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- Centenarians Exhibit Modestly Greater Genetic Protection from Alzheimer's Disease
- A Review of the Present State of Epigenetic Reprogramming to Treat Aging
- Deriving Aging Biomarkers from the Dog Aging Project's Metabolomic Data
- More Evidence for Impaired Cerebrospinal Fluid Drainage to Contribute to Neurodegeneration
- Human Umbilical Cord Mesenchymal Stem Cell Transplantation as a Senomorphic Therapy
- The Usual Concerns Regarding the Growth in Longevity Clinics
- PURPL Inhibition Partially Reverses Cellular Senescence
- More Evidence for a Biological Component to the Correlation Between Intelligence and Longevity
- A Longevity-Reducing Genetic Variation that Replicates in Multiple Study Populations
- Wearable Device Measurement of Blood Circulation as a Basis for an Aging Clock
- Mixed Clinical Study Evidence for the Calorie Restriction Mimetic Spermadine to Slow Cognitive Decline
- Misfolded α-Synuclein Breaks Down ATP, Harming Cell Function in the Brain
- Degeneration of the Tectorial Membrane in Age Related Hearing Loss
- The Role of Mitochondrial Dysfunction in Sarcopenia
- Incompletely Understood Changes in Immunoglobulins Take Place with Age
Centenarians Exhibit Modestly Greater Genetic Protection from Alzheimer's Disease
https://www.fightaging.org/archives/2025/10/centenarians-exhibit-modestly-greater-genetic-protection-from-alzheimers-disease/
The low (and still falling) cost of modern omics technologies ensure that databases of genetic information are expanding at a fast pace. Researchers who study aging have amassed a wealth of information on the biochemistry of people at various ages, but considerable focus has been placed on the genetics of extremely old individuals. The hope has always been to identify particular genes or protein interactions or other aspects of cellular biochemistry that are meaningfully protective, and thus could serve as a starting point for the development of therapies that will slow aging.
Unfortunately what has emerged from this research is (a) the likelihood that previous estimates of the contribution of genetic variants to life expectancy were too high, (b) that very few gene variants show even modest correlations with life span in multiple study populations, and © that the landscape of the genetics of longevity is likely one in which thousands of gene variants provide individually tiny, conditional effects that vary from individual to individual. This is not to say that surprises do not exist, see the sizable effect of the very rare PAI-1 loss of function mutation for example, but these surprises are not relevant to the overwhelming majority of people.
Today's open access paper fits squarely into this new view of the genetics of longevity, while focusing specifically on risk of Alzheimer's disease and its association with genetic variants other than the well-known APOE gene. Like all such studies, many associations are found when analyzing prevalence of gene variants in very old people. But few were found elsewhere, and few will be replicated in other studies. Further, correlations between the presence of variants and Alzheimer's disease risk appear modest at best. So: small effect sizes, nothing that could be the basis for therapies, and more reinforcement of the view of genetics noted above.
Increased genetic protection against Alzheimer's disease in centenarians
While the effect of the apolipoprotein E (APOE) gene on Alzheimer's disease (AD) is well-characterized, the search for additional reliable genetic factors for AD has been ongoing. A recent genome-wide association study (GWAS) analysis identified a total of 83 genetic variants associated with AD using 111,326 clinically diagnosed/"proxy" AD cases and 677,663 controls of White/European ancestry. In this list of genetic variants, 44 were novel loci at the time of publication. Given that individual single-nucleotide polymorphisms (SNPs) typically have a limited impact on disease risk, polygenic risk scores that aggregate the effect of multiple genetic loci have been developed for various human diseases and phenotypes.
We constructed a polygenic protective score specific to Alzheimer's disease (AD PPS) based on the current literature among the participants enrolled in five studies of healthy aging and extreme longevity in the USA, Europe, and Asia. This AD PPS did not include variants on apolipoprotein E (APOE) gene. Comparisons of AD PPS in different data sets of healthy agers and centenarians showed that centenarians have stronger genetic protection against AD compared to individuals without familial longevity. The current study also shows evidence that this genetic protection increases with increasingly older ages in centenarians (centenarians who died before reaching age 105 years, semi-supercentenarians who reached age 105 to 109 years, and supercentenarians who reached age 110 years and older). However, the genetic protection was of modest size: the average increase in AD PPS was approximately one additional protective allele per 5 years of gained lifetime. Additionally, we show that the higher AD PPS was associated with better cognitive function and decreased mortality.
Taken together, this analysis suggests that individuals who achieve the most extreme ages, on average, have the greatest protection against AD. This finding is robust to different genetic backgrounds with important implications for universal applicability of therapeutics that target this AD PPS.
A Review of the Present State of Epigenetic Reprogramming to Treat Aging
https://www.fightaging.org/archives/2025/10/a-review-of-the-present-state-of-epigenetic-reprogramming-to-treat-aging/
The Yamanaka transcription factors can be used to recreate the transformation of cell type that occurs in early embryonic development, inducing a process of reprogramming that can transform any somatic cell into an induced pluripotent stem cell. Initially, this discovery was applied to the development of cell therapies and tissue engineering, a way to produce cells of a specific type matched to the recipient, or to generate cell banks able to reliably supply cells of specific types, or to chase the grail of universal cell lines that can be used in any patient. After nearly twenty years of development, some of the first therapies to transplant cells derived from induced pluripotent stem cells have reached clinical trials - progress in the highly regulated field of medicine is slow at best.
