA (mRNA) molecules encoding a receptor protein that binds to CD19 as well as a modified version of another protein that is highly expressed in prostate cancer cells but is rare in other tissue. This second protein allows the researchers to trace the generation and movement of the recipient cells noninvasively using a common medical imaging technique called positron emission tomography. Finally, they designed the surface of the nanoparticles to include an antibody that binds to a protein called CD5 that is primarily found on T cells. Once the nanoparticle latches onto the T cell, it is engulfed, the lipid bubble disintegrates and the mRNA molecules are released into the interior of the cell to be made into proteins.

When researchers injected the nanoparticles into mice with a type of B cell lymphoma, they were able to track the generation of the CAR-T cells in the animals - or "in situ" - and see that they traveled to the location of the animals' tumors. The in situ method generated about 3 million CAR-T cells per animal, which is similar to the cell numbers infused into patients undergoing conventional CAR-T therapy. Importantly, the newly generated CAR-T cells were efficient cancer killers; six out of eight mice with lymphoma were tumor-free 60 days after treatment began, and tumor growth in the remaining two was controlled.

Link: https://med.stanford.edu/news/all-news/2025/07/in-situ-t-cell.html

In recent years, researchers have turned their attention to the long-term health and aging of the few remaining populations of hunter-gatherers, such as the Tsimane that are the subject of today's open access paper. The lifestyle led by these individuals is characterized by high levels of exercise and a diet low in all of the usual line items that we know are not that good for us, such as processed sugars. Hunter-gatherer populations exhibit dramatically lower levels of cardiovascular disease and dysfunction than is the case for people in wealthier parts of the world. Their existence is a mirror, held up to show the rest of us just how much harm can be done by a sedentary life and a bad diet.

The Tsimane have been the subject of a range of studies of late. They exhibit slower onset of neurodegeneration, minimal degrees of atrial fibrillation, little hypertension and obesity, superior metabolic health, little to no increase in systemic inflammation with age, and so forth. We should all be so lucky - but there is no luck involved here, this is all the outcome of a particular lifestyle. Today's open access paper produces the expected data on arterial stiffness to accompany other published work on the cardiovascular health of the Tsimane; there are a few eye-opening numbers in that data set. The few metabolically unhealthy Tsimane are outperforming the healthy US populations in the metric of arterial stiffness, for example. We might take that as a measure of the degree to which a sedentary lifestyle is actively harmful to long-term health.

Arterial Stiffness in Heart-Healthy Indigenous Tsimane Forager-Horticulturalists

We conducted a cross-sectional study comparing 3 arterial stiffness metrics among Tsimane forager-horticulturalists with 2 representative US cohorts. Tsimane participants exhibited superior arterial health compared with US cohorts, with higher elasticity and lower stiffness. Stiffness measures were 47.3% and 35.7% better than US cohort participants by age 40 years, respectively, and differences remained sustained throughout adulthood. The carotid-femoral pulse wave velocity in Tsimane participants was 33.9% lower and showed a minimal age-related increase, with carotid-femoral pulse wave velocity only higher by age 70+. Tsimane participants with ≥2 comorbidities (hypertension, obesity, and diabetes) had ≈25% higher arterial elasticity than healthy Americans with no comorbidities.

The disparities in arterial stiffness between Tsimane and urbanized cohorts can be attributed to their subsistence-oriented lifestyle and environmental context, which align with key metrics in cardiovascular health promotion, such as a lean diet, high physical activity, and consistently low blood glucose and blood pressure. The combined effect of the aforementioned factors might promote optimal vascular health from early life and contribute to sustained cardiovascular well-being. In fact, Tsimane individuals lifestyle exemplifies many of the core principles outlined in the American Heart Association's Life's Essential 8 metrics, a framework that emphasizes proactive cardiovascular health improvement and preservation across the life course. Based on that framework, the primary distinctions between Tsimane and their urbanized peers are diet and physical activity, the 2 criteria in which US adults scored the lowest among all 8 cardiovascular health metrics between 2013 and 2020.

Tsimane individuals typically engage in high levels of low- and moderate-intensity activities year-round, despite seasonality of production tasks. Men and women typically engage in physical activity for 6 to 7 hours/day and 4 to 6 hours/day, respectively, averaging ≈17,000 steps daily. Activity levels remain relatively high throughout adulthood, though decline at late ages. Studies have reported an attenuated age-related arterial stiffness increase in physically active populations. A recent meta-analysis found that sustained aerobic exercise interventions reduce arterial stiffness, particularly measures of pulse wave velocity. The underlying mechanism involves improved vessel wall homeostasis through a combination of pathways, including decreased vascular oxidative stress, increased endothelial nitric oxide bioavailability, and upregulation of vascular growth factors. Moreover, the diet of Tsimane individuals is best characterized as high-carbohydrate, fiber-rich, and low-fat, with a high intake of micronutrients, such as potassium and magnesium. This dietary pattern, centered on cultigens, freshwater fish, and wild game, closely resembles the recommended heart-healthy diet, with an emphasis on healthy fats, dietary fiber, whole grains, healthy-sourced proteins, and limited refined sugars and processed foods.

Exercise is demonstrably beneficial, but does little to lengthen maximum life span in mice. It does compress morbidity, in the sense of extending the period of healthy life and increasing median life span without increasing maximum life span. The study noted here is an example of this sort of outcome. Mice were put through a program of exercise in early life, roughly equivalent of teenage human years through to mid-20s, and were shown to have a longer healthspan but not a longer lifespan. This might suggest that exercise affects many of the forms of damage and dysfunction that cause aging, but that there are some processes it has little effect on. It is the consequences of the unaffected processes that eventually produce mortality, regardless of a slowing of other aspects of aging.

It is well-known that physical activity exerts health benefits, yet the potential impacts of early-life regular exercise on later-life health and lifespan remains poorly understood. Here, we demonstrate that 3 months of early-life exercise in mice results in lasting health benefits, extending healthspan, but not lifespan. C57BL/6J mice underwent swimming exercise from 1 to 4 months of age, followed by detraining for the remainder of their lives.

While early-life exercise did not extend the overall lifespan, it significantly improved healthspan in both male and female mice, as evidenced by enhanced systemic metabolism, cardiovascular function, and muscle strength, as well as reduced systemic inflammation and frailty in aged mice. Multiple-organ transcriptome analyses identified enhanced fatty acid metabolism in skeletal muscles as a major feature in aged mice that underwent early-life exercise. These findings reveal the enduring long-term health benefits of early-life exercise, highlighting its pivotal role in improving healthspan.

Link: https://doi.org/10.1038/s41467-025-61443-4

Researchers here present an interesting approach to epigenetic clock development. Based on a large set of training data, the researchers used epigenetic data to predict clinical biomarkers, in this case circulating proteins measured in a blood sample that are relevant to the chronic inflammation of aging, an assessment of the inflammatory state of the immune system. Then the researchers used the predicted biomarkers of inflammation as a basis for predicting age. This approach to clock development has the advantage of producing results that are more explicable than a direct prediction of age from epigenetic data, as one can theorize more readily about the role of specific inflammatory markers than is the case for specific epigenetic changes. We will likely see more of these two-stage clocks developed in the future.

We introduce EpInflammAge, a novel deep learning framework that bridges the epigenetic and inflammatory aspects of aging. Our results demonstrate three key advances: (1) successful prediction of inflammatory markers from DNA methylation data, (2) accurate age estimation using synthetic inflammatory profiles, and (3) robust disease sensitivity across multiple pathological conditions

One of the primary objectives of this research was to integrate the two hallmarks of aging - namely, epigenetic modifications and immunosenescence. To this end, we conducted a simultaneous examination of DNA methylation data and levels of cytokines and chemokines. We developed models for estimating inflammatory marker levels from epigenetic profiles and subsequently evaluated their performance on a large cohort of healthy and diseased samples. As measuring inflammation is clinically significant, the developed model enables the acquisition of epigenetic data and the prediction of inflammatory biomarkers based on methylation. This development presents an opportunity to progress in the direction of evaluating inflammaging, which is characterized by low-grade inflammation associated with age and age-related diseases.

EpInflammAge achieves competitive performance metrics against 34 epigenetic clock models, including an overall mean absolute error of 7 years and a Pearson correlation coefficient of 0.85 in healthy controls, while demonstrating robust sensitivity across multiple disease categories. Explainable AI revealed the contribution of each feature to the age prediction. The sensitivity to multiple diseases due to combining inflammatory and epigenetic profiles is promising for both research and clinical applications. EpInflammAge is released as an easy-to-use web tool that generates the age estimates and levels of inflammatory parameters for methylation data, with the detailed report on the contribution of input variables to the model output for each sample.

Link: https://doi.org/10.3390/ijms26136284

Life on earth evolved in an environment of gravity; ubiquitous, always there. Take it away, and cellular biochemistry can run awry. Microgravity exposure in higher animals, studied in astronauts who have spent prolonged periods of time in orbit, is a harmful exercise. The longer the exposure, the worse the harms. Many of the changes that microgravity exposure causes to cell and tissue function can be viewed as analogous to those produced by aging. That said, it is important to recognize that microgravity exposure is not aging, just as progeroid conditions resulting from DNA repair deficiency are not aging, the unpleasant dysfunction of type 2 diabetes is not aging, and obesity is not aging. These line items involve the accumulation of forms of damage and dysfunction, but each is a different mix, and the details matter when it comes to trying to draw conclusions about process A when studying process B.

Still, researchers work in an environment that is very sensitive to expenditure of funds and time. Models of degeneration that are at least somewhat similar to aging, and that can be established rapidly, are favored over the old fashioned approach of waiting for animals and people to get old, even though the relevance of the results might be questionable. While one might not think of putting materials into orbit to experience microgravity as a cost-effective approach, it can be when someone else is paying for the necessary facilities in orbit and lift capacity to get there.

An interesting point is made by the authors of today's open access paper about the principle way in which microgravity exposure differs from other models that might resemble aging enough to be interesting, which is that people recover from microgravity exposure, and that exposure can be turned on and off quickly. This is an easier alteration of circumstances for scientists to engineer in human subjects than, say, removal of type 2 diabetes or obesity. One could argue that there may well be interesting biochemistry to be found somewhere in this reversal of dysfunction. Will it be in any way applicable to the production of therapies to treat aging? Without looking, that is impossible to say.

Microgravity Therapy as Treatment for Decelerated Aging and Successful Longevity

Given the growing aging population, understanding the mechanisms driving the decline in bodily functions with age has become increasingly essential. Identifying strategies to slow down or even prevent these changes could enhance public health and extend longevity, while yielding significant economic benefits for society. This task is complicated by the long follow-up timeframes needed for such studies, even short-lived rodent models take about three years to observe lifespan changes, and studies in primates can last anywhere from 15 to 30 years. The need for a short-duration human aging model is challenging, and decades of research have not generated one. Recently, we proposed a model that may overcome these challenges.

Gravity plays a crucial role in shaping human physiology, and prolonged exposure to microgravity during space missions can lead to various pathologies that mirror age-related changes. Astronauts frequently experience significant bone density loss, muscle atrophy, cardiovascular deconditioning, immunological, cerebrovascular, cognitive alterations, and metabolic problems. These changes, observed in both aging populations and astronauts in microgravity, reveal striking similarities that highlight the potential of utilizing space as a model for accelerated aging research. In microgravity, aging-like processes are accelerated by up to ten times, occurring over days or weeks rather than years. This makes the space environment a unique model for studying aging in an accelerated format, offering insights that are otherwise unattainable on Earth.

Transcriptomic analyses of human cell lines exposed to both real and simulated microgravity have identified a panel of eleven candidate genes exhibiting consistent differential expression. Upregulated genes include CSGALNACT2, CSNK2A2, HIPK1, MBNL2, PHF21A, and RAP1A, which are involved in pathways such as glycosaminoglycan biosynthesis, chromatin remodeling, RNA splicing, and cytoskeletal organization. In contrast, down-regulated genes such as DNPH1, EXOSC5, L3MBTL2, LGALS3BP, and SPRYD4 reflect impairments in nucleotide metabolism, RNA degradation, chromatin compaction, and intercellular communication, processes that are frequently disrupted during aging. Similar transcriptional signatures have also been observed in human iPSC-derived cardiac progenitor cells cultured aboard the International Space Station, including upregulation of cell cycle regulators (CCND1, CCND2), the proliferation-associated growth factor (IGF2), and the cardiac differentiation marker (TBX3), accompanied by downregulation of extracellular matrix genes. These changes suggest a shift toward increased proliferation and structural remodeling.

Engineered human heart tissues exposed to long-term microgravity similarly displayed downregulation of contractile and calcium signaling genes, alongside increased expression of genes related to oxidative stress, mitochondrial dysfunction, and inflammation, consistent with aging-associated cardiac decline. Additional evidence from single-cell RNA sequencing of immune cells revealed altered expression of genes involved in cytoskeletal organization, IL-6 signaling, and sirtuin-regulated metabolic control, suggesting disruption of immune homeostasis and activation of inflammaging-related pathways. Collectively, these findings define a core set of microgravity-regulated genes in human cells whose altered expression mirrors aging-related molecular deterioration. Their functional roles in key cellular pathways highlight their potential as biomarkers of microgravity adaptation and as therapeutic targets for promoting resilience in aging tissues

Some species, such as salamanders and zebrafish, are capable of reactivating programs of embryonic development following injury in order to regrow limbs and even major portions of vital internal organs. Since mammals share the same ability to conduct embryonic development, it is hoped that all of the necessary biochemical machinery to also conduct complete regeneration of organs still exists in adult mammals, merely suppressed in some way. Researchers investigate the exceptional regeneration of species like zebrafish in search of controlling mechanisms that might be manipulated to turn on the same exceptional regeneration in humans and other mammals. It remains to be seen as to how long this will take, and whether the options will be as straightforward as hoped for.

Humans can't regenerate heart muscle damaged by disease, but scientists have long known that some animals, such as zebrafish, can. The heart is made up of many kinds of cells that comprise muscle, nerve, and blood vessel tissue. A portion of these heart cells - in zebrafish, around 12 to 15% - originate from a specific population of stem cells called neural crest cells. Humans have analogous neural crest cells that give rise to varied cell types in almost every organ of the body, ranging from the facial skeleton to the nervous system. For some reason, zebrafish and a few other animals retain the ability as adults to rebuild tissues derived from the neural crest - the jaw, skull and heart, for example - while humans have lost that ability. These animals are not merely repairing damaged tissue, however. In the heart, cells around an injury revert to an undifferentiated state and then go through development again to make new heart muscle, or cardiomyocytes.

In the newly reported research, the scientists used single-cell genomics to profile all the genes expressed by developing neural crest cells in zebrafish that will differentiate into heart muscle cells. They then pieced together the genes expressed after they snipped away about 20% of the fish's heart ventricle. This procedure seemed not to affect the fish, and after about 30 days their hearts were whole again. By knocking out specific genes with CRISPR, they identified a handful of genes that were essential to reactivation after injury, all of which are utilized during embryonic development to build the heart. One in particular, called egr1, seems to activate the circuit first and perhaps triggers the others, suggesting a potential role in regeneration. The researchers also identified the enhancers that turn on these genes. Enhancers are promising targets for CRISPR-based therapies, since they can be manipulated to dial up or down the expression of the gene.

Link: https://news.berkeley.edu/2025/07/09/repairing-the-heart-if-zebrafish-can-do-it-why-not-humans/

Studies of forms of brain cancer and other slow, progressive damage to specific regions of the brain have demonstrated that the information stored in at least some parts of the brain can move around. Undamaged parts of the brain can be repurposed in response to damage. This means that it is in principle possible to place new, functional tissue into some portions of the living brain and expect that tissue to become used and useful over time, a replacement for damaged tissue. Researchers are initially focused on the neocortex, one of the most plastic areas of the brain. The biggest challenge is to be able to engineer suitable neocortical tissue for transplantation, growing it from a patient's own cells.

