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Considering Mutation Rates in Cancer Risk and Species Life Span
https://www.fightaging.org/archives/2025/06/considering-mutation-rates-in-cancer-risk-and-species-life-span/
Today’s open access paper merges discussion of a number of related topics. Firstly mutation rate in cancer tissue and its relationship to success in immunotherapy, secondly mutation rate in normal tissues as a risk factor for the development of cancer, and thirdly the radically different cancer risks exhibited by different mammalian species. It is well known that long-lived, large species have a much reduced cancer risk relative to short-lived, small species, and as researchers note here, this relationship is better mapped to mutation rates rather than to size or life span. Separately, within a species, cancer is clearly an age-related condition, where risk relates to the accumulated burden of somatic mutations within tissues.
Can the comparative biology of cancer and DNA damage lead to novel approaches to treat cancer or reduce cancer risk in humans? As for all aspects of comparative biology, it is entirely unclear as to whether even the discovery of an influential single genetic difference could give rise to a useful basis for therapy in the near term. On some time scale humanity will engineer itself, create better genomes. We stand a fair way removed from the ability to safely adopt even single gene differences at this time, however. Delivery of gene therapies to desired tissues in adults is a challenge, understanding second order effects is a challenge, and we don’t know what we don’t know.
Super-high tumor mutational burden predicts complete remission following immunotherapy: from Peto’s paradox to druggable cancer hallmark
The somatic mutation theory predicts that cancer risk should scale proportionally with lifetime cell divisions; yet large-bodied and long-lived species exhibit lower-than-expected cancer incidence – a long-standing contradiction termed Peto’s paradox. Although Peto’s paradox has puzzled scientists for nearly half a century, its underlying mechanisms remain incompletely understood. This study clarifies this enigma by presenting novel evidence: larger-bodied animals generally exhibit a lower-than-expected cancer incidence relative to their body mass, whereas life expectancy only weakly correlates with cancer risk across species. In sharp contrast, cancer incidence in humans is strongly age-dependent, rising exponentially after the age of 40, indicating that chronological aging contributes to the majority (more than 80%) of lifetime cancer risk.
Through comparative analysis of cross-species mutation rates, this study reconciles the conflict between the age-dependent cancer risk in humans and the inter-species variability encapsulated in Peto’s paradox. As an iconic example, elephants have evolved enhanced DNA repair mechanisms, notably through expanded copies of the TP53 gene, to curb mutagenesis and preserve genomic integrity, effectively suppressing mutational accumulation within a tolerable amount despite their massive body size and long lifespans. Conversely, smaller and short-lived animals like mice accumulate mutations at a much faster rate, which corresponds to their higher-than-expected cancer incidence.
Notably, this study unifies these observations by identifying a universal pattern: both somatic mutation rate and cumulative lifetime mutation burden correlate strongly with cancer risk across species, positioning mutational burden as a fundamental and evolutionarily conserved hallmark of cancer, transcending species boundaries.
Healthcare Must Change as We Become More Capable of Intervening in Aging
https://www.fightaging.org/archives/2025/06/healthcare-must-change-as-we-become-more-capable-of-intervening-in-aging/
The present approach to aging in the healthcare community is uncomfortably close to being a matter of Cnut the Great on the beach telling the tide to go back. In clinical practice most of the major diseases of aging remain irreversible for the average individual, a progression that can only be modestly slowed. The only way to achieve the possibility of turning back these conditions is to repair the forms of accumulated cell and tissue damage that maintain the body and brain in a diseased state – to use rejuvenation therapies. The development of these therapies is painfully slow. It has been clear that clearance of senescent cells is very promising for a decade now, but it will be years yet before any large scale human data emerges for senolytic approaches that work well.
The point of today’s open access commentary is that the establishment of even crude and limited capabilities for rejuvenation will necessarily require a major upheaval in the way the clinical community engages with aging and age-related disease. The heroic model of coping with the inevitable must be abandoned. Something more useful must take its place. The author here argues that the medical community must shift its primary focus away from end stage disease towards earlier intervention to prevent that disease. This already exists as a major focus of the cardiovascular disease community, even if the preventative technologies used there are not all that great in the grand scheme of things. But for much of the rest of the medical community enacting such a change will be a sizable upheaval.
Rethinking healthcare through aging biology
Modern medicine has revolutionized the way we diagnose and treat diseases, achieving remarkable success in extending life expectancy. Yet, despite these advances, the traditional disease-centric healthcare model has significant limitations. This approach typically kicks in only after pathology has manifested-when patients exhibit symptoms, seek treatment, receive a diagnosis, and begin therapy. While reactive care has its merits, it increasingly falls short in addressing the needs of aging populations. As people age, they often develop a constellation of chronic conditions – multimorbidity – that strains the healthcare system and diminishes quality of life. Conditions such as cardiovascular disease, type 2 diabetes, osteoarthritis, neurodegeneration, and cancer frequently coexist, leading to complex and often ineffective treatments. Polypharmacy – the use of multiple medications to treat co-existing diseases – introduces further complications, including drug interactions, side effects, reduced adherence to treatment regimens, and increased hospitalizations.