Separately, researchers have discovered that reprogramming doesn't just change cell type, it also rejuvenates a cell by restoring youthful epigenetic control over gene expression. That in turn restores youthful mitochondrial function and numerous other aspects of cell behavior and performance. It cannot repair DNA damage, and cannot enable cells to break down molecular waste that even youthful cells struggle to handle. Nonetheless, there is a great deal of interest in finding ways to use this phenomenon as a basis for therapy. What is known as partial reprogramming involves exposing cells to the Yamanaka factors for long enough to produce this desirable outcome of epigenetic rejuvenation, but not long enough to turn cells into induced pluripotent stem cells. Cells retain their state, with improved function.
Today's open access review provides a good introduction to the science behind the promise and the challenges of partial reprogramming as a basis for therapy. Positive results have been produced in animal studies, but sizable hurdles are involved in trying to reprogram large portions of the body rather than employing a very narrow, restricted use in isolated tissues such as the retina. Different cell types in different tissues have different requirements and restrictions for partial reprogramming. What is good for lung cells is bad for liver cells. What is good for one type of cell in the liver is bad for its neighbor. "Bad" in this context means cell death, tissue dysfunction, and cancer. There is no good solution at this time that would lead to a simple partial reprogramming therapy that affects the whole body without either (a) watering it down to produce negligible benefits, or (b) causing severe issues in some tissues.
Organ-Specific Dedifferentiation and Epigenetic Remodeling in In Vivo Reprogramming
The advent of in vivo reprogramming through transient expression of the Yamanaka factors (OCT4, SOX2, KLF4, and c-MYC, abbreviated OSKM) holds strong promise for regenerative medicine, despite ongoing concerns about safety and clinical applicability. This review synthesizes recent advances in in vivo reprogramming, focusing on its potential to restore regenerative competence and promote rejuvenation across diverse tissues, including the retina, skeletal muscle, heart, liver, brain, and intestine.
In physiologically aged mice, long-term cyclic induction of OSKM restores youthful multi-omics signatures - including DNA methylation, transcriptomic, and lipidomic profiles - across multiple organs such as the spleen, liver, skin, kidney, lung, and skeletal muscle. Importantly, this regimen also promotes functional regeneration: while short-term reprogramming enhances muscle repair through local niche control, sustained cyclic reprogramming improves wound healing and reduces fibrosis in both muscle and skin. Consistent with these findings, even a single 1-week cycle of OSKM in aged mice (55 weeks old) elicits systemic rejuvenation, evidenced by DNA methylation reprogramming across the pancreas, liver, spleen, and blood.
Nevertheless, significant challenges to its application remain, including tumor formation, intestinal and liver failure, and loss of cellular identity. Achieving precise spatiotemporal control over reprogramming will be essential to minimize these risks while preserving therapeutic benefits. Future efforts should prioritize refining delivery methods and exploring safer alternatives such as small molecules or modified gene sets.
Interest in this field is rapidly growing within the biotech sector, summarized in recent reviews which provide detailed accounts of company pipelines and translational strategies. In this review, we instead focus on mechanistic insights into injury-induced and OSKM-induced reprogramming, offering a framework for understanding how regenerative competence can be harnessed across tissues. With careful modulation, OSKM-based approaches hold strong potential to transform regenerative medicine and the treatment of age-related diseases.
Deriving Aging Biomarkers from the Dog Aging Project's Metabolomic Data
https://www.fightaging.org/archives/2025/10/deriving-aging-biomarkers-from-the-dog-aging-projects-metabolomic-data/
The Dog Aging Project has in recent years enrolled thousands of companion animals into multiple cohorts and studies, including a study of the effects of rapamyin as a treatment to slow aging in dogs. Much of the value of the Dog Aging Project taken as a whole lies in the generation of a large database of omics data that can then be mined for insights into aging in this species, some fraction of which will be applicable more generally to aging in other mammals - such as our own species.
In today's open access paper, researchers present their findings from an analysis of metabolomic data derived from the Dog Aging Project's smaller Precision Cohort, 784 dogs for whom more extensive biological data was gathered. Aging modifies circulating levels of a sizable fraction of the 133 metabolites measured in blood plasma from this cohort, which could be used as the basis for an aging clock, or inspected more closely for single measures that serve as biomarkers of aging.
The data points to increased levels of various acetylated amino acids as biomarkers of aging, the acetylated forms of phenylalanine, tryptophan, alanine, and glutamine that are produced when acetylated proteins are broken down. Changes in levels of these modified amino acids correlate with declining kidney function. It will be interesting to see whether human data exhibits a similar pattern; there is a fair amount of literature on the connection between protein acetylation and aging, similarly for protein acetylation and cellular senescence, and for other related topics.
