Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe or unsubscribe from the newsletter,please visit:https://www.fightaging.org/newsletter/
Longevity Industry Consulting Services
Reason, the founder of Fight Aging! and Repair Biotechnologies, offers strategic consulting services to investors, entrepreneurs, and others interested in the longevity industry and its complexities. To find out more: https://www.fightaging.org/services/
- Higher Serum BDNF Correlates with Lower Risk of Mild Cognitive Impairment
- Household Use of Solid Fuel Correlates with a Sizable Increase in Age-Related Disease
- Therapeutic Plasma Exchange Reduces Epigenetic Age Acceleration in Some Clocks
- Evidence Against Mitochondrial Mutator Mice as Support for the Importance of Mitochondrial DNA Damage
- Sustained Midlife Weight Loss in Overweight Individuals Correlates with Reduced Incidence of Later Age-Related Disease
- Being Sedentary Correlates with Accelerated Brain Aging
- An Example of Continued Efforts to Expand the Portfolio of Antihypertensive Drugs
- Estimating the Cardiovascular Disease Burden Resulting from Particular Matter Pollution
- Injected 25-Hydroxycholesterol is Senolytic in the Vasculature of Mice
- Reviewing What is Known of Epigenetic Changes in Aged T Cells
- One Measure of Brain Age May Be Insufficient
- Silent X Chromosome Activation as a Contribution to Sex Differences in Aging
- A New Pace of Aging Built From Clinical Measures
- Blood Pressure Control Reduces Dementia Risk
- Calorie Restriction Improves Measures of Ovarian Aging in Non-Human Primates
Higher Serum BDNF Correlates with Lower Risk of Mild Cognitive Impairment
https://www.fightaging.org/archives/2025/06/higher-serum-bdnf-correlates-with-lower-risk-of-mild-cognitive-impairment/
Bone-derived neurotrophic factor (BDNF) is a circulating signal molecule know to produce neuroprotective effects, aiding neurons to resist stress. It may be involved in supporting some of the functions of neurons. Further, it encourages neurogenesis, the production of new neurons from neural stem cell populations and their integration into existing neural circuits. This is essential for memory, learning, and what little capacity for regeneration exists in the central nervous system. More circulating BDNF produces more neuroprotection, more neurogenesis, better defense against the aging of the brain. Today's open access paper provides one example from the many lines of evidence to support this assertion.
From what is presently known, BDNF appears to be one of a short list of circulating signal proteins for which increased levels (presumably up to some safe upper bound) produce effects that are near all beneficial. Others include α-klotho, follistatin, and VEGF. Circulating proteins with this characteristic are good targets for long-lasting gene therapies that can make use of proven, low-cost technologies. One can use a single fat pad injection of a small amount of even an inefficient gene therapy vector, such as off-patent AAV serotypes or PEI conjugated plasmids, to transduce enough cells to make a difference. The transduced cells become factories for the production of the desired signal molecule, and that production can last for years to decades.
Serum BDNF and progression to MCI in cognitively normal older adults: A prospective cohort study
Brain derived neurotrophic factor (BDNF) is the most abundant and extensively researched neurotrophin in the mammalian brain. It protects neurons from stress and neurotoxicity, and supports neurogenesis, development, and differentiation of neurons. Furthermore, BDNF production and signaling are associated with neurophysiological processes such as long-term potentiation (LTP). During the aging process, BDNF levels increase in response to oxidative stress, providing partial antioxidant defense.
In humans, directly measuring BDNF levels in the brain is challenging. Instead, BDNF levels in blood are used as a proxy, as supported by animal studies demonstrating that BDNF can cross the blood-brain barrier bidirectionally and that peripheral and central BDNF levels are closely associated. Regarding human studies, higher blood BDNF levels have been associated with a slower rate of cognitive decline in Alzheimer's disease, and a reduced risk of conversion to dementia. However, it remains uncertain whether blood BDNF levels are associated with the risk of progression to mild cognitive impairment (MCI), which is considered as a pre-dementia state or a high risk stage of dementia, in cognitively normal (CN) individuals. Given that various modifiable lifestyle factors, including physical and cognitive activities, and dietary habits, can increase blood BDNF levels, elucidating the association between BDNF levels and progression to MCI is very meaningful in terms of the prevention of late-life cognitive decline.
