Longevity Papers

Chronological age overlooks the heterogeneity in aging. In response, a wide range of molecular aging biomarkers has been developed to better capture an individual's aging rate. Yet, a comprehensive comparison of modeling choices in the development of these biomarkers is lacking. In this study, we trained aging biomarkers on the Rockwood frailty index (FI) and all-cause mortality using UK Biobank Olink proteomics and metabolomics (1H-NMR) data (n=40,696). We systematically established the impact of model choice, target outcome, and molecular data source on several age-related outcomes. From this, we developed ProteinFrailty (ProtFI), an elastic net model using a minimal set of proteins to predict FI. ProtFI outperformed established aging biomarkers in relation to diverse outcomes, including incident cardiovascular disease, handgrip strength, and self-rated health, both in internal validation and two Dutch external cohorts (n=996, n=500). Our findings show that an efficient frailty-trained proteomic biomarker robustly predicts age-related decline.

Background: Since Horvath (2013) and Hannum (2013), DNA methylation has emerged as a reliable biomarker for estimating age. Predictive models, called epigenetic clocks, are being built across the tree of life, including humans, other mammals and vertebrates and, recently, invertebrates. However, it always involves cross-fertilizing organisms, thus presenting a high level of genetic diversity. To decipher the exact role of epigenetics in adaptation and evolution, distinguishing true epigenetic variation from changes that reflect genetic variation is essential. Results: Here, we used the mangrove rivulus, the only self-fertilizing vertebrate, to study epigenetic aging in the brain and construct an epigenetic clock. We generated a reduced representation bisulfite sequencing dataset of 90 brain tissues from individuals aged 60-1100 days to construct a highly accurate age predictor using 40 CpG sites (R squared > 0.96, mean absolute error of 28.7 days). We associated the CpG sites with their respective closest genes and explored their biological functions. Genes relevant to aging include lamin-A (responsible for several age-related processes), aryl hydrocarbon receptor (whose absence causes premature aging) and several genes associated with Alzheimer\'s disease identified in human studies. We also propose several methods to improve classic epigenetic clock regression. Conclusions: This study is the first construction of an epigenetic clock in a self-fertilizing species, demonstrating that DNA methylation patterns undergo consistent changes across the lifespan of isogenic individuals. These findings emphasize putative changes in DNA methylation related to functional changes across aging in the brain.

Background: Circadian rest-activity rhythmicity, a manifestation of circadian rhythms, characterizes 24-hour activity patterns. Growing evidence links disruption of circadian rhythms in late life to adverse outcomes, including functional and cognitive declines. Yet, most studies have been cross-sectional or restricted to a single monitoring period, lacking longitudinal assessment. Consequently, it remains unknown whether deterioration or improvement in circadian rest-activity rhythmicity reflects late-life vulnerability in aging populations. Methods: We analyzed data from the National Health and Aging Trends Study (NHATS), a nationally representative U.S. cohort of adults aged [≥]70 years. In Cycles 11 and 12, participants completed 7-day wearable monitoring and assessments of functional, cognitive, and neuropsychiatric outcomes. Circadian biomarkers were derived using cosinor and non-parametric methods (amplitude, MESOR, acrophase, pseudo-F, RA, IS, IV, M10, L5). Participants were classified into four transition groups (Optimal, Improved, Deteriorated, Adverse). Survey-weighted regression and Cox models adjusted for demographics and comorbidities estimated associations, with multiple testing correction. Results: At baseline, weaker rhythm intensity (low amplitude, MESOR, M10, RA) and poor stability (high fragmentation, low regularity) were associated with greater ADL disability, lower SPPB, weaker grip strength, and poorer recall. Longitudinal analyses revealed a graded hierarchy of risk. Participants with deteriorating rhythms represented the most dynamic risk state: declining amplitude was linked to reduced SPPB ({beta}= -0.71, 95% CI: -0.98 to -0.44) and diminished immediate recall ({beta}= -0.60, 95% CI: -0.91 to -0.29). Declining regularity was also associated with impaired function (SPPB: {beta}= -0.52, 95% CI: -0.82 to -0.21) and cognition (immediate recall: {beta}= -0.43, 95% CI: -0.68 to -0.18, delayed recall: {beta}= -0.45, 95% CI: -0.70 to -0.20). By contrast, rhythmicity improvement aligned with stabilization. For neuropsychiatric outcomes, high fragmentation was linked to probable dementia, while poor regularity was tied to anxiety/depression. Conclusion: Circadian rest-activity rhythmicity is a robust and dynamic determinant of late-life outcomes. Persistent weakness or deterioration in intensity and regularity was linked to accelerated decline in function and cognition, whereas improvement aligned with stabilization. These findings position circadian rhythmicity as both an early biomarker of vulnerability and a potential modifiable target. Digital phenotyping via wearables offers a scalable, noninvasive framework for early risk detection, personalized intervention, and resilience promotion in aging populations.