The Advanced Research Projects Agency for Health (ARPA-H), an agency within the U.S. Department of Health and Human Services (HHS), today unveiled its groundbreaking Functional Repair of Neocortical Tissue (FRONT) program, a transformative initiative to restore brain function. The neocortex, the largest part of the brain, is critical for sensory perception, motor control, and decision-making. Damage to this area - due to conditions like stroke, traumatic injury, or neurodegeneration, such as Alzheimer's disease - has long led to irreversible damage, leaving individuals dependent on costly therapies or caregivers. The FRONT program aims to change that, using cutting-edge neurodevelopmental principles and stem cell technology to regenerate brain tissue and restore lost functions.

FRONT will work to develop a curative therapy for over 20 million U.S. adults suffering from chronic neocortical brain damage caused by stroke, neurodegeneration, and trauma, providing life-changing treatments for these individuals. The FRONT program spans five years, with strict performance metrics and a focus on preparing for human clinical trials. ARPA-H will solicit proposals under its Innovative Solutions Opening (ISO) in two key areas: graft tissue generation and engraftment procedures for functional brain recovery. ARPA-H encourages collaboration among experts across disciplines to meet the program's ambitious goals.

Link: https://arpa-h.gov/news-and-events/arpa-h-launches-program-restore-brain-function-and-return-patients-independence

The dominant view of the regulation of medicine within academia and government is more or less that (a) people should not have the right to choose their own risks and make their own mistakes, (b) the role of regulators is to remove as much risk as possible, and (c) that the high cost of medicine and slow pace of introduction of new drugs is a better problem to have than greater freedom for patients. This is the background against which one can find papers such as today's open access discussion of rapamycin and the state of its use as a means to improve late life health and modestly slow degenerative aging.

Rapamycin has long been approved for use as an immunosuppressive drug, but of late has attracted far more attention for its ability to upregulate autophagy, slow aging, and extend life in animal studies. This has led to a significant degree of off-label prescription of rapamycin by physicians. Physicians have the discretion to prescribe any approved drug for any use that is defensible, but this only happens when there is a body of work to suggest that the novel use could be safe and useful.

Thus rapamycin is in the nebulous state occupied by many drugs that are prescribed off-label: animal studies indicate that it could be used in a novel way at a novel dose, in this case to slow aging at lower doses than its established immunosuppressive use, but little to no concrete human data exists to confirm that new use. That data is unlikely to emerge any time soon because clinical trials are expensive and generic drugs cannot produce enough revenue to justify that cost. Meanwhile, a good fraction of academics and regulators are appalled by off-label use, as one might expect given their views on freedom, risk, and the purpose of regulators.

Rapamycin for longevity: the pros, the cons, and future perspectives

Rapamycin, an antibiotic discovered in the 1970s, has become a critical tool in biomedical research. Initially recognized for its potent antifungal and immunosuppressive properties, rapamycin has recently gained significant attention for anti-aging therapy and seizure treatment via mTOR pathway inhibition. The mechanistic target of the rapamycin (mTOR) pathway is an evolutionarily conserved metabolic signaling cascade that regulates cell division, growth, and survival. There is growing evidence that mTOR pathway activity accelerates aging and the development of age-related diseases including cancer, atherosclerosis, diabetes, and declining immune function. Therefore physicians and "biohackers" are using mTOR inhibition via rapamycin (and rapamycin analogs) off-label for prevention of age-related conditions despite not being widely recognized as a treatment by the broader clinical community.

As rapamycin gains popularity for its anti-aging potential, online longevity clinics have emerged offering access to the drug with minimal medical oversight. This semi-regulated availability raises ethical concerns regarding patient safety, misinformation, and the potential for serious harm. This is best illustrated by the widely publicized case of tech entrepreneur Bryan Johnson, who undertook an elaborate self-directed anti-aging regimen involving rapamycin, metformin, and over 100 daily supplements. Despite extensive physiological tracking, Johnson ultimately discontinued rapamycin and expressed regret over its use citing side effects such as elevated blood glucose, susceptibility to infection, and impaired healing. This case highlights the risks of bypassing peer-reviewed science in favor of anecdotal "biohacking" culture. Clinical literature has long documented rapamycin-associated toxicities that mirror the complaints reported by Johnson and others. The use of such a powerful immunosuppressant outside established indications, especially in otherwise healthy individuals, demands stronger ethical scrutiny and public education.

Lastly, while the FDA does not recognize aging as a disease, there is growing interest in approving therapeutics that enhance healthspan, or delay aging-related decline. However, FDA approvals are structured around specific, diagnosable indications, rather than generalized syndromes. Should rapamycin or related compounds demonstrate efficacy, they would be approved for specific indications (e.g., Alzheimer's) rather than aging per se under the current approval standards. Nonetheless, even within this evolving framework, it is important to note that most off-label prescribing-despite it being common clinical practice-rarely achieves FDA approval, as only about 30% of off-label prescribing is supported by adequate scientific evidence despite any clinically observed positive outcomes. These regulatory and evidentiary constraints must be considered when evaluating rapamycin's future clinical and research trajectory.

After a protein is created in the cell, it must be folded into the right conformation in order to function correctly. A complex set of mechanisms is focused on (a) achieving correct folding and (b) removing misfolded proteins when the process fails. Research into protein misfolding is weighted heavily to the consideration of the comparatively few proteins that form solid aggregates when misfolded, largely because this is an evident and measurable form of pathology that is demonstrably a cause of pathology in conditions such as Alzheimer's disease and the varied forms of amyloidosis. What about all of the other misfolded proteins, however, those that remain soluble? Researchers here point out that hundreds of different misfolded proteins can be found in the aged rat brain, and we might reasonably think that their collective role in neurodegeneration is significant.

Many studies have found that the proteostasis network, which functions to keep proteins properly folded, is impaired with age, suggesting that there may be many proteins that incur structural alterations with age. Here, we have used limited proteolysis mass spectrometry (LiP-MS) to identify proteins that vary in structure in the hippocampus of aged rats with or without cognitive impairment, which we have defined as CASC proteins.

We identified 215 CASC proteins in the CA1 hippocampal region. Research in aging, dementia, and neurodegenerative disease has long made a connection between these disease processes and protein misfolding; however, emphasis has historically been paid to proteins that form amyloids or other insoluble aggregates. We have focused on the soluble fraction of the hippocampal proteome and used a methodology that can sensitively detect subtle changes in protein structure. The results enable us to conclude that protein misfolding is perhaps a more pervasive feature in cognitive decline than previously appreciated and that many of these misfolded forms persist as soluble species.

This finding suggests that there may be previously unidentified avenues for potential therapeutic targets and diagnostic biomarkers for cognitive decline than the small subset of amyloid-forming proteins frequently studied. Of course, these interventions would need to be conformation specific, creating additional opportunities and challenges.

Link: https://doi.org/10.1126/sciadv.adt3778

Researchers here demonstrate that the GrimAge and GrimAge2 epigenetic clocks beat out other clocks while performing more or less equivalently to one another when it comes to predicting mortality in a novel study population. The higher a patient's epigenetic age relative to their chronological age, the higher the risk of future mortality. Epigenetic clock results are not actionable, however. Since researchers do not yet understand how the specific epigenetic marks incorporated into the clock algorithm correlate with mechanisms of age-related dysfunction and disease, they cannot describe why a result is bad or good, nor inform any action taken in response. So at the present time it doesn't matter what an epigentic clock result looks like - one should seek to improve one's health in the same ways regardless.

Epigenetic clocks have been widely applied to assess biological ageing, with Age Acceleration (AA) serving as a key metric linked to adverse health outcomes, including mortality. However, the comparative predictive value of AAs derived from different epigenetic clocks for mortality risk has not been systematically evaluated. In this retrospective cohort study based on 1,942 NHANES participants (median age 65 years; 944 women), we examined the associations between AAs from multiple epigenetic clocks and the risks of all-cause, cancer-specific, and cardiac mortality.

Restricted cubic spline models were used to assess the shape of these associations, and Cox proportional hazards regression was employed to quantify risk estimates. Model performance was compared using the Akaike Information Criterion (AIC) and concordance index (C-index).

Our findings revealed that only GrimAge AA and GrimAge2 AA demonstrated approximately linear and positive associations with all three mortality outcomes. Both were significantly associated with increased risks of death, and these associations were consistent across most subgroups. GrimAge and GrimAge2 AAs showed very similar performance in predicting all-cause, cancer, and cardiac mortality, with only small differences in AIC values and C-index scores. These findings suggest that both GrimAge and GrimAge2 are effective epigenetic biomarkers for mortality risk prediction and may be valuable tools in future ageing-related research.

Link: https://doi.org/10.1080/15592294.2025.2530618

Researchers here provide evidence for expression of the hormone ACBP to be detrimental, an accelerator of degenerative aging. Knocking down ACBP improves kidney and heart resilience in a number of circumstances, while circulating ACBP levels correlate with aspects of aging and age-related loss of function. At the present time therapies to reduce circulating levels of a given protein (such as monoclonal antibodies or forms of gene therapy targeted to the cells expressing the protein) are relatively expensive, though given a broadly beneficial use case one might imagine that costs will fall commensurate with the scale of use.

The tissue hormone acyl coenzyme A-binding protein (ACBP, encoded by the gene diazepam-binding inhibitor, DBI) has been implicated in various facets of pathological aging. Here, we show that ACBP plasma concentrations are elevated in (close-to-)centenarians (mean ± SD age 99.5 ± 4.5 y) commensurate with their health deterioration, correlating with a reduced glomerular filtration rate and a surge in senescence-associated cytokines. ACBP neutralization by means of a monoclonal antibody (mAb) improved health span in a strain of progeroid mice.

In a mouse model of chronic kidney injury induced by cisplatin, anti-ACBP mAb administration counteracted both histopathological and functional signs of organ failure. ACBP inhibition also prevented the senescence of tubular epithelial cells and glomerular podocytes induced by cisplatin or doxorubicin, respectively, as measurable by the immunohistochemical detection of cyclin-dependent kinase inhibitor 1A (CDKN1A, best known as p21). Senescence was also prevented by anti-ACBP monoclonal antibody treatment in additional mouse models of accelerated aging. This applied to liver damage induced by a combination of high-fat diet and carbon tetrachloride, where hepatic cells become senescent.

Moreover, administration of anti-ACBP monoclonal antibody prevented natural and doxorubicin-accelerated cardiomyocyte senescence. We performed single-nucleus RNA sequencing to study the transcriptome of hearts that had been exposed to doxorubicin and/or anti-ACBP in vivo. In cardiomyocytes, doxorubicin caused an anti-ACBP-reversible dysregulation of mRNAs coding for cardioprotective proteins involved in autophagy, fatty acid oxidation, mitochondrial homeostasis, and oxidative phosphorylation. Altogether, these findings plead in favor of a broad age-promoting effect of ACBP across different organ systems.

Link: https://doi.org/10.1073/pnas.2501584122

Psilocybin is a plant derived hallucinogen with a long history of use and shorter history of prohibition that suppressed earnest efforts to research its biochemistry. Efforts to guide psilocybin from the state of prohibition into a form of therapy for neurological conditions have been underway for some years now, however. Increased interest in this compound in research and funding circles, alongside the ability to run studies on psilocybin without censure, inevitably leads to new discoveries. In today's open access paper, for example, researchers provide evidence to suggest that psilocybin acts to slow aging.

Mice given monthly doses of psilocybin starting in late life exhibit at 10-15% increase in overall median life span. The researchers conducted cells studies that suggest that psilocybin touches on a few well-studied pathways known to influence mammalian life span, and reduces the burden of cellular senescence. Treated versus untreated mice exhibited a similar body weight, so the animal study results don't appear to be the result of inadvertent calorie restriction. All in all, this is quite interesting, but a great deal more work is needed in order to dig into the mechanisms involved. Additionally, one should bear in mind that most mechanisms shown to slow aging have much larger effects in short-lived species than in long-lived species such as our own.

Psilocybin treatment extends cellular lifespan and improves survival of aged mice

To date, more than 150 clinical studies with psilocybin have been completed or are ongoing for various clinical indications, including psychiatric (anxiety, depression, addiction), neurodegenerative (Alzheimer's), pain, and more. Human studies have demonstrated that a single-dose of psilocybin can improve debilitating physical and psychological symptoms - with durable effects (up to ~5 years). Despite considerable clinical evidence supporting the therapeutic benefits of psilocybin, the molecular mechanisms responsible for these impacts remain enigmatic. Studies with psilocybin have predominantly focused on neurological impacts and/or behavioral outcomes; few studies have evaluated alternative or systemic mechanisms which may also contribute to its beneficial effects.

The "psilocybin-telomere hypothesis" postulates that psilocybin interventions may quantifiably impact telomere length, which offers a potential explanation for its efficacy across a wide range of clinical indications. This hypothesis is based on a large corpus of studies linking mental health to biological aging markers. However, no prior studies have experimentally investigated the direct impact of psilocybin on biological aging.

To evaluate the impact of psilocybin on cellular aging, we employed an in vitro model of replicative senescence. Cells were serially passaged with media containing psilocin or vehicle until they reached replicative senescence. Psilocin treatment (10 μM) resulted in a 29% extension of cellular lifespan. Results were more striking using a higher dose of psilocin in the same cell type (100 μM treatment led to a 57% extension in cellular lifespan). Results were more striking using a higher dose of psilocin in the same cell type (100 μM treatment led to a 57% extension in cellular lifespan. Telomere length was preserved in psilocin-treated age-matched cells. This data suggest that psilocin impacts signaling pathways associated with cellular aging.

To evaluate the impact of psilocybin on longevity in vivo, aged (19 month) female mice were treated with vehicle or psilocybin once/month for 10 months. Mice were initially given a low-dose (5 mg/kg) for the first treatment followed monthly high-dose (15 mg/kg) treatment for a total of 10 treatments. We elected to utilize 19-month old mice, which is roughly equivalent to 60-65 human years, in order to evaluate its therapeutic potential as a clinically-relevant anti-aging intervention. Notably, psilocybin treated mice demonstrated significantly higher survival (80%), compared to vehicle (50%). Although not quantitatively measured, psilocybin-treated mice exhibited phenotypic improvements in overall fur quality, including hair growth and reductions in white hair compared to vehicle-treated mice. In summary, we provide the first experimental evidence demonstrating that psilocybin treatment can enhance survival in aged mice.

Senescent cells generate inflammatory signaling that is disruptive to tissue structure and function when sustained for the long term. The lingering presence of senescent cells is considered a driving mechanism for many inflammatory conditions, including intervertebral disc degeneration. Here, researchers demonstrate in cell models that recombinant PDGF can be used to suppress the markers of the presence of cellular senescence, though it remains to be seen as to whether it achieves this outcome by destroying senescent cells, reprogramming them, or preventing their creation.

Low back pain (LBP), ranked as the first cause of years lived with disability, is a prevalent condition. Although the etiology of LBP is multifactorial, a major contributor of LBP is intervertebral disc (IVD) degeneration. The IVD consists of three compartments: the gelatinous nucleus pulposus (NP), fibrous annulus fibrosus (AF), and cartilaginous endplate.

Cellular senescence, triggered by normal cells in response to various intrinsic and extrinsic stressors, is a fundamental mechanism underlying age-related chronic diseases. Senescent cells are featured by irreversible growth arrest and acquire a senescent-associated secretory phenotype (SASP) and the secretion of pro-inflammatory cytokines, chemokines, and tissue-damaging proteases. In the IVD, it has been well established that the number of senescent cells increases with aging and IVD degeneration.