In this study, we aimed to investigate whether higher serum BDNF levels are associated with a reduced likelihood of progressing to MCI over a four-year follow-up period in CN older adults. Longitudinal analyses were conducted using follow-up data from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease, an ongoing prospective cohort study. Among the 274 participants, 26 developed MCI during follow-up. The high BDNF group had a significantly lower incidence of MCI compared to the low BDNF group (hazard ratio , 0.27. This association persisted even after adjusting for BDNF Val66Met polymorphism, amyloid PET positivity, vascular risk factors, cholesterol levels, triglycerides, homocysteine, BMI, smoking, alcohol, TBI history, CES-D, and MMSE scores (HR, 0.14). Subgroup analyses further revealed that the association was significant only in women, individuals younger than 75 years, those with less than a college degree, and amyloid PET-negative individuals.
These findings suggest a protective role of BDNF against clinical progression to MCI in cognitively healthy older individuals. This effect appears to be more prominent in women, as well as in relatively younger, less educated, and amyloid PET-negative individuals.
Household Use of Solid Fuel Correlates with a Sizable Increase in Age-Related Disease
https://www.fightaging.org/archives/2025/06/household-use-of-solid-fuel-correlates-with-a-sizable-increase-in-age-related-disease/
One of the larger sources of harmful particulate air pollution is the use of solid fuel (wood, coal, and the like) for heating and cooking at home. This is much more prevalent in poor populations and regions than in wealthier parts of the world, but when it comes to risk a coal fireplace is a coal fireplace regardless of how wealthy one is. A large weight of evidence links exposure to particulate matter with an accelerated progression of age-related conditions and increased mortality. The more particulate matter, the worse the outcome. The primary mechanism is thought to be chronic inflammation resulting from the reaction of respiratory system tissues to inhaled particles.
In today's open access paper, researchers process epidemiological data from Chinese populations to quantify the harms done by exposure to solid fuel particulate matter in the home. The effect size is quite large. The fraction of people who age into their 60s without developing a chronic disease or sizable loss of cognitive function is 30% to 40% lower for those who use solid fuel. It is worth noting that fewer than 1 in 10 individuals in this population made it into their late 60s without developing some form of age-related disease or significant loss of function - a reminder that dysfunction and disability lies in all of our futures, if nothing is done to accelerate the development of rejuvenation therapies.
Association between with household solid fuel use and successful aging among older people in China: a cross-sectional and perspective study from CHARLS
A total of 4,047 participants (2,347 men and 1,700 women with the average age of 67.05 ± 6.05 years) from the China Health and Retirement Longitudinal Study 2011 were included in cross-sectional analyses. 2,517 participants at baseline were included in longitudinal analyses and were followed up in 2018. Successful aging was defined according to five components (without major diseases; without disability; high cognitive functioning; without depressive symptoms; active engagement with life).
In cross-sectional analyses, the participants who used solid fuel (coal or crop residue/wood) for cooking and heating had lower prevalence of successful aging than those who used clean fuel (solar energy, natural gas, liquefied petroleum gas or electricity). During the follow-up, 175 (6.95%) participants experienced successful aging. In the longitudinal analysis, after multivariable adjustment of age, sex and other risk factors, individuals who used solid fuel for cooking showed a lower ratio of successful aging, with corresponding odds ratio of 0.66. Consistently, individuals reported solid fuels use for heating were associated with lower odds ratios of successful aging (odds ratio = 0.59). In addition, a self-reported switch from clean to solid fuel or from solid fuel to clean were also significantly associated with successful aging.
Therapeutic Plasma Exchange Reduces Epigenetic Age Acceleration in Some Clocks
https://www.fightaging.org/archives/2025/06/therapeutic-plasma-exchange-reduces-epigenetic-age-acceleration-in-some-clocks/
Researchers have been generating aging clocks for going on twenty years now, and as one might expect there are now lot of these clocks. Even just counting the epigenetic clocks one has a great deal of choice. Most studies that make use of clocks choose to assess only a few of the more prominent options, but as today's report on a clinical trial of therapeutic plasma exchange makes clear, the right way to go about this is to assess every single clock one can obtain access to - more than 30 clocks and clock variants in this case. The primary challenge in the use of aging clocks as a means to assess the quality of a potential rejuvenation therapy is that one has no idea how any given clock will react to a specific class of intervention. Is the clock usefully weighing specific parameters that change in response to the intervention? Or weighing too little? Or weighing too much?