To evaluate associations of glycemic status with incident early-onset dementia (EOD) and late-onset dementia (LOD), dementia-free life expectancy, brain MRI structure measures, as well as the mediation pathway of depressive episode.

Calorie restriction (CR) is the reduction in calorie intake while avoiding malnutrition. CR increases longevity and attenuates the development of many age-related diseases, although some unfavourable responses have been reported. In response to CR, energy is withdrawn from tissues to correct the energy deficit. Changes in tissue mass over short-term, 3 months graded CR (STCR) were complex and while most tissues reduced size, some grew. Employing a graded long-term CR (LTCR) protocol in male C57BL/6J mice, tissue utilisation, digestive efficiency, bone health and motor coordination was investigated. Mice were restricted by 10-40% over 580 days/19 months and sacrificed at 24 months old. Control mice fed ad libitum in the 12hr darkphase only (12AL) were regarded as 0CR. The patterns of tissue weights, digestive efficiency, and bone measurements across the levels of CR were consistent between the STCR and LTCR studies, highlighting shared similarities over both experiments. Notable differences were enhanced utilisation of the reproductive accessory organs which could be linked to a shutdown of the reproductive axis; reduced utilisation of the spleen, changes in the hierarchy of investment in the digestive organs which was not linked to digestive efficiency. The vital organs were protected from utilisation, with preservation of the brain by CR, presumably linked to reduced neurodegeneration and sustained coordination. The favourable effects of LTCR on bone health contradict previous negative reports. Overall, morphological changes determined within 3 months of CR, persisted to 19 months. The pattern of tissue utilisation may be critical to the beneficial effects of CR.

The progressive functional decline associated with aging is a primary risk factor for numerous chronic diseases. The discovery of natural compounds that can modulate conserved longevity pathways offers a promising strategy for promoting healthy aging. Hyperoside, a flavonoid abundant in edible plants such as hawthorn, possesses various pharmacological activities, but its specific role and molecular mechanisms in geroprotection remain poorly understood. This study aimed to elucidate the anti-aging effects of hyperoside and its underlying mechanisms using the model organism Caenorhabditis elegans (C. elegans). Our results showed that hyperoside treatment significantly extended the mean lifespan of wild-type C. elegans by up to 19.97% and robustly enhanced healthspan by improving motility and reducing the accumulation of the aging biomarker lipofuscin. Hyperoside could also alleviate Parkinsonism in neurodegeneration models, without disrupting lipid homeostasis or reproduction. Furthermore, hyperoside conferred increased resistance to thermal, oxidative, and pathogenic stress. Mechanistically, the lifespan-extending effects of hyperoside requires the transcription factors DAF-16/FOXO, SKN-1/Nrf2, and HSF-1, and factors involved in immune and anti-oxidative response, including the MAPKK SEK-1 and p38 MAPK PMK-1. Hyperoside treatment promoted the nuclear translocation of DAF-16 and SKN-1 and upregulated their respective downstream target genes, including sod-3 and gst-4. Hyperoside also increased the expression of genes that are the downstream target of both PMK-1 and SKN-1. Since the role of SKN-1 in immune and anti-oxidative response were regulated by PMK-1. Therefore, the beneficial effects of hyperoside might be mediated primarily by activating SEK-1 /PMK-1/ SKN-1 pathway, which subsequently activate HSF-1 to maintain proteostasis. These findings underscore the potential of hyperoside as a dietary-derived agent for combating age-related functional decline.