Moreover, this disease-specific focus neglects the underlying causes of age-related decline – the very mechanisms that fuel the development of these diseases. However, recent breakthroughs in aging research have unveiled an exciting opportunity: the shared biological roots of many age-related diseases. These mechanisms, known as the hallmarks of aging, often precede the onset of disease by decades. Targeting these aging processes before diseases fully develop offers a bold new approach: not just treating diseases, but preventing them in the first place.
This shift in focus from reactive disease management to proactive healthspan extension is transformative. By intervening early in the aging process, we could delay or even prevent multiple diseases, addressing not just the symptoms, but the biological declines that underlie them. In this context, cutting-edge interventions such as senolytics and rapalogs exemplify the promising potential of targeting aging itself. Senolytics, which selectively eliminate senescent cells that accumulate with age and contribute to chronic inflammation and tissue dysfunction, have shown promise in extending healthspan and alleviating a range of age-related conditions. Likewise, rapalogs – drugs that target the mTOR pathway, a central regulator of cell growth and metabolism – have demonstrated the ability to extend lifespan and improve healthspan by promoting autophagy, enhancing immune function, and reducing inflammation. As clinical trials continue, these interventions are poised to transform aging medicine, but the road to widespread clinical application remains challenging.
Excess Lipids in Muscle Cells as a Contribution to Muscle Aging
https://www.fightaging.org/archives/2025/06/excess-lipids-in-muscle-cells-as-a-contribution-to-muscle-aging/
Repair Biotechnologies, the company I co-founded, develops therapies based on the ability to selectively clear only excess cholesterol inside cells. This is normally an undruggable target. Cholesterol is essential to cell function, but expensive to manufacture. Species evolved a central factory for cholesterol production, the liver, and a complicated system of distribution that delivers cholesterol to and from the liver as needed. The vast majority of cells in the body neither manufacture nor break down cholesterol, but are completely dependent on it. Worse, too much cholesterol is toxic, and cells have little ability to deal with that toxicity when it occurs due to age-related or obesity-related dysregulation of cholesterol transport.
While Repair Biotechnologies focuses on reversal of atherosclerosis, an arguably equally important confirmation to come out of ongoing work at the company is that the presence of excess cholesterol inside cells – and likely other lipids as well – is an important contribution to age-related dysfunction in many tissues throughout the body. Whenever the Repair Biotechnologies scientists branch out to assess a new tissue in mice following treatment to clear intracellular cholesterol and see functional or structural improvement, that is a demonstration of the relevance of intracellular cholesterol to pathology in that tissue.
Thus it is always interesting to see some portions of the research community discussing the excess lipid issue with a focus on their specific tissue or organ of interest. Today’s open access paper argues for the importance of excess cholesterol and other lipids in muscle cells. The infiltration of fat into muscle tissue with age and obesity is known to be a bad thing, but here the focus is more on the presence of excess lipids inside muscle cells and how that can be thought to contribute to the cellular dysfunctions that give rise to age-related loss of muscle mass and strength. The Repair Biotechnologies team has not assessed muscle tissue and muscle cells in any great detail to date, as this isn’t on the roadmap to treating atherosclerosis, but perhaps they should.
Targeting intramyocellular lipids to improve aging muscle function
Decline of skeletal muscle function in old age is a significant contributor to reduced quality of life, risk of injury, comorbidity, and disability and even mortality. While this loss of muscle function has traditionally been attributed to sarcopenia (loss of muscle mass), it is now generally appreciated that factors other than mass play a significant role in age-related muscle weakness. One such factor gaining increased attention is the ectopic accumulation of lipids in skeletal muscle, in particular, intramyocellular lipids (IMCLs). It has been appreciated for some time that metabolic flexibility of several tissues/organs declines with age and may be related to accumulation of IMCLs in a “vicious cycle” whereby blunted metabolic flexibility promotes accumulation of IMCLs, which leases to lipotoxicity, which can then further impair metabolic flexibility.
The standard interventions for addressing lipid accumulation and muscle weakness remain diet (caloric restriction) and exercise. However, long-term compliance with both interventions in older adults is low, and in the case of caloric restriction, may be inappropriate for many older adults. Accordingly, it is important, from a public health standpoint, to pursue potential pharmacological strategies for improving muscle function. Because of the success of incretin-analog drugs in addressing obesity, these medications may potentially reduce IMCLs in aging muscles and thus improve metabolic flexibility and improve muscle health. A contrasting potential pharmacological strategy for addressing these issues might be to enhance energy provision to stimulate metabolism by increasing NAD + availability, which is known to decline with age and has been linked to reduced metabolic flexibility.