The only way to arrive at a comprehensive answer is to calibrate a clock against a given therapy, a lengthy process of assessing aging the old-fashioned way, by waiting to see what happens. No-one is going to run life span studies of interventions in humans for this purpose any time soon, though we might see results emerge from longitudinal studies of exercise and other lifestyle choices over the next decade or two as the use of aging clocks expands. In the absence of those studies, a next best approach is to assess as many clocks as possible for as many interventions as possible, to get a feel for how the results vary. The data in today's paper shows just how much different clocks can vary for one intervention, therapeutic plasma exchange, where it is reasonable to believe that treatment will to some degree reduce some of the dysfunctions of aging. It would be very interesting to see equivalent data for senolytics, mTOR inhibitors, and so forth.
Multi-Omics Analysis Reveals Biomarkers That Contribute to Biological Age Rejuvenation in Response to Single-Blinded Randomized Placebo-Controlled Therapeutic Plasma Exchange
We conducted a randomized, placebo-controlled trial to assess the safety and biological age (BA) effects of various therapeutic plasma exchange (TPE) regimens in healthy adults over 50. Participants received bi-weekly TPE with or without intravenous immunoglobulin (IVIG), monthly TPE, or placebo. Randomization was based on entry date, and treatments were blinded to maintain objectivity. Primary objectives were to assess long-term TPE safety and changes in biological clocks. Secondary goals included identifying optimal regimens. Exploratory analyses profiled baseline clinical features and longitudinal changes across the epigenome, proteome, metabolome, glycome, immune cytokines, iAge, and immune cell composition.
We demonstrate in 42 individuals randomized to various treatment arms or placebo that long-term TPE was found to be safe, with only two adverse events requiring discontinuation and one related to IVIG. TPE significantly improved biological age markers, with 15 epigenetic clocks showing rejuvenation compared to placebo. Biweekly TPE combined with intravenous immunoglobulin (TPE-IVIG) proved most effective, inducing coordinated cellular and molecular responses, reversing age-related immune decline, and modulating proteins linked to chronic inflammation. Integrative analysis identified baseline biomarkers predictive of positive outcomes, suggesting TPE-IVIG is particularly beneficial for individuals with poorer initial health status. This is the first multi-omics study to examine various TPE modalities to slow epigenetic biologic clocks, which demonstrate biological age rejuvenation and the molecular features associated with this rejuvenation.
Evidence Against Mitochondrial Mutator Mice as Support for the Importance of Mitochondrial DNA Damage
https://www.fightaging.org/archives/2025/06/evidence-against-mitochondrial-mutator-mice-as-support-for-the-importance-of-mitochondrial-dna-damage/
One of the major challenges in aging research is establishing the relative importance of the various well-known different mechanisms, hallmarks, and dysfunctions of aging. This is large part because biological systems and their relationships to one another are not fully mapped and understood at the detail level. Mitochondrial dysfunction is a great example; mitochondria are enormously complex, and even very important processes such as mitophagy are not completely understood in detail. Thus there is considerable debate over the importance of mitochondrial DNA damage to aging.
One of the pillars of supporting evidence for the importance of mitochondrial DNA damage in aging comes from the harmful effects of mutated mitochondrial DNA polymerase gamma (POLG) in mice. This genetic change impairs mitochondrial DNA maintenance machinery in a way that produces a large burden of mutations in mitochondrial DNA, loss of mitochondrial function, and accelerated measures of aging and age-related disease. In today's open access paper, researchers produce a similar burden of mitochondrial DNA in mice without the full presence of the disabling mutation in POLG - and these animals do not exhibit the expected dramatic loss of mitochondrial function. This lets us hypothesize that other functions of POLG are important in mitochondrial function, and undermines the argument for the importance of stochastic mitochondrial DNA damage.
Mitochondrial Respiratory Dysfunction Is Not Correlated With Mitochondrial Genotype in Premature Aging Mice
Mitochondrial DNA (mtDNA) mutator mice (Polgmut/mut mice) have reinforced the mitochondrial theory of aging. These mice accumulate multiple mutations in mtDNA with age due to a homozygous proofreading-deficient mutation in mtDNA polymerase gamma (Polg), resulting in mitochondrial respiratory dysfunction and premature aging phenotypes. However, whether the accumulation of multiple mutations in Polgmut/mut mice induces mitochondrial respiratory dysfunction remains unclear.