Sleep deprivation (SD) and aging are linked to chronic inflammation, a contributor to age-associated diseases. Circadian rhythms, governed by suprachiasmatic nucleus (SCN), regulate immune and inflammatory responses. While aging and SD elevate pro-inflammatory cytokines such as IL-1β, TNF-α, and IL-6, their impact on temporal dynamics of inflammation across tissues and age groups remains unclear. This study examines age-dependent effects of chronic total SD on daily expression rhythms of inflammatory markers in central (SCN) and peripheral (cerebral cortex, liver, intestine) clocks of male Wistar rats aged 3 (adult), 12 (middle-aged), and 24 (old) months (m). Nitric oxide (NO), linked to inflammation and metabolism, was also evaluated in liver and intestine. Animals were sampled at four Zeitgeber (ZT) times. Further, the study examined the effects of melatonin, a circadian-regulated antioxidant, anti-inflammatory agent, and sleep synchronizer, on daily rhythms of inflammatory markers with aging and upon SD were studied. The mRNA expression levels of rTnf-α, rIl-6 and rIl-1β were assessed using qRT-PCR. NO levels were measured using Griess assay. Rats were grouped as control, SD, SD + melatonin and vehicle control groups. Significant SD-induced misalignment, especially in rIl-6 and rTnf-α in cerebral cortex and liver was observed in 12 m. SD altered circadian phases and expression levels were significantly greater in older rats (24 m > 12 m > 3 m) and in peripheral clock as compared to central clock liver > cerebral cortex > intestine > SCN. Melatonin differentially restored these rhythms, most effectively for rIl-1β and in the cerebral cortex and liver. SCN showed highest resilience, reinforcing its role as the central circadian pacemaker, while the liver and cerebral cortex emerged as the most vulnerable to SD and aging.

Hutchinson Gilford Progeria Syndrome (HGPS) is an ultra-rare pediatric premature aging disorder. The disease is caused by a point mutation in the LMNA gene leading to the production of the dominant-negative progerin isoform of the nuclear envelope protein lamin A. Disease severity and progression amongst the population of ~140 known patients is variable. Most of the mechanistic insights into the disease have come from studies using cellular or mouse models of HGPS. To probe the clinical relevance of previously implicated cellular pathways and to address the extent of gene expression heterogeneity between patients, we have performed transcriptomic analysis of a comprehensive set of HGPS patients. We find misexpression of several cellular pathways across the patient population, particularly of multiple signaling pathways as well as the Unfolded Protein Response (UPR) and mesodermal cell fate specification. Variability amongst individual patients was limited, with misregulation of the major pathways observed in most patients. Comparing the transcriptome of patients with an inducible HGPS cell model, we distinguished immediate-early cellular response pathways from secondary adaptive pathways and identified mTORC1, the UPR, UV response, apoptosis and TNFalpha signaling via NF-kB as primary targets of the disease-causing progerin protein.

Recent focus on United States longevity stagnation at higher ages has focused on comparisons with other high-income countries, with less attention paid to its performance relative to peer nations in the Americas. This study examines changes in life expectancy at age 65 (LE65) in the United States, Canada, and seven Latin American countries-Argentina, Brazil, Chile, Costa Rica, Colombia, Mexico, and Peru-between 2000 and 2019, disaggregated by sex and cause of death.

Parental age at conception can have both short- and long-term consequences on the health, survival, and reproduction of their offspring. To date, most of our knowledge comes from laboratory studies, and considers the effects of maternal age and a "snapshot" of the life history trajectory of the offspring. Here, we use a multigenerational demographic dataset in a free-living, long-lived (median lifespan is 7 years old) bird, the Alpine swift (Tachymarptis melba), to investigate the effects of maternal and paternal age on offspring traits, from nestling to adulthood, and considering all major life history traits, from growth and age at first reproduction to reproductive success and lifespan. Parental age affected offspring phenotype before fledging and lifespan, but differently so for sons and daughters. Offspring from old-age mothers (≥ 11 years old) and fathers (≥ 9 years old) were bigger and less infested by ectoparasites before fledging, except sons from old-age fathers that show no reduction in ectoparasite load. We also report evidence of negative effects of paternal age on the lifespan of their offspring (i.e., Lansing effect), with sons (but not daughters) from old-age fathers having shorter lifespans. Our findings highlight the importance of the transgenerational effects of parental age at conception on the reproductive performance, survival and phenotype of their offspring.

