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Age-Related Loss of Selenoprotein P in Macrophages Impairs Muscle Regeneration
https://www.fightaging.org/archives/2025/07/age-related-loss-of-selenoprotein-p-in-macrophages-impairs-muscle-regeneration/
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.
Reduced Lysosomal Acid Lipase in the Pathology Alzheimer’s Disease
https://www.fightaging.org/archives/2025/07/reduced-lysosomal-acid-lipase-in-the-pathology-alzheimers-disease/
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.
Cellular Senescence in Osteoblasts as a Contributing Cause of Osteoporosis
https://www.fightaging.org/archives/2025/07/cellular-senescence-in-osteoblasts-as-a-contributing-cause-of-osteoporosis/
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.
Mitrix Bio Set to Test Mitochondrial Transplantation in Volunteers
https://www.fightaging.org/archives/2025/07/mitrix-bio-set-to-test-mitochondrial-transplantation-in-volunteers/
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.”
Too Much Klotho Increases Cancer Risk in Cancer Survivors
https://www.fightaging.org/archives/2025/08/too-much-klotho-increases-cancer-risk-in-cancer-survivors/
An infrequently discussed topic in aging circles is the point that we should probably expect any therapy that improves tissue maintenance and regeneration in old people to also increase cancer risk. There isn’t much in the way of evidence to support that position, but it seems worthy of consideration. Cancer is a numbers game, and the greater the activity undertaken by stem cells and progenitor cells, the greater the likelihood of cancerous mutations. The only exceptions are interventions that act to improve the function of the immune system in addition to any other benefits that they produce; such treatments could lead to a net reduction in cancer risk, due to improved immunosurveillance of potentially cancerous cells. A plausible example of this type of treatment is telomerase gene therapy, though it remains to be demonstrated that improved immune function is the mechanism by which cancer risk is reduced in animal studies.
With this in mind, researchers here show that too much klotho can increase cancer risk in cancer survivors. Cancer survivors exhibit a greater risk of later cancer mortality than other age-matched individuals. This is in part due to the risk of recurrence of the treated cancer, but also because chemotherapy and radiotherapy stress cell populations to produce an increased burden of cellular senescence in these patients. Greater levels of klotho correlate with greater longevity in the population at large, but to the degree that greater longevity goes hand in hand with increased cell activity, regenerative capacity, and tissue maintenance, then it will also increase the risk of cancer. It should be easier to quantify that risk in the epidemiological data for cancer survivors than in the general population, and hence this study.
Circulating Klotho and mortality patterns among US cancer survivors: A cohort study
Klotho, a longevity hormone, exerts diverse anticancer activities. However, evidence regarding the association between serum Klotho and mortalities among cancer survivors is lacking. We examined the association between serum Klotho and the risks of all-cause and cancer mortalities among 1602 cancer adults from the National Health and Nutrition Examination Survey (NHANES) (2007-2016) using multivariate Cox proportional hazard models. The nonlinear relationship was determined using the likelihood ratios test, and the inflection points and 2-piecewise Cox proportional hazards regression models were computed.
After a median follow-up period of 84.0 months, U-shaped associations between circulating Klotho and all-cause and cancer mortality were observed, with identified inflection points (pg/mL) of 765.5 for all-cause and 767.6 for cancer mortality. Klotho below these thresholds was inversely associated with all-cause mortality (Hazard ratio, HR = 0.72) and cancer mortality (HR = 0.61; Klotho above the threshold showed a trend of positive associated with cancer mortality (HR = 1.22). Effect modification of age was apparent; Klotho was associated positively with cancer mortality risk among participants aged under 60 (HR = 1.50). The U-shaped associations between serum Klotho and all-cause and cancer mortality indicate that maintaining an ideal Klotho level in cancer patients could reduce mortality risks.
Circadian Rhythm Disruption in Parkinson’s Disease
https://www.fightaging.org/archives/2025/07/circadian-rhythm-disruption-in-parkinsons-disease/
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.
Further Exploring How the Hypoxic Response Slows Aging
https://www.fightaging.org/archives/2025/07/further-exploring-how-the-hypoxic-response-slows-aging/
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.
Screening for Compounds that Reduce Age-Related Transcriptional Changes in Brain Cells
https://www.fightaging.org/archives/2025/07/screening-for-compounds-that-reduce-age-related-transcriptional-changes-in-brain-cells/
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.
Targeting the Hallmarks of Aging
https://www.fightaging.org/archives/2025/07/targeting-the-hallmarks-of-aging/
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.
Increased PAI-1 Expression Contributes to Degenerative Aging
https://www.fightaging.org/archives/2025/07/increased-pai-1-expression-contributes-to-degenerative-aging/
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.