In this narrative review, we present information related to IMCL accumulation and metabolic flexibility in old age and how the two major lifestyle interventions, caloric restriction and exercise, can affect these factors. Finally, we discuss the potential benefits and risks of select pharmacologic interventions in older adults.
Reviewing What is Known of the Role of the Gut Microbiome in Aging
https://www.fightaging.org/archives/2025/06/reviewing-what-is-known-of-the-role-of-the-gut-microbiome-in-aging-2/
The gut microbiome is made of thousands of microbial species in various proportions, some helpful, some harmful. The development of means to accurately measure the composition of the gut microbiome, by sequencing the 16S rRNA gene that exhibits characteristic species-level differences, has enabled the scientific community to connect changes in the gut microbiome to aging, health, and disease. This mapping of the gut microbiome as a contributing factor in aging and age-related diseases is still in the relatively early stages, but as the field progresses we should expect to see increased interest in the development of novel, improved means to alter the gut microbiome as form of therapy.
The composition of the gut microbiome is fairly resilient to short-term changes induced by diet, present probiotic and prebiotic supplements, mild antibiotic use, and the like. It will bounce back. Over decades of life, however, changes do occur in the balance of microbial populations, and they are not favorable. Inflammatory microbes grow in number at the expense of microbes that generate metabolites necessary for optimal tissue function. Some of this is a consequence of long-term shifts in diet in older individuals, some of it is the decline of the immune system in its role as gardener of the gut microbiome, some of it is other factors. The relative importance of each of these items has yet to be concretely determined.
Fortunately there are ways to permanently change the gut microbiome. Flagellin immunization will direct the immune system to more aggressively remove problem microbes, reshaping the whole microbiome into a more favorable configuration of populations. Fecal microbiota transplantation from a young donor to an old recipient will rejuvenate the balance of populations, and has been shown to produce health and longevity benefits in animal studies. The problem there is that it is unclear as to what exactly constitutes a beneficial microbe, and so it seems likely that fecal microbiota transplantation will be discarded in favor of culturing specific known mixes of microbes that can be delivered once via enteric capsules or similar to achieve a similar but more controlled outcome.
The gut microbiota and aging: interactions, implications, and interventions
Aging is associated with notable shifts in the composition and function of the gut microbiota. Research indicates a decrease in microbial diversity and changes in the abundance of specific bacterial groups in older individuals compared to younger counterparts. For instance, there tends to be an increase in Escherichia coli and other Proteobacteria and a decrease in beneficial bacteria like Bacteroides and Bifidobacterium, essential for gut health and overall wellbeing. Centenarians, a unique subset of elderly individuals, serve as a fascinating model for studying longevity and investigating gut microbiota alterations that could potentially facilitate healthier aging. Centenarians exhibit a noteworthy trend: an elevation in genera such as Akkermansia, which holds potential implications for longevity.
These alterations in the gut microbiota are influenced by several factors, including dietary changes, reduced physical activity, increased medication use, and physiological changes in the gastrointestinal tract such as decreased gut motility. The decline in beneficial bacteria and the proliferation of potentially pathogenic microbes contribute to an imbalanced gut environment, often referred to as dysbiosis. Dysbiosis in the elderly has been associated with various age-related conditions, like inflammaging, cognitive decline, neurodegeneration, insulin resistance, type 2 diabetes mellitus, cardiovascular disease, and cancer.
Given the critical role of the gut microbiota in aging and age-related diseases, there is a growing interest in microbiota-targeting interventions to promote healthy aging. In addition to dietary modifications, probiotics, non-viable probiotics (paraprobiotics), prebiotics, synbiotics, and microbial soluble factors (postbiotics) have garnered significant attention for their potential to modulate the gut microbiota and enhance the health of the elderly. Although still in the experimental stages for age-related conditions, fecal microbiota transplantation (FMT) has shown promise in restoring a healthy microbiota and improving metabolic and immune functions in older adults, based on animal studies.
Is LDL Cholesterol Actually Important to Cardiovascular Risk Across the Whole Population?
https://www.fightaging.org/archives/2025/06/is-ldl-cholesterol-actually-important-to-cardiovascular-risk-across-the-whole-population/
Cholesterol attached to LDL particles leaves the liver to be transported in the bloodstream to tissues throughout the body. Along the way, this is expected to contribute to development of atherosclerosis in blood vessel walls via deposition of excessive cholesterol in some locations. Patients with homozygous familial hypercholesterolemia, who exhibit loss of function mutations in the LDL receptor and enormously elevated LDL cholesterol in blood, demonstrate that past a certain point there is a dramatic acceleration of atherosclerosis resulting from too much transported cholesterol. Untreated, these patients typically die in their 30s from heart attack or stroke.