Previous studies have highlighted that platelet-derived growth factor (PDGF) mitigated IVD degeneration through anti-apoptosis, anti-inflammation, and pro-anabolism. However, its impact on IVD cell senescence remains elusive. PDGF is a major constituent of platelet rich plasma (PRP), which is widely used in the clinical setting for tissue regeneration and repair. It can be made of a homodimer of A, B, C, and D polypeptide chains, or an AB heterodimer. Among these, PDGF-AB and -BB are the predominant forms in PRPs. In this study, human NP and AF cells derived from aged, degenerated IVDs were treated with recombinant human (rh) PDGF-AB/BB for 5 days and changes of transcriptome profiling were examined through mRNA sequencing.

PDGF-AB/BB treatment resulted in downregulation of gene clusters related to neurogenesis and response to mechanical stimulus in AF cells while the downregulated genes in NP cells were mainly associated with metabolic pathways. In both NP and AF cells, PDGF-AB and BB treatment upregulated the expression of genes involved in cell cycle regulation, mesenchymal cell differentiation, and response to reduced oxygen levels, while downregulating the expression of genes related to the SASP, including oxidative stress, reactive oxygen species (ROS), and mitochondrial dysfunction. The rhPDGF-AB/BB treatment mitigated the senescence progression through increased cell population in the S phase, reduced SA-β-Gal activity, and decreased expression of senescence related regulators including P21, P16, IL6, and NF-κB. Our findings reveal a novel anti-senescence role of PDGF in the IVD, making it a promising potential candidate to delay aging-induced IVD degeneration.

Link: https://doi.org/10.7554/eLife.103073.2

The evidence is compelling for the age-related accumulation of senescent cells to be an important driving mechanism of degenerative conditions in bone tissue. As for many other age-related conditions, animal study data suggests that clearance of senescent cells via the use of senolytic therapies is a promising form of treatment for age-related dysfunction in bone tissue. Human data is arriving only slowly, and initially only in small clinical trials more focused on safety than efficacy. Few trials are being conducted for the first generation, low-cost senolytics such as the dasatinib and quercetin combination, because there is no financial incentive for the industry to pay for this work, while the clinical development of novel senolytics is proceeding at the usual glacial pace.

Cellular senescence and other age-related mechanisms synergistically lead to impaired bone cell function, facilitating the onset and progression of bone diseases, such as osteoporosis (OP), intervertebral disc degeneration (IVDD), and osteoarthritis (OA). Cellular senescence is a particular cellular state characterized by irreversible arrest of the cell cycle and the emergence of a distinctive senescence-associated secretory phenotype (SASP), which is one of the key mechanisms in the development and progression of skeletal diseases. In addition, other age-related mechanisms occur in the skeletal system that synergistically contribute to the development of bone diseases. For example, the impaired intercellular crosstalk leads to an abnormal accumulation of senescence phenotypes in the bone marrow, the generation of a disturbed microenvironment promotes senescence in the skeletal system.

The elderly population has a high prevalence of age-related bone diseases. Particularly in elderly individuals (aged 65 and above), age-related bone diseases represent the leading cause of disability worldwide. The associated pain and limited mobility lead to a decrease in quality of life, posing a significant healthcare burden to the government. Prospects for the development of drugs targeting skeletal aging diseases are currently not optimistic, largely owing to a lack of understanding of the cellular senescence and other age-related mechanisms that lead to bone dysfunction during aging. In this review, we summarize the current understanding of cellular senescence and other age-related mechanisms in the pathogenesis of bone diseases, highlighting the diversity of the mechanisms involved in cellular senescence within different skeletal aging microenvironments. Moreover, we provide an overview of therapeutic approaches involving selective elimination or the reversion of cellular senescence.

Link: https://doi.org/10.1038/s41413-025-00448-7

The neurons of the brain form intricate, shifting networks of synaptic connections. Synapses are constantly created and destroyed in regions important to memory and learning, and supporting cell populations of the brain aid in this process. Microglia, for example, are innate immune cells of the central nervous system, analogous to macrophages elsewhere in the body. Ingesting and destroying unwanted synapses is one of the tasks undertaken by this cell population. In recent years, researchers have focused on dysfunction in microglia as an important contribution to pathology in inflammatory neurodegenerative conditions. Microglia become more inflammatory, change their behavior in other ways, and a fraction of these cells become senescent. Senescent cells cease to replicate, further alter their behavior, and generate a potent mix of pro-inflammatory and pro-growth signaling.

In today's open access paper, researchers investigate how senescent microglia might contribute to the known pathologies observed in inflammatory neurodegenerative conditions. The scientists demonstrate in mice that the presence of senescent microglia causes an increased pace of destruction of synapses. Some destruction is necessary to adjust neural networks, but too much destruction causes cognitive dysfunction, an outcome characteristic of brain inflammation. It is possible to clear microglia generally, using CSF1R inhibitors, or selectively destroy only senescent cells in the brain using some of the first generation senolytics - the dasatinib and quercetin combination passes the blood-brain barrier. This approach to treatment will likely be beneficial, but progress towards clinical use in this context is slow.

Senescent Microglia Mediate Neuroinflammation-Induced Cognitive Dysfunction by Selective Elimination of Excitatory Synapses in the Hippocampal CA1

Microglia-mediated neuroinflammation has been shown to exert an important effect on the progression of a growing number of neurodegenerative disorders. Prolonged exposure to detrimental stimuli leads to a state of progressive activation and aging-related features in microglia (also termed as senescent microglia). However, the mechanisms by which senescent microglia contribute to neuroinflammation-induced cognitive dysfunction remain to be elucidated.

Here, we developed a mouse model of neuroinflammation induced by lipopolysaccharides at 0.5 mg/kg for 7 consecutive days. To evaluate cognitive function, C57BL/6J mice were employed and subjected to a series of behavioral assessments, including the open field, Y-maze, and novel object recognition tests. Employing single-cell RNA sequencing technology, we have delved into the differential expressions of RNA within microglia. Furthermore, to investigate anatomic and physiological alterations of pyramidal neurons, we utilized Golgi staining and whole-cell patch-clamp recordings, respectively. Validation of our results in protein expression was performed using western blotting and immunofluorescence.

We specifically identified senescent microglia with a high expression of p16INK4a and observed that microglia in the hippocampal CA1 region of the model exhibited signatures of elevated phagocytosis and senescence. A senolytic by ABT-737 treatment alleviated the production of senescence-associated secretory phenotypes, the accumulation of senescent microglia, and the microglial hyperphagocytosis of excitatory synapses following LPS exposures. This treatment also restored reduced excitatory synaptic transmission, impaired long-term potentiation, and cognitive function in the model. These results indicate that reducing senescent microglia may potentially serve as a therapeutic approach to prevent neuroinflammation-related cognitive dysfunction.

A great deal of funding and effort goes into attempts to quantify the effects of lifestyle choices on long-term health, incidence of disease, and age-related mortality. Perhaps more than is useful, given what we know about the limits of the possible. Exercise improves the quality of later life, but you can't exercise your way out of being physically aged and ultimately dying from age-related disease. Animal studies demonstrate that some forms of treatment, such as senolytics, can achieve degrees of delay or reversal of aspects of aging beyond that of any lifestyle choice. Research attention might be better focused on that sort of exploration. Further, one might argue that more data on the benefits of a better lifestyle is not actionable: it doesn't instruct us to do anything that we didn't already know that we should be doing. Still, today's open access paper is representative of a sizable body of work and ongoing effort on the part of the scientific community.

The American Heart Association introduced Life's Essential 8 (LE8) as a comprehensive set of eight metrics that reflect health behaviours that support cardiovascular health (CVH), with the aim to help older individuals maintain CVH and live longer and healthier. These eight measures are categorized into two major areas: health behaviours (eating healthier foods, being more active, quitting tobacco, getting healthy sleep) and health factors (managing weight, controlling cholesterol, managing blood glucose, managing blood pressure). Beyond its association with CVH, LE8 is increasingly recognized for its impact on neurological health. Recent studies linked higher LE8 scores with neuroimaging markers of better brain health.

This cross-sectional study utilized data from the UK Biobank. Regional fractional anisotropy measures from diffusion tensor imaging (DTI) data were used to predict white matter brain age via random forest regression. The white matter brain age gap (BAG) was calculated by subtracting chronological age from predicted brain age. As compared to other neuroimaging markers like brain volume and white matter hyperintensities, white matter BAG is more sensitive to early and subtle change in WM integrity. The analysis included 18,817 participants (mean age 55.45). Higher LE8 scores were associated with a lower white matter BAG, indicating delayed brain ageing. The effect was more pronounced in non-APOE4 carriers (124 days younger per 10-point increase) compared to APOE4 carriers (84 days younger per 10-point increase). Potential interaction between APOE4 and LE8 on brain ageing was observed for some age and sex groups but with only borderline significance, further investigation in larger and more targeted studies is needed to validate the finding.

Link: https://doi.org/10.1016/j.ebiom.2025.105723

The STING protein is a point of convergence for a range of molecular sensors in a cell that detect damage or infection. Triggering STING activity produces an inflammatory response. Unfortunately, cell dysfunctions characteristic of aging produce issues such as the escape of fragments of mitochondrial and nuclear DNA into the cell cytosol, where they trigger sensors evolved to detect infectious agents, and thus activate STING. This contributes to the chronic inflammation of aging. For this and other reasons, researchers are considering STING inhibition as a potential form of therapy for a range of inflammatory age-related conditions. This approach has the obvious downside of also inhibiting necessary, short-term inflammatory responses, just like existing immunosuppressive therapies - but as researchers note here, STING inhibition may also produce other, less obvious harmful side effects.

The Stimulator of Interferon Genes (STING) pathway is pivotal in innate immunity, facilitating the detection of cytosolic DNA and initiating type I interferon-dependent responses. In addition to its immunological roles, STING has been increasingly associated with metabolic regulation, since research indicates that its inhibition can diminish inflammation, lipid accumulation, and tissue damage in obesity and other metabolic disorders. The findings have prompted the suggestion of STING inhibition as a viable treatment approach for metabolic illness. Nonetheless, the physiological function of STING in lipid homeostasis under normal settings remains largely unexplored, as does the impact of its absence on metabolism throughout various life stages in the absence of disease. This information deficit is crucial, particularly in light of the increasing interest in the long-term pharmacological suppression of STING.

o examine the function of STING in lipid metabolism during physiological, non-pathological conditions throughout the lifespan, we assessed wild type (WT) and STING knockout (STINGKO) mice at various ages and discovered that STING deficiency results in a consistent increase in body weight, independent of alterations in locomotor activity or food consumption. STINGKO mice exhibited markedly increased circulation levels of triglycerides and total cholesterol. Histological and morphological analysis demonstrated augmented fat accumulation in adipose and hepatic tissues, despite the lack of nutritional or genetic metabolic stress. These findings indicate a crucial function for STING in the control of lipid homeostasis across the lifespan, and caution against the prolonged use of STING inhibitors, as chronic STING suppression may lead to detrimental metabolic effects.

Link: https://doi.org/10.1186/s40659-025-00624-3

Any life scientist who has written a meta-analysis or systematic review of preclinical or clinical studies is likely capable of complaining at length and in detail about the lack of standardization, the myriad ways in which small differences in study design can sabotage any attempt at comparison, the critical details missing from published study methods, the misleading interpretations and summaries observed in the abstracts of a sizable minority of papers, and so forth. From some perspectives the literature is a mess, as you might expect when thousands of people with little incentive to conform to any one viewpoint set forth to pursue their own ideas about how to run a study.

Paper-length complaints about this situation can be found in the literature. You might recall a recent discussion of the harms done by non-standard controls in life span studies, for example. In today's preprint, researchers work through a database of preclinical studies in order and outline all of the problems that they encountered in trying to build any sort of broader body of understanding from a field in which every scientific group takes a different approach when it comes to assessing the effects of interventions on aging. Beyond standardization, rigor is clearly also an issue.

Reporting quality, effect sizes, and biases for aging interventions: a methodological appraisal of the DrugAge database

There is increasing interest in interventions targeting the aging process. The "geroscience hypothesis" posits that a shared pathophysiology of aging shapes most chronic diseases and interventions targeting aging will confer larger health benefits than those targeting any individual disease. Research into such anti-aging interventions has grown substantially, including trials repurposing commonly used drugs such as metformin. Given the possible substantial health benefits of slowing aging, the quality of preclinical studies in this area may be especially important. However, alongside the challenges translating results from one species to another, model organism studies have a long history of shortcomings and design flaws.

Here, we systematically analyzed 667 studies from DrugAge, a curated database of preclinical experiments investigating the effects of interventions on aging and lifespan in non-human animals. We aimed to evaluate the quality of reporting and methodological rigor of this literature, assess the distribution of observed effect sizes, and probe for the presence of diverse biases. We also investigated how these features changed over time. We found significant shortcomings in reporting of crucial design features such as randomization and blinding, as well as large variation in reporting quality and effects across species. Non-mammal findings typically did not translate to mammals. For 36 compounds with both mammal and non-mammal experiments, only eight showed a significant lifespan increase in both non-mammals and mammals; the number of experiments and sample sizes for these results were limited. These results are exploratory, and the numbers are small, but they raise hesitation about the direct translation of these results to more complex organisms such as humans.

Furthermore, previous work has suggested that some interventions may have different effects if started late in an organism's lifespan rather than early, and there is significant interest in discovering interventions that slow aging in older adults. In our assessment, we found that most preclinical experiments started the anti-aging intervention early in the organism's lifespan, often prior to sexual maturity, when key senescence mechanisms may lack relevance. Although we did not find a significant difference in the effect of interventions between early and late start experiments, the sparsity of late start results makes this comparison uncertain. Our study clearly highlights the paucity of late start experiments in the literature, a deficit of evidence that needs to be remedied.

In individuals with normal immune function, cytomegalovirus infection goes unnoticed and produces no immediately evident ill effects. It is very prevalent in the human population. By the time old age is reached, something like 90% of individuals test positive for persistent cytomegalovirus presence. Like other herpesviruses, cytomegalovirus cannot be cleared by the immune system and lurks in the body for the remainder of life. Unfortunately, it appears that the presence of cytomegalovirus does cause harm over time in older individuals, provoking the aged immune system into an ever greater focus on this one virus at the expense of retaining capacity to address other threats, one part of the bigger picture of age-related immune dysfunction. It is one that could perhaps be addressed by a suitably selective destruction of immune cells with specific molecular markers, using well established gene therapy tools, but little work has taken place on this sort of approach to therapy.

Cytomegalovirus (CMV) infection is one of the most common infections in humans, and CMV antigens are the major drivers of repetitive T-cell stimulation as a part of a well-adapted immune response in immunocompetent individuals. With higher age, the recurrent clonal expansion of CMV-specific T cells results in high frequencies of CMV-specific effector T cells. Further on, CMV seropositivity has been linked to an increased risk of developing cardiovascular diseases (CVD). Here we investigated the frequency and phenotype of CMV-specific T cells in the circulation of a population cohort of 650 individuals focusing on the age group over 60 years.

We add to previous knowledge by showing that the frequency of CMV-specific CD8+ T cells is associated with the total percentage and absolute counts of CD8+ and CD4+CD8+ double-positive T cells within leukocytes, and further with systolic blood pressure (SBP) and history of CVD. An investigation into the differentiation status of CMV-specific T cells revealed an association of higher age and increased frequencies of both effector memory (TEM) and CD27-expressing terminally differentiated effector re-expressing CD45RA (TEMRA) cells. In contrast, higher CMV-IgG titers were found to be associated with TEM and CD27- TEMRA cell frequencies. SBP significantly correlated with CMV-specific effector CD8+ T cells, which was mostly reflected by CD27- TEMRA cells.

In conclusion, within the circulating CMV-specific T cell population, different effector T-cell subtypes were associated with age, serostatus, and SBP. This suggests that it is not age or infection per se that render CMV-positive individuals susceptible to CVD, but rather the cellular immune response to CMV. Detailed immunophenotyping may identify individuals whose immune systems are strongly influenced by the response to CMV, leading to health consequences and impairing healthy aging.