Here, we determined the accurate mtDNA genotype, including the frequency of total mutations and the number of non-synonymous substitutions and pathogenic mutations, using next-generation sequencing in the progeny of all three genotypes obtained from the mating of heterozygous mtDNA mutator mice (Polg+/mut mice) and examined their correlation with mitochondrial respiratory activity. Although Polg+/mut mice showed equivalent mtDNA genotype to Polg+/+ (wild-type) mice, the mitochondrial respiratory activity in the Polg+/mut mice was mildly reduced.
To further investigate the causal relationship between mtDNA genotype and mitochondrial respiratory activity, we experimentally varied the mtDNA genotype in Polg mice. However, mitochondrial respiratory activity was mildly reduced in Polg+/mut mice and severely reduced in Polgmut/mut mice, regardless of the mtDNA genotype. Moreover, by varying the mtDNA genotype, some Polg+/+ mice showed mtDNA genotype equivalent to those of Polgmut/mut mice, but mitochondrial respiratory activity in Polg+/+ mice was normal.
These results indicate that the mitochondrial respiratory dysfunction observed in mice with proofreading-deficient mutation in Polg is correlated with the nuclear genotype of Polg rather than the mtDNA genotype. Thus, the mitochondrial theory of aging in Polgmut/mut mice needs further re-examination.
Sustained Midlife Weight Loss in Overweight Individuals Correlates with Reduced Incidence of Later Age-Related Disease
https://www.fightaging.org/archives/2025/06/sustained-midlife-weight-loss-in-overweight-individuals-correlates-with-reduced-incidence-of-later-age-related-disease/
An extensive literature of epidemiology demonstrates that being overweight correlates with increased age-related disease, increased medical expenditure, and increased mortality. The greater the excess weight, the worse the outcome. While human studies can largely only uncover correlations between lifestyle choice and health, animals studies convincingly demonstrate that carrying too much visceral fat is disruptive to health and life span. Visceral fat tissue is metabolically active, promoting increased chronic inflammation via a range of mechanisms.
The human evidence leans in the direction of harms being proportional to both the amount of excess visceral fat and the length of time for which that fat is carried. For example, consider the studies in which the highest lifetime waist circumference measure produces better correlations with outcomes in aging than more recent measures of weight and visceral fat burden. In a similar vein, in today's open access paper, researchers show that overweight individuals who achieved sustained weight loss starting in mid-life exhibit a much reduced risk of chronic disease in later life. The point to take away from all of this is that excess visceral fat tissue is very harmful.
Weight Loss in Midlife, Chronic Disease Incidence, and All-Cause Mortality During Extended Follow-Up
Few studies have examined long-term health benefits among individuals with sustained weight loss beyond its association with decreased diabetes risk. This cohort study analyzed data from 3 cohorts that included repeated height and weight measurements: the Whitehall II study (WHII; baseline, 1985-1988), Helsinki Businessmen Study (HBS; baseline, 1964-1973), and Finnish Public Sector study (FPS; baseline, 2000). Participants were categorized into 4 groups based on their first 2 weight assessments and followed up for morbidity and mortality outcomes. Data analyses were conducted between February 11, 2024, and February 20, 2025. Midlife BMI change was categorized as persistent BMI less than 25, BMI change from 25 or greater to less than 25, BMI change from less than 25 to 25 or greater, and persistent BMI of 25 or greater.
There were 23,149 participants, including 4,118 men and women (median age at first visit, 39 years) from WHII, 2,335 men (median age at first visit, 42 years) from HBS, and 16,696 men and women (median age at first visit, 39 years) from FPS. During a median follow-up of 22.8 years, after adjusting for smoking, systolic blood pressure, and serum cholesterol at the first evaluation, WHII participants with weight loss had a decreased risk of developing chronic disease (hazard ratio , 0.52) compared with participants with persistent overweight. This finding was replicated after excluding diabetes from the outcome (HR, 0.58). The corresponding HR in FPS was 0.43 over a median follow-up of 12.2 years. In HBS, weight loss was associated with decreased mortality (HR, 0.81) during an extended follow-up (median 35 years).