What about the rest of the population with a more normal varied range of LDL cholesterol levels, however? The consensus on lowering LDL cholesterol as the dominant approach to reduce atherosclerotic cardiovascular disease risk is not without its challengers. Physicians note that most of the aged patients who present with a first heart attack or stroke do not have elevated LDL cholesterol. Epidemiologists note that the data suggests that the mechanisms of atherosclerosis vary considerably across the population. People respond very differently to cholesterol levels and pharmacological strategies to reduce them. This is one of the reasons why very large trials are needed to see effect sizes resulting from lowered LDL cholesterol.
Today’s open access paper is an example of the body of literature that challenges the consensus on the practice of setting targets for LDL cholesterol levels, and the relevance of LDL cholesterol to disease. A reasonable view of the situation is that some fraction of the population does suffer when LDL cholesterol is too high, and thus does benefit from the therapeutic strategy of lowering LDL cholesterol – but at present there is no good way to identify in advance whether any given individual is in that group. The underlying biochemistry is not fully understood, and outcomes arise only slowly over time, a situation in which producing greater understanding is necessarily expensive, and thus few groups are willing to make the effort.
Is Targeting LDL-C Levels Below 70 mg/dL Beneficial for Cardiovascular and Overall Health? A Critical Examination of the Evidence
Over the past two decades, the strategy for managing cardiovascular disease (CVD) risk with lipid-lowering therapy has changed significantly. LDL-cholesterol (LDL-C) targets in guidelines have been progressively lowered from 100 mg/dL (2.6 mmol/L) or less to 70 mg/dL (1.8 mmol/L) or less for high-risk patients and 55 mg/dL (1.4 mmol/L) or less for very high-risk patients. The reduction in target LDL-C levels was stated as justified based on the appearance that intensive lipid-lowering therapy offered additional cardiovascular benefits compared to the standard regimens.
The establishment of low LDL-C targets in CVD prevention was based on the premise that there is a linear relationship between LDL-C levels and CVD risk. However, this premise faces several challenges: (1) The supposed direct correlation between LDL-C levels and atherosclerosis progression is questionable; (2) The systematic reviews that provided the foundation for this assumption have several limitations, including extrapolation of results for LDL-C levels beyond observed data; (3) Potential bias due to the ecological fallacy stemming from meta-regression results based on study-level rather than patient-level analyses; (4) Inconsistent findings from trials specifically designed to investigate the relationship between LDL-C targets and CVD risk; (5) Research documenting greater longevity of elderly individuals with familial – as well as non-familial – hypercholesterolemia contradicts the premise that lower LDL-C levels are ideal.
In this paper, we address these challenges point by point, providing evidence to support each argument. We also point out that LDL-C is a hybrid measure composed of heterogeneous particles, with varying atherogenicity depending on the size of the particles. Finally, we address evidence that pleiotropic effects of lipid-lowering therapies, particularly statins, may contribute to cardiovascular benefits, independent of LDL-C reduction. This paper, therefore, presents evidence to challenge current LDL-C targets of 70 mg/dL or less in patients at high CVD risk.
Calorie Restriction Improves Measures of Ovarian Aging in Non-Human Primates
https://www.fightaging.org/archives/2025/06/calorie-restriction-improves-measures-of-ovarian-aging-in-non-human-primates/
Calorie restriction is well known to slow aging in mammals. Short-term improvements in metabolism are fairly similar across mammalian species, but short-lived mammals show a much greater extension of life span in response to calorie restriction than is the case in long-lived mammals such as our own species. Why this is the case remains to be determined, but one might suspect that the answer lies somewhere in the still incompletely cataloged details of autophagy – how exactly autophagy changes with age, and how exactly autophagy differs between species. Researchers have demonstrated that the cellular maintenance processes of autophagy are required to function correctly in order for a slowing of aging to result from calorie restriction, making it the first place to look.
Ovarian aging results in decreased fertility and endocrine function. In mice, caloric restriction (CR) maintains ovarian function. In this study, we determined whether CR also has a beneficial effect on reproductive longevity in the nonhuman primate (NHP). Ovaries were collected from young (10-13 years) and old (19-26 years) rhesus macaques who were either on a diet of moderate caloric restriction or a control diet for three years. To test the effect of CR on follicle number, follicles were analyzed in histological sections from animals across experimental cohorts: Young Control, Young CR, Old Control, Old CR (n = 4-8/group).
In control animals, there was an age-dependent decrease in follicle numbers across all follicle stages. Although there was no effect of diet on total follicle number, the follicle distribution in the Old CR cohort more closely resembled that of young animals. The subset of Old CR animals that were still cycling, albeit irregularly, had more primordial follicles than controls. Assessment of collagen and hyaluronic acid matrices revealed that CR attenuated age-related changes to the ovarian microenvironment. Overall, CR may improve aspects of reproductive longevity in the NHP, but the timing of when it occurs during the reproductive lifespan is likely critical.