Link: https://doi.org/10.1186/s12979-025-00523-x

One of the default modes of life science research focused on age-related diseases is a protein by protein consideration of potential targets of interest, investigating the biochemistry of a relatively small number of specific proteins that are both fairly well understood and involved in mechanisms relevant to aging and disease. Fashions and levels of interest in specific proteins change over time; as a given protein attracts greater attention from the scientific community, researchers shift their priorities in order to incrementally expand that understanding, while at the same time exploring ways to alter protein expression levels or interfere in or enhance specific interactions with other proteins. The output of this process is a body of knowledge and some number of potential therapies, most of which of which never make it into further development, let alone clinical use.

The angiopoietin-like protein 4 (ANGPTL4), also known as fasting-induced adipose factor, is a secreted glycoprotein that belongs to the ANGPTL protein family. Due to its expression in various cell types and tissues and its interactions with other proteins, ANGPTL4 plays diverse roles within its family, exhibiting a wider range of molecular functions. For instance, ANGPTL4 is intricately involved in modulating central energy metabolism and enhancing exercise endurance, while also acting as a pivotal mediator in the interaction between gut microbiota and host lipid metabolism.

The expression of ANGPTL4 is directly controlled by aging-related signaling pathways. Its excessive activation accelerates the aging process by triggering mechanisms like heightened oxidative stress, epithelial-mesenchymal transition (EMT) and fibrosis, abnormal lipid accumulation, and cellular arrest, thereby advancing the development of age-related diseases. Given the pivotal roles of ANGPTL4 and its associated molecules in organ fibrosis and cancer advancement, targeting ANGPTL4 emerges as a promising therapeutic approach. However, the intricate and sometimes conflicting functions of the two cleavage fragments of ANGPTL4, namely N-terminal fragment (nANGPTL4) and C-terminal fragment (cANGPTL4), in different chronic diseases - exerting inhibitory or stimulatory effects depending on the disease stage - have posed challenges to the progress of ANGPTL4 antibody therapy.

This review provides an overview of the biological mechanisms of ANGPTL4, its dual impact on fibrosis and tumorigenesis, and highlights its recent advancements as a potential biomarker in age-related diseases and inflammation-related conditions. ANGPTL4 is a high-potential but complex target, requiring mechanism-driven strategies for safe clinical translation.

Link: https://doi.org/10.2147/CIA.S522049

The axonal connections between neurons are sheathed in myelin, which acts as an insulator to enable the propagation of electrical impulses along the axon. Like all molecular structures in the body and brain, myelin sheathing is subject to ongoing damage and must continually be maintained in order to prevent dysfunction in the nervous system. A population of cells known as oligodendrocytes undertakes this task. Conditions in which excessive loss of myelin occurs, such as the autoimmune condition multiple sclerosis, are particularly debilitating. But a lesser degree of myelin damage occurs to everyone in old age, in part due to reduced oligodendrocyte function, and this damage contributes to cognitive impairment.

Thus it is interesting to keep an eye on that part of the research community focused on dymelinating conditions such as multiple sclerosis. It is plausible that future therapies capable of achieving at least some degree of remyelination in patients with severe demyelination could also help to restore meylin loss in aged individuals - it all depends on the fine details. Therapies that compensate for damage and dysfunction by increasing oligodendrocyte activity will probably be effective in both aged individuals and patients with multiple sclerosis, while curative therapies that directly address the autoimmune causes of multiple sclerosis will likely be of little use in aged individuals.

Delivering neural stem cells into the brain has been tested as a therapy of many forms of neurodegeneration, at least in animal models. Bringing this sort of therapy into human trials has progressed very slowly indeed over recent decades, with ongoing programs of research and development largely focused on Parkinson's disease while the state of the art advanced from fetal cells to embryonic stem cells to induced pluripotent stem cells. Today's open access paper is an example of the more broad application of neural stem cells in animal models, in which the transplanted cells induce remyelination to repair severe damage to myelin sheathing in the brain.

Remyelination of chronic demyelinated lesions with directly induced neural stem cells

The limited ability of central nervous system (CNS) progenitor cells to differentiate into oligodendrocytes limits the repair of demyelinating lesions and contributes to the disability of people with progressive multiple sclerosis (PMS). Neural stem cell (NSC) transplantation has emerged as a safe therapeutic approach in people with PMS, where it holds the promise of healing the injured CNS. However, the mechanisms by which NSC grafts could promote CNS remyelination need to be carefully assessed before their widespread clinical adoption.

In this study, we used directly induced NSCs (iNSCs) as a novel transplantation source to boost remyelination in the CNS. Using a mouse model of focal lysophosphatidylcholine (LPC)-induced demyelination, we found that mouse iNSCs promote remyelination by enhancing endogenous oligodendrocyte progenitor cells differentiation and by directly differentiating into mature oligodendrocytes. Transplantation of mouse iNSCs in LPC-lesioned Olig1 knockout mice, which exhibits impaired remyelination, confirmed the direct remyelinating ability of grafts and the formation of new exogenous myelin sheaths. We also demonstrated that the xenotransplantation of human iNSCs (hiNSCs) is safe in mice, with hiNSCs persisting long-term in demyelinating lesions where they can produce graft-derived human myelin.

Our findings support the use of NSC therapies to enhance remyelination in chronic demyelinating disorders, such as PMS.

It is by now well understood in the research community that the balance of microbial populations making up the gut microbiome changes with age in ways that promote tissue dysfunction and chronic inflammation. Animal studies of varied approaches to the restoration of a more youthful gut microbiome have produced extended life and improved long-term health, demonstrating that an altered gut microbiome is likely an important component of degenerative aging. That said, the fine details of those alterations remain to be fully mapped and understood. Similarly, effective and deterministic approaches to the recreation of a youthful gut microbiome have yet to be created. While fecal microbiota transplantation from a young donor to an old recipient works to rejuvenate the gut microbiome, it is far from deterministic. The direction taken by the research and development community will likely involve greatly expanding the capabilities of the probiotics industry to culture well-defined artificial microbiomes of thousands of species, given to patients in enteric-coated capsules for oral adminstration.

The human gut microbiome, a densely populated and diverse microbial community, exists in symbiotic harmony with the host and within itself, continually adapting and realigning in response to the host's environment and lifestyle across the lifespan. However, disruptions in the gut microbiome, driven by intrinsic or extrinsic elements, can disrupt microbial homeostasis, leading to a state of "dysbiosis," which can induce or exacerbate the onset of different age-related diseases (ARDs) through multidirectional communication axes involving host intestinal, cardiometabolic, immune, and/or neurocognitive health.

Recent research demonstrates the potential of microbiome-targeting therapeutics to promote healthy aging by preventing/ameliorating ARDs. Thus, a precise understanding of natural and environmentally induced microbiome alterations, including disease-specific taxa and their metabolic functions, is crucial for developing personalized therapies for older adults. Aging-associated changes in the gut microbiome may serve as primary determinants of late-life health. In this context, novel and emergent strategies to optimize the microbiome for therapeutic purposes could extend healthspan and lifespan, while reducing global healthcare costs.

To this end, we herein present a perspective on emerging research wherein we deliberate the topical concept of targeting the gut microbiome and dysbiosis as a potential therapeutic target for ARDs. Sequentially, we summarize and deliberate recent advances pertaining to the incipient potential of microbiome-based therapeutics to promote healthy aging and longevity. Finally, we introduce and propose the term "biome-aging" to denote the concept of such aging-associated microbiome transformations during different stages of our lifespan. In introducing biome-aging, we emphasize how cumulative changes in the gut environment - from shifts in barrier integrity and nutrient absorption to the effects of polypharmacy - progressively remodel microbial communities. This dynamic favors a decrease in beneficial microbes, an upsurge in pathobionts, and heightened inflammatory responses at both the local and systemic levels. By defining biome-aging, we underscore the importance of preserving a balanced gut ecosystem in older adults and open new possibilities for mitigating health risks tied to accelerated or pathological aging.

Link: https://doi.org/10.1186/s13073-025-01493-x

Klotho is well established as a longevity-associated gene. Greater expression, and thus higher circulating levels of the soluble klotho protein fragment secreted by cells, induces a longer life span in mice and correlates with a longer life span, improved function, and reduced incidence of age-related disease in humans. While the mechanisms by which klotho improves health and slows aging are far from fully cataloged and understood, a number of companies are working on therapies based on delivery of soluble klotho or upregulation of expression. Meanwhile, the research community continues to generate human data on circulating soluble klotho and health metrics in older individuals.

Klotho has been found to be an anti-aging gene, of which the protein expression level declines with age. Lower levels of klotho protein were found to be associated with a variety of chronic diseases including hypertension, chronic kidney disease, and depression. In this study, we aim to investigate the association between serum klotho and pulmonary function parameters among American adults. A total of 6,385 participants aged 40-79 years from the National Health and Nutrition Examination Survey 2007-2012 were included in this cross-sectional study. Multivariate linear regression and restricted cubic spline were conducted to estimate the association between serum klotho levels and forced expiratory volume 1st second (FEV1), forced vital capacity (FVC), peak expiratory flow rate (PEF) and forced expiratory flow between 25% and 75% of vital capacity (FEF25-75%).

Compared with the participants of the first quartile of klotho (545.61pg/ml), those who with the second (733.14 pg/ml), third (897.18 pg/ml) and fourth (1270.51 pg/ml) quartile klotho were of higher FEV1 and FEF25-75%; in addition, those who with the third and fourth quartile klotho were likely to perform higher FVC and PEF. Restricted cubic spline visualized there were nonlinear correlation between klotho and FEV1, FVC, PEF, FEF25-75%. Subgroup analysis by gender and age group indicated that there were positive associations between klotho and pulmonary function parameters in males and the 60-79-years-old participants. In conclusion, there was a comprehensive positive correlation between serum klotho and pulmonary function parameters in the adults.

Link: https://doi.org/10.1186/s12890-025-03746-2

Human epidemiological data exhibits a web of correlations between intelligence, education, wealth, lifestyle choices, social status, and longevity. Correlations are simple enough to discover, but determining causal relationships is much harder, particularly when pulling in the possible role of biological mechanisms. Nonetheless, there is an intriguing thread of research suggesting that there is some biological contribution to the correlation between intelligence and longevity. It may be that some aspects of the natural variation between individuals in physical robustness, or in resilience to age-related cell and tissue damage, can contribute to both intelligence and longevity.

As today's open access paper makes clear, the measurement of intelligence is a tricky business. One can argue about the merits of the various approaches taken in humans, but an entirely different set of issues arises when trying to measure intelligence in lower species. The paper is an addition to the body of knowledge regarding the correlation between intelligence and longevity in flies, but there is room to argue that the assessment used may not be a measure of intelligence per se, or at least not in a way that is easily related to the way we measure intelligence in humans. Flies are presented with a left or right choice in a simple T maze and there is food in one direction that can be sensed by smell. Are flies that head towards the food actually more intelligent, or is this instead a measure of drive, olfactory capability, or some other line item? One sees the challenge. Since the successful flies lived longer, there is clearly some interesting biology here relating to robustness in cell function, but it is far from clear that intelligence is involved.

Genetic association of intelligence with longevity in Drosophila melanogaster

Epidemiological studies in different populations, in different countries, and in different epochs consistently showed that high intelligence is positively correlated with longevity. The link between high intelligence and longevity has remained unknown, only to be assumed as a consequence of the socioeconomic difference associated with intelligence in human population.

Here, we report that genome stability contributes both to lifespan and intelligence in Drosophila melanogaster. The intelligence of the genetically heterogenous flies was determined by T-maze olfactory memory assay, and the flies moving to the right direction defined as intelligent flies (INT) were separated from the flies moving to the wrong direction defined as non-intelligent flies (NINT). INT male and female lived 26.40% and 21.35% longer than NINT male and female, respectively, suggesting a possible genetic linkage between intelligence and longevity.

The bidirectional selective breeding based on intelligence extended lifespans gradually generation by generation in INT breeding contrast to the reversed pattern in NINT breeding. INT of F12 generation lived longer than NINT of F12 generation, 63.91% for male and 67.88% for female, as a result from slower aging. The whole-genome transcriptome analysis showed the activation of the genes in ribosome and autophagy in INT and the pathways of genome stability and immune reaction in NINT. Especially, the genetic pathway associated with genome stability was most noticeable, indicating that genome stability contributes both to lifespan and intelligence in D. melanogaster.

In recent years there has been considerable interest in the inhibition of mTOR signaling as a mechanism to upregulate autophagy, a form of calorie restriction mimetic strategy for drug development. While there are a number of safe, low cost, off-patent small molecules that achieve this goal, rapamycin being the most well studied of these options, interest in a mechanism will ensure that researchers eventually work their way through the entire portfolio of approved drugs and drug candidate libraries in search of more options. Even if two small molecules ostensible target the same mechanism, there will always be differences in tissue specificity, side-effects, cost-effectiveness, and so forth. Here find one example of this sort of work, in which researchers add to the body of knowledge regarding the ability of niclosamide to inhibit mTOR signaling.

Niclosamide (NIC) is a medication that has been included in the World Health Organization's list of essential medicines since the 1960s, and is used to treat tapeworm infection. The mechanism of action of NIC involves uncoupling oxidative phosphorylation in the mitochondria, which disrupts the tapeworm's ability to survive. NIC has also been shown to affect various signal transduction pathways, such as Wnt/β-catenin, mammalian target of rapamycin (mTOR), STAT3, NFκB, and Notch pathways. Recent studies have also explored the potential of NIC as a therapeutic agent against cancer, bacterial or viral infections, and metabolic diseases. Studies have shown that NIC promotes autophagy in both small-cell lung carcinoma cells and mouse model, by inducing tumor cell death through the activation of autophagy and apoptosis via the AMPK/AKT/mTOR pathway. Furthermore, NIC improves insulin and glucose homeostasis by activating autophagy in metabolic disease cells and mouse models.

Despite these promising results, no study has focused on its effects on aging. Therefore, in this study, we aimed to evaluate the effects of NIC on natural aging models. We report that NIC promotes healthy aging in C. elegans and mice. NIC increases physical function and mitochondrial function in skeletal muscles, which are reduced with aging. We found that NIC inhibited the expression of muscle atrophy-related genes by suppressing hyperactivated mTORC1 and enhancing autophagic flux, thereby improving age-related decline. Our results demonstrate a new function of the NIC in contributing to healthy aging, particularly skeletal muscle health.

Link: https://doi.org/10.1016/j.jare.2025.04.027

It has long been established in mice that adult animals exhibit neurogenesis in the brain, the creation of new neurons that integrate into existing neural networks. There remains some debate over whether new neurons are created in the adult human brain, however, despite the consensus being that it would be unexpected to find that humans differ from mice in this way. Neurogenesis is thought to be essential to the function of learning and memory. That this process does occur would in principle make it easier to produce regenerative therapies that generate new neurons in the living brain to restore lost function. Establishing beyond doubt that this neurogenesis occurs in living humans brains has been challenging for a number of technical and logistical reasons. Nonetheless, progress has been made in establishing the necessary data.

The extent and significance of the formation of new neurons (neurogenesis) are still debated. There has been no clear evidence that the cells that precede new neurons, known as neural progenitor cells, actually exist and divide in adult humans. In a new study, the researchers combined several advanced methods to examine brain tissue from people aged 0 to 78 years from several international biobanks. They used a method called single-nucleus RNA sequencing, which analyses gene activity in individual cell nuclei, and flow cytometry to study cell properties.

By combining this with machine learning, they were able to identify different stages of neuronal development, from stem cells to immature neurons, many of which were in the division phase. To localise these cells, the researchers used two techniques that show where in the tissue different genes are active: RNAscope and Xenium. These methods confirmed that the newly formed cells were located in a specific area of the hippocampus called the dentate gyrus. This area is important for memory formation, learning, and cognitive flexibility.