Being Sedentary Correlates with Accelerated Brain Aging
https://www.fightaging.org/archives/2025/06/being-sedentary-correlates-with-accelerated-brain-aging/
It is well established that exercise improves long-term health in animal studies and correlates with improved health in human studies. Here, researchers show a correlation between sedentary behavior and accelerated brain aging. This is one of many, many similar studies that demonstrate a link between level of exercise and functional outcomes in older individuals. It remains the case that maintaining physical fitness into later life has by far the greatest weight of supporting evidence of all the approaches known to modestly slow aging.
Evidence suggests that midlife physical activity may reduce Alzheimer's disease (AD) risk. In at-risk individuals, we investigated midlife physical activity changes in relation to AD-related pathologies. We included 337 cognitively unimpaired adults with baseline and follow-up physical activity evaluations within 4.07 ± 0.84 years. We performed multiple regressions considering follow-up amyloid-PET burden and MRI-based medial temporal lobe cortical thickness as outcomes.
Remaining sedentary was associated with lower cortical thickness compared to doing limited physical activity, maintaining adherence, or becoming adherent to WHO recommendations on physical activity. Becoming adherent to recommendations was linked to lower amyloid burden compared to becoming non-adherent. Increased activity amounts showed a dose-dependent association with lower amyloid burden.
An Example of Continued Efforts to Expand the Portfolio of Antihypertensive Drugs
https://www.fightaging.org/archives/2025/06/an-example-of-continued-efforts-to-expand-the-portfolio-of-antihypertensive-drugs/
The nature of small molecule drugs and human metabolic variability is that effect sizes are usually modest and responses usually vary widely across the population. Some patients see little benefit, some patients have side-effects that limit use, and there is always the opportunity to find an alternative path to a new drug that can be used by those people. Separately, investors don't like risk, and tend to favor investment into development focused on proven markets and proven mechanisms of action. Thus wherever there is a sizable market for small molecule drugs for a specific outcome, such as control of blood pressure, there will be continued development to produce ever more small molecule drugs aimed at that outcome. Whether this is good or bad is a matter of perspective, but a large fraction of investment and activity in the pharmaceutical industry is focused on producing "me too" drugs and incremental improvements.
The data from the Launch-HTN trial show that lorundrostat, an aldosterone synthase inhibitor, is a safe and effective treatment for people with uncontrolled or resistant hypertension, demonstrating consistent blood pressure reductions across a large and diverse patient population. It is the largest phase three trial of an aldosterone synthase inhibitor for the treatment of hypertension. The results are a major milestone toward delivering the first targeted aldosterone synthase inhibitor treatment for uncontrolled or resistant hypertension, which could benefit millions of people affected by the conditions.
"Despite available treatments, more than 40% of adults with hypertension worldwide are not reaching their blood pressure goal. There's a major need to explore novel therapies for hypertension and the Launch-HTN trial addressed this need. The aldosterone pathway plays important role in blood pressure regulation, and leads to blood pressure related complications such as heart failure and kidney problems." 30% of people with hypertension have dysregulated aldosterone, meaning that the body's natural mechanism for controlling aldosterone is disrupted. Lorundrostat was designed to reduce aldosterone levels by inhibiting CYP11B2, the enzyme responsible for its production.
The Launch-HTN trial was a global, randomized, double-blinded, placebo-controlled Phase 3 trial, which enrolled eligible adult participants who failed to achieve their blood pressure goal despite being on two to five antihypertensive medications. Lorundrostat 50 mg dosed once daily demonstrated clinically meaningful and sustained reductions in systolic blood pressure, with a 16.9 mmHg reduction at Week 6 (-9.1 mmHg placebo adjusted) and a 19 mmHg reduction at Week 12 (-11.7mm placebo adjusted).
Estimating the Cardiovascular Disease Burden Resulting from Particular Matter Pollution
https://www.fightaging.org/archives/2025/06/estimating-the-cardiovascular-disease-burden-resulting-from-particular-matter-pollution/
A sizable body of epidemiological evidence indicates that particulate air pollution accelerates the onset and progression of age-related disease. The most plausible mechanism is an increase in chronic inflammation via the interaction of these particles with respiratory system tissues. A few very compelling natural experiments exist, in which similar populations happen to have different exposure to particulates, such as in parts of China or the Puget Sound region. Here, researchers take a more model-based approach to estimating future trends for cardiovascular disease resulting from particulate matter exposure. Of note, and as often the case in this sort of studies, individual risk is falling while overall incidence is rising. This is the demographic transition in action. The average age of the population is increasing, and there are more older people to suffer age-related disease.