Protein Catabolites as Blood-Based Biomarkers of Aging Physiology: Findings From the Dog Aging Project
Our understanding of aging has grown through the study of systems biology, including single-cell analysis, proteomics, and metabolomics. Studies in lab organisms in controlled environments, while powerful and complex, fall short of capturing the breadth of genetic and environmental variation in nature. Thus, there is now a major effort in geroscience to identify aging biomarkers that might be applied across the diversity of humans and other free-living species. To meet this challenge, the Dog Aging Project (DAP) aims to identify cross-sectional and longitudinal patterns of aging in complex systems, and how these are shaped by the diversity of genetic and environmental variation among companion dogs.
Here we surveyed the plasma metabolome from the first year of sampling of the Precision Cohort of the DAP, 784 animals. By incorporating extensive metadata and whole genome sequencing, we overcome the limitations inherent in breed-based estimates of genetic effects, and probe the physiological basis of the age-related metabolome. We identified effects of age on approximately 36% of the 133 measured metabolites. We also discovered a novel biomarker of age in the post-translationally modified amino acids (ptmAAs). The ptmAAs, which are generated by protein hydrolysis, covaried both with age and with other biomarkers of amino acid metabolism, and in a way that was robust to diet. The only known source of free ptmAAs is the breakdown of protein, and we found additional evidence for protein catabolism within the metabolome. We found that clinical measures of kidney function at least partially mediate the age associations of the ptmAAs. These results suggest that ptmAAs accumulate with age among dogs and may serve as a biomarker of aging physiology.
This work identifies ptmAAs as robust indicators of age in dogs, and points to kidney function as a physiological mediator of age-associated variation in the plasma metabolome.
More Evidence for Impaired Cerebrospinal Fluid Drainage to Contribute to Neurodegeneration
https://www.fightaging.org/archives/2025/10/more-evidence-for-impaired-cerebrospinal-fluid-drainage-to-contribute-to-neurodegeneration/
While the biochemistry of the brain is segregated from the biochemistry of the rest of the body by the blood-brain barrier, a lining of specialized cells wrapping blood vessels that pass through the brain, large amounts of cerebrospinal fluid flow through the brain and exit into the body, carrying away metabolic waste. The major known pathways include (a) channels in the bone of the cribriform plate that drain the olfactory bulb region of the brain, and (b) the glymphatic system that is made up of fluid filled channels that parallel blood vessels where they enter and exit the brain. Both of these pathways decline in efficiency with age: the cribriform plate channels ossify and close, while the glymphatic system loses its ability to drive fluid flow by pulsation. Researchers hypothesize that impaired drainage of cerebrospinal fluid contributes to neurodegeneration by causing a harmful buildup of metabolic waste in the brain.
The ability to measure flow of cerebrospinal fluid through the glymphatic system is a fairly recent innovation, indeed the structure and function of the glymphatic system itself is a relatively recent discovery. Now, however, researchers can use features of magnetic resonance imaging (MRI) in some portions of the glymphatic system to create a measure of the fluid flow exiting the brain. This works because MRI can measure the scatter of water molecules, and if that scatter is heavily biased in one direction, that can be taken as a flow - a technique given the unwieldy name of diffusion tensor image analysis along the perivascular space (DTI-ALPS). All that is needed is a good straight stretch of glymphatic vessel, and there is a location in human physiology that suffices for this purpose. Thus the research community can produce studies such as the one noted here, in which reduced cerebrospinal fluid drainage through the glymphatic system is correlated to dementia risk.
MRI markers of cerebrospinal fluid dynamics predict dementia and mediate the impact of cardiovascular risk
Impaired cerebrospinal fluid (CSF) dynamics may contribute to dementia, but human evidence is limited. Recently, a number of magnetic resonance imaging (MRI)-based proxies have been proposed allowing different aspects of CSF dynamics to be non-invasively studied in humans. These include perivascular space (PVS) volume, diffusion tensor image analysis along the PVS (DTI-ALPS), blood oxygen level-dependent CSF (BOLD-CSF) coupling, and choroid plexus volume. Using the UK Biobank, we measured CSF dynamics: PVS volume, DTI-ALPS), BOLD-CSF coupling, and choroid plexus volume. We assessed cardiovascular risk factors and their associations with CSF dynamics and dementia based on general practitioner, mortality, and hospital records. Mediation analysis evaluated CSF dysfunction in cardiovascular risk-dementia relationships.
Lower DTI-ALPS, lower BOLD-CSF coupling, and higher choroid plexus volume predicted dementia, but PVS volume did not. DTI-ALPS and choroid plexus volume mediated the effect of white matter hyperintensities and diabetes duration on dementia. In conclusion, we demonstrated three MRI proxies of CSF dynamics markers predict future dementia risk. Strategies to improve CSF dynamics may reduce dementia risk, although this needs testing in intervention studies.
Human Umbilical Cord Mesenchymal Stem Cell Transplantation as a Senomorphic Therapy
https://www.fightaging.org/archives/2025/10/human-umbilical-cord-mesenchymal-stem-cell-transplantation-as-a-senomorphic-therapy/
Today's open access paper links a number of different areas of research and development of interest. Firstly, that senescent cells accumulate with age to disrupt tissue structure and function with their inflammatory secretions. Secondly, that the innate immune cells known as microglia become overly active and inflammatory in the aging brain, and a growing body of evidence supports a significant role for these inflammatory microglia in the development of neurodegenerative conditions. Some of these inflammatory microglia are senescent. Thirdly, the stem cell therapies pioneered over the last thirty years, and the more modern use of extracellular vesicles such as exosomes derived from stem cell cultures, appear to largely produce benefits via a sustained reduction in chronic inflammation in older individuals. The transplanted cells do not tend to survive in large numbers, and it is a short burst of signaling following transplantation that produces months-long changes in immune behavior via its effect on native cells.