The results show that the progenitors of adult neurons are similar to those of mice, pigs, and monkeys, but that there are some differences in which genes are active. There were also large variations between individuals - some adult humans had many neural progenitor cells, others hardly any at all. "Our research may also have implications for the development of regenerative treatments that stimulate neurogenesis in neurodegenerative and psychiatric disorders."

Link: https://news.ki.se/new-research-confirms-that-neurons-form-in-the-adult-brain

Research into reprogramming aims to induce some aspects of the dramatic change in gene expression and cell function that take place during early embryonic development, when adult germline cells shed the epigenetic changes characteristic of age to become young embryonic stem cells. Cell function becomes youthful, mitochondrial function is restored. Researchers can recapture the entire process, which is what happens when somatic cells are reprogrammed into induced pluripotent stem cells via exposure to the Yamanaka factors, but present efforts are turning to finding effective ways to induce only rejuvenation of function, without inducing pluripotency and loss of cell type.

Exploration of what has come to be called partial reprogramming, rejuvenation without pluripotency or other undesirable cell state changes, started with the use of genetic technologies to produce short-term expression of one or more Yamanaka factors. A few companies are slowly moving in the direction of clinical trials with initial gene therapies that focused on carefully narrow use cases, such as diseases of the eye or aspects of skin aging. Gene therapy vectors cannot at present effectively deliver their cargo to the whole body, and many organs remain impossible to target with vectors in any way other than direct injection. Thus there is interest in the alternative path of development of small molecules that can induce reprogramming, as small molecules are capable of reaching the entire body.

Much of the work on small molecule reprogramming is presently focused on a small number of compounds, those that go into the 7c and 2c combinations discussed in today's open access paper. 7c includes some undesirably toxic molecules, and researchers have thus focused more of their recent efforts on 2c, the combination of RepSox and tranylcypromine. This relatively narrow range of possibilities is characteristic of early stage research and development. Companies and research groups are undertaking the search for other starting points in the design of small molecule reprogramming agents, but one should expect progress on that front to emerge only slowly over a span of years.

Chemical reprogramming ameliorates cellular hallmarks of aging and extends lifespan

During development, cellular reprogramming induces zygotic and primordial germ cell formation following a dramatic chromatin reorganization to create totipotent and pluripotent cells free of aged molecular defects, demonstrating that both cell identity and age are reversible. Importantly, this manipulation of cell identity has been recapitulated in vitro by several methods, including somatic cell nuclear transfer, forced expression of transcription factors, and most recently treatment with small molecules.

Although restoration of aged phenotypes such as telomere length, mitochondrial function, proliferation, and transcriptomic signature in vitro was demonstrated over a decade ago, application of cellular reprogramming in vivo was initially proven unsafe due to the loss of cellular identity leading to tumor and teratoma formation. To overcome this issue, in vivo partial reprogramming by short-term cyclic induction of Oct4, Sox2, Klf4, and c-Myc (OSKM) was a critical advance as it avoided the detrimental loss of cellular identity. Importantly, this limited cyclic expression of OSKM was sufficient to ameliorate multiple aging hallmarks and extend the lifespan of a progeroid mouse strain. Improved regenerative capacity and function has also been demonstrated following therapeutic application of cellular reprogramming in multiple tissues and organs including the intervertebral disc, heart, skin, skeletal muscle, liver, optic nerve, and dentate gyrus.

Here, we report that short-term treatment of human cells with seven small molecules (7c - CHIR99021, DZNep, Forskolin, TTNPB, Valproic acid, Repsox, and Tranylcypromine), previously identified for their capacity to induce pluripotent stem cells, leads to the improvement of molecular hallmarks of aging. In addition, we show that an optimized cocktail, containing only two of these small molecules (2c - Repsox and Tranylcypromine), is sufficient to restore multiple aging phenotypes, including genomic instability, epigenetic dysregulation, cellular senescence, and elevated reactive oxygen species. Finally, in vivo application of this 2c reprogramming cocktail extends both lifespan and healthspan in C. elegans.

It is a great deal easier to theorize about aging than it is to produce technologies that repair specific forms of damage and disarray in aged tissues. The results of animal studies using those technologies are needed in order to prove or disprove specific lines of thought regarding which mechanisms are and are not important in aging, and thus set the stage for more concrete inferences about the evolution of aging. But this is a far greater challenge than the production of more theory. So the aging research community theorizes a great deal on the nature of aging and its evolution, and these days much of that work is aided by computer modeling of pseudo-organisms and evolutionary scenarios.

Aging is an extensive biological process characterized by morphological and functional alterations in cellular and extracellular components, resulting in a systematic decline in biological functions ultimately leading to death. Although substantial advancements have been made in manipulating lifespan in model organisms like C. elegans and mice through genetic, dietary, and pharmacological means, the fundamental mechanisms driving aging in humans remain elusive and widely debated. In addition, there is no comprehensive computational platform capable of making predictions on aging in multicellular systems and integrating the multiscale competency of lifeforms.

We focus on the processes that build and maintain a complex anatomy toward a specific target morphology, and propose the hypothesis that aging arises even in the absence of accumulated cellular or genetic damage, because a homeodynamic system left without any goal in anatomical morphospace will start degrading. This can occur in biological systems because evolution typically prioritizes development over morphostasis, leaving organisms with limited reinforcement of anatomical goals after development.

Using an in silico model of homeostatic morphogenesis with a multiscale competency architecture and information dynamics analysis, we find: (1) Absence of Long-Term Morphostasis: Aging emerges naturally after development due to the lack of an evolved regenerative goal, rather than just specific detrimental properties of developmental programs (e.g., antagonistic pleiotropy or hyperfunction); (2) Acceleration Factors vs. Root Cause: Cellular misdifferentiation, reduced competency, communication failures, and genetic damage all accelerate aging but are not its primary cause; (3) Information Dynamics in Aging: Aging correlates with increased active information storage and transfer entropy, while spatial entropy measures distinguish two dynamics - loss of structure and morphological noise accumulation; (4) Dormant Regenerative Potential: Despite organ loss, spatial information persists in the cybernetic tissue, indicating a memory of lost structures, which can be reactivated for organ restoration through targeted regenerative information; and (5) Optimized Regeneration Strategies: Restoration is most efficient when regenerative information includes differential patterns of affected cells and their neighboring tissue, highlighting strategies for rejuvenation.

These findings provide a novel perspective on aging dynamics with significant implications for longevity research and regenerative medicine.

Link: https://www.preprints.org/manuscript/202412.2354/v3

The chronic inflammation of aging is a major contribution to the onset and progression of age-related disease. The immune system reacts to forms of molecular damage and dysfunction characteristic of aging in a maladaptive way, and the long-term consequences are unfortunate. Short-term inflammation is necessary and important, needed in contexts ranging from infection to suppression of cancer to regeneration following injury. Sustained, unresolved inflammation is disruptive to tissue structure and function, however.

The biggest challenge in finding ways to suppress long-term inflammation is that it appears to use the same systems of regulation as short-term inflammation, and thus successful approaches not only sabotage undesirable inflammation, but also degrade the effectiveness of the immune system. If there is a way to work around this problem, we should all be very interested, as it could form the basis for therapies that reduce age-related inflammation without harming the necessary functions of the immune system.

Chronic inflammation occurs when the immune system is stuck in attack mode, sending cell after cell to defend and repair the body for months or even years. Diseases associated with chronic inflammation, like arthritis or cancer or autoimmune disorders, weigh heavily on human health. A new study identified a protein called WSTF that could be targeted to block chronic inflammation. Crucially, this strategy would not interfere with acute inflammation, allowing the immune system to continue responding appropriately to short-term threats, such as viral or bacterial infection.

Using chronically inflamed human cells, the researchers found that WSTF interacts with other proteins inside cell nuclei, which prompts its excretion and degradation. Since WSTF is responsible for concealing pro-inflammatory genes, this nucleus-eviction reveals those genes and, in turn, amplifies inflammation. The researchers confirmed that WSTF loss could promote inflammation in mouse models of aging and cancer. They also found, using human cells, that WSTF loss only occurred in chronic inflammation, not acute. Using these findings, the researchers designed a WSTF-restoring therapeutic to suppress chronic inflammation and observed preliminary success in mouse models of aging, metabolic dysfunction-associated steatohepatitis (MASH), and osteoarthritis.

The researchers went further to examine tissue samples from patients with MASH or osteoarthritis. They found that WSTF is lost in the livers of patients with MASH, but not in the livers of healthy donors. Using cells from the knees of osteoarthritis patients undergoing joint replacement surgery, they showed that WSTF-restoring therapeutic reduces chronic inflammation from the inflamed knee cells. These findings highlight the potential of developing new treatments targeting WSTF to combat chronic inflammatory diseases.

Link: https://www.massgeneralbrigham.org/en/about/newsroom/press-releases/new-protein-targets-chronic-inflammation

Transfusion of blood fractions from young individuals into old individuals has so far produced quite variable animal data and disappointing human clinical trial outcomes. Even so, researchers continue to search for molecules in young blood that might be a basis for therapy. That transfusions have not performed as desired doesn't rule out the existence of specific molecules that might be delivered in larger amounts than exist in a transfusion in order to produce benefits. That stem cell therapies produce benefits based on signals secreted by the transplanted cells indicates that cell signaling is important, a path to favorably altering the behavior of native cells in order to reduce inflammation, improve tissue function, and so forth. It is a question of identifying the right signals and the right doses.

Thus a steady flow of publications is emerging, with today's open access paper as an example of the type, in which researchers report on the discovery of one or more specific molecules mined from young blood that appear to produce benefits in older animals. It is a little early to say whether or not this will lead to a sizable number of novel potential therapies and biotech companies to develop those therapies, but some of the early demonstrations of benefits in mice are quite interesting. As with other investigations of cell signaling derived from young tissues, reduced inflammation is the most common outcome.

Plasma Extracellular Vesicle-Derived miR-296-5p is a Maturation-Dependent Rejuvenation Factor that Downregulates Inflammation and Improves Survival after Sepsis

There is a progressive decline in physiological function with age, and aging is associated with increased susceptibility to injury and infection. However, several reports have indicated that the agility of youth is characterized by transferable rejuvenating molecular factors, as was observed previously in heterochronic parabiosis experiments. These experiments demonstrated a rejuvenating effect of young blood in old animals.

There have been several efforts to characterize these youthful or maturation-associated factors in the young blood. In this report, we demonstrate the resilience of young mice, at or before puberty, to polymicrobial sepsis and show an age-dependent effect of small extracellular vesicles (EVs) from plasma on the outcome following sepsis. The EVs from the young mice were cytoprotective, anti-inflammatory, and reduced cellular senescence markers.

MicroRNA sequencing of the EVs showed an age-associated signature and identified miR-296-5p and miR-541-5p to progressively reduce their levels in the blood plasma with increasing age. We further show that the levels of these miRNAs decline with age in multiple organs. The miRNAs miR-296-5p and miR-541-5p showed a reparatory effect in an in vitro wound healing model and the miR-296-5p, when given intraperitoneally, reduced mortality in the mouse model of sepsis.

In summary, our studies demonstrate that EVs from very young mice have a reparative effect on sepsis, and the reparative factors are likely maturation-dependent. Our observation that miR-296-5p and miR-541-5p are plasma EV constituents that significantly reduce with age and can reduce inflammation suggests a therapeutic potential for these microRNAs in inflammation and age-associated diseases.

It is well established that exposure to particulate air pollution increases mortality and risk of age-related conditions. The primary mechanism is thought to be increased chronic inflammation resulting from the interactions of inhaled particles with the cells of epithelial and other tissues. One of the consequences of chronic inflammation is increased fibrosis, a dysfunction in normal tissue maintenance in which excessive extracellular matrix is created, forming scar-like structures that impair tissue function. Here, researchers correlate increased fibrosis in heart tissue with long-term exposure to particulate matter, an outcome that isn't all that surprising given the established epidemiological data linking cardiovascular disease to particulate exposure.

Fine particulate matter with 2.5-µm or smaller aerodynamic diameter (PM2.5) is the most thoroughly studied component of air pollution. PM2.5 is associated with an increased risk of cardiovascular diseases - including myocardial infarction, heart failure, and stroke - and promotes the development of cardiovascular risk factors such as hypertension and diabetes. The World Health Organization estimates that 31% of cardiovascular disease is attributable to environmental factors.

However, the underlying pathophysiologic mechanisms by which exposure to PM2.5 leads to adverse cardiovascular outcomes are unclear. Hypothesized mechanisms include oxidative stress, inflammation, and autonomic stimulation, potentially leading to activation of cardiac fibroblasts and increased extracellular matrix protein deposition. Given its role in maladaptive left ventricular remodeling, myocardial fibrosis could potentially mediate the adverse cardiovascular effects of particulate air pollution and help explain some of the variability in heart failure progression and other adverse cardiac events that are not explained by traditional cardiovascular risk factors.

This retrospective study aimed to determine the relationship between long-term exposure to ambient PM2.5 air pollution and the extent of diffuse myocardial fibrosis quantified with cardiac MRI. Patients with dilated cardiomyopathy (DCM) or controls with normal cardiac MRI findings were included. Diffuse myocardial fibrosis was quantified using cardiac MRI native T1 mapping z scores. A total of 694 patients (mean age, 47 years) were included. In multivariable models, each 1-µg/m3 increase in 1-year mean PM2.5 exposure was associated with a 0.30 higher native T1 z score in patients with DCM and 0.27 higher native T1 z score in controls. In conclusion, higher long-term exposure to ambient fine particulate air pollution is associated with greater diffuse myocardial fibrosis.

Link: https://doi.org/10.1148/radiol.250331

Researchers here report an advance in understanding the biochemistry of pathological interactions between cell types in the context of vascular dementia. After mapping gene expression levels in healthy and diseased vascular tissue, the researchers find a possible basis for therapy in one specific set of altered expression levels observed in microglia and oligodendrocyte. They present initial evidence for restored expression of two genes to reduce vascular dysfunction and pathology. This sort of approach is inherently compensatory, to eliminate a maladaptive reaction without addressing underlying causes. Is likely to be more limited in benefits than addressing those causes, because the causes will continue to produce other harms. Nonetheless, this is the way that the research community usually proceeds.

Vascular dementia (VaD) accounts for approximately 25% of all dementia cases. Currently, there are no direct treatments for VaD, and existing symptomatic therapies, such as cholinesterase inhibitors and memantine, demonstrate limited efficacy and fail to target the underlying vascular pathology. VaD arises from impaired cerebral blood flow due to cerebrovascular pathologies, including ischemic stroke, microinfarcts, or chronic small vessel disease.

A major barrier to advancing VaD research is the incomplete understanding of cell-type-specific responses within the neurovascular unit (NVU) - a dynamic interplay of multiple cell types. This NVU maintains cellular homeostasis and orchestrates responses to injury through intricate cell-cell interactions mediated by ligand-receptor (L-R) signaling. In VaD, ischemic injury originates in endothelial cells and propagates through the neurovascular niche, disrupting intercellular communication and leading to tissue damage and cognitive decline. The intercellular networks or "interactome" specific to VaD remains largely unexplored.

To address these challenges, we performed cell-type-specific RNA-seq to profile transcriptional changes in glial and vascular cells. Notably, WM glial and vascular cells exhibit specific transcriptional profiles compared with cortical and whole-brain datasets. The ischemic lesions also perturb WM-associated aging genes. We constructed a comprehensive VaD interactome, identifying conserved signaling pathways altered in both human and mouse, and prioritized two candidate L-R systems for functional validation: (1) the extracellular matrix component Serpine2 and its receptor Lrp1, which regulate oligodendrocyte differentiation and myelination, and (2) the CD39-A3AR signaling axis, which modulates microglial activation and tissue repair. Reduced Serpine2 expression enhances oligodendrocyte progenitor cell (OPC) differentiation, promoting repair, while an A3AR-specific agonist - currently in clinical trials for psoriasis - restores tissue integrity and behavioral function in the VaD model. This study reveals intercellular signaling targets and provides a foundation for developing innovative therapies for VaD.