This study aims to analyze the global trends and projected burden of cardiovascular diseases (CVD) attributable to particulate matter (PM) pollution. The objectives are to assess spatiotemporal trends, sociodemographic variations, and gender differences and to forecast the future burden using data from the Global Burden of Disease (GBD) 2021 study.
We utilized data from GBD 2021 to evaluate age-standardized mortality rates (ASMR) and disability-adjusted life years (DALYs) of CVD attributable to PM from 1990 to 2021. Age-period-cohort models and Joinpoint regression analysis were employed to evaluate temporal trends. The Bayesian age-period-cohort (BAPC) model, which incorporates prior information to improve prediction stability, was selected to project the future burden up to 2045 due to its robustness in handling long-term epidemiological trends.
Between 1990 and 2021, global number of deaths and DALYs for CVD attributed to PM increased by 91.68% and 78.89%, respectively. Despite these increases, ASMR and age-standardized DALYs rates declined significantly, especially among females. The burden disproportionately affected low- and middle- Sociodemographic Index (SDI) regions, with significant gender and age differences. The elderly population and regions with lower SDI will bear the greater burden. Predictions indicate that by 2045, the number of deaths and DALYs will increase by approximately three times, with females experiencing a more pronounced rise.
Injected 25-Hydroxycholesterol is Senolytic in the Vasculature of Mice
https://www.fightaging.org/archives/2025/06/injected-25-hydroxycholesterol-is-senolytic-in-the-vasculature-of-mice/
Researchers here provide evidence for 5 days of injections with 25-hydroxycholesterol to be senolytic in the vasculature of mice, reducing the harmful burden of senescent cells to reduce age-related aortic stiffness. There may be other mechanisms involved, but the researchers focused on clearance of senescent cells and the potential pathways by which this occurs in response to increased levels of 25-hydroxycholesterol. The comparison with the genetic model of senescent cell clearance is particularly interesting. Whether this treatment also provokes programmed cell death of senescent cells meaningfully in other tissues is an open question left unexamined in this short paper, though earlier work did test the senolytic capacity of 25-hydroxycholesterol in a number of different cell types in vitro.
Stiffening of the aorta is a key antecedent to cardiovascular diseases (CVD) with aging. Age-related aortic stiffening is driven, in part, by cellular senescence - a hallmark of aging defined primarily by irreversible cell cycle arrest. In this study, we assessed the efficacy of 25-hydroxycholesterol (25HC), an endogenous cholesterol metabolite, as a naturally occurring senolytic to reverse vascular cell senescence and reduce aortic stiffness in old mice.
Old (22-26 months) p16-3MR mice, a transgenic model allowing for genetic clearance of p16-positive senescent cells with ganciclovir (GCV), were administered vehicle, 25HC, or GCV to compare the efficacy of the experimental 25HC senolytic versus genetic clearance of senescent cells. We found that short-term (5 day) treatment with 25HC reduced aortic stiffness in vivo, assessed via aortic pulse wave velocity to a similar extent as GCV. Ex vivo 25HC exposure of aorta rings from the old p16-3MR GCV-treated mice did not further reduce elastic modulus (measure of intrinsic mechanical stiffness), demonstrating that 25HC elicited its beneficial effects on aortic stiffness, in part, through the suppression of excess senescent cells.
Improvements in aortic stiffness with 25HC were accompanied by favorable remodeling of structural components of the vascular wall (e.g., lower collagen-1 abundance and higher α-elastin content) to a similar extent as GCV. Moreover, 25HC suppressed its putative molecular target CRYAB, modulated CRYAB-regulated senescent cell anti-apoptotic pathways, and reduced markers of cellular senescence. The findings from this study identify 25HC as a potential therapy to target vascular cell senescence and reduce age-related aortic stiffness.
Reviewing What is Known of Epigenetic Changes in Aged T Cells
https://www.fightaging.org/archives/2025/06/reviewing-what-is-known-of-epigenetic-changes-in-aged-t-cells/
Immune system function declines with age. Immune cells become more inflammatory, but at the same time less capable. Further, populations of malfunctioning and harmful immune cells grow in number. The immune system is enormously complex, and one might argue that this is the primary reason why researchers have yet to produce a full accounting of the details of immune aging. Producing data is straightforward, but connecting the many different views of cell state that can be produced via omics technologies into a coherent whole is very much more challenging. Here, researchers focus on epigenetic changes, and the summary is illustrative of the present degree to which gene expression data can be readily connected to specific functions.