Because stem cell transplants work via a brief period of signaling, they also tend to work when human cells are transplanted into animals. Here, researchers show that one source of human stem cells for transplantation has positive effects on cognitive function in old mice. Using cell culture experiments, the researchers demonstrate that the signaling generated by stem cells has a senomorphic effect on harmful senescent microglia, meaning that it dampens the worst aspects of the senescent state and thereby improves cognitive function by reducing the ongoing harm done to the function of the brain. We might expect that extracellular vesicles derived from the same source as the stem cells used in this study to produce similar outcomes. The results reported here are in line with other studies in which senescent cells are removed, or their signaling is reduced via other means; senescent cells clearly actively maintain dysfunction in tissues, and matters improve when their are restrained or removed.
Human Umbilical Cord Mesenchymal Stem Cells Ameliorate Cognitive Decline by Restoring Senescent Microglial Function via NF-κB-SREBP1 Pathway Inhibition
Microglia, the resident immune cells of the central nervous system (CNS), play a critical role in maintaining neural homeostasis by monitoring the CNS microenvironment, remodeling and pruning synapses, and clearing cellular debris through phagocytosis. Recent studies have identified a distinct subpopulation of microglia termed lipid droplet-accumulating microglia (LDAM), which exhibit a unique phenotype characterized by metabolic reprogramming, elevated oxidative stress, and heightened pro-inflammatory responses. These alterations disrupt microglial homeostasis, impair their ability to clear amyloid-beta plaques and tau protein aggregates, and contribute to the progression of neurodegenerative diseases such as Alzheimer's disease (AD).
Lipid droplets (LDs) are lipid-rich organelles enveloped by a phospholipid monolayer, primarily composed of triglycerides and cholesterol esters. Under physiological conditions, the homeostasis of intracellular LDs is tightly regulated. However, under pathological conditions, this balance is disrupted, leading to lipid droplet accumulation and subsequent cellular dysfunction. Accumulating evidence shows that LD content in microglia and neurons increases with age. In microglia, LD enrichment is linked with a pro-inflammatory phenotype and exhibits reduced phagocytic capacity toward cellular debris and protein aggregates.
Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have been extensively studied for their significant potential in anti-aging. In this study, we demonstrated that hUC-MSCs ameliorate age-related cognitive decline and downregulate senescence-associated markers in the aged hippocampus. Furthermore, co-culture experiments showed that senescent microglia exacerbate neuronal senescence and neuroinflammation, while also suppressing the apoptosis of senescent neurons. These findings suggested that senescent microglia contribute to age-related cognitive decline by exacerbating neuronal damage and impairing senescent neurons' clearance. We showed that hUC-MSCs reduce senescence-associated markers, decrease lipid droplet accumulation, and restore phagocytic function in senescent microglia through the inhibition of the NF-κB-SREBP1 pathway. This pathway modulation attenuates neuronal damage and promotes the apoptosis of senescent neurons, facilitating the clearance of damaged neurons.
The Usual Concerns Regarding the Growth in Longevity Clinics
https://www.fightaging.org/archives/2025/10/the-usual-concerns-regarding-the-growth-in-longevity-clinics/
The growth in the number of longevity clinics over the past few years might be viewed as analogous to the establishment of stem cell clinics twenty years ago. It is an attempt (in most cases a responsible attempt) to deliver interventions to patients without going through the very slow, very expensive processes of medical regulation. Absent these clinics, treatments would remain largely unavailable, as the cost of regulatory compliance serves to dramatically slow progress. On the one hand, this is a good thing if it leads to greater choice for patients, while on the other hand this seems likely to follow exactly the same track as the medical tourism industry for stem cell therapies - meaning that little to no robust data on patient outcomes will result, clinics will pad their offerings with useless, low value interventions, and the potentially useful therapies will prove to be highly varied in efficacy from clinic to clinic and patient to patient.
The idea of slowing, or even reversing, human aging has long occupied both science and imagination. While basic research over the past two decades has revealed hallmarks of aging and pointed toward possible interventions, the translation of these insights into accessible healthcare solutions remains in its infancy. Against this backdrop, longevity clinics, sometimes named age-management practices, personalized health centers, or wellness-longevity hybrids, have rapidly emerged across the globe. From USA to Switzerland, Singapore to Dubai, these clinics market comprehensive programs promising to monitor, manage, and mitigate biological aging
At their core, longevity clinics claim to combine cutting-edge diagnostics with personalized interventions aimed at extending healthspan. A typical client may undergo genomic sequencing, multi-omics profiling, advanced imaging, full body scans, immune system assessments, microbiome analyses, and epigenetic testing. The results are then used to design individualized regimens that can include exercise prescriptions, nutritional guidance, nutraceuticals, sleep optimization, stress-management strategies, hormone replacement, or more experimental therapies such as stem-cell infusions, injection of peptides, plasma exchange, and others. This approach gives a good example of what the medicine of the future should be: proactive, preventive, and fully personalized. However, some see it as a costly experiment bordering on pseudoscience.