Link: https://doi.org/10.1016/j.cell.2025.06.002

Modern hunter-gatherer populations such as the Tsimane, Hazda, and others, are increasingly of interest to researchers following publications of recent years indicating that these groups exhibit very little cardiovascular disease in comparison to populations in wealthier parts of the world. One might look at high and sustained levels of physical activity as a primary cause of this difference, although diet may also play a role. It is one of the better examples of the degree to which lifestyle influences the progression of aging, even while it fails to extend life out beyond the usual limits.

In today's research materials, the authors focus on differences in inflammation between first world populations and hunter-gatherers. One lesson that we might take away from this is that not all inflammation is the same: the hunter-gatherers exhibit higher levels of inflammation in youth, perhaps due to a greater burden of infectious disease, but nonetheless that burden of inflammation does not increase meaningfully into later life as it does in wealthier populations. As noted above the hunter-gatherers exhibit a far, far lower burden of cardiovascular diseases, age-related conditions well known to be driven by the chronic inflammation of aging.

Researchers analyzed data from four populations: two industrialized groups - the Italian InCHIANTI study and the Singapore Longitudinal Aging Study (SLAS) - and two Indigenous, non-industrialized populations - the Tsimane of the Bolivian Amazon and the Orang Asli of Peninsular Malaysia. While the inflammaging signature was similar between the two industrialized populations, it did not hold in the Indigenous groups, where inflammation levels were largely driven by infection rather than age.

Interestingly, while the indigenous populations, particularly the Tsimane, had high constitutive levels of inflammation, these did not increase with age and, crucially, did not lead to the chronic diseases that plague industrialized societies. In fact, most chronic diseases - diabetes, heart disease, Alzheimer's, etc. - are rare or largely absent in the Indigenous populations, meaning that even when young Indigenous people have profiles that look similar on the surface to those of older industrialized adults, these profiles do not lead to pathological consequences.

Inflammaging, an age-associated increase in chronic inflammation, is considered a hallmark of aging. However, there is no consensus approach to measuring inflammaging based on circulating cytokines. Here we assessed whether an inflammaging axis detected in the Italian InCHIANTI dataset comprising 19 cytokines could be generalized to a different industrialized population (Singapore Longitudinal Aging Study) or to two indigenous, nonindustrialized populations: the Tsimane from the Bolivian Amazon and the Orang Asli from Peninsular Malaysia. We assessed cytokine axis structure similarity and whether the inflammaging axis replicating the InCHIANTI result increased with age or was associated with health outcomes.

The Singapore Longitudinal Aging Study was similar to InCHIANTI except for IL-6 and IL-1RA. The Tsimane and Orang Asli showed markedly different axis structures with little to no association with age and no association with age-related diseases. Inflammaging, as measured in this manner in these cohorts, thus appears to be largely a byproduct of industrialized lifestyles, with major variation across environments and populations.

Transcranial magnetic stimulation has been shown to produce benefits in some studies, but reproduction in this field is challenging. There are many options for equipment, frequency, power, duration of treatment, and so forth, and many of these parameters are (a) likely important in determining whether or not the treatment has any beneficial effect and (b) incompletely specified in publications. Further, the mechanisms by which transcranial magnetic stimulation produces benefits are far from completely understood, making it much harder to calibrate potential therapies than would otherwise be the case. Here find an example of research in this part of the field, in which scientists explore the effects of transcranial magnetic stimulation on some of the smaller structures in neurons and neural connections.

Axonal boutons are specialized endings of an axon, which is the long slender part of a neuron that connects neurons by transmitting neural signals. These are sites where synapses form, allowing neurons to communicate. Therefore, any change in the number or function of these boutons can have profound effects on brain connectivity. In this study, the researchers observed structural changes of two types of excitatory boutons, namely "terminaux boutons" (TBs) (short protrusions from the axon shaft typically connecting neurons in a local area) and "en passant boutons" (EPBs) (small bead-like structures along axons typically connecting distal regions). They used two-photon imaging to visualize individual axons and synapses in the brain of a live animal.

The study was conducted on the APP/PS1 x Thy-1GFP-M strain of mice, which is a cross between the APP/PS1 strain (genetically modified to show Alzheimer's disease (AD)-like symptoms seen in humans) and the Thy1-GFP-M strain, which expresses a fluorescent protein in certain neurons. This combination causes axons to glow during imaging, enabling precise tracking of synaptic bouton changes over time. The team monitored the dynamics of the axonal boutons in these mice at 48-hour intervals for eight days, both before and after a single repetitive transcranial magnetic stimulation (rTMS) session. They then compared these findings to healthy wild-type (WT) mice.

They found that both TBs and EPBs in the AD mouse model had comparable density to those in healthy WT mice. However, the turnover of both bouton types was significantly lower in the AD mouse model before rTMS, likely due to the amyloid plaque buildup, a key marker of dementia, and potentially causing diseases like AD. After a single session of low-intensity rTMS, the turnover of TBs in both strains increased significantly, while there was no change in the EPB turnover. Furthermore, in the AD mouse model, this increased turnover was comparable to the turnover levels in the WT mice seen before stimulation. This indicates that low-intensity rTMS can potentially restore the synaptic plasticity of TBs to those seen in healthy mice. Moreover, the fact that only TBs, and not EPBs, responded to rTMS points to the possibility that the mechanisms of rTMS might be cell-type specific.

Link: https://spie.org/news/low-intensity-brain-stimulation-may-restore-neuron-health-in-alzheimers-disease

As researchers note here, the LAG-3 receptor on T cells acts as a checkpoint to suppress T cell activity. Like other such receptors that reduce T cell activity, it has been explored in the context of checkpoint inhibitor therapies to treat cancer by preventing tumor-induced reductions in immune activity. Interfering in the activity of LAG-3 was not effective enough in the context of cancer for potential treatments to emerge, but LAG-3 becomes more interesting as a target in autoimmune conditions. It remains to be seen as to whether this will lead to useful therapies, but the data presented here is intriguing.

T cells exhibit both T-cell receptors (TCRs) and checkpoints. TCRs, although shaped so that bits of invading bacteria or viruses fit into them to activate the T cell, are turned on by the body's own proteins in autoimmune diseases. Checkpoints like LAG-3 are also turned on by specific signaling partners, but when this occurs they have the opposite effect of TCRs, suppressing the T cell's activity. TCR-triggering molecules must be presented to T cell receptors by another set of immune cells that ingest foreign (e.g., microbial) or bodily substances in order to display on their surfaces, through protein groups called major histocompatibility complexes (MHC-II), just the small protein pieces that activate a given TCR.

Mechanistically, the research team found that the proximity of LAG-3 lets it loosely stick to part of the T cell receptor called CD3ε (like two oily globs interacting). This attachment was found to pull on CD3ε enough to disrupt its interaction an enzyme called Lck, which is crucial for T cell activation. MHC-II can theoretically attach to LAG-3 and TCR at the same time, but not frequently enough to maximize LAG-3's ability to dial down T cells.

LAG-3 turns off T cells, but less easily due to its spatial requirements than another checkpoint called PD-1. This feature makes LAG-3 inhibitors weaker as anti-cancer cancer treatment than PD-1-inhibiting antibody treatments that have become a mainstay, but likely better when the immune system is overactive, and targeted T cell suppression is required for maximum safe effect. Based on their discovery of the critical role of TCR proximity in LAG-3 function, the research team designed a molecule that enforces LAG-3/TCR proximity to achieve better LAG-3-dependent TCR inhibition and suppression of T cell responses. Their "bi-specific" antibody held LAG-3 and the T cell receptor together more strongly than MHC-II, and without depending on it.

The bispecific antibody, named the LAG-3/TCR Bispecific T cell Silencer or BiTS, potently suppressed T cell responses and lessened inflammatory damage to insulin-producing cells in BiTS-treated mice with a version of Type 1 diabetes. In autoimmune models of hepatitis, BiTS treatment reduced T cell infiltration and liver damage. With the diabetes and hepatitis disease models largely driven by one type of T cells (CD8+), the team also used a mouse model of multiple sclerosis known to be driven by a second major T cell type (CD4+). The team treated mice prone to develop multiple sclerosis with short-term, preventive BiTS prior to the onset of disease symptoms, and BiTS-treated mice had reduced disease by a standard measure.

Link: https://www.eurekalert.org/news-releases/1089253

Atherosclerosis is the name given to the growth of fatty plaques in artery walls. It is universal in later life, and the primary cause of human mortality via heart attack, stroke, heart failure, and so forth. Once a plaque grows past a given size, the mechanisms that caused its creation fade in importance in comparison to very simple feedback loop. The plaque is an inflammatory, damaged environment that attracts macrophage cells from the bloodstream and surrounding tissues. The macrophages attempt to ingest cholesterol and cell debris, passing the cholesterol back into the bloodstream to return to the liver for reuse or excretion, but instead become overwhelmed. The plaque environment and cholesterol excess forces macrophages into an inflammatory and dysfunctional state. The cells eventually die to add their mass to the plaque. A plaque is a macrophage graveyard, continually calling more macrophages to their doom.

Given this, some lines of research aim to make macrophages more resilient. In principle, if macrophages were not overwhelmed by excess cholesterol and other toxic aspects of the plaque environment, these cells would in time complete their task, dismantling the plaque and repairing the blood vessel wall. Nobody would die from atherosclerosis. A number of approaches have been suggested to at least modestly increase the resilience of macrophages to the plaque environment, and are in various stages of development. Today's open access paper adds another possibility to the list, another way to manipulate macrophage metabolism to sabotage the maladaptive reaction to the plaque environment in order to maintain repair activities.

Can enzyme behind high cholesterol be turned off?

"We found that by blocking the enzyme IDO1, we are able to control the inflammation in immune cells called macrophages." Inflammation plays a crucial role in the immune system, helping the body fight infections and heal injuries. But when inflammation becomes abnormal it can damage cells, disrupt normal functions and increase the risk of serious diseases. During these periods, macrophages can't absorb cholesterol properly, which can lead to chronic disease. Researchers found that the enzyme IDO1 becomes activated during inflammation, producing a substance called kynurenine that interferes with how macrophages process cholesterol.

When IDO1 is blocked, however, macrophages regain their ability to absorb cholesterol. This suggests that reducing IDO1 activity could offer a new way to help prevent heart disease by keeping cholesterol levels in check. The researchers also found that nitric oxide synthase (NOS), another enzyme linked in inflammation, worsens the effects of IDO1. They believe that inhibiting NOS could provide another potential therapy for managing cholesterol problems driven by inflammation.

HDLR-SR-BI Expression and Cholesterol Uptake are Regulated via Indoleamine-2,3-dioxygenase 1 in Macrophages under Inflammation

Macrophages play crucial roles in inflammation, and their dysfunction is a contributing factor to various human diseases. Maintaining the balance of cholesterol and lipid metabolism is central to macrophage function, and any disruption in this balance increases the risk of conditions such as cardiovascular disease, atherosclerosis, and others. The receptor HDLR-SR-BI (SR-BI) is pivotal for reverse cholesterol transport and cholesterol homeostasis. Our studies demonstrate that the expression of SR-BI is reduced along with a decrease in cholesterol uptake in macrophages, both of which are regulated by the activation of NF-κB.

Furthermore, we have discovered that indoleamine-2,3-dioxygenase 1 (IDO1), which is a critical player in tryptophan (Trp) catabolism, is crucial to the regulation of SR-BI expression. Inflammation leads to elevated levels of IDO1 and the associated Trp catabolite kynurenine (KYN) in macrophages. Interestingly, knockdown or inhibition of IDO1 results in the downregulation of lipopolysaccharide (LPS)-induced inflammation, decreased KYN levels, and the restoration of SR-BI expression as well as cholesterol uptake in macrophages. Beyond LPS, stimulation with pro-inflammatory cytokine IFNγ exhibits similar trends in inflammatory response, IDO1 regulation, and cholesterol uptake in macrophages. These observations suggest that IDO1 plays a critical role in SR-BI expression and cholesterol uptake in macrophages under inflammation.

Aging is an accumulation of forms of cell and tissue damage, and a complex network of downstream consequences of that damage that interact with one another to accelerate further dysfunction. It should not be too surprising to find that other approaches to producing damage in a living individual resemble aging, at least superficially. This is the case in DNA repair deficiency conditions, and, as researchers note here, it is the case in the aggressive use of chemotherapy to treat cancer.

While chemotherapy can be lifesaving, it also damages DNA and leads to cognitive issues known as "chemo brain." These effects resemble the memory and learning problems seen in older adults. There are several parallels in these two situations. In both, there is decreased blood flow in the brain when it is at rest and a smaller increase in blood flow when the brain is active. In addition, the blood-brain barrier, a protective layer that prevents harmful substances from entering the brain, is disrupted, which triggers inflammation in the brain. Finally, there is an accumulation of senescent cells in both brains. Senescent cells are in a suspended state of not being dead nor being able to fulfill their normal function, which also causes inflammation.

The research team studied several chemotherapy drugs in mice for their effects on the brain, including the commonly used paclitaxel and cisplatin. They found that even though the chemo drugs caused DNA damage in different ways, their characteristics were the same in how they affected cognition. Because of the blood-brain barrier, chemotherapy drugs do not directly enter and damage the brain. Instead, chemotherapy harms endothelial cells, the type of vascular cell most susceptible to damage. When the endothelial cells are impaired, they become senescent and produce inflammatory substances that compromise the blood-brain barrier.

The researchers also studied ways to improve cognition. They tested senolytics in aging mice. Senolytics are drugs that can induce senescent cells to die through apoptosis, the typical process by which cells are removed. By selectively removing senescent cells, cognition improved. Researchers took the study a step further to determine the ideal time window for administering senolytics to have the most positive effect on the brain's vasculature and cognition. They tested senolytics in mice of all ages and ultimately discovered the drug was most effective when the mice were about 16 months old, which researchers believe equates to 50 to 55 years old in humans.

Link: https://www.ou.edu/news/articles/2025/june/chemo-brain-and-the-Aging-brain-researchers-examine-similarities-in-search-for-improved-cognition

A burden of lingering senescent cells contributes to the chronic inflammation of aging and is disruptive to tissue structure and function. Excess visceral fat tissue is know to generate an increased burden of senescent cells. It does also dysregulate metabolism and provoke chronic inflammation in a range of other ways, however. So while senescent cells appear to be important in the damage done by obesity, it remains unclear as to what degree the use of senolytic drugs to selectively destroy senescent cells will reduce the consequences of obesity. Answers will emerge in time, but, as ever, making progress towards larger clinical trials and sufficient human data is a slow and expensive process. There is little incentive for industry to fund work on the existing cheap, off-patent senolytics, such as the dasatinib and quercetin combination, and the usual alternative path of developing and testing expensive, new, patented drugs takes as long as it takes.

Obesity and type 2 diabetes mellitus (T2DM) represent currently major health threats worldwide owing to their rapidly increasing prevalence and debilitating long-term chronic complications. Senescent cells play an important role in T2DM pathogenesis via direct impact on pancreatic β-cell function, since reduced pancreatic β-cell mass and subsequent defects in insulin secretion are major factors in the pathogenesis and progression of T2DM. Preferential accumulation of senescent cells in visceral adipose tissue (VAT) is then associated with an inappropriate expansion of adipocytes (hypertrophy), insulin resistance, and dyslipidemia and represents the nexus of mechanisms involved in aging and age-related metabolic dysfunctions. On the other hand, changes induced by long-standing, poorly controlled T2DM are linked to the accumulation of premature senescent cells in various tissues, contributing to the development of chronic irreversible complications. Thus, senescence is both a cause and a consequence of obesity and T2DM.

