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- A Novel Approach to Improve Mitochondrial Function in Aged Tissues via G Proteins
- An Example of Continued Efforts to Correlate Gut Microbiome Features with Late Life Health
- In Search of Antagonistic Pleiotropy in Human Data
- Reviewing the State of Clinical Evidence for Rapamycin as an Age-Slowing Treatment
- Evidence for Quality of Genetic Translation to Contribute to Species Life Span Differences
- A View into the Neuroplasticity of the Aging Brain
- CaMKII Contributes to Muscle Aging
- Too Little Research into Relationships Between Exercise, Fitness, and Epigenetic Aging
- Microbial 10-HSA Encourages Repair of an Injured Intestine and Liver
- Mechanisms Involved in the Acceleration of Aging via Persistent Infection
- Reviewing the Mechanisms of Cardiovascular Aging
- Intranasal Oxytocin Delivery as an Anti-Aging Treatment
- Fat Tissue Contributes to the Production of a Population of Age-Associated T Cells
- The Gut Microbiome Contributes to the Progression of Heart Failure
- The Characteristics of Age-Related Disease in Very Long-Lived Individuals
A Novel Approach to Improve Mitochondrial Function in Aged Tissues via G Proteins
https://www.fightaging.org/archives/2025/08/a-novel-approach-to-improve-mitochondrial-function-in-aged-tissues-via-g-proteins/
Mitochondria manufacture the chemical energy store molecule adenosine triphosphate needed to power biochemical processes. They are the distant descendants of ancient symbiotic bacteria, hundreds of mitochondria found in each cell. Mitochondrial function declines with age for a range of complex reasons involving damage, changes in gene expression that affect mitochondrial proteins, and dysfunction in the quality control mechanisms of mitophagy, processes that should promptly remove damaged mitochondria but falter with age. A variety of approaches to improving mitochondrial function in aged tissue have been proposed, but none of the readily available methods can much improve on the effects of exercise.
Today's research materials discuss a novel approach to coercing mitochondria in aged tissues into better performance. Researchers have produced a proof of concept demonstration in mouse models of neurodegenerative disease, showing improved cognitive function following treatment. In brief, researchers have found that forms of G protein-coupled receptors found on mitochondrial membranes can be stimulated to improve mitochondrial function via their interactions with G proteins inside mitochondria. They designed an artificial receptor that can be stimulated in a controlled way by delivery of a small molecule drug, and used mice equipped with this receptor to dial up mitochondrial function and thus reduce age-related dysfunction in tissues.
Since mitochondrial transplantation is an approach under development for the treatment of age-related disease, it is easy to imagine a future in which cultured mitochondria are engineered in various ways prior to transplantation. Artificial receptors on those mitochondrial that allow for boosted mitochondrial function on demand, in response to ingesting a safe drug, may well be one of the more useful of the many possible enhancements to possess.
Neurodegenerative diseases: What if the key lies in the mitochondria?
Neurodegenerative diseases are characterized by a progressive impairment of neuronal functions leading to the death of brain cells. Researchers developed for the first time a tool that allows to temporarily stimulate mitochondrial activity. They hypothesized that if this stimulation led to an improvement of symptoms in animals, this would mean that the impairment of mitochondrial activity precedes the loss of neurons in the context of a neurodegenerative disease.
In previous studies, the research teams already described the specific role of G proteins in the modulation of mitochondrial activity in the brain. In the present paper, the researchers succeeded in generating an artificial receptor, called mitoDreadd-Gs, able to activate G proteins directly in the mitochondria, thereby stimulating mitochondrial activity. The stimulation of mitoDreadd-Gs in the brain led to the normalisation of both mitochondrial activity and memory performance of dementia mouse models.
Potentiation of mitochondrial function by mitoDREADD-Gs reverses pharmacological and neurodegenerative cognitive impairment in mice
Many brain disorders involve mitochondrial alterations, but owing to the lack of suitable tools, the causal role of mitochondrial dysfunction in pathophysiological processes is difficult to establish. Heterotrimeric guanine nucleotide-binding (G) proteins are key regulators of cell functions, and they can be found within mitochondria. Therefore, we reasoned that the activation of stimulatory mitochondrial G proteins (Gs) could rapidly promote the activity of the organelle and possibly compensate for bioenergetic dysfunction.
Here, we show that a mitochondria-targeted recombinant designer receptor exclusively activated by designer drugs (mitoDREADD-Gs) can acutely trigger intramitochondrial signaling to increase mitochondrial membrane potential and oxygen consumption. In vivo activation of mitoDREADD-Gs abolished memory alterations in cannabinoid-treated mice and in two mouse models of Alzheimer's disease and frontotemporal dementia. Thus, mitoDREADD-Gs enables the establishment of causal relationships between mitochondria and biological or disease-related processes and represents an innovative potential therapeutic approach for disorders associated with mitochondrial impairment.
An Example of Continued Efforts to Correlate Gut Microbiome Features with Late Life Health
https://www.fightaging.org/archives/2025/08/an-example-of-continued-efforts-to-correlate-gut-microbiome-features-with-late-life-health/
A broad range of evidence points to the composition of the gut microbiome providing a similar degree of influence on long-term health as is the case for lifestyle choices in diet and degree of physical activity. The relative proportions of microbial species making up the gut microbiome change with age, and much of this change appears unfavorable. Microbes that manufacture beneficial metabolites necessary for tissue function throughout the body decline in number, while microbes that provoke chronic inflammation or manufacture harmful metabolites increase in number.