A Role for STING Mediated Inflammation in Neurodegenerative Conditions
https://www.fightaging.org/archives/2025/06/a-role-for-sting-mediated-inflammation-in-neurodegenerative-conditions/
Neurodegenerative conditions are clearly associated with the chronic inflammation of aging. Unresolved inflammatory signaling is harmful to tissue structure and function, and a broad range of evidence points to dysregulated immune cell function in the brain as an important contribution to pathology. Inflammatory signaling is complex, however, and finding ways to intervene in unwanted sustained inflammatory reactions that do not also sabotage normal necessary short-term inflammatory reactions has so far proven to be challenging. Here, researchers focused on a well-studied innate immune regulator of inflammation, STING, and show that disabling it can reduce both inflammation in the brain and the progression of Alzheimer’s pathology in a mouse model of the condition.
While immune dysfunction has been increasingly linked to Alzheimer’s disease (AD) progression, many major innate immune signaling molecules have yet to be explored in AD pathogenesis using genetic targeting approaches. To investigate a role for the key innate immune adaptor molecule, stimulator of interferon genes (STING), in AD, we deleted STING in the 5xFAD mouse model of AD-related amyloidosis and evaluated the effects on pathology, neuroinflammation, gene expression, and cognition.
Genetic ablation of STING in 5xFAD mice led to improved control of amyloid beta (Aβ) plaques, alterations in microglial activation status, decreased levels of neuritic dystrophy, and protection against cognitive decline. Moreover, rescue of neurological disease in STING-deficient 5xFAD mice was characterized by reduced expression of type I interferon signaling genes in both microglia and excitatory neurons. These findings reveal critical roles for STING in Aβ-driven neurological disease and suggest that STING-targeting therapeutics may offer promising strategies to treat AD.
Aged Neurons Exhibit Dysregulated RNA Processing and are More Vulnerable to Stress
https://www.fightaging.org/archives/2025/06/aged-neurons-exhibit-dysregulated-rna-processing-and-are-more-vulnerable-to-stress/
One might view this paper as a companion to a recent discussion of the greater vulnerability of the aged brain to amyloid-β toxicity. Here, researchers point out the dysregulation of RNA splicing in aged neurons, and note its contribution to a greater vulnerability to forms of cell stress. Degenerative aging is formed of many contributions, and every perturbation in normal cell metabolism leaves cells vulnerable to other forms of change and damage. It builds upon itself, degrading function, until some major catastrophe results, both at the level of individual cells and their survival, and at the level of tissues and organs. Addressing the dysregulation of RNA splicing is the subject of a few programs in academia and startup biotech companies such as SENISCA, but these remain at relatively early stages of development.
Aging is one of the most prominent risk factors for neurodegeneration, yet the molecular mechanisms underlying the deterioration of old neurons are mostly unknown. To efficiently study neurodegeneration in the context of aging, we transdifferentiated primary human fibroblasts from aged healthy donors directly into neurons, which retained their aging hallmarks, and we verified key findings in aged human and mouse brain tissue.
Here we show that aged neurons are broadly depleted of RNA-binding proteins, especially spliceosome components. Intriguingly, splicing proteins – like the dementia- and ALS-associated protein TDP-43 – mislocalize to the cytoplasm in aged neurons, which leads to widespread alternative splicing. Cytoplasmic spliceosome components are typically recruited to stress granules, but aged neurons suffer from chronic cellular stress that prevents this sequestration. We link chronic stress to the malfunctioning ubiquitylation machinery, poor HSP90α chaperone activity, and the failure to respond to new stress events.
Together, our data demonstrate that aging-linked deterioration of RNA biology is a key driver of poor resiliency in aged neurons.
Reviewing the Measurement and Treatment of Immune System Aging
https://www.fightaging.org/archives/2025/06/reviewing-the-measurement-and-treatment-of-immune-system-aging/
With age the immune system becomes (a) ever less capable, but also (b) ever more inflammatory and overactive. Sustained inflammation is disruptive to tissue structure and function, contributing to age-related conditions, while the growing incapacity leads to an inability to sufficiently defend against infectious pathogens, destroy senescent cells, and destroy cancerous cells. The immune system is complex, the regulation of inflammation particularly so, and there are any number of measures that to some degree reflect the aging of the immune system. Not all of them are good, different measures are better or worse in specific contexts, and there is some degree of uncertainty over the quality of any given measure.
Identifying biomarkers of aging is essential for understanding their effects on health, disease, and responses to longevity-promoting interventions. Immunological biomarkers can help differentiate between changes that are driven by aging and those specific to diseases, which is particularly important for conditions that predominantly affect the elderly.