The presence of T2DM and its complications is the major reason for the massive financial burden of the treatment of T2DM. It is estimated that therapy of diabetic complications consumes up to two-thirds of the overall T2DM treatment costs. Despite the availability of novel glucose-lowering drugs, the number of patients with T2DM and related chronic complications keeps increasing at a high rate. Current pharmacological approaches address the pathophysiological defects present in T2DM rather than preventing the processes contributing to its development. Therapeutic targeting and elimination of senescent cells with suppression of the SASP production by senolytics may therefore be an effective strategy for a novel approach in the treatment of metabolic diseases.

Link: https://doi.org/10.3389/fcell.2025.1622107

In today's open access paper, researchers argue that the regeneration of outer, visible ear tissue is a useful area of focus for understanding why mammals are limited in their regenerative capacity. Species such as salamanders and zebrafish can regenerate limbs and internal organs, and researchers would like to understand how to enable this capability in mammals. The ear is interesting in this respect because some mammals are capable of regeneration of ear tissue, while others are not, giving a starting point for a closer comparison of the relevant biochemistry between more similar species. Mice are incapable of ear tissue regeneration, which is why ear notching is a common means of animal identification used in laboratories. Interestingly, this is how the exceptional regenerative capacity of MRL mice was discovered - the ear notches healed.

This leads to the advance noted today, in which researchers identified mechanisms that allow some mammals to regenerate ear tissue. They succeeded in reproducing this outcome in mice via upregulation of ALDH1A2 and consequent changes in fibroblast behavior in injured tissues. In most mammals, scarring forms in place of complete regeneration of lost tissue following injury. Fibroblasts are the cells responsible for depositing the extracellular matrix that forms scar tissue. Other lines of work have pointed to differences in the behavior of macrophages and senescent cells in species with different regenerative capacities, and all of these cell populations interact in complex ways following injury and during regeneration. A complete picture remains to be established, but this ALDH1A2 overexpression research has practical implications for human regenerative medicine; there may be a basis for forms of therapy here.

Reactivation of mammalian regeneration by turning on an evolutionarily disabled genetic switch

Regeneration is well maintained in some animal lineages but has been lost in many others during evolution and speciation. Identification of the causal mechanism underlying the failure of regeneration in mammals through comparative strategies is usually entangled by the large phylogenetic distance from highly regenerative species (mostly lower vertebrates). Exploration of principles in the evolution of regeneration demands an organ with easy accessibility and diverse regenerative capacities. One such mammalian organ is the ear pinna, which evolved to funnel sound from the surrounding environment for better distinguishing between ambient noise and predators or prey. The ear pinna possesses complex tissues such as skin and cartilage and exhibits remarkable diversity in the ability to regenerate full-thickness holes punched through this organ in placental mammals.

By performing a side-by-side comparison between regenerative species (rabbits, goats, and African spiny mice) and nonregenerative species (mice and rats), we found that the failure of regeneration in mice and rats was not due to the breakdown of tissue-loss triggered blastema formation and proliferation. Single-cell RNA sequencing and spatial transcriptomic analyses of rabbits and mice identified the response of wound-induced fibroblasts (WIFs) as a key difference between the regenerating and nonregenerating ear pinna.

Gene overexpression studies discovered that Aldehyde Dehydrogenase 1 Family Member A2 (Aldh1a2), encoding a rate-limiting enzyme for the synthesis of retinoic acid (RA) from retinaldehyde, was sufficient to rescue mouse ear pinna regeneration. The activation of Aldh1a2 upon injury was correlated with the regenerative capacity of the tested species. Furthermore, we demonstrated that the deficiency of Aldh1a2 expression, together with the augmented activity of the RA degradation pathway, contributed to insufficient RA production after injury and eventually the failure of regeneration. An exogenous supplement of RA - but not the synthetic precursor retinol - was sufficient to induce regeneration by directing WIFs to form new ear pinna tissues. The inactivation of multiple Aldh1a2-linked regulatory elements accounted for the injury-dependent deficiency of Aldh1a2 in mice and rats. Importantly, activation of Aldh1a2 was sufficient to promote ear pinna regeneration in transgenic mice.

Microglia are innate immune cells of the brain, similar to macrophages elsewhere in the body. A growing body of evidence points to maladaptive inflammatory behavior of microglia in the aging brain as an important contribution to the onset and progression of neurodegenerative conditions such as Alzheimer's disease. Some microglia become inflammatory in response to the damaged environment of aged brain tissue, but others have become senescent. Senescent cells cease replication and instead turn their efforts to secreting disruptive inflammatory signals, harmful to tissue structure and function when sustained over the long term.

Emerging evidence suggests that senescent microglia play a role in β-amyloid (Aβ) pathology and neuroinflammation in Alzheimer's disease (AD). Targeting senescent cells with naturally derived compounds exhibiting minimal cytotoxicity represents a promising therapeutic strategy. This study aimed to investigate whether delphinidin, a naturally occurring anthocyanin, can alleviate AD-related pathologies by mitigating microglial senescence and to elucidate the underlying molecular mechanisms.

We employed APP/PS1 mice and naturally aged mice. Delphinidin treatment significantly alleviated cognitive deficits, synapse loss, amyloid-β peptides plaques of APP/PS1 mice via downregulated senescent microglia gene signature, prevented cell senescence, including senescence-associated β-galactosidase activity, senescence-associated secretory phenotype (SASP), oxidative stress, p21, and p16. And delphinidin treatment also prevented microglial senescence in naturally aged mice. Further research indicated that delphinidin treatment enhanced the AMPK/SIRT1 signaling pathway. Additionally, delphinidin was found to directly interact with SIRT1. It's noteworthy that AMPK inhibitor Compound C inversed the protective effect of delphinidin against microglial senescence.

These findings highlight delphinidin as a promising natural anti-aging agent against the development of aging and age-related diseases.

Link: https://doi.org/10.1186/s13195-025-01783-x

A mountain of human epidemiological data demonstrates that physical activity and fitness correlate with a reduced incidence of age-related disease, a slower age-related decline of function. Adding to that, researchers here show that cumulative physical activity over the long term correlates with slowed loss of cognitive function. While human data can only reliably produce correlations, animal studies convincingly demonstrate that exercise does in fact improve long-term health. It remains one of the most robust interventions for slowing the aging process, the bar to beat when developing novel therapies to treat aging.

Given the lack of effective pharmacological interventions for dementia patients, modifying risk factors associated with dementia has become a critical area of research. Current evidence shows that physical activity (PA) has emerged as one of the most promising protective measures against all-cause dementia, as well as Alzheimer's disease (AD), vascular dementia, and Parkinson's disease. PA has the potential to reduce dementia risks by 2%. Prior to the dementia onset, a growing body of research has consistently shown that higher levels of PA are associated with better cognitive function, a slower rate of cognitive decline, and a lower risk of cognitive impairment.

First, PA has been shown to improve cognitive reserve, the brain's ability to adapt and compensate in the face of changes due to age, pathology, or insult without developing cognitive impairment. Besides, PA improves blood flow to the brain, reduces inflammation, which improves brain function, and assists in maintaining cognitive performance. These mechanisms suggest that PA not only plays a critical role in sustaining cognitive health but may also have a preventive effect on cognitive decline throughout the aging process.

While some evidence suggests that increased PA may help delay cognitive decline, findings from a randomized clinical trial reported no significant improvement following a six-month PA intervention. To the best of our knowledge, there is still a lack of robust evidence on the association of sustained, long-term engagement in PA with cognitive decline over time for older age. Thus, this study aims to fill this gap in the literature by examining the longitudinal association between cumulative PA over time and subsequent cognitive decline in cognitively healthy adults aged 50 years and older.

This study included 13,450 cognitively healthy participants from the Health and Retirement Study, 2004-2020, with a mean follow-up duration of 11.06 years. Higher cumulative PA was associated with delayed declines in global cognition, memory, and executive function, and such protective benefits grew over the 16-year study period. Longer PA engagement was associated with progressively delayed cognitive decline. We conclude that PA engagement over long timeframes may better maintain cognitive performance.

Link: https://doi.org/10.1016/j.tjpad.2025.100194

Variants of the APOE gene (the most common labeled as APOE-ε2, APOE-ε3, and APOE-ε4) have been show to alter the risk of developing Alzheimer's disease. Work in recent years has pointed to effects on the behavior of microglia in the aging brain as the important mechanism is driving risk. Bad variants of APOE, predominantly APOE-ε4 in the population at large, lead to greater inflammation driven by activated and dysfunctional microglia. Good variants suppress that inflammation. Various lines of evidence suggest that lipid metabolism in microglia becomes disrupted with age, driving inflammatory behavior. APOE plays a number of important roles in lipid metabolism, and there are significant differences in the capabilities of the different APOE variants.

While some consensus exists in the research community regarding the high level view of the biochemistry noted above, there is much left to accomplish when it comes to fleshing out the fine details. Today's open access paper is an example of this research, aimed at better mapping the connection between APOE and inflammatory signaling. The researchers show that a rare APOE variant suppresses the cGAS-STING innate immune pathway that reacts to forms of molecular damage in the cell with inflammatory signaling. This reaction is useful in youth, but becomes maladaptive in cells in aged tissues, burdened with damage that provokes constant and excessive inflammation. That inflammation in turn drives the onset and progression of neurodegenerative conditions such as Alzheimer's disease.

Alzheimer's Protective Mutation Works by Taming Inflammation in the Brain

Alzheimer's disease has long defied scientific efforts to understand its causes and develop effective treatments. Growing evidence suggests that tau - not amyloid - is the key driver of neurodegeneration and cognitive decline. What determines an individual's susceptibility or resistance to tau toxicity remains poorly understood. The mutation APOE3-R136S - known as the "Christchurch mutation" as it was discovered in Christchurch, New Zealand - protects against tau pathology and cognitive deterioration despite extensive amyloid buildup, offers an important clue.

This rare mutation is found in the APOE gene encoding a cholesterol transport protein (apolipoprotein E). In 2019, scientists studying a Colombian family with hereditary early-onset Alzheimer's, which typically strikes by age 50, reported that one family member, who had two copies of the Christchurch mutation, remained cognitively healthy into her 70s. Despite high brain amyloid, she exhibited low levels of tau. Subsequent research, mostly in mouse models, has confirmed the Christchurch mutation's beneficial effects - but researchers still aren't sure how it exerts protection.

In the new study, researchers engineered the Christchurch mutation into the APOE gene in mice that develop tau accumulation, and found that it protected the animals from hallmark Alzheimer's features -including tau accumulation, synaptic damage, and disruptions in brain activity. These protective effects were traced to suppression of the cGAS-STING pathway, an innate immune signaling cascade normally activated in response to viral threat but is chronically activated in Alzheimer's disease.

Researchers further discovered that the protective mechanism of the Christchurch mutation can be largely attributed to taming microglia, brain-resident immune cells. These cells and their inflammatory state in Alzheimer's have long been seen as potential drivers of the disease process. When the researchers treated mice with tau pathology using a small-molecule inhibitor of cGAS-STING signaling, they observed synapse-protecting effects and molecular changes in brain cells that closely resembled those seen with the protective mutation.

The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway

The Christchurch mutation (R136S) in the APOE3 (E3S/S) gene is associated with attenuated tau load and cognitive decline despite the presence of a causal PSEN1 mutation and high amyloid burden in the carrier. However, the molecular mechanisms enabling the E3S/S mutation to mitigate tau-induced neurodegeneration remain unclear.

Here, we replaced mouse Apoe with wild-type human APOE3 or APOE3S/S on a tauopathy background. The R136S mutation decreased tau load and protected against tau-induced synaptic loss, myelin loss, and reduction in hippocampal theta and gamma power. Additionally, the R136S mutation reduced interferon responses to tau pathology in both mouse and human microglia, suppressing cGAS-STING pathway activation.

Treating E3 tauopathy mice with a cGAS inhibitor protected against tau-induced synaptic loss and induced transcriptomic alterations similar to the R136S mutation across brain cell types. Thus, suppression of the microglial cGAS-STING-interferon pathway plays a central role in mediating the protective effects of R136S against tauopathy.

The signal molecules secreted by senescent cells can encourage other nearby cells to also become senescent. Thus the high burden of lingering senescent cells in aged tissues is both directly harmful to tissue structure and function, but also indirectly harmful by encouraging further growth of that burden of cellular senescence. The research community has investigated which of the many different components of the senescence-associated secretory phenotype (SASP) are most important in producing bystander senescence. Here, researchers presents evidence for the unoxidized form of HMGB1 to be a good target for suppression of this transmission of the senescent state between cells.

Cellular senescence spreads systemically through blood circulation, but its mechanisms remain unclear. High mobility group box 1 (HMGB1), a multifunctional senescence-associated secretory phenotype (SASP) factor, exists in various redox states. Here, we investigate the role of redox-sensitive HMGB1 (ReHMGB1) in driving paracrine and systemic senescence. We applied the paracrine senescence cultured model to evaluate the effect of ReHMGB1 on cellular senescence. Each redox state of HMGB1 was treated extracellularly to assess systemic senescence both in vitro and in vivo. In vivo, young mice were administered ReHMGB1 systemically to induce senescence across multiple tissues. A muscle injury model in middle-aged mice was used to assess the therapeutic efficacy of HMGB1 blockade.

Extracellular ReHMGB1, but not its oxidized form, robustly induced senescence-like phenotypes across multiple cell types and tissues. Transcriptomic analysis revealed activation of RAGE-mediated JAK/STAT and NF-κB pathways, driving SASP expression and cell cycle arrest. Cytokine profiling confirmed paracrine senescence features induced by ReHMGB1. ReHMGB1 administration elevated senescence markers in vivo, while HMGB1 inhibition reduced senescence, attenuated systemic inflammation, and enhanced muscle regeneration. Thus targeting extracellular HMGB1 may offer therapeutic potential for preventing aging-related pathologies.

Link: https://doi.org/10.1016/j.metabol.2025.156259

Base editing, such as via the various CRISPR-based approaches, is a powerful technology for making small changes to DNA sequences. It only works in the nuclear genome, however. Researchers have recently demonstrated base editing that works for the hundreds of mitochondrial genomes present in a cell. This is good for patients with single detrimental inherited mitochondrial mutations, but it remains to be seen as to whether base editing can be applied usefully to the problem of stochastic DNA damage in aging. How does one repair a million different mutations in a trillion different genomes? That capability seems beyond reach at the present time. Other ways forward appear more achievable, such as replacing stem cell populations with youthful, minimally damaged cells, allowing tissues to be slowly cleared of mutational burden over time, or delivering large numbers of undamaged mitochondria that cells take up to replace the existing damaged populations.

Mutations in the mitochondrial genome can cause maternally inherited diseases, cancer, and aging-related conditions. Recent technological progress now enables the creation and correction of mutations in the mitochondrial genome, but it remains relatively unknown how patients with primary mitochondrial disease can benefit from this technology. Here, we demonstrate the potential of the double-stranded DNA deaminase toxin A-derived cytosine base editor (DdCBE) to develop disease models and therapeutic strategies for mitochondrial disease in primary human cells.

Introduction of the m.15150G > A mutation in liver organoids resulted in organoid lines with varying degrees of heteroplasmy and correspondingly reduced ATP production, providing a unique model to study functional consequences of different levels of heteroplasmy of this mutation. Correction of the m.4291T > C mutation in patient-derived fibroblasts restored mitochondrial membrane potential. DdCBE generated sustainable edits with high specificity and product purity.

To prepare for clinical application, we found that mRNA-mediated mitochondrial base editing resulted in increased efficiency and cellular viability compared to DNA-mediated editing. Moreover, we showed efficient delivery of the mRNA mitochondrial base editors using lipid nanoparticles, which is currently the most advanced non-viral in vivo delivery system for gene products. Our study thus demonstrates the potential of mitochondrial base editing to not only generate unique in vitro models to study these diseases, but also to functionally correct mitochondrial mutations in patient-derived cells for future therapeutic purposes.