Studies involving the transfer of fecal material between young and old individuals, carried out in relatively short-lived species such as killifish and mice, give us some idea as to the importance of the gut microbiome. In killifish, old fish receiving a fecal microbiota transplant from young fish lived an average of ~40% longer than their untreated peers. Effect sizes in very short-lived species are typically much larger than is the case in mammals, but even in mice there are clear signs that transplantation of a young microbiome into an old animal produces a lasting rejuvenation of the gut microbiome and significant improvement in health.
These and other equally interesting results from animal studies in recent years have provoked a serious effort to produce a map of correlations in humans between clearly measurable health metrics and specific differences in composition in the gut microbiome. Even a partial map would pave the way for the development of therapies that use a much simpler composition of microbial species than is the case for a donor microbiome, making it possible to predict, understand, and assess the profile of possible side-effects. Transplanting a standard mix of three (or ten, or twenty) species is a much easier proposition to put in front of regulators than transplanting a varied mix of thousands of species taken from donors, if the goal is ultimately to treat large fractions of the population, a scenario in which a very high bar for safety will be set.
Healthy Ageing and Gut Microbiota: A Study on Longevity in Adults
Many studies have focused on ageing and gut microbiota, but the correlation between gut microbiota and physical function in older adults, especially those with longevity, remains obscure and deserves further exploration. In this study we investigated changes in the gut microbiota and the association between gut microbiota and physical function in adults with longevity. This is a prospective observational study. Fifty-one older adults aged ≥ 60 years (including 27 participants aged 90 years and above) were enrolled. Information on clinical data, physical function including intrinsic capacity by Integrated Care for Older People (ICOPE) tool, and dietary habits of participants was collected and analysed. Gut microbiota structure and functional pathways were analysed by Metagenomics.
Intrinsic capacity (measured as ICOPE scores) of adults' longevity (aged 90-98, LONGE group) was significantly lower than older adults aged 60-89 years (CON group) (5.44 ± 2.15 vs. 6.71 ± 1.46). Gut microbiota of the LONGE group is enriched in Akkermansia and Bifidobacterium, which may be beneficial to health. Gut microbiota was closely related to daily milk consumption, anxiety, and physical function including grip strength by the Short Physical Performance Battery (SPPB).
Bacteroides plebeius and Bacteroides eggerthii were increased in long-living adults with better physical function. Escherichia coli was more abundant in frail young-old adults. Grip strength is positively correlated with the abundance of Roseburia hominis, Eubacterium rectale, Eubacterium eligens, and Roseburia intestinalis. Pathways related to amino acid synthesis that include L-isoleucine, L-valine, and L-threonine were over-presented in long-living adults of better physical function. Adults with longevity showed comparable gut microbiota abundance to younger elderly individuals. The gut microbiota of long-living adults showed higher abundance of potentially beneficial bacteria, and the altered bacteria are closely associated with physical function.
Changes in the gut microbiota may precede clinical indicators during the process of ageing. Gut microbiota may be a potential biomarker for longevity and healthy ageing. Nutrition and emotional state can be important influencing factors.
In Search of Antagonistic Pleiotropy in Human Data
https://www.fightaging.org/archives/2025/08/in-search-of-antagonistic-pleiotropy-in-human-data/
Antagonistic pleiotropy is a term used to describe a biological mechanism that is helpful in one context, harmful in another. As most often used, this means helpful when young, harmful when old. The concept of antagonistic pleiotropy sits at the heart of any serious discussion of the evolution of aging, as well as the relationships between known mechanisms of aging and hallmarks of aging. The dominant view of aging is that it is a side-effect of natural selection operating more strongly on the characteristics of young individuals than on the characteristics of old individuals, favoring the evolution of mechanisms that enhance early survival and reproductive success at the expense of later survival and reproductive success. Optimizing for initial success no matter the later consequences is a winning strategy for near all ecological niches.
Examples of specific mechanisms and circumstances that illustrate the reality of antagonistic pleiotropy have been established in a number of species. Researchers are very interested in finding examples in humans, however. Given vast genetic and epidemiological databases, researchers have searched for longevity-associated mutations that also affect reproductive success, for example. This is challenging, as longevity-associated mutations with even modest effect sizes and replication in multiple study populations are thin on the ground. There is some debate over whether any of the human data is in fact a good demonstration of antagonistic pleiotropy. Nonetheless, researchers continue to work on the problem, as illustrated by today's open access paper.
Early menarche and childbirth accelerate aging-related outcomes and age-related diseases: Evidence for antagonistic pleiotropy in humans
Aging can be understood as a consequence of the declining force of natural selection with age. Consistent with this, the antagonistic pleiotropy theory of aging proposes that aging arises from trade-offs that favor early growth and reproduction. However, evidence supporting antagonistic pleiotropy in humans remains limited. In this study, Mendelian randomization (MR) was applied to investigate the associations between the ages of menarche or first childbirth and age-related outcomes and diseases. Ingenuity Pathway Analysis was employed to explore gene-related aspects associated with significant single-nucleotide polymorphisms (SNPs) detected in MR analysis. The associations between the age of menarche, childbirth, and the number of childbirths with several age-related outcomes were validated in the UK Biobank by conducting regression analysis of nearly 200,000 subjects.