Reviewing the Potential of Gene Therapies to Treat Aging
https://www.fightaging.org/archives/2025/07/reviewing-the-potential-of-gene-therapies-to-treat-aging/
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.
Accelerated Biological Age Measures Correlate with a Higher Risk of Disease and Mortality
https://www.fightaging.org/archives/2025/07/accelerated-biological-age-measures-correlate-with-a-higher-risk-of-disease-and-mortality/
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.
Further Assessment of an Organ-Specific Proteomic Aging Clock
https://www.fightaging.org/archives/2025/07/further-assessment-of-an-organ-specific-proteomic-aging-clock/
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.
Reviewing the Aging of the Intestines
https://www.fightaging.org/archives/2025/08/reviewing-the-aging-of-the-intestines/
Humans tend to die from cardiovascular aging, while flies tend to die from intestinal aging. The intestines of humans age and become dysfunctional, as they do in flies, of course. But intestinal aging usually isn’t a severe enough cause of issues in and of itself to win out over cardiovascular disease, pulmonary disease, and the other more common causes of death. It may well contribute meaningfully to all of those other causes of mortality! The converse can be said for the aging of the cardiovascular system in flies; the consequences are usually less severe than those of intestinal aging in that species. Nonetheless, researchers spend a good deal of time with flies in the study of intestinal aging, as this review paper makes clear.
Intestinal aging is central to systemic aging, characterized by a progressive decline in intestinal structure and function. The core mechanisms involve dysregulation of epithelial cell renewal and gut microbiota dysbiosis. In addition to previous results in model organisms like Drosophila melanogaster, recent studies have shown that in mammalian models, aging causes increased intestinal permeability and intestinal-derived systemic inflammation, thereby affecting longevity. Therefore, anti-intestinal aging can be an important strategy for reducing frailty and promoting longevity.
There are three key gaps remaining in the study of intestinal aging: (1) overemphasis on aging-related diseases rather than the primary aging mechanisms; (2) lack of specific drugs or treatments to prevent or treat intestinal aging; (3) limited aging-specific dysbiosis research. In this review, the basic structures and renewal mechanisms of intestinal epithelium, and mechanisms and potential therapies for intestinal aging are discussed to advance understanding of the causes, consequences, and treatments of age-related intestinal dysfunction.
An Example of the Harms Done by Too Little Circulating Klotho
https://www.fightaging.org/archives/2025/08/an-example-of-the-harms-done-by-too-little-circulating-klotho/
When people talk about klotho, they usually mean α-klotho, and specifically the soluble fragment of α-klotho that is secreted by cells to circulate in the body. Researchers have demonstrated in animal studies that high levels of α-klotho slow aging to extend life while low levels accelerate aging to shorten life. In humans, higher circulating levels of α-klotho correlate with a lower risk of age-related disease and longer life expectancy, and vice versa. Enumerating the mechanisms by which α-klotho affects the pace of aging, and determining which are more or less important than the others, remains a work in progress. The research noted here is an example of this ongoing work, and is focused on the effects that α-klotho has on muscle tissue.
Muscle wasting and weakness are important clinical problems that impact quality of life and health span by restricting mobility and independence, and by increasing the risk for physical disability. The molecular basis for this has not been fully determined. Klotho expression is downregulated in conditions associated with muscle wasting, including aging, chronic kidney disease, and myopathy. The objective of this study was to investigate a mechanistic role for Klotho in regulating muscle wasting and weakness.
Body weight, lean mass, muscle mass, and myofiber caliber were reduced in Klotho-deficient mice. In the tibialis anterior muscle of Klotho null mice, type IIa myofibers were resistant to changes in size, and muscle composition differed with a higher concentration of type IIb fibers to the detriment of type IIx fibers. Glycolytic enzymatic activity also increased. The composition of the soleus muscle was unaffected and myofiber caliber was reduced comparably in type I, IIa, and IIx fibers. Muscle contractile function declined in Klotho-deficient mice, as evidenced by reduced absolute twitch and torque, and decreased rates of contraction and relaxation.
RNA-sequencing analysis identified increased transcriptional expression of synaptic and fetal sarcomeric genes, which prompted us to test effects on muscle innervation. Klotho-deficiency induced morphological remodeling of the neuromuscular junction, myofiber denervation, and a functional loss of motor units. Loss of motor units correlated with absolute torque. Collectively, our findings have uncovered a novel mechanism through which Klotho-deficiency leads to alterations to the muscle synapse affecting motor unit connectivity that likely influences muscle wasting and weakness.