Biochemical and molecular mechanisms associated with testicular aging are still poorly understood. Here, using the Syrian hamster as a natural model of aging, we observed a disturbed spermatogenesis with reduction of the testicular weight and the gonadosomatic index, altered histology including tubular wall fibrosis, increased collagen deposition, and diminished steroidogenesis in testes of aged animals. These changes took place in parallel with an increase in the levels of inflammatory and oxidative stress markers and a reduction in the cell proliferative, survival, DNA repair, and autophagic capacities. Metformin, beyond its current clinical applications, has been proposed as an anti-aging drug. In vitro incubations of testicular fragments from old hamsters with metformin revealed beneficial effects of this drug on the testicular inflammatory-oxidative state together with stimulation of autophagy and cell ability to fix DNA damage. However, in vivo daily oral administration of metformin to aged hamsters for 2 months in a dose equivalent to that usually received by patients with type 2 diabetes mellitus, reduced body and testicular weights, gonadosomatic index and blood glucose, concomitantly with increased levels of indicators of testicular inflammation, oxidation and fibrosis, decreased signs of autophagy, steroidogenesis and DNA repair capacity, and impaired spermatogenesis. Overall, while in vitro studies suggested beneficial effects of metformin in the aging testis evidenced through anti-inflammatory, anti-oxidant, and pro-autophagic actions, in vivo experiments in aged hamsters supplemented with metformin exhibited completely opposite effects. Therefore, the future of metformin as a testicular anti-aging agent should be further investigated, thoroughly reconsidered and, should the need arise, disregarded.

Periodontitis is a chronic inflammatory disease that leads to progressive destruction of periodontal tissues and eventual tooth loss, significantly affecting the patient's quality of life. Dysregulated mechanistic target of rapamycin (mTOR) signaling contributes to periodontitis pathogenesis by influencing inflammation, autophagy, senescence, and bone metabolism. Rapamycin, a well-established mTOR inhibitor with geroprotective properties, has emerged as a promising therapeutic candidate in mitigating periodontal inflammation and preserving alveolar bone.

The mechanisms of aging are becoming increasingly well mapped; however, there remains ongoing debate about the ultimate and proximate causes of aging. The recent development of highly precise aging clocks led to a resurgence of arguments in support of a biological program of aging. However, the declining force of natural selection after the onset of reproduction means that cellular function could deteriorate without requiring a specific program. Here, we argue that aging clocks do not imply an intrinsic program but rather reflect the stochastic accumulation of molecular errors and damage. Damage accumulates due to insufficient maintenance and repair and contributes to system-wide entropy. In support of this, cross-species comparisons indicate that enhanced DNA repair capacity is a key determinant of exceptional longevity in mammals. By better understanding the nature of the stochasticity that governs the aging process, we will have a stronger mechanistic basis for developing geroprotective interventions to promote healthy aging in humans.

Ovarian aging is a significant biological process characterized by the gradual decline of ovarian function and fertility in women as they age. It is a multifaceted process that involves various molecular mechanisms. This review article delves into the complex nature of ovarian aging, marked by reductions in both the quantity and quality of oocytes, hormonal imbalances, and heightened risks of infertility and pregnancy complications. It consolidates current understanding of the physiological, cellular, and molecular mechanisms driving ovarian aging, such as mitochondrial dysfunction, oxidative stress, telomere shortening, DNA (Deoxyribonucleic Acid) damage, inflammation, and apoptosis. This review primarily focuses on human ovarian aging, while also integrating relevant insights from animal models particularly rodent studies that have contributed to our understanding of underlying mechanisms. It explores key signaling pathways involved in aging, including AMPK (AMP-Activated Protein Kinase), mTOR (mammalian target of rapamycin), Nrf2 (Nuclear Factor Erythroid 2-Related Factor 2), SIRT1 (Sirtuin 1), and FOXO3 (Forkhead Box O Transcription Factor) pathways. The review also discusses emerging therapeutic strategies designed to delay or reverse ovarian aging, which include antioxidants, hormone replacement therapy, stem cell-based treatments, CRMs (CR mimetics), gene therapy, and traditional medicines. Additionally, the article examines the potential role of polyamines in ovarian function and aging. By thoroughly analyzing the current research landscape and identifying future research directions, this review offers valuable insights for researchers and clinicians dedicated to improving reproductive health and quality of life for aging women.