Using MR, we demonstrated that later ages of menarche or first childbirth were genetically associated with longer parental lifespan, decreased frailty index, slower epigenetic aging, later menopause, and reduced facial aging. Moreover, later menarche or first childbirth was also genetically associated with a lower risk of several age-related diseases, including late-onset Alzheimer's disease, type 2 diabetes, heart disease, essential hypertension, and chronic obstructive pulmonary disease. We identified 158 significant SNPs that influenced age-related outcomes, some of which were involved in known longevity pathways, including insulin-like growth factor 1, growth hormone, AMP-activated protein kinase, and mTOR signaling. Our study also identified higher body mass index as a mediating factor in causing the increased risk of certain diseases, such as type 2 diabetes and heart failure, in women with early menarche or early pregnancy.
We validated the associations between the age of menarche, childbirth, and the number of childbirths with several age-related outcomes in the UK Biobank by conducting regression analysis of nearly 200,000 subjects. Our results demonstrated that menarche before the age of 11 and childbirth before 21 significantly accelerated the risk of several diseases and almost doubled the risk for diabetes, heart failure, and quadrupled the risk of obesity, supporting the antagonistic pleiotropy theory.
Reviewing the State of Clinical Evidence for Rapamycin as an Age-Slowing Treatment
https://www.fightaging.org/archives/2025/08/reviewing-the-state-of-clinical-evidence-for-rapamycin-as-an-age-slowing-treatment/
From a starting point of the small list of options to treat aging that are presently accessible to the average individual, if pushed to list the interventions with the most useful human evidence for safety, the most robust and replicated animal data for efficacy, and with relatively well-explored mechanisms of action, then one might start with (a) calorie restriction, (b) exercise, © rapamycin, and then (d) the senolytic combination of dasatinib and quercetin. Note that I say nothing of effect sizes when arranging that list. Rapamycin appears better than exercise in mice, but is not as good as calorie restriction when it comes to extending life span. None of those three produce anywhere near the rapid, impressive reversal of measures of aging and age-related disease in mice as have resulted from the use of first generation senolytic treatments, such as dasatinib and quercetin.
Today's open access paper might be read as a companion piece to a recent conservative review of the merits of rapamycin as a treatment to slow aging. When it comes to moving from data obtained in animal studies to data obtained from human clinical trials, well, there is very little human data for the use of rapamycin at the relatively low doses thought to be optimal for slowing aging. The long history of rapamycin use in humans is largely focused on high dose immunosuppression, and we can learn little from that.
This absence of a robust body of evidence was the point made in the above mentioned review, and it is the point made in today's open access paper. We might reasonably expect a calorie restriction mimetic like rapamycin, a drug that upregulates the operation of autophagy, to be capable of producing some degree of benefit in humans. The data to make a compelling case in humans remains absent. We should probably not hold our collective breath awaiting for that human data to arrive, unfortunately. Rapamycin is a generic drug, cheap, hard to monopolize in the way that pharmaceutical companies must in order to justify the vast investment of funds needed for regulators to grant clinical approval. So clinical trials for an age-slowing application of rapamycin are not a priority for the industry, and few other groups have deep enough pockets.
What is the clinical evidence to support off-label rapamycin therapy in healthy adults?
Rapamycin therapy is considered a promising approach for lifespan extension and the delay of age-related disease, with numerous preclinical studies documenting benefit. These benefits have inspired some patients to seek rapamycin therapy from specialty practitioners. Yet, the clinical evidence of benefit associated with low-dose rapamycin use in healthy human adults has not been established, and there may exist signals indicating caution with off-label use at non-immunosuppressive doses.
While the benefit of rapamycin therapy has been demonstrated in non-human models, nonetheless, the clinical evidence for low-dose mTOR inhibitors such rapamycin as a therapy for extending lifespan or delaying the onset of age-related disease in healthy adults remains unestablished. Here, we provide a critical appraisal of studies evaluating low-dose rapamycin therapy in healthy adults and offer considerations for its potential use as an off-label longevity drug in humans.
Longevity data in humans is difficult to acquire. Any well-designed trial that attempts to assess the longevity impact for any drug in people will be time consuming, expensive, and complicated by uncertainties in clinically valid endpoints. Since rapamycin is a generic medication, there is little incentive for any private group to fund such a study, which further complicates acquisition of high quality evidence with regard to low-dose rapamycin therapy. Accordingly, the clinical evidence evaluating low-dose rapamycin, or its analogues, in healthy participants is scant, with less than a dozen known trials exploring a variety of biomarkers, including immune function, protein synthesis, and hematologic parameters.
What emerges is a complex picture that remains insufficient to affirm or negate the longevity and healthspan extending benefits attributed to rapamycin. Despite the preclinical evidence supporting the use of sirolimus to enhance mean and maximal lifespan, the data in humans has yet to establish that rapamycin, or its analogues, is an effective senotherapeutic to delay aging in healthy older adults.