Epigenetic regulation, including DNA methylation and histone modifications, play a pivotal role in shaping T cell functionality throughout life. With aging, these epigenetic changes profoundly affect gene expression, altering T cell plasticity, activation, and differentiation. These modifications contribute significantly to immunosenescence, increasing susceptibility to infections, cancer, and autoimmune diseases.
In CD8+ T cells, chromatin closure at key regulatory regions suppresses activation and migration, while chromatin opening in pro-inflammatory gene loci amplifies inflammation. These changes drive terminal differentiation, characterized by increased expression of senescence-associated markers, impaired migration and loss of epigenetic plasticity. CD4+ T cells experience fewer but critical epigenetic alterations, including disrupted pathways, a skewed Th1/Th2 balance, and reduced Treg functionality. These epigenetic changes, compounded by metabolic dysfunctions, such as mitochondrial deficiency and oxidative stress, impair T-cell adaptability and resilience in the aging organism.
Understanding the interplay between epigenetic and metabolic factors in T cell aging offers promising therapeutic opportunities to mitigate immunosenescence and enhance immune function in aging populations.
One Measure of Brain Age May Be Insufficient
https://www.fightaging.org/archives/2025/06/one-measure-of-brain-age-may-be-insufficient/
The brain is a complex organ. In this era of aging clocks, a number of approaches have been developed to assess the biological age of the brain from neuroimaging and other data. Is one metric for brain age sufficient, however? Here researchers present evidence for different portions of the brain to undergo age-related change at different rates. The researchers correlate their novel imaging-based models of brain aging to measures of cognitive performance in their study population, which gives more weight to the work than would have been the case for modeling alone.
Brain age is a biological clock typically used to describe brain health with one number, but its relationship with established gradients of cortical organization remains unclear. We address this gap by leveraging a data-driven, region-specific brain age approach in 335 neurologically intact adults, using a convolutional neural network (volBrain) to estimate regional brain ages directly from structural MRI without a predefined set of morphometric properties.
Six distinct gradients of brain aging are replicated in two independent cohorts. For example, frontal association cortices exhibited accelerated brain aging relative to sensorimotor cortices in older adults. Spatial patterns of accelerated brain aging in older adults quantitatively align with the archetypal sensorimotor-to-association axis of cortical organization. Other brain aging gradients reflect neurobiological hierarchies such as gene expression and externopyramidization.
Participant-level correspondences to brain age gradients are associated with cognitive and sensorimotor performance and explained behavioral variance more effectively than global brain age. These results suggest that regional brain age patterns reflect fundamental principles of cortical organization and behavior.
Silent X Chromosome Activation as a Contribution to Sex Differences in Aging
https://www.fightaging.org/archives/2025/06/silent-x-chromosome-activation-as-a-contribution-to-sex-differences-in-aging/
Regulation of gene expression is a matter of control over the structure of packaged nuclear DNA, determining which regions are accessible to transcription proteins. This control becomes dysfunctional with age. Evidently there will be sex differences in the outcomes of this dysfunction because males and females have different chromosomes. It remains an open question as to which of these classes of difference are important in male versus female life expectancy and outcomes in aging, and why. Here, researchers discuss the phenomenon of silent X chromosome activation in older females, and whether it might provide a significant contribution to sex differences in aging.
Unlike men, who carry one X chromosome and one Y chromosome, women have two X chromosomes in each cell. However, one of the two X chromosomes is effectively silenced. It folds into a compact structure known as the Barr body and can no longer be read. Without this mechanism, the genes on the X chromosome would be read twice as often in women as in men. Scientists have known for some time that some genes can escape inactivation in the Barr body, resulting in higher gene activity in women. These genes are suspected to influence disease.
Researchers examined the major organs of mice at different stages of life. In the older animals, the proportion of genes that had escaped was on average twice as high as in adult animals - six percent instead of three percent of the genes on the X chromosome. In some organs, the numbers were even higher: in the kidneys, for instance, nearly 9 percent. "With aging, epigenetic processes gradually loosen the tightly packed structure of the inactive X chromosome. This mainly happens at the ends of the chromosome, allowing for genes located in those regions to be read again."