Novel biomarkers, such as the inflammatory aging clock (iAge), leverage deep learning to quantify chronic systemic inflammation and have shown strong correlations with multimorbidity and frailty. Additionally, immune cell proportion changes have been identified as significant biomarkers of aging. Recent studies using single-cell RNA sequencing (scRNA-seq) have revealed novel shifts in immune cell compositions, highlighting the complex and dynamic nature of immune aging. Moreover, lifestyle modifications, including diet and exercise, have shown promise in improving immune aging by positively impacting immunosenescence biomarkers. Additionally, certain drug interventions, such as metformin or mTOR inhibitors, offer targeted therapeutic benefits for conditions associated with immune aging.
This review aims to update the understanding of the clinical significance of immune aging, including its phenotypic and functional changes, and model immune aging in humans. We explore novel biomarkers and their roles, as well as potential strategies for mitigating the adverse effects of immunosenescence through targeted therapies and lifestyle modifications.
Fecal Microbiota Transplantation from Young Mice to Old Mice Improves Health
https://www.fightaging.org/archives/2025/06/fecal-microbiota-transplantation-from-young-mice-to-old-mice-improves-health/
The gut microbiome is made up of thousands of microbial species in various proportions. The balance of populations shifts with age to favor harmful, inflammatory microbes over beneficial microbes that manufacture metabolites necessary to normal tissue function. This contributes to degenerative aging to some degree. One of the few ways to permanently alter the gut microbiome is to transplant fecal matter from one animal to another. Fecal microbiota transplantation from a young donor to an old recipient rejuvenates the gut microbiome, restoring youthful population levels. The study here is one of a number to demonstrate that this procedure improves health in old mice, removing much of the contribution of an aged gut microbiome to degenerative aging of the body and brain.
The gut microbiota evolves over a lifetime and significantly impacts the aging process. Targeting the gut microbiota represents a novel avenue to delay aging and aging-related physical and mental decline. However, the underlying mechanism by which the microbiota modulates the aging process, particularly age-related physical and behavioral changes is not completely understood.
We conducted fecal microbiota transplantation (FMT) from young or old male donor mice to the old male recipients. Old recipients with young microbiota had a higher alpha diversity than the old recipients with old microbiota. Compared to FMT with old microbiota, FMT with young microbiota reduced body weight and prevented fat accumulation in the old recipients. FMT with young microbiota also lowered frailty, increased grip strength, and alleviated depression and anxiety-like behavior in the old recipients.
Consistent with observed physical changes, untargeted metabolomic analysis of serum and stools revealed that FMT with young microbiota lowered age-related long-chain fatty acid levels and increased amino acid levels in the old recipients. Bulk RNAseq analysis of the amygdala of the brain showed that FMT with young microbiota downregulated inflammatory pathways and upregulated oxidative phosphorylation in the old recipients. Our results demonstrate that FMT with young microbiota has substantial positive influences on age-related body composition, frailty, and psychological behaviors. These effects are associated with changes in host lipid and amino acid metabolism in the periphery and transcriptional regulation of neuroinflammation and energy utilization in the brain.
A Dose-Response Curve for Physical Activity and Slowed Brain Aging
https://www.fightaging.org/archives/2025/06/a-dose-response-curve-for-physical-activity-and-slowed-brain-aging/
Studies of the dose-response curve for exercise have typically shown that little exercise is much better than no exercise, and gains continue at a slowing pace up to a fair way above the recommendation of 150 minutes of moderate to vigorous physical activity per week. See research showing that two to four times that amount further improves outcomes, for example. At some point, however, diminishing returns tip over into harm. There is such as thing as too much physical activity, though few people reach that point. The study here, in which researchers generate a brain aging metric derived from neuroimaging data and correlate its progression with physical activity, is interesting for producing a dose-response curve that looks very similar to those derived from data on physical activity versus incidence of age-related disease or mortality.
A neuroimaging-derived biomarker termed the brain age is considered to capture the degree and diversity in the aging process of the brain, serving as a robust indicator of overall brain health. The impact of different levels of physical activity (PA) intensities on brain age is still not fully understood. A total of 16,972 eligible participants with both valid T1-weighted neuroimaging and accelerometer data from the UK Biobank were studied. Brain age was estimated using an ensemble learning approach called Light Gradient-Boosting Machine (LightGBM).
Over 1,400 image-derived phenotypes (IDPs) were initially chosen to undergo data-driven feature selection for brain age prediction. A measure of accelerated brain aging, the brain age gap (BAG) can be derived by subtracting the chronological age from the estimated brain age. A positive BAG indicates accelerated brain aging. PA was measured over a 7-day period using wrist-worn accelerometers, and time spent on light-intensity PA (LPA), moderate-intensity PA (MPA), vigorous-intensity PA (VPA), and moderate- to vigorous-intensity PA (MVPA) was extracted. The generalized additive model was applied to examine the nonlinear association between PA and BAG after adjusting for potential confounders.