Evidence for Quality of Genetic Translation to Contribute to Species Life Span Differences
https://www.fightaging.org/archives/2025/08/evidence-for-quality-of-genetic-translation-to-contribute-to-species-life-span-differences/
Translation is the process by which cells manufacture many copies of a protein from one messenger RNA sequence encoding that protein. This takes place in one of the many ribosomes present in the cell, after which a newly assembled protein is folded within the endoplasmic reticulum. Translation is important, and so has evolved to be highly efficient. Errors nonetheless occur, and are corrected by various processes that identify broken, misfolded, and other problem proteins and ensure they are broken down for recycling. Those quality assurance processes have also evolved to be highly efficient. Correctly formed proteins are necessary for cell function, and malformed proteins will tend to cause harm in proportion to their numbers.
Nonetheless, different species exhibit different degrees of efficiency in translation. A range of evidence suggests that these differences provide a meaningful contribution to species life span. For example, naked mole-rats live as much as nine times longer than similarly sized mice, and exhibit exceptionally low rates of translation error. Like most long-lived species, however, naked mole-rats also exhibit many other adaptations that probably influence longevity, and it is ever a challenge to determine the degree to which each each of these distinct characteristics contributes to slowed aging and increased life span.
In today's open access paper, researchers provide an interesting demonstration of the effects of differences in translation error rates on longevity. They used yeast as a model. It is possible to produce thousands of distinct genomes by crossing two yeasts, and people have done this. It is a fairly standard approach if wanting to use small differences in similar organisms as a way to illuminate some aspect of cellular biochemistry. From that starting point, the researchers identified a gene variant that has a sizable effect on translation error rate, and also increases life span by 8%. Yeast, being a lower form of life, tends to respond to interventions with a large change in lifespan; one would expect effect sizes in mice to be smaller, but the next thing to do would be to try a similar genetic change in a mouse lineage and see what results.
Translational fidelity and longevity are genetically linked
A number of theories have been proposed to explain aging from various perspectives. One of the most influential of them is the Error-Catastrophe Theory of Aging, first proposed in 1963. According to this theory, errors that inevitably occur during messenger RNA (mRNA) translation will, sooner or later, happen to the proteins involved in the molecular machinery of translation. Consequently, translational fidelity will be reduced, resulting in a vicious circle towards even more errors, thus the decline of physiological function and eventually the death of the organism.
Based on the Error-Catastrophe Theory of Aging, there are three major directions to test the role of translation error in aging. First, the theory predicts that aged cells will produce more erroneous proteins than young cells. However, this has not been supported by a large body of experimental results from a variety of organisms. Second, the theory predicts a correlation between longevity and translational fidelity, which has been demonstrated by comparisons across species. A third prediction of the theory is that longevity should change accordingly as translational fidelity is manipulated. Early experiments in this direction, in which streptomycin was used to enhance translation error rates, had largely negative results. But more recently, some positive results have been obtained when paromomycin or mutant ribosomal proteins are used to increase translation error rate. While the use of specific antibiotics or artificial mutations might not reflect the natural conditions, these findings demonstrated that increased translational fidelity can indeed enhance longevity, and prompted renewed interest in the theory.
Measuring the lifespan and translational fidelity of a panel of BY x RM yeast recombinant haploid progenies, we validate the fidelity-longevity correlation. Genome-wide quantitative trait loci (QTL) analyses reveal that both fidelity and longevity are most strongly associated with a locus encoding vacuolar protein sorting-associated protein 70 (VPS70). Replacing VPS70 in BY yeast by its RM yeast allele reduces translation error by ~8.0% and extends lifespan by ~8.9% through a vacuole-dependent mechanism. These results collectively demonstrated the genetic basis for the correlation between translation error and aging, which strongly support the role of translational fidelity in intra-specific longevity variations.
A View into the Neuroplasticity of the Aging Brain
https://www.fightaging.org/archives/2025/08/a-view-into-the-neuroplasticity-of-the-aging-brain/
The brain is a plastic organ throughout life, neural networks adapting to use and experience. Many of the changes that occur with age are taking place in response to patterns of use, not just in response to damage and dysfunction. It isn't entirely straightforward to determine which is which. The research noted here doesn't give any particular insight into how to address undesirable changes in the aging brain, but does provide an interesting view into how the brain strives and succeeds to retain function in capacities that receive constant use.
The human cerebral cortex is only a few millimetres thick and arranged in numerous folds. This tissue usually becomes thinner with age. "This is a hallmark of aging. It is attributed, among other things, to the loss of neurons. As a result, some abilities deteriorate. In any case, it is generally assumed that less brain volume means reduced function. However, little is known about how exactly the cortex actually ages. That is why we examined the situation with high-resolution brain scans."
Researchers focused on the primary somatosensory cortex, a part of the cerebral cortex where signals from the tactile sense are processed. Using magnetic resonance imaging (MRI), the researchers were able to map this area of the cerebral cortex with unprecedented accuracy. "Until now, it had not been considered that the primary somatosensory cortex consists of a stack of several extremely thin layers of tissue, each with its own architecture and function. We have now found that these layers age differently. Although the cerebral cortex becomes thinner overall, some of its layers remain stable or, surprisingly, are even thicker with age. Presumably because they are particularly solicited and thus retain their functionality. We therefore see evidence for neuroplasticity, that is, adaptability, even in senior people."