The major issue is that longevity clinics not yet embedded within mainstream medical practice. They illustrate well both the enormous opportunities but also the very high risks inherent in translating geroscience into society. Understanding their potential, their limitations, and the conditions under which they might mature into credible engines of progress is crucial if we want the longevity movement to benefit populations.
PURPL Inhibition Partially Reverses Cellular Senescence
https://www.fightaging.org/archives/2025/10/purpl-inhibition-partially-reverses-cellular-senescence/
The state of cellular senescence is normally irreversible; a senescent cell ceases replication and generates pro-inflammatory signaling to attract the attention of the immune system. That the immune system becomes less efficient in clearing senescent cells is one of the reasons why a growing burden of senescent cells exists in later life, their signaling producing chronic inflammation, damage, and dysfunction. Researchers have found a number of ways to reverse the normally irreversible senescent state by adjusting levels of regulatory molecules, but the question of whether this is a good basis for therapy remains. Some senescent cells are senescent for good reasons, such as potentially cancerous DNA damage. It remains to be seen as to whether the positive can outweigh the negative for reversal of senescence as a way to alleviate the harms done by the senescent cell population in old individuals.
Cellular senescence is a fundamental driver of ageing and age-related diseases, characterized by irreversible growth arrest and profound epigenetic alterations. While long non-coding RNAs (lncRNAs) have emerged as key regulators of senescence, their potential for senescent cell rejuvenation remains unexplored. Here, we established lncRNA PURPL as a key regulator of cellular senescence, bridging the connection between epigenetic modifications and the transcriptional regulation of senescence-associated genes.
Our findings demonstrate that PURPL is significantly upregulated in both replicative senescence and doxorubicin-induced senescence models. Manipulation of PURPL profoundly impacts the senescence phenotype. These findings extend and are consistent with previous studies on ageing regulators such as EGR1, SERPINE1, and other lncRNAs, and provide novel mechanistic insights into how PURPL regulates ageing through epigenetic remodelling, highlighting its significant theoretical and clinical implications.
Although several studies have reported a strong correlation between increased PURPL expression and senescence at both the cellular and tissue levels, few have demonstrated causality. Recently, RNA interference was used to knock down PURPL expression in senescent cells, resulting in some morphological improvements. However, no changes in molecular markers such as p21 were observed. In this study, we employed a more persistent method of lentivirus-mediated CRISPR/Cas9 interference to knock down PURPL. Not only did we observe significant morphological changes, but we also detected decreased levels of CDKN1A/p21 (a tumour suppressor protein) at both the RNA and protein levels. Furthermore, we overexpressed PURPL in young cells to mimic the increased PURPL levels observed during cellular senescence. This overexpression accelerated cellular senescence, as evidenced by increased SA-β-gal activity, elevated p21 levels, and reduced LMNB1 levels. This study provides the first definitive evidence that PURPL acts as a driver of senescence.
More Evidence for a Biological Component to the Correlation Between Intelligence and Longevity
https://www.fightaging.org/archives/2025/10/more-evidence-for-a-biological-component-to-the-correlation-between-intelligence-and-longevity/
Why does intelligence correlate with life expectancy? This is one component of a web of correlations involving longevity, intelligence, socioeconomic status, and education, among others. While it seems likely that greater intelligence enables better access to and use of medical technology and maintenance of health, a range of evidence suggests that there is a biological component to this relationship, in that more intelligent individuals also tend to be more physically robust. Here, researchers compare data on correlations between genetic variations, measures of intelligence, and measures of mortality risk to estimate the degree to which genetic variation may explain correlations between intelligence and longevity. The result are supportive of some degree of shared genetic causation.
The goal of the research field of cognitive epidemiology is to describe and explain phenotypic associations between cognitive function tested in youth (which largely avoids reverse causation) and later-life health and death. Analyses of long-term follow-up data from large cohorts sourced from the UK, Denmark, Israel, and Sweden show that higher scores on cognitive function tests in youth (childhood, adolescence, or young adulthood) are associated with lower risk of mortality from all causes by mid to late adulthood.
What causes this association? The cognition-longevity relationship was not confounded by childhood socioeconomic position, was present across a range of cognitive ability, and was present in both men and women. Might part of the cognition-longevity association be caused by genetic differences? Large genome-wide association studies (GWASs) have been conducted to examine the molecular genetic etiology of people's differences in cognitive function test scores. There are also GWASs on longevity. These GWAS data enable a comparison between traits; that is, one may compare the loci that attain genome-wide statistical significance in cognition with those that are genome-wide significant in longevity.
To date, we are not aware of any genetic correlation having been reported between cognitive function tested in childhood and longevity. In order to address this lacuna in cognitive epidemiology, we use data from two GWASs to estimate the genetic correlation between cognitive function assessed in childhood and longevity (combined mothers' and fathers' attained age). Using study data on childhood cognitive function (n = 12,441) and on parental longevity (n = 389,166) we found a positive genetic correlation of r = 0.35 between childhood cognitive function and parental longevity. These results add to the weight of evidence that the phenotypic link between childhood cognitive function and longevity is partly accounted for by shared genetic etiology.