The brain age estimated by LightGBM achieved an appreciable performance (r = 0.81, mean absolute error [MAE] = 3.65), which was further improved by age bias correction (r = 0.90, MAE = 3.03). We found that LPA (F = 2.47), MPA (F = 6.49), VPA (F = 4.92), and MVPA (F = 6.45) exhibited an approximate U-shaped relationship with BAG, demonstrating that both insufficient and excessive PA levels adversely impact brain aging. Improved brain health may be attainable through engaging in moderate amounts of objectively measured PA irrespectively of intensities.
An Epigenetic Clock For Intrinsic Capacity
https://www.fightaging.org/archives/2025/06/an-epigenetic-clock-for-intrinsic-capacity/
Researchers continue to produce a fair number of new aging clocks every year to attempt to measure biological age. One might at this point ask whether the life science community should instead focus on better understanding and utilizing the best of the existing clocks. No new clock can be applied naively to the assessment of potential therapies to slow or reverse aging, as a new clock arrives with no understanding of how exactly the measures making it up relate to specific forms of damage and dysfunction that drive aging. One cannot predict whether the clock will accurately reflect changes in biological age or risk of age-related disease if, for example, senescent cells are cleared, or mitochondrial function improved. Nonetheless, it seems that more effort goes to making new clocks than is put towards the calibration of existing clocks.
In 2015, the World Health Organization (WHO) introduced the concept of intrinsic capacity (IC), defined as the sum of all physical and mental capacities that an individual can draw on at any point in their life. The International Classification of Diseases, 11th Revision, recently added ‘aging-associated decline in IC’ under code MG2A10, standardizing the clinical use of IC globally as a metric of functional aging. Since the inception of IC, many studies have developed IC scores and demonstrated its association with health-related factors.
Despite the advantages of using IC to assess functional ability, current methods to quantify it require equipment and trained personnel, and the molecular and cellular mechanisms underlying its age-associated decline are still poorly understood. Here we used the INSPIRE-T cohort (1,014 individuals aged 20 to 102 years) to construct the IC clock, a DNA methylation-based predictor of IC, trained on the clinical evaluation of cognition, locomotion, psychological well-being, sensory abilities, and vitality. In the Framingham Heart Study, DNA methylation IC outperforms first-generation and second-generation epigenetic clocks in predicting all-cause mortality, and it is strongly associated with changes in molecular and cellular immune and inflammatory biomarkers, functional and clinical endpoints, health risk factors, and lifestyle choices. These findings establish the IC clock as a validated tool bridging molecular readouts of aging and clinical assessments of IC.
Caveolin-1 Gene Therapy Reduces Cognitive Decline in an Alzheimer’s Mouse Model
https://www.fightaging.org/archives/2025/06/caveolin-1-gene-therapy-reduces-cognitive-decline-in-an-alzheimers-mouse-model/
Researchers here assess a compensatory approach to the neurodegeneration of Alzheimer’s disease, meaning an enhancement of the ability of cells to operate in the face of damage rather than addressing the damage itself. This can inevitably only slow progression of the condition, and is not a path to a curative therapy. Nonetheless, tinkering with cell metabolism in order to slow disease progression is arguably the dominant approach to the development of new therapies. The research community needs to do better than this if we’re to see major advances in the treatment of aging and age-related conditions.
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by progressive synaptic loss and cognitive decline. Gene therapy that augments intrinsic neuroprotective pathways offers a promising strategy to mitigate neurodegeneration and prevent further cognitive loss. Caveolin-1 (Cav-1), a membrane lipid raft (MLR) scaffolding protein, regulates multiple pro-growth and pro-survival signaling pathways within plasmalemmal microdomains. Previously, we showed that AAV9-Synapsin-promoted Cav-1 (SynCav1) delivered to presymptomatic AD mice preserved cognitive functions and MLR-associated neurotrophic signaling. However, the therapeutic potential of SynCav1 delivered at the symptomatic stage of AD had not been tested. Therefore, the current study investigated the effect of hippocampal SynCav1 delivery at symptomatic age in two distinct preclinical AD models of amyloid pathology: PSAPP and APPKI mice.
Our results demonstrated that SynCav1 delivery to PSAPP and APPKI mice at symptomatic age consistently preserved hippocampal-dependent memory. Transcriptome profiling revealed that PSAPP-SynCav1 mice exhibited a similar transcript profile to age-matched wild-type mice. Gene Ontology enrichment analysis indicated downregulation of neurodegeneration-specific pathways and upregulation of synaptic and cognitive-related pathways in PSAPP-SynCav1 mice. In vitro, SynCav1-transfected mouse primary cortical neurons exhibited increased p-CaMKII and p-CREB expression, suggesting that SynCav1 may protect the central nervous system by enhancing neuronal and synaptic activity. Furthermore, activity-dependent neuroprotective protein (ADNP) was identified as a potential candidate mediating SynCav1’s neuroprotective effects on cognition. Subcellular membrane fractionation revealed that SynCav1 preserved MLR-localized pituitary adenylate cyclase-activating polypeptide type I receptor (PAC1R), a well-known regulator of ADNP expression. Together, these findings highlight SynCav1 as a unique and promising gene therapy candidate in the treatment of AD.