Only the deeper layers of the cerebral cortex showed age-related degeneration: they were thinner in older study participants than in younger ones. "The middle and upper layers of the cortex are most directly exposed to external stimuli. They are permanently active because we have constant contact with our environment. The neural circuits in the lower layers are stimulated to a lesser extent, especially in later life. I therefore see our findings as an indication that the brain preserves what is used intensively. That is a feature of neuroplasticity."
CaMKII Contributes to Muscle Aging
https://www.fightaging.org/archives/2025/08/camkii-contributes-to-muscle-aging/
Researchers have in the past identified the activities of CaMKII as potential issue in degenerative aging, particularly in muscle tissue. Species differences in its activities are in fact a good example of antagonistic pleiotropy, in that mammalian CaMKII exhibits specific structural differences versus the analogous proteins in lower species that act to produce both better muscle function in youth and worse harms to muscle function in later life. Unfortunately CaMKII has many functions in many different tissues, so it isn't a straightforward target for therapies. Here, researchers use a tissue-specific inhibition in aged muscle to demonstrate that reduced CaMKII expression can reverse some of the characteristic age-related changes in muscle cell biochemistry and improve aspects of muscle function in old mice.
Sarcopenia, the age-related loss of muscle strength and mass, contributes to adverse health outcomes in older adults. While exercise mitigates sarcopenia by transiently activating calcium (Ca2+)-dependent and reactive oxygen species (ROS)-dependent signaling pathways that enhance muscle performance and adaptation, these same signals become chronically elevated in aged skeletal muscle and promote functional decline.
Researchers have in the past identified the activities of Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a key transducer of both Ca2+ and ROS signals during exercise. Here we show that CaMKII is chronically activated in aged muscles, promoting muscle dysfunction. Muscle-specific expression of a constitutively active CaMKII construct in young mice recapitulates features of aging muscles, including impaired contractility, progressive atrophy, mitochondrial disorganization, formation of tubular aggregates, and an older transcriptional profile characterized by the activation of inflammatory and stress response pathways. Mediation analysis identified altered heme metabolism as a potential mechanism of CaMKII-induced weakness, independent of muscle atrophy. Conversely, partial inhibition of CaMKII in aged muscle improved contractile function and shifted the transcriptome toward a more youthful state without inducing hypertrophy.
These findings identify chronic CaMKII activation as a driver of functional and molecular muscle aging and support the concept that CaMKII exemplifies antagonistic pleiotropy, whereby its beneficial roles in promoting muscle performance and adaptation during youth may incur deleterious consequences in aging. We propose that persistent CaMKII activation in aged skeletal muscle reflects unresolved cellular stress and promotes maladaptive remodeling. Enhancing physiological reserve capacity through exercise, in combination with temporally targeted CaMKII inhibition, may help restore adaptive CaMKII signaling dynamics and preserve muscle function in aging.
Too Little Research into Relationships Between Exercise, Fitness, and Epigenetic Aging
https://www.fightaging.org/archives/2025/08/too-little-research-into-relationships-between-exercise-fitness-and-epigenetic-aging/
Researchers here note that the state of research into the relationships between exercise, physical fitness, and epigenetic aging (or indeed, any other assessment of biological age provided by forms of aging clock) is patchy at best. There are at present too few studies and too little data for researchers to be able to confidently describe the degree to which various levels of exercise and fitness affect aging clocks, as compared to what it is possible to achieve for well-investigated outcomes such as risk of age-related disease and mortality.
The concept of an epigenetic clock is a predictive model based on DNA methylation patterns that provides a more accurate estimate of biological age than chronological age. Physical activity has emerged as a modifiable lifestyle factor that can influence the epigenetic clock and may serve as a geroprotective intervention to extend the health span and possibly the life span. However, some studies have discussed these effects without clearly distinguishing between physical activity, physical fitness, and exercise, which are closely related terms.
These foundational terms - physical activity, exercise, and physical fitness - are often used interchangeably in the general population; however, they have distinct physiological and epidemiological implications, particularly in aging research. For instance, while light-intensity physical activity, such as casual walking, contributes to energy expenditure and general health maintenance, it may not provide a sufficient stimulus to induce the molecular and cellular adaptations typically associated with geroprotective effects. In contrast, structured exercise programs, especially those incorporating moderate-to-vigorous intensity, are more likely to elicit systemic responses such as improved mitochondrial function, enhanced insulin sensitivity, and modulation of epigenetic markers. Furthermore, physical fitness, particularly cardiorespiratory fitness (CRF) and muscular strength, has been shown to be a robust predictor of morbidity and mortality in older adults. It is important to note that while physical activity and exercise are behaviors, physical fitness represents an integrated outcome influenced by genetics, training status, and overall health.
In human studies, one group showed that exercise training helps retain a more youthful methylome and gene expression profile in skeletal muscles. In another study, sedentary middle-aged and older females underwent eight weeks of combined (aerobic and strength) training. The group with a higher epigenetic age prior to the intervention showed a significant decrease in epigenetic age after the intervention. These findings suggest that structured exercise training can effectively reverse or rejuvenate blood- and skeletal muscle-based epigenetic clocks and the aging methylome.