A Longevity-Reducing Genetic Variation that Replicates in Multiple Study Populations
https://www.fightaging.org/archives/2025/10/a-longevity-reducing-genetic-variation-that-replicates-in-multiple-study-populations/
Despite considerable effort, and the development of vast databases of genetic information, very few associations between specific genetic variants and longevity replicate across study populations, and the effect sizes are near all small. Based on the evidence to date, we should expect the genetic contribution to longevity to be small for most people, and across a population to be made up of tiny, conditional effects from thousands of gene variants. In this landscape, any new longevity-associated variant that occurs in multiple study populations is an unusual discovery worthy of note, even if the effect size is modest and it acts to reduce the odds of survival in later life.
Prior research on the genetics of human longevity has identified only a few robust associations. While these studies highlight the importance of metabolic processes for longevity, the contribution of immune genes, specifically those in the highly polymorphic human leukocyte antigen (HLA) region, remains understudied. We conducted an initial case-control study, comparing imputed HLA alleles from a German longevity cohort with younger controls. Subsequently, significant associations were tested for replication in two additional populations of similar ancestry: a Danish longevity cohort and the UK Biobank.
Our analysis revealed a novel male-specific association of HLA-DRB1*15:01:01 with longevity. In Germans, HLA-DRB1*15:01:01 was less frequent among male cases (10%) than controls (15%), whilst female cases exhibited no substantial decrease (14%), suggesting that men carrying this allele have a lower chance of becoming long-lived. This finding was replicated in the UK Biobank and found to be consistent in the Danish cohort. Computational predictions further revealed that HLA-DRB1*15:01 is more likely to trigger an immune response against an apolipoprotein B-100 (APOB-100) epitope than other HLA-DRB1 alleles. Furthermore, the overall predicted APOB-100 immunogenicity of all HLA-DRB1 alleles was significantly associated with longevity.
In conclusion, the novel male-specific association between HLA-DRB1*15:01 and longevity has been observed in three independent cohorts. The anti-longevity effect of this association is perhaps a consequence of an increase in Alzheimer's disease (AD)-related mortality in men carrying this allele.
Wearable Device Measurement of Blood Circulation as a Basis for an Aging Clock
https://www.fightaging.org/archives/2025/10/wearable-device-measurement-of-blood-circulation-as-a-basis-for-an-aging-clock/
Any sufficiently large body of biological data taken from individuals at varying ages can be used to produce an aging clock via machine learning techniques. The clock provides a measure that should reflect biological age, the burden of cell and tissue damage and consequent risk of dysfunction, but that isn't a given and must be assessed for any new clock. Researchers have been creating new clocks from varied types of data at a fairly rapid pace for some years now. Here, researchers use data on blood flow obtained from consumer devices worn on the wrist. Photoplethysmography is the formal name for the use of devices that illuminate the skin and measure changes in light absorption in order to assess parameters of blood flow, and the growing popularity and low cost of these devices have given rise to large databases suitable for the development of aging clocks.
Aging biomarkers play a vital role in understanding longevity, with the potential to improve clinical decisions and interventions. Existing aging clocks typically use blood, vitals, or imaging collected in a clinical setting. Wearables, in contrast, can make frequent and inexpensive measurements throughout daily living. Here we develop PpgAge, an aging clock using photoplethysmography at the wrist from a consumer wearable.
Using the Apple Heart and Movement Study (n = 213,593 participants; >149 million participant-days), our observational analysis shows that this non-invasive and passively collected aging clock accurately predicts chronological age and captures signs of healthy aging. Participants with an elevated PpgAge gap (i.e., predicted age greater than chronological age) have significantly higher diagnosis rates of heart disease, heart failure, and diabetes. Elevated PpgAge gap is also a significant predictor of incident heart disease events (and new diagnoses) when controlling for relevant risk factors. PpgAge also associates with behavior, including smoking, exercise, and sleep. Longitudinally, PpgAge exhibits a sharp increase during pregnancy and concurrent with certain types of cardiac events.
Mixed Clinical Study Evidence for the Calorie Restriction Mimetic Spermadine to Slow Cognitive Decline
https://www.fightaging.org/archives/2025/10/mixed-clinical-study-evidence-for-the-calorie-restriction-mimetic-spermadine-to-slow-cognitive-decline/
The practice of calorie restriction is well established to slow aging, albeit to a lesser degree in long-lived species than in short-lived species. Calorie restriction memetics are compounds that trigger some of the same beneficial mechanisms involved in the response to reduced calorie intake. They do not capture the full effect, but the best of them (such as rapamycin) are nonetheless still beneficial enough to command attention from the research community.
Like rapamycin, the calorie restriction mimetic spermadine has been shown to upregulate the operation of autophagy, an effect presently thought to be the most important aspect of the response to calorie restriction. Long-term treatment with spermadine modestly extends life in mice, to a lesser degree than rapamyin (~10% versus ~25%). Here, researchers focus on clinical trials that measured spermadine levels or treated with spermadine and observed the outcome on cognitive function; the data is mixed, but also not all that consistent, a common issue in the field.