Many of the genes that become active again with age are associated with disease. What effects the reactivated genes may have on disease development will need to be investigated in future studies. This doubled gene activity could have positive effects in some cases and negative effects in others. ACE2, for example - a gene that escapes in the lungs with age - can help limit pulmonary fibrosis. Increased activity of the gene TLR8 in old age, however, may play a role in autoimmune diseases such as late-onset lupus.
A New Pace of Aging Built From Clinical Measures
https://www.fightaging.org/archives/2025/06/a-new-pace-of-aging-built-from-clinical-measures/
The original Pace of Aging that emerged from analysis of Dunedin Study data was a form of epigenetic clock. Here, what the researchers are calling Pace of Aging is instead a form of aging clock derived from clinical chemistry and other simple measures of function such as grip strength. Further, it was generated from data obtained from different study populations. It is not the same at all! There is nothing in common between these assessments. It seems unhelpful to keep the same name. That said, at the present time the use of clinical data as a basis for an aging clock seems more helpful than use of omics data, as one can at least make some attempt to hypothesize regarding the underlying causes for changes in the aging clock output following interventions.
Originally developed using data from the Dunedin Study - a longitudinal study of individuals born in 1972-73 - the initial Pace of Aging tool focused on changes from young adulthood through midlife. A newly refined method for measuring the Pace of Aging in population-based studies provides a powerful tool for predicting risks associated with aging. The team analyzed data from two large-scale, nationally representative studies: the U.S. Health and Retirement Study (HRS) and the English Longitudinal Study of Aging (ELSA). These long-term studies follow adults aged 50 and older - along with their spouses - and collect detailed information on health, cognition, socioeconomic status, and family dynamics. The studies have been ongoing for decades and periodically enroll new participants.
The new approach makes use of data from dried blood spots, physical exams, and performance tests given to participants in their homes at up to three timepoints over eight-year follow-up intervals. Pace of Aging was examined in 19,045 participants who contributed data over 2006-2016, with additional follow-up to determine disease, disability, and mortality through 2022. In the US study, Pace of Aging was measured from C-reactive protein (CRP), Cystatin-C, glycated hemoglobin (HbA1C), diastolic blood pressure, waist circumference, lung capacity (peak flow), balance, grip strength, and gait speed.
"Our findings establish that we can measure important variability in the pace of aging in older people with a relatively limited set of measurements. These metrics consistently predict future health outcomes, including disease onset, disability, and death. And they reveal important differences in aging trajectories across population subgroups. For example, the study reported signs of accelerated aging in people with lower levels of education."
Blood Pressure Control Reduces Dementia Risk
https://www.fightaging.org/archives/2025/06/blood-pressure-control-reduces-dementia-risk/
Raised blood pressure is damaging in a range of ways, the most obvious of which is pressure damage to sensitive tissues. For example, high blood pressure increases the pace of rupture of capillaries. In the brain these microbleeds leave areas of permanent damage known as hyperintensities for their appearance in imaging of brain tissue. This form of harm adds up over time, and is well demonstrated to correlate with loss of cognitive function and the development of dementia.
Dementia is a leading cause of death and disability worldwide. Here we tested the effectiveness of blood pressure (BP) reduction on the risk of all-cause dementia among 33,995 individuals aged ≥40 years with uncontrolled hypertension in rural China. We randomly assigned 163 villages to a non-physician community healthcare provider-led intervention and 163 villages to usual care. In the intervention group, trained non-physician community healthcare providers initiated and titrated antihypertensive medications according to a simple stepped-care protocol to achieve a systolic BP goal of <130 mmHg and a diastolic BP goal of <80 mmHg, with supervision from primary care physicians.
Over 48 months, the net reduction in systolic BP was 22.0 mmHg and that in diastolic BP was 9.3 mmHg in the intervention group compared to usual care. The primary outcome of all-cause dementia was significantly lower in the intervention group than in the usual care group (risk ratio: 0.85). Additionally, serious adverse events occurred less frequently in the intervention group (risk ratio: 0.94). This cluster-randomized trial indicates that intensive BP reduction is effective in lowering the risk of all-cause dementia in patients with hypertension.
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.
View the full article at FightAging