Reversing the aging process may yield significant benefits in people with multiple sclerosis (PwMS), as accelerated biological aging is observed in this population. Secondary analyses of 2 previously conducted dietary interventions including a 6-month modified ketogenic diet in 39 participants and an 8-week randomized comparison of intermittent and daily calorie restriction versus a weight-stable regimen in 36 participants demonstrated significant decreases in metabolomic age (mAge) following the ketogenic diet (p = 0.009) and intermittent calorie restriction (p = 0.04), whereas daily calorie reduction had no effect. These findings indicate that fasting-mimicking diets (FMDs) can reverse accelerated metabolomic aging in PwMS. ANN NEUROL 2025.

Microglia, the brain's resident immune cells, are crucial for maintaining healthy brain homeostasis. However, as the brain ages, microglia can shift from a neuroprotective to a neurotoxic phenotype, contributing to chronic inflammation and promoting neurodegenerative processes. Despite the importance of understanding microglial aging, there are currently few human in vitro models to study these processes. To address this gap, we have developed a model in which human microglia undergo accelerated aging through inducible progerin expression. HMC3-Progerin cells display key age-related markers such as activation of the senescence-associated secretory phenotype (SASP) as well as an increase in DNA damage. These prematurely aged HMC3 cells show a reduced response to LPS activation, exhibit impairments in essential microglial functions including decreased migration and phagocytosis as well as transcriptomic alterations including a shift observed in aging and neurodegeneration. Additionally, we observed an impaired stress response and a defect in nucleocytoplasmic transport, especially affecting the amyotrophic lateral sclerosis (ALS) associated protein FUS. This suggests that microglia play a contributory role in driving neurodegenerative processes in the aging brain. Our microglia aging model offers a valuable tool for exploring how aged microglia affect brain function, enhancing our understanding of their role in brain aging.

The interaction between sleep, circadian rhythms and cardiovascular resilience is a crucial yet underexplored research area with important public health implications. Disruptions in sleep and circadian rhythms exacerbate hypertension, diabetes mellitus and obesity, conditions that are increasingly prevalent globally and increase the risk of cardiovascular disease. A National Heart, Lung, and Blood Institute workshop examined these connections, as well as the emerging concept of cardiovascular resilience as a dynamic and multifaceted concept spanning molecular, cellular and systemic levels across an individual's lifespan. The workshop emphasized the need to expand the focus from solely understanding whether and how sleep and circadian rhythm disturbances contribute to disease, to also exploring how healthy sleep and aligned circadian rhythms can increase cardiovascular resilience. To develop a Roadmap towards this goal, workshop participants identified key knowledge gaps and research opportunities, including the need to integrate biological, behavioural, environmental and societal factors in sleep and circadian health with cardiovascular research to identify therapeutic targets. Proposed interventions encompass behavioural therapies, chronotherapy, lifestyle changes, organizational policies and public health initiatives aimed at improving sleep and circadian health for better cardiovascular outcomes. Future cross-disciplinary research and translation of discoveries into public health strategies and clinical practices could improve cardiovascular resilience across the lifespan in all populations.