Few studies have examined the relationship between physical fitness obtained through exercise and epigenetic aging. For example, researchers developed DNAmFitAge, which incorporates physical fitness measures into DNA methylation data, and found that bodybuilders had significantly lower DNAmFitAge compared to age-matched controls. These findings suggest that maintaining a high level of physical fitness delays epigenetic aging; however, these studies did not establish a causal relationship.
Microbial 10-HSA Encourages Repair of an Injured Intestine and Liver
https://www.fightaging.org/archives/2025/08/microbial-10-hsa-encourages-repair-of-an-injured-intestine-and-liver/
Researchers here describe a metabolite produced by gut microbes, 10-HSA, that encourages repair of tissue in the intestines and liver. As researchers dig more deeply into the mechanisms by which some configurations of the gut microbiome are more favorable to health than others, one should expect more discoveries of this nature. The research here involves treatment of chemical injury to the intestines and liver of mice, so it would be interesting to see an analogous study carried out in aged mice, to see if the same mechanisms promote a greater function and resilience in age-damaged rather than chemically damaged tissues.
A new study revealed that 10-hydroxy-cis-12-octadecenoic acid (10-HSA), a compound produced by Lactobacillus bacteria, successfully restored gut-liver health in mice exposed to aflatoxin. Aflatoxin is a toxic substance made of mold commonly found in peanuts, corn and other crops. It is known to cause liver injury. The gut and the liver are intricately linked. They communicate through bile acids, immunity responses, and lipid metabolism - a relationship known as the gut-liver axis. When one organ is damaged, the other suffers too. In diseases like metabolic dysfunction-associated steatotic liver disease (MASLD), this connection becomes a key therapeutic target.
Researchers used a mouse model mimicking MASLD. Exposing mice to aflatoxin B1 (AFB1), a toxic compound made by Aspergillus fungi, triggered liver injury, inflammation, and damage to the gut lining. But when these mice were treated with 10-HSA, the researchers saw a dramatic reversal of the liver and gut damage: gut epithelial barrier was restored; key bile acid metabolites like cholesterol and deoxycholate returned to healthy levels; energy metabolism and the detoxification functions in the liver improved; gut immune responses normalized.
Chronic liver diseases like MASLD and cirrhosis are driven in part by the suppression of PPARα signaling. 10-HSA activates PPARα, a protein that regulates lipid metabolism. By activating PPARα, the molecule repaired liver tissue and supported gut health. With strong preclinical evidence and no toxicity concerns, the researchers are preparing for human clinical trials, especially in people with fatty liver disease or metabolic issues.
Mechanisms Involved in the Acceleration of Aging via Persistent Infection
https://www.fightaging.org/archives/2025/08/mechanisms-involved-in-the-acceleration-of-aging-via-persistent-infection/
Persistent infection via HIV, herpesvirus, or a range of other pathogens capable of evading or subverting the immune system might reasonably be thought of as producing accelerated aging. The dysfunction produced by these infections usually centers around the immune system, but this in turn negatively affects the function of tissues and systems throughout the body. Aging is an accumulation of damage, and persistent infection produces forms of damage that overlap with those generated during the normal course of aging. Here, researchers discuss the range of mechanisms thought to be involved.
Many models of aging assume that processes such as cellular senescence or epigenetic alteration occur under sterile conditions. However, humans sustain infection with viral, bacterial, fungal, and parasite pathogens across the course of a lifetime, many of which are capable of long-term persistence in host tissue and nerves. These pathogens - especially members of the human virome like herpesviruses, as well as intracellular bacteria and parasites - express proteins and metabolites capable of interfering with host immune signaling, mitochondrial function, gene expression, and the epigenetic environment.
This paper reviews these and other key mechanisms by which infectious agents can accelerate features of human aging. This includes hijacking of host mitochondria to gain replication substrates, or the expression of proteins that distort the signaling of host longevity-regulating pathways. We further delineate mechanisms by which pathogen activity contributes to age-related disease development: for example, Alzheimer's amyloid-β plaque can act as an antimicrobial peptide that forms in response to infection.
Overall, because many pathogens dysregulate mTOR, AMPK, or related immunometabolic signaling, healthspan interventions such as low-dose rapamycin, metformin, glutathione, and NAD+ may exert part of their effect by controlling persistent infection. The lack of diagnostics capable of detecting tissue-resident pathogen activity remains a critical bottleneck. Emerging tools - such as ultrasensitive protein assays, cell-free RNA metagenomics, and immune repertoire profiling - may enable integration of pathogen detection into biological age tracking. Incorporating infection into aging models is essential to more accurately characterize drivers of senescence and to optimize therapeutic strategies that target both host and microbial contributors to aging.