Increasing evidence suggests that caloric restriction (CR) and intermittent fasting may elevate endogenous levels of spermidine (SPD), a polyamine compound now being investigated as a natural caloric restriction mimetic (CRM) candidate. Beyond its endogenous role in cellular metabolism, SPD can be obtained from dietary intake and synthesised by commensal gut microbiota. SPD is involved in several critical biological processes, including cell growth, differentiation, and autophagy, a fundamental mechanism for cellular maintenance and repair. Recognised as a natural inducer of autophagy, SPD is considered an antiageing compound with properties resembling those of CR, positioning it as a potential CRM.
This article provides a comprehensive synthesis of current evidence on the impact of SPD on cognitive ageing, drawing from both observational and interventional studies. A systematic search of major electronic databases identified 22 relevant studies, comprising 4 interventional trials and 18 observational studies. Observational evidence suggests a potential association between SPD levels and cognitive function, with indications of a protective effect against cognitive decline. However, the variability in results, driven by inconsistencies in SPD measurement methods (eg, brain tissue, blood serum/plasma, red blood cells, or dietary intake), poses challenges to drawing definitive conclusions.
Interventional studies offer preliminary evidence suggesting that SPD supplementation may serve as a potential strategy to mitigate age-related cognitive decline. Some studies have indicated positive cognitive effects of SPD supplementation on cognitive function, such as improvements in memory performance and cognitive assessments. However, inconsistencies remain. The observed differences may be potentially due to variations in SPD dosage, the sensitivity of cognitive assessment tools, and other methodological differences.
Misfolded α-Synuclein Breaks Down ATP, Harming Cell Function in the Brain
https://www.fightaging.org/archives/2025/10/misfolded-%ce%b1-synuclein-breaks-down-atp-harming-cell-function-in-the-brain/
Synucleinopathies such as Parkinson's disease are caused by the spread of misfolded α-synuclein through the brain. α-synuclein is one of a small number of proteins that, when misfolded, can encourage other molecules of the same protein to misfold in the same way, aggregating to form toxic solid deposits and a halo of disrupted biochemistry. Misfolded α-synuclein is particularly pernicious as it can pass from cell to cell, spreading pathology as it goes. Here, researchers explore one of the ways in which misfolded α-synuclein harms cells, by interfering in the supply of the energy store molecule adenosine triphosphate (ATP) that is produced by mitochondria and is essential to cell function.
Parkinson's disease (PD) is the second most common neurodegenerative disorder and the most frequent movement disorder today, for which there is only symptomatic treatment. Amyloid fibers of the protein α-synuclein (αSyn) constitute the major content of pathological intraneuronal inclusions, Lewy bodies, found in dopaminergic neurons in PD patient brains. Amyloid toxicity has been attributed to the ability to seed new amyloids, to translocate between cells, to deteriorate membranes, to be a sink for functionally relevant proteins by binding, and to sterically block cellular functions. Amyloids were considered chemically inert until we showed that αSyn amyloids catalyzed hydrolysis of ester and phosphoester bonds in vitro.
Lewy pathology, i.e., amyloids, is also found in the nuclei of cells, and our earlier work showed αSyn monomers to interact with DNA. When we extended this to amyloids, we found that αSyn amyloid interactions with DNA promote strand breaks in the DNA. Thus, the chemical reactivity of αSyn amyloids may contribute to the noted widespread DNA damage observed in PD patients.
Neurons have disproportionately high energy demands compared to other organs but lack energy fuel storage (such as fatty acids and glucogen). In contrast to many other cells, neurons must continuously produce ATP from glucose to meet the cellular demands and maintain energy homeostasis. Decline in brain ATP levels has been connected to both Alzheimer's and PD. There is evidence that αSyn amyloids perturb mitochondria, resulting in lower ATP production.
Here, we combine biochemical, biophysical, computational, and structural methods to probe the interaction between αSyn amyloids and ATP. We report that αSyn amyloids display catalytic activity toward ATP hydrolysis in vitro. We propose that ATP depletion by αSyn amyloid hydrolysis may disturb the local energy balance in neuronal cells.
Degeneration of the Tectorial Membrane in Age Related Hearing Loss
https://www.fightaging.org/archives/2025/10/degeneration-of-the-tectorial-membrane-in-age-related-hearing-loss/
Researchers here propose a novel form of damage and dysfunction contributing to the development of age-related hearing loss. Much of the focus of past years of research has been placed upon loss of connectivity between sensory hair cells of the inner ear and the brain, or outright loss of hair cells themselves. But there are other components of the overall problem of loss of function, as noted here, and the question of what to do about it doesn't always have as straightforward a path towards practical therapies as exists for loss of cells.
Age-related hearing loss is common among older adults and can result from several problems in the inner ear. The disorder is usually classified into three types: (a) Neural: due to damage to auditory nerve fibres, (b) Sensory: caused by the loss of the sensory cells that detect sound, and (b) Metabolic: involving degeneration of the cells in the cochlea's wall that help maintain the ear's internal environment.