Atherosclerosis Remains the Silent Killer
https://www.fightaging.org/archives/2025/06/atherosclerosis-remains-the-silent-killer/
Rupture of the atherosclerotic plaque that grows in arteries leads to the death of more than a quarter of humanity via heart attack and stroke. It is the single largest cause of human mortality. Imaging approaches for characterizing size and composition of atherosclerotic plaques have improved immensely over the past twenty years, but remain expensive enough in clinical practice to ensure they are used far less often then they might be. The average older individual in wealthier parts of the world may know that he or she has plaque, has been imaged within the past few years, but is unlikely to keep apace of how exactly that plaque is changing. As researchers note here, plaque doesn’t just grow over time, it quietly changes composition to form more dangerous, unstable structures.
Atherosclerotic plaques are accumulations of fat, cholesterol, and other substances in the arteries, and over time these plaques can calcify. The degree of calcification is thought to promote plaque stability, which then potentially reduces the risk of possible rupture. Ruptured plaques can lead to the formation of a blood clot and possible stroke. “It is important to remember that plaques that don’t yet cause symptoms can rapidly evolve in ways that make them more dangerous. One of the key findings of our work is that calcified plaques may not be as harmless as once thought, since these plaques were found to be at risk of intraplaque bleeding, which in itself is the most important cause of plaque rupture and subsequent stroke.”
For the study, researchers followed 802 patients from the Rotterdam Study – an ongoing large-scale, population-based study – aged 45 years and older with subclinical carotid artery atherosclerosis. Baseline MRIs of carotid plaque compositions were conducted and then repeated after six years. All participants were in pre-symptomatic stages of their disease.
Over the course of the research, plaques became more complex, developing multiple components such as calcification, bleeding, and fatty deposits. Changes towards more complex plaque composition were more common in men than in women. The study showed that compared to plaques without calcification, plaques that already had calcification were twice as likely to develop internal bleeding, which is a key indicator of plaque vulnerability and potential rupture. The researchers also did a simulation to predict plaque evolution beyond the six years. A simulated 30-year evolution showed that more than half of the participants who had single component plaques would develop into complex multicomponent plaques by the age of 70. “Even if there are no symptoms, early signs of plaque in your carotid arteries can quietly become more dangerous over time.”
The Mitochondrial Electron Transport Chain as a Target for Age-Slowing Therapies
https://www.fightaging.org/archives/2025/06/the-mitochondrial-electron-transport-chain-as-a-target-for-age-slowing-therapies/
Mitochondria are power plants, hundreds of them in every cell. A mitochondrion is descended from symbiotic bacteria, essentially a wrapper around the electron transport chain, which is a complex system that produces either heat or molecules of adenosine triphosphate (ATP), a chemical energy store used to power the cell. It also produces reactive oxidative molecules as a side-effect of its energetic process of operation, which the cell treats as both a source of damage to be repaired and a signal to adjust operations. Improving mitochondrial function slows aging. Interesting, so does mild sabotage of the electron transport chain, causing the cell to react to the reduced supply of ATP and increased generation of oxidative molecules by increasing its maintenance and defense efforts – the benefits outweigh the harms. This is all very complex, however; any change cascades to produce second order effects, and it is hard to predict in advance whether a novel mitochondrially targeted intervention will be beneficial or harmful in aggregate. Once the results are demonstrated it is then hard to understand why it is beneficial or harmful.
Damage to mitochondrial DNA (mtDNA) results in defective electron transport system (ETS) complexes, initiating a cycle of impaired oxidative phosphorylation (OXPHOS), increased reactive oxygen species (ROS) production, and chronic low-grade inflammation (inflammaging). This culminates in energy failure, cellular senescence, and progressive tissue degeneration. Rapamycin and metformin are the most extensively studied longevity drugs. Rapamycin inhibits mTORC1, promoting mitophagy, enhancing mitochondrial biogenesis, and reducing inflammation. Metformin partially inhibits Complex I, lowering reverse electron transfer (RET)-induced ROS formation and activating AMPK to stimulate autophagy and mitochondrial turnover. Both compounds mimic caloric restriction, shift metabolism toward a catabolic state, and confer preclinical – and, in the case of metformin, clinical – longevity benefits.
More recently, small molecules directly targeting mitochondrial membranes and ETS components have emerged. Compounds such as Elamipretide, Sonlicromanol, SUL-138, and others modulate metabolism and mitochondrial function while exhibiting similarities to metformin and rapamycin, highlighting their potential in promoting longevity. The key question moving forward is whether these interventions should be applied chronically to sustain mitochondrial health or intermittently during episodes of stress. A pragmatic strategy may combine chronic metformin use with targeted mitochondrial therapies during acute physiological stress.