Reviewing the Mechanisms of Cardiovascular Aging
https://www.fightaging.org/archives/2025/08/reviewing-the-mechanisms-of-cardiovascular-aging/
While all tissues age into dysfunction, the primary cause of human mortality is the aging of the cardiovascular system into heart failure, stroke, and heart attack, combined with the consequences of progressively worsening cardiovascular function in other organs. The way in which cardiovascular aging manifests is well documented, and the underlying processes of aging that contribute to the observed outcomes are also fairly well understood at the high level. The challenge lies in establishing exactly how the low-level mechanisms of aging give rise to changes and loss of function in the heart and vasculature. This is a task that may not even be needed, if instead the research community focused on ways to repair the molecular damage of aging. We don't need to fully understand how exactly any specific harm contributes to cardiovascular disease if we build a means to address it and observe benefits to result from the use of that therapy.
Aging is a slow, progressive, and inevitable process that affects multiple organs and tissues, including the cardiovascular system. The most frequent cardiac and vascular alterations that are observed in older adults (especially patients aged ≥80 years) are diastolic and systolic dysfunction, progressive stiffening of the vascular wall and endothelial impairment usually driven by an excess of extracellular matrix (ECM) and profibrotic substances, reduced levels of matrix metalloproteinases (MMPs), or by amyloid and calcium deposits in myocardium and valves (especially in aortic valves). Moreover, deformation of the heart structure and shape, or increased adipose tissue and muscle atrophy, or altered ion homeostasis, chronotropic disability, reduced heart rate, and impaired atrial sinus node (SN) activity are other common findings.
Interestingly, aging is often associated with oxidative stress, alterations in the mitochondrial structure and function, and a low-grade proinflammatory state, characterized by high concentrations of cytokines and inflammatory cells, without evidence of infectious pathogens, in a condition known as 'inflammaging'. Aging is a well-recognized independent risk factor for cardiovascular disease and easily leads to high mortality, morbidity, and reduced quality of life. Recently, several efforts have been made to mitigate and delay these alterations, aiming to maintain overall health and longevity. The primary purpose of this review was to provide an accurate description of the underlying mechanisms while also exploring new therapeutic proposals for oxidative stress and inflammaging. Moreover, combining serum biomarkers with appropriate imaging tests can be an effective strategy to stratify and direct the most suitable treatment.
Intranasal Oxytocin Delivery as an Anti-Aging Treatment
https://www.fightaging.org/archives/2025/08/intranasal-oxytocin-delivery-as-an-anti-aging-treatment/
Circulating oxytocin levels decline with age, and researchers have shown that restoring oxytocin to youthful levels has beneficial effects in aged animal models. Oxytocin is produced in the hypothalamus, and thus a range of different delivery mechanisms could work to replace this source. Here, researchers use an intranasal route for the introduction of replacement oxytocin, and show that it produces the expected benefits in aged mice.
While it is well-documented that plasma oxytocin (OXT) levels decline with age, the underlying mechanisms remain elusive. This study aimed to elucidate the physiological mechanisms contributing to this age-related decrease in plasma OXT and the possible use of OXT supplementation on improving age-related decline of neural function. Comparing young (9 weeks) and aged (older than 45 weeks) mice, aged mice showed reduced plasma OXT levels, an increase in the inflammation marker hs-CRP, and decreased OXT-positive neurons in the hypothalamus.
Aged mice showed signs of epigenetic changes in the hypothalamus as indicated by decreased ten-eleven translocation (TET) family mRNA expression, decreased 5-hydroxymethylcytosine (5hmC) positive neurons, and downregulated mitochondrial respiratory complex IV (COX IV) expression. Nasal application of OXT (10 μg/day) for 10 days to aged mice resulted in normalized plasma OXT and inflammation levels and a recovery of OXT-positive neurons, TET2 mRNA levels, 5hmC positive neurons, and COX IV expression.
TET2, COX IV, and 5hmC in the hypothalamus and hippocampus were also found to be decreased in oxytocin receptor (OXTR) knockout mice, compared with age-matched wild type mice, directly confirming a role for OXTR signaling. Furthermore, we show that methylation as a result of aging decreases OXT production in hypothalamic neurons, thereby reducing circulating plasma OXT levels, which can be reversed by nasal OXT treatment. The data presented here suggest that aging, DNA methylation, mitochondrial dysfunction, inflammation, and senescence are interconnected in a vicious cycle, which can be successfully interrupted by OXT treatment.
Fat Tissue Contributes to the Production of a Population of Age-Associated T Cells
https://www.fightaging.org/archives/2025/08/fat-tissue-contributes-to-the-production-of-a-population-of-age-associated-t-cells/
The immune system ages in complex ways, but the result of all of this complexity is chronic inflammation and incapacity, the states of inflammaging and immunosenescence. An aged immune system causes tissue dysfunction on the one hand, while failing to protect against infectious pathogens and malfunctioning cells on the other hand. Focused on one specific part of this big picture, researchers here explore the origins of a dysfunctional population of T cells that emerges in later life to contribute to overall immune dysfunction. They find that fat tissue appears important in encouraging this population to expand from its progenitor cell of origin.
In our previous work using aged mice, we identified a novel population of CD8+ T cells that accumulates across multiple tissues with age. These age-associated CD8+ T cells (TAA cells) are distinct from conventional effector and memory subsets and are also increased in the peripheral blood of older humans. At the transcriptional level, TAA cells are marked by high expression of Gzmk, a granzyme implicated in both cytolytic and non-cytolytic functions, including promotion of pro-inflammatory responses. TAA cells also exhibit co-expression of activation and exhaustion signature.