Periodontal disease (PD) is a chronic inflammatory condition linked to systemic health issues, yet its relationship with intrinsic capacity (IC)-a key determinant of healthy aging-remained underexplored. The present study investigated the associations between moderate/severe PD and IC domains in older adults in a cross-sectional analysis from the National Health and Nutrition Examination Survey (NHANES) 2009-2014. From the 30,468 NHANES subjects, we included participants aged ≥ 60 years with available PD and IC data. IC was assessed across five domains: locomotion, cognition, psychological well-being (depressive symptoms/anhedonia), sensory function (vision/hearing), and vitality (nutrition/weight loss). PD was classified as moderate or severe using CDC/AAP criteria. After applying exclusion criteria, 551 participants were included in the analyses. The prevalence of PD was 68.97% (moderate PD:51.91%/severe PD:15.06%). Severe PD was associated with reduced locomotion [odds ratio(OR):2.30, 95% confidence interval(CI):1.27-4.16), impaired psychological well-being (depressive symptoms) (OR:1.79, 95%CI:1.01-3.16), and sensory function (vision) (OR:2.37, 95%CI:1.24-4.56), while moderate PD was linked to reduced locomotion (OR:1.66, 95%CI:1.06-2.66) and impaired sensory function (hearing) (OR:1.93, 95%CI:1.04-3.75). Higher mean clinical attachment loss and probing pocket depth (PPD) were associated with reduced locomotion (OR:1.15, 95%CI:1.00-1.31 and OR:1.35, 95%CI:1.05-1.73, respectively). Mediation analysis indicated that multimorbidity had minimal influence on these associations, except for stroke, accounting for 13.3% of the relationship between mean PPD and locomotion. The present findings highlighted the potential role of periodontal health in maintaining overall functional capacity in older adults, underscoring the need for integrated oral and systemic health strategies in aging populations.

Presbycusis, or age-related hearing loss (ARHL), is a progressive condition that involves a steady decline in auditory function, primarily caused by the physiological alterations that occur with aging. This disorder arises from the combined effect of multiple interconnected factors that progressively affect the auditory system over time. Genome-wide association studies (GWAS) and transcriptomic analyses in human populations are valuable approaches for identifying potential genes associated with ARHL. This research seeks to assess the potential of protective drugs or strategies for treating ARHL by analyzing target gene-miRNA interactions identified in human blood and associated with presbycusis. We performed RNA sequencing to analyze the transcriptomes of peripheral blood leukocytes from ARHL patients. To identify genes associated with ARHL, the RNA-sequencing data from the peripheral blood leukocytes were compared and further validated by real-time polymerase chain reaction (RT-qPCR) using whole blood samples from the same ARHL patients. To explore the involvement of target genes and microRNAs (miRNAs) in ARHL, we examined miRNA expression patterns using RT-qPCR and reporter gene assays. We found that four genes were up-expressed in ARHL serum: Fas Ligand (FASLG), Neural Cell Adhesion Molecule 1 (NCAM1), Nectin Cell Adhesion Molecule 1 (NECTIN1), Macrophage Receptor with Collagenous Structure (MARCO). The up-expressed FASLG is associated with cell apoptosis and aging. Additionally, we showed that miR‑5195 and miR-3941 regulated FASLG expression in House Ear Institute-Organ of Corti 1 (HEI-OC-1) and HeLa cells via targeting of FASLG using luciferase reporter assays. Finally, the over-expression of the FASLG gene may be associated with the development of ARHL, and the inhibitory role of miR-5195 and miR-3941 could be a key factor in the prevention or protection against ARHL.

Rapamycin (RAPA) and related mTOR-inhibitors have been shown to enhance healthy aging in animal models (2-10) and to be generally safe and tolerable in older people (11-13). However, studies to assess their effects on specific age-related pathologies in humans are limited. Since improvements in cardiovascular function with RAPA treatment have been reported in preclinical studies (5, 9, 10, 14-17), we posited that RAPA could be similarly efficacious in humans. Towards this end, we performed a pilot "proof of concept" trial to examine RAPA's effects on cardiovascular and endothelial functions that are known to decline with age (18, 19). We hypothesized that RAPA would elicit beneficial cardiovascular effects in men. A cohort of older male subjects with no known cardiac disease (ages 70-76 years) were enrolled in the open-label study and received 1 mg RAPA/day for 8 weeks. To assess cardiovascular function, cardiac MRI (CMR) was performed twice: prior to initiation of the intervention and again after 8 weeks of treatment. Endothelial function was examined using laser-Doppler flowmetry (LDF) by measuring cutaneous, endothelium-dependent, local thermal hyperemic responses pre-intervention and after 4 and 8 weeks of RAPA (1). In all 6 subjects, transmitral blood flow, peak flow rate, and maximal blood acceleration showed statistically significant improvements while endothelial function also improved over the 8-week course of RAPA treatment. Thus, cardiac and endothelial function improvements with RAPA were found and support future placebo-controlled studies in larger cohorts of healthy older persons as well as in patients with compromised diastolic and endothelial function (20, 21).