In the metabolic type, often considered the most common one, the positive electrical potential normally found close to the sensory cells is much reduced - and without this positive potential, sensory cells cannot function normally. However, the possibility that degeneration in the cochlea's wall could affect the hearing organ in other ways has not been considered.
We used a physiologically based animal model to investigate what happens when cells in the cochlea's wall stop working. Using advanced imaging techniques, we discovered that calcium levels near the sensory cells dropped. This is an important observation because calcium is a key regulator of sensory cell function. We also found that the tectorial membrane - which helps transmit sound-evoked vibration to the sensory cells - often detached from the sensory cells. This detachment made it nearly impossible for sound to reach the sensory cells. To confirm that these findings are relevant for the human disorder, we examined samples from people with metabolic age-related hearing loss. We saw the same tectorial membrane detachment, and the extent of detachment predicted the severity of hearing loss.
The Role of Mitochondrial Dysfunction in Sarcopenia
https://www.fightaging.org/archives/2025/10/the-role-of-mitochondrial-dysfunction-in-sarcopenia/
The hundreds of mitochondria present in every cell work to produce the chemical energy store molecule adenosine triphosphate (ATP), necessary for cell function. With age, some combination of damage to mitochondrial DNA and changes in the epigenetic control of gene expression act to degrade mitochondrial ATP production and otherwise ensure that mitochondria function progressively less effectively. This stresses cells and negatively affects tissue function. Here, researchers review what is known of mitochondrial loss of function in muscle tissue, leading to the characteristic loss of muscle mass and strength that occurs with aging and leads to sarcopenia.
Sarcopenia is a progressive age-related decline in skeletal muscle mass, strength, and function, representing a significant health burden in older adults. Diagnostic criteria have been established that integrate measures of muscle mass, strength, and physical performance. Mechanistically, sarcopenia is driven by hormonal changes, chronic inflammation, cellular senescence, and, importantly, mitochondrial dysfunction. Age-related declines in sex hormones and activation of myostatin impair muscle regeneration and metabolism, while chronic low-grade inflammation disrupts protein synthesis and accelerates proteolysis via the ubiquitin-proteasome system (UPS) and autophagy-lysosome pathway (ALP). The accumulation of senescent cells and their secretory phenotype further exacerbates muscle degeneration and functional decline.
Mitochondrial dysfunction plays a central role, characterized by impaired biogenesis, excessive reactive oxygen species (ROS) production, compromised autophagy/mitophagy, and accumulation of mitochondrial DNA (mtDNA) mutations. These defects collectively disrupt muscle energy homeostasis, promoting atrophy. The AMPK/SIRT1/PGC-1α and mTORC1 signaling pathways, along with PINK1/Parkin-mediated and receptor-dependent mitophagy, are essential for regulating mitochondrial biogenesis, protein synthesis, and mitochondrial quality control.
Current and emerging therapeutic approaches include resistance and endurance exercise, nutritional and pharmacological agents targeting mitochondrial health, and hormonal modulation. Innovative treatments such as senolytics, exerkines, and gene therapies show promise but require further validation. Future advances in mechanistic understanding, diagnostics, and therapeutic strategies offer hope for mitigating sarcopenia and improving the quality of life in aging populations.
Incompletely Understood Changes in Immunoglobulins Take Place with Age
https://www.fightaging.org/archives/2025/10/incompletely-understood-changes-in-immunoglobulins-take-place-with-age/
Immunoglobulin proteins are also known as antibodies, and can circulate freely or be bound to cell surfaces. They serve to tag specific structures for recognition and attack by the immune system, so a very broad range of variants on the basic structure are manufactured by plasma cells derived from B cells in response to the presence of immune-provoking antigens. These immunoglobulins then go on to shape the behavior of the immune system as a whole. Here, researchers take a tour of what is known of age-related changes in immunoglobulins, an area of study in which all too little is completely mapped or understood. To understand what is observed, one would have to also understand a great deal about what exactly the immune system is doing, and how those activities are affected with age. While the big picture is well understood, at the detail level the exploration of the intricate complexities of the aging immune system remains an ongoing process.
Aging is a complex biological phenomenon, which involved in a large number of diseases such as cancer, neurodegeneration, and cardiovascular diseases. Understanding the mechanism of aging may facilitate the development of preventive strategies of age-related diseases. Immunoglobulin (Ig) includes proteins with antibody (Ab) activity or membrane-bound proteins that share a chemically analogous structure to Ab. Ig can recognize and neutralize numerous antigens, which constitutes the main characteristic of adaptive immunity.
The quantity, glycosylation, and function of Ig change with advancing age. Some Ig is found to be accumulated in aged tissues and appear to be regarded as a potential marker for aging, which indicates the critical role of Ig in aging. B cells are main producers of antibodies and undergo aging-related changes, leading to increased autoimmune responses and reduced vaccine responses. The immune dysregulation of B cells is also intensively involved in the alteration of Ig.
In this review, we focus on the current research findings on Ig, discuss the relation between Ig and aging, highlight the complex interplay among B cell, gut microbiota, Ig, and aging, and explore potential therapeutic strategy. We hope this review may provide an insight for investigating the regulatory mechanism of Ig in aging, as well as for evaluating the therapeutic potential in treating age-related diseases.
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