Although TAA cells make up a significant fraction of the aged CD8+ T cell compartment, the pathway underlying their development remains unknown. In this study, we demonstrate that TAA cell development is cell-extrinsic and requires antigen exposure within aged non-lymphoid tissues. Using a novel mouse model, we show that systemic low-grade inflammation, characteristic of inflammaging, accelerates CD8+ T cell aging and promotes early accumulation of TAA cells. Through detailed analysis of TAA cell heterogeneity, we identified a progenitor subpopulation enriched in the aged adipose tissue.
Using heterochronic transplantation, we show that adipose tissue acts as a functional niche, supporting progenitor maintenance and driving the conversion of young CD8+ T cells into the aged phenotype. Taken together, our findings reveal how aging of non-lymphoid tissues orchestrates the reorganization of the CD8+ T cell compartment and highlight adipose tissue as a promising target for therapeutic strategies aimed at modulating immune aging.
The Gut Microbiome Contributes to the Progression of Heart Failure
https://www.fightaging.org/archives/2025/08/the-gut-microbiome-contributes-to-the-progression-of-heart-failure/
In recent years, research has indicated that the composition of the gut microbiome is influential on long-term heath and the progression of aging and age-related conditions, perhaps to a similar degree as the better studied influences of weight and exercise. The scientific community has made inroads into correlating specific microbial species and metabolites with specific conditions, and has demonstrated that altering the balance of populations making up the gut microbiome can improve health and extend life in aged animals. Here, researchers review what is known of the ways in which age-related changes in the composition of the gut microbiome can contribute to the progression of heart failure.
Heart failure (HF) occurs in the end stage of various cardiovascular diseases (CVDs), such as hypertension, myocardial infarction, and myocarditis. It is characterized by cardiac remodeling, which involves various structural and functional changes in the myocardium that develop in response to chronic stress or injury to the heart. These changes help maintain heart function to some extent. However, in the long term, they tend to accelerate the progression of CVDs and ultimately lead to HF.
Recently, the role of the gut microbiota in HF has received extensive attention. In HF patients, substantial changes occur in the gut microbiota, characterized by a decline in beneficial bacteria and an overgrowth of potentially harmful bacteria. These changes indicate that gut dysbiosis plays an important role in the development of HF, and therapy targeting the gut microbiota may become a new treatment approach. Furthermore, increasing evidence suggests that microbiota-derived metabolites, such as trimethylamine N-oxide (TMAO), bile acids (BAs), short-chain fatty acids (SCFAs), and amino acids (AAs), may influence the development of myocardial remodeling. Modulating the composition of the gut microbiota appears to help ameliorate myocardial fibrosis and delay the development of HF.
In the past few years, there has been an explosion of reports regarding gut microbiota, and many excellent review articles have summarized the interactions between the gut microbiota and various organs in the body. Here, we focus on the role of gut microbiota in HF and its significance in cardiac remodeling. Although emerging evidence suggests that gut dysbiosis significantly influences the progression of HF, the specific mechanisms remain unclear. We discuss the potential advantages and challenges of novel therapeutic approaches targeting the gut microbiota, aiming to bridge the knowledge gap between gut health and HF, thereby laying a foundation for future research and clinical advancements.
The Characteristics of Age-Related Disease in Very Long-Lived Individuals
https://www.fightaging.org/archives/2025/08/the-characteristics-of-age-related-disease-in-very-long-lived-individuals/
Aging is accumulated damage, with age-related disease as the most visible dysfunction that results from that damage. Eventually one of those dysfunctions becomes large enough to cause death. The only way to live longer is to have a lower burden of damage, and thus exhibit lesser degrees of dysfunction. In human populations, this appears to be the case. The study noted here is one of a number to show that centenarians develop fewer and less severe age-related conditions than their peers who fail to live as long. The most interesting observation is that centenarians exhibit a relatively larger incidence of cancer as a fraction of all conditions. One might theorize that this is because their cells are undertaking a greater degree of maintenance activities in the age-damaged tissue environment. Cancer is a numbers game, and the more replication of cells taking place in tissues, particularly stem cells, the greater the odds of a cancer occurring.
Previous research suggests that centenarians reach exceptional ages primarily by avoiding major diseases rather than surviving them. However, how they manage multiple conditions over the life course remains less understood. We conducted a nationwide historical prospective study including all individuals born in Sweden between 1920 and 1922 (n = 274,108), tracking their health from age 70 for up to 30 years. Disease trajectories of centenarians were compared to those of shorter-lived peers using national health registers. We analysed disease burden, the rate of disease accumulation, and patterns of multimorbidity across age groups.
Centenarians had fewer diagnosed conditions and accumulated diseases at a slower rate than non-centenarians. Cardiovascular diseases were the most common diagnoses in all age groups, but contributed less to the overall disease burden among centenarians. In contrast, malignancies accounted for a relatively larger share of their disease profile. Neuropsychiatric conditions were consistently less common among centenarians, showing the largest relative difference across all ages. Centenarians also had fewer co-occurring diseases and were more likely to have conditions confined to a single disease group.
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