Nucleosomes are the minimal repeating units of chromatin. Their dynamic assembly and disassembly underpins chromatin organization and genome regulation. However, it remains unclear how intrinsic nucleosome stability contributes to higher-level yet fundamental cellular and organismal properties, such as preservation of cell identity, lineage specification, stress resilience and ultimately healthy aging. To address this, we tested the impact of decreased intrinsic nucleosome stability across multiple cell, tissue and organismal models by introducing histone mutants that weaken histone/histone interactions. While nucleosome instability did not broadly alter global chromatin accessibility, DNA damage, cell proliferation or viability, it impaired lineage-specific gene expression programs, altered lineage specification and activated intrinsic inflammatory and stress pathways in a manner reminiscent of aging in mouse tissues and human cells. Consistently, nucleosome instability accelerated the onset of age-associated transcriptional alterations and functional decline in Caenorhabditis elegans and Drosophila melanogaster, and reduced cellular resilience to exogenous perturbations, including environmental, epigenetic and mitotic stress in human cells and Saccharomyces cerevisiae. These cross-species findings identify nucleosome stability as an evolutionarily conserved epigenetic safeguard that preserves cell identity and stress resilience and supports organismal function and healthy aging.

Based on the importance of redox homeostasis, the concept of precision redox regulation has received widespread attention. As the main source of Reactive Oxygen Species (ROS) production, mitochondria play a dual role in this process: facilitating beneficial signal transmission and causing excessive oxidative damage. Numerous studies have demonstrated that this duality is not only dependent on the quantity of ROS produced but also on the different sites of production, each showing varying effects. This insight underscores the necessity and importance of accurately regulating mitochondrial redox. However, the precise regulatory system remains unclear. In our study, we discovered that specifically knocking down the atad-3 (ATAD3A) gene significantly increased the level of mitochondrial ROS in nematodes and mammalian cells. We found that ATAD3A directly interacts with the complex I subunit NDUFS8, playing an integral role in complex I assembly and activity. Knocking down atad-3 reduces complex I activity and proton leakage, increases mitochondrial membrane potential, thereby inducing reverse electron transport (RET) to produce more ROS. The induced RET-ROS may serve as a protective response to impaired mitochondrial function, activating antioxidant systems that enhance stress resistance and extend longevity in nematodes. Our findings reveal a novel function and mechanism of knocking down ATAD3A to precisely regulate mitochondrial ROS production. They provide evidence for the beneficial role of RET-ROS as a signal promoting longevity and underscore the importance of precision redox.

Obesity is a global public health priority and a major risk factor for cardiovascular disease (CVD). Emerging evidence indicates variation in pathologic consequences of obesity deposition across different body compartments. Biological heart age may be estimated from imaging measures of cardiac structure and function and captures risk beyond traditional measures. Using cardiac and abdominal magnetic resonance imaging (MRI) from 34,496 UK Biobank participants and linked health record data, we investigated how compartment-specific obesity phenotypes relate to cardiac ageing and incident CVD risk. Biological heart age was estimated using machine learning from 56 cardiac MRI phenotypes. K-means clustering of abdominal visceral (VAT), abdominal subcutaneous (ASAT), and pericardial (PAT) adiposity identified a high-risk cluster (characterised by greater adiposity across all three depots) associated with accelerated cardiac ageing - and a lower-risk cluster linked to decelerated ageing. These clusters provided more precise stratification of cardiovascular ageing trajectories than established body mass index categories. Mediation analysis showed that VAT and PAT explained 13.7% and 11.9% of obesity-associated CVD risk, respectively, whereas ASAT contributed minimally, with effects more pronounced in males. Thus, cardiovascular risk appears to be driven primarily by visceral and pericardial rather than subcutaneous fat. Our findings reveal a distinct risk profile of compartment-specific fat distributions and show the importance of pericardial and visceral fat as drivers of greater cardiovascular ageing. Advanced image-defined adiposity profiling may enhance CVD risk prediction beyond anthropometric measures and enhance mechanistic understanding.