Link: https://doi.org/10.1371/journal.pbio.3003207

Mitochondrial uncoupling is the process by which mitochondria in cells switch from producing the chemical energy store molecule adenosine triphosphate (ATP) to releasing that energy as heat. This is of interest in the context of aging because upregulation of mitochondrial uncoupling via a range of strategies appears to somewhat slow aging in animal studies. Sustained upregulation of mitochondrial uncoupling also produces a reduction in fat tissue and weight loss. Humans being humans, there is considerably more interest in that outcome than in effects on aging, particularly now that weight loss drugs have become a large revenue source for the major pharma companies.

Historically, researchers have struggled to produce mitochondrial uncoupling drugs that will not kill people through overheating if taken at a high enough dose. One of the first such drugs to be developed and fairly widely used, back in the early 20th century, was 2,4-dinitrophenol (DNP). While there is very little literature on accidental deaths as a result of its use, it is certainly possible to take enough DNP to die from hyperthermia within a few days without any immediate sign that a fatal dose was ingested, and without any recourse once realization sets in. Any drug that directly upregulates uncoupling in the same way will likely have similar characteristics.

In today's research materials, the authors claim to have found a safe approach that bypasses the mechanism used by past approaches to upregulate uncoupling, meaning to influence the activity of uncoupling protein 1 (UCP1). In this approach, UCP1 is not involved in the switch from ATP generation to thermogenesis, and further the effect only occurs in adipose cells, not body-wide. Given present biases in funding and interest, the researchers of course pitch this as a strategy for weight loss, but it could be interesting in the context of aging as well.

Article presents innovative drug for controlling weight and blood sugar

The experimental drug, currently called SANA (short for "salicylate-based nitroalkene"), is a derivative of salicylate, a chemical compound with analgesic and anti-inflammatory properties found naturally in plants and used to make drugs such as aspirin (acetylsalicylic acid). Researchers initially sought to develop an anti-inflammatory drug. To this end, they tested several chemical modifications to the salicylate molecule. "We wanted the precursor used to be as safe as possible. Salicylate is the drug that's been known the longest, and many people consume its derivatives daily. However, we observed that instead of protecting against inflammation, the molecule we synthesized protects against diet-induced obesity."

Two different models were used to test this effect in animals. In the first model, SANA was administered to mice alongside a high-fat diet, which prevented any weight gain. Meanwhile, the animals in the control group gained between 40% and 50% of their body weight over eight weeks. In the second model, treatment began after the animals were obese. After three weeks, the mice had lost 20% of their body mass. There was also a reduction in blood sugar, improved insulin sensitivity, and a decrease in fat accumulated in the liver (a condition known as hepatic steatosis for which there is still no effective pharmacological treatment).

Experiments showed that SANA specifically targets adipose tissue, activating thermogenesis through an unconventional mechanism. It can therefore be considered the first in a new class of anti-obesity drugs. It does not affect the central nervous system or digestive system or appetite. Thermogenesis is typically mediated by a protein called UCP1, which is found within mitochondria. UCP1 is activated in certain situations, such as exposure to cold. It then interferes with the synthesis of ATP (adenosine triphosphate), the cellular fuel. This causes the energy generated by cellular respiration to dissipate as heat. However, this is not the case with SANA. The new drug causes adipocytes to use creatine, a compound formed by three amino acids (arginine, glycine, and methionine), as an energy source to produce heat without involving the UCP1 protein.

According to the researchers, the observed impact on body temperature is small and does not pose a significant health risk. "Older thermogenic agents, such as dinitrophenol, have an effect on the mitochondria of the entire body, causing a large increase in temperature and overloading the cardiovascular system, which needs to increase blood pressure for blood to reach the periphery and dissipate heat. But in the case of SANA, there's only action on the mitochondria of adipose tissue."

A nitroalkene derivative of salicylate, SANA, induces creatine-dependent thermogenesis and promotes weight loss

Through phenotypic drug discovery, we developed promising nitroalkene-containing small molecules for obesity-related metabolic dysfunctions. Here, we present SANA, a nitroalkene derivative of salicylate, demonstrating notable efficacy in preclinical models of diet-induced obesity. SANA reduces liver steatosis and insulin resistance by enhancing mitochondrial respiration and increasing creatine-dependent energy expenditure in adipose tissue, functioning effectively in thermoneutral conditions and independently of uncoupling protein 1 and AMPK activity.

Finally, we conducted a randomized, double-blind, placebo-controlled phase 1A/B clinical trial, which consisted of two parts, each with four arms: (A) single ascending doses (200-800 mg) in healthy lean volunteers; (B) multiple ascending doses (200-400 mg per day for 15 days) in healthy volunteers with overweight or obesity. The primary endpoint assessed safety and tolerability. Secondary and exploratory endpoints included pharmacokinetics, tolerability, body weight, and metabolic markers. SANA shows good safety and tolerability, and demonstrates beneficial effects on body weight and glucose management within 2 weeks of treatment.

The trends in cardiovascular disease over the past 50 years are a success story for public health and medical progress. Even as demographic aging leads to more older people suffering more age-related disease, the risk for any given individual of suffering the most severe outcomes of cardiovascular disease has fallen. Still, atherosclerotic cardiovascular disease remains the single largest cause of human mortality, and the growth of obstructive atherosclerotic plaque in arteries remains largely irreversible. For every fortunate individual who experiences some plaque regression with an aggressive combination of lifestyle change and medication, there are many more who see no benefit. As severe outcomes such as heart attack have declined in incidence, deaths now occur as a result of other consequences of atherosclerotic plaque. New approaches and better therapies are much needed.

While heart disease has been the leading cause of death in the U.S. for over a century, the past 50 years have seen a substantial decrease (66%) in overall age-adjusted heart disease death rates, including a nearly 90% drop in heart attack deaths, according to new research. During that time, there have been major shifts in the types of heart disease people are dying from, with large increases in deaths from heart failure, arrhythmias, and hypertensive heart disease.

In an analysis of data from the U.S. Centers for Disease Control and Prevention, researchers reviewed the age-adjusted rates of heart disease deaths among adults ages 25 and older from 1970 to 2022. Over this 52-year period, heart disease accounted for nearly one-third of all deaths (31%). During this time, heart disease death rates decreased substantially, from 41% of total deaths in 1970 to 24% of total deaths in 2022. In 1970, more than half of all people who died from heart disease (54%) died because of a heart attack - a type of acute ischemic heart disease. The age-adjusted death rate decreased 89% by 2022, when less than one-third of all heart disease deaths (29%) were caused by a heart attack. Conversely, during this time, the age-adjusted death rate from all other types of heart disease (including heart failure, hypertensive heart disease and arrhythmia) increased by 81%, accounting for 9% of all heart disease deaths in 1970 and 47% of all heart disease deaths in 2022.

Link: https://newsroom.heart.org/news/still-top-cause-of-death-the-types-of-heart-disease-people-are-dying-from-is-changing

Researchers have considered a role for dysregulation of insulin metabolism in the development of Alzheimer's disease, to the point of suggesting that it might be classified as a type 3 diabetes. Epidemiological data shows that Alzheimer's is nowhere near as clearly a direct, reliable consequence of obesity and consequent metabolic dysfunction as is the case for type 2 diabetes, however, indicating that the story is probably more complex. Here, researchers discuss the role of insulin resistance in Alzheimer's disease and the existing body of evidence, pro and con, relating to approaches to therapy based on insulin delivery.

The increasing prevalence of metabolic disorders and neurodegenerative diseases has uncovered shared pathophysiological pathways, with insulin resistance and mitochondrial dysfunction emerging as critical contributors to cognitive decline. Insulin resistance impairs neuronal metabolism and synaptic function, fostering neurodegeneration as observed in Alzheimer's disease and Down syndrome. Indeed, Down syndrome, characterized by the triplication of the APP gene, represents a valuable genetic model for studying early-onset Alzheimer's disease and accelerated aging.

Building on the link between metabolic dysfunctions and neurodegeneration, innovative strategies addressed brain insulin resistance as a key driver of cognitive decline. Intranasal insulin has shown promise in improving cognition in early Alzheimer's disease and type 2 diabetes, supporting the concept that restoring insulin sensitivity can mitigate neurodegeneration. However, insulin-based therapies risk desensitizing insulin signaling, potentially worsening the disease. Incretins, particularly glucagonlike peptide 1 receptor agonists, offer neuroprotective benefits by enhancing insulin sensitivity, metabolism, and synaptic plasticity while reducing oxidative stress and neuroinflammation.

This review focuses on current knowledge on the metabolic and molecular interactions between insulin resistance, mitochondrial dynamics (including their roles in energy metabolism), and oxidative stress regulation, as these are pivotal in both Alzheimer's disease and Down syndrome. By addressing these interconnected mechanisms, innovative treatments may emerge for both metabolic and neurodegenerative disorders.

Link: https://doi.org/10.4103/NRR.NRR-D-25-00144

Leakage of DNA fragments from either the nucleus or mitochondria into the cell cytosol is characteristic of a wide range of forms of cell stress, dysfunction, and damage. One component of the innate immune system is that all cells incorporate mechanisms to recognize the presence of inappropriately localized DNA and raise the alert via the secretion of inflammatory signals. This is in part a defense against bacterial and viral infection, but the mechanisms are sufficiently non-specific to also react to a cell's own DNA when it is mislocalized. This is an important mechanism in converting molecular damage and stress into a broader call to the immune system for assistance in a specific location.

The interaction between cGAS and STING is one amongst a number of innate immune pathways that sense molecular damage. cGAS is a sensor for DNA in the cytosol, and its interaction with STING then drives the consequence changes in cell state and inflammatory signaling. Researchers are increasingly interested in the cGAS-STING pathway as a target to suppress maladaptive overactivation of the immune system in aged tissues and inflammatory diseases. Unfortunately, as for all such efforts at present, cGAS-STING interactions are also involved in the normal, beneficial activation of the immune system. This presents challenges and limits the use of a very aggressive suppression of those regulatory systems known to be involved in the chronic inflammation of aging. Better approaches are needed, aimed at removing the damage of aging that causes of STING activation.

Photoaging: UV radiation-induced cGAS-STING signaling promotes the aging process in skin by remodeling the immune network

Excessive exposure of the skin to UV radiation (UVR) accelerates the aging process and leads to a photoaging state which involves similar pathological alterations to those occurring in chronological aging. UVR exposure, containing both UVA and UVB radiation, triggers cellular senescence and a chronic inflammatory state in skin. UVR promotes oxidative stress and a leakage of double-stranded DNA (dsDNA) from nuclei and mitochondria into the cytoplasm of keratinocytes and fibroblasts. It is recognized that cytosolic dsDNA is a specific danger signal which stimulates cytoplasmic DNA sensors. The activation of the signaling through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) is a major defence and survival mechanism combatting against tissue injuries.

There is abundant evidence that UVR exposure of skin stimulates cGAS-STING signaling which promotes cellular senescence and remodels both the local and systemic immune network. cGAS-STING signaling activates the IRF3 and NF-κB signaling pathways which trigger both pro-inflammatory and immunosuppressive responses. Moreover, cGAS-STING signaling stimulates inflammatory responses by activating the NLRP3 inflammasomes. Senescent fibroblasts secrete not only cytokines but also chemokines and colony-stimulating factors which induce myeloid differentiation and recruitment of immune cells into inflamed skin.

Photoaging is associated with an immunosuppressive state in skin which is attributed to an expansion of immunosuppressive cells, such as regulatory T cells. UVR-induced cGAS-STING signaling also stimulates the expression of PD-L1, a ligand for inhibitory immune checkpoint receptor, which evokes an exhaustion of effector immune cells. There is clear evidence that cGAS-STING signaling can also accelerate chronological aging by remodeling the immune network.

Some forms of respiratory infection can cause lasting issues and loss of function. It has been suspected that an increased burden of senescent cells is one of the mechanisms involved in post-infection effects. While senescent cells are created constantly throughout life, a population of lingering senescent cells grows with age to disrupt tissue structure and function via inflammatory signaling. An increase in this burden of senescent cells is already known to cause increased mortality and risk of age-related disease in cancer survivors treated with chemotherapy and radiotherapy, so it should not be surprising to find this outcome occurring in other conditions and treatments that place a great deal of stress on cells for an extended period of time.

Influenza A virus (IAV) infection causes acute and long-term lung damage. Here, we used immunostaining, genetic, and pharmacological approaches to determine whether IAV-induced cellular senescence causes prolonged alterations in lungs. Mice infected with a sublethal dose of H1N1p2009 exhibited cellular senescence, as evidenced by increased pulmonary expression of p16, p21, β-galactosidase and the DNA damage marker gamma-H2A.X. Cellular senescence began 4 days post-infection (dpi) in the bronchial epithelium, then spread to the lung parenchyma by 7 and 28 dpi (long after viral clearance), and then declined by 90 dpi. At 28 dpi, the lungs showed severe remodeling with structural bronchial and alveolar lesions, abrasion of the airway epithelium, and pulmonary emphysema and fibrotic lesions that persisted up to 90 dpi.

In mice and nonhuman primates, persistence of senescent cells in the bronchial wall on 28 dpi was associated with abrasion of the airway epithelium. In p16-ATTAC mice, depletion of p16-expressing cells with AP20187 reduced pulmonary emphysema and fibrosis and led to complete recovery of the airway epithelium at 28 dpi, indicating a marked acceleration of the epithelial repair process. Treatment with the senolytic drug ABT-263 also accelerated epithelial repair without affecting pulmonary fibrosis or emphysema. These positive effects occurred independently of viral clearance and lung inflammation at 7 dpi. Finally, AP20187 treatment of p16-ATTAC mice at 15 dpi led to complete recovery of the airway epithelium at 28 dpi.

Thus, virus-induced senescent cells contribute to the pulmonary sequelae of influenza; targeting senescent cells may represent a new preventive therapeutic option.

Link: https://doi.org/10.1111/acel.70140

Infectious disease is a major cause of late life mortality, the result of the age-related decline of immune function. The sizable investment in time and funding that goes into efforts to enhance the efficacy of vaccines in older adults is one example of the costs of attempting to cope with the consequences of aging. Developing new vaccines and better vaccination techniques is an expensive process. Yet coaxing the aged immune system into greater efforts via the use of adjuvants and other more sophisticated vaccine engineering cannot produce the degree of benefit that a much more crude vaccination will produce in a younger adult - one is inherently limited by the aging of the immune system. This is one of many areas in which rejuvenation of youthful function is a far better goal to aim for.

Older persons (65 and above) comprise the world´s fastest-growing age group today. Enabling older individuals to live independently, remain socially engaged, and manage or prevent chronic illnesses contributes to reducing healthcare costs and improving overall quality of life. Infectious diseases are a major cause of morbidity and mortality in the older population. In 2021, COVID-19 alone was the third most frequent cause of death for people over 65 (10.9% of all deaths) in the EU. This highlights the devastating effect infectious diseases can have on older populations. Co-morbidities, such as chronic heart or lung disease and diabetes, further increase the risk for severe infections.

The overall morbidity of infectious diseases in older adults is frequently underestimated. In addition to the immediate impact of the acute disease, there are several other risks and sequelae associated with infections in this age group. Many older persons do not recover fully after an acute episode of infection. A study in Canada reported 12% mortality in patients aged 65 and older hospitalized for influenza infection, and 20% suffered a decrease in their functional status (9% moderate decrease, 11% catastrophic disability) after recovery.

Therefore, preventing infectious disease is an important measure to ensure healthy aging and preserve the quality of life. Vaccines against influenza and pneumococcal disease have long been available. This review focuses on novel developments regarding vaccines for older adults including strategies to improve and advance existing vaccines and the recent development of vaccines against additional pathogens, such as Respiratory Syncytial virus. There are still many additional pathogens, for which vaccines are highly desirable for older adults. Age-associated changes of the immune system can impair the immunogenicity and protective effect of vaccines and therefore specific strategies to protect this vulnerable population are necessary.

Link: https://doi.org/10.1080/21645515.2025.2517931