Alzheimer's disease (AD) remains without effective treatment, largely due to the fact that clinical symptoms emerge only after decades of silent pathological progression. It is urgently needed to identify modifiable risk factors in earlier life stages, when preventive interventions may still be effective. Functional connectivity (FC) has emerged as a promising neuromarker for both neurodegenerative processes and behavioral traits, making it a potential bridge between early-life health profiles and late-life AD risk. In this work, we introduce a novel integrative framework that models how early-life lifestyle and physiological factors influence AD risk through their impact on brain FC. Our approach combines a modified variational autoencoder (VAE) that simulates FC changes under interventions with a predictive model that estimates AD risk based on FC patterns. This design enables training of the generative and predictive components under different datasets and populations, with FC acting as the bridge between early-life modifiable factors and late-life disease risk. Applying our framework to data from the Human Connectome Project (HCP), UK Biobank (UKB), and Alzheimer's Disease Neuroimaging Initiative (ADNI), we validate its ability to capture known risk factors, such as age and polygenic risk score, on FC-mediated AD risk. We also identify earlier-life modifiable factors including tobacco use, sleep quality, physical activity and weight/BMI that significantly influence AD risk. Notably, we observe a U-shaped relationship between blood pressure and AD risk, and highlight the brain visual and somatomotor networks as key mediators of risk through FC. Our approach provides a powerful tool for investigating the effect pathways linking early-life interventions to neurodegenerative outcomes, with broad applicability to other brain-related disorders.

Understanding epigenetic aging prior to midlife is gaining interest as a potentially intervenable period to address factors that influence health and cognitive aging. Epigenetic changes associated with aging may point to differential biological aging rates; however, methylation profiles may not be substitutable across tissues. We compared DNA methylation in three tissues collected in 91 siblings and twins from the Colorado Adoption/Twin Study of Lifespan and behavior and cognitive aging (CATSLife1): saliva, buffy coat (BC), and peripheral blood mononuclear cells (PBMC). Overall, across five methylation clocks and two blood-derived and one saliva-derived tissues, moderate to strong associations between chronological age and methylation ages were observed. Moreover, PBMC methylation age values correlate more strongly with BC values (Spearman r = 0.66 to 0.87), whereas saliva showed weaker correlations with either form of blood-derived measures (Spearman r = 0.25 to 0.69) although still moderate to strong magnitudes. Saliva demonstrated significantly older methylation ages across four of five clocks, whereas PBMC and BC did not differ. Twins were more strongly correlated for BC and PBMC derived clocks with weaker and inconsistent patterns among Saliva clocks. DunedinPACE age acceleration showed no significant tissue differences and on average demonstrated the largest divergence of similarity between monozygotic (MZ) versus dizygotic (DZ) twins (rMZ= .56, rDZ= .21). In summary, saliva-derived methylation is not a direct substitute for blood-derived methylation whereas blood-derived methylation values were comparable across buffy coat and peripheral blood mononuclear cell tissues.

Olfactory dysfunction is among the earliest signs of many age-related neurodegenerative diseases and has been associated with increased mortality in older adults; however, its genetic basis remains largely unknown. Therefore, here we aimed to elucidate its genetic architecture through a genome-wide association study meta-analysis (GWMA).

Negative wealth shocks can pose a serious threat to health, however, there has been no research exploring the potential link between negative wealth shocks and epigenetic aging. This study aims to explore the relationship between negative wealth shocks and epigenetic aging in middle-aged and older adults.

The quantitative evaluation and diagnosis of muscle function in patients with sarcopenia are crucial to mitigate functional decline and the health burden in aging populations. This study proposed a method for the classification of sarcopenia and the evaluation of muscle function scores based on EIT technology. We recruited 31 participants, including individuals with sarcopenia (n = 11), healthy elderly (n = 10), and healthy young adults (n = 10), obtained muscle clinical fitness assessment scores and EIT-derived parameters, conducted intergroup comparisons of EIT parameters and clinical scores, and constructed a machine learning classification model for sarcopenia. EIT parameters conductivity (σ) were significantly different among the three groups (p < 0.05). Clinical muscle function scores showed a strong positive correlation with the σ (r = 0.73, R² = 0.54, p < 0.001), while negatively correlated with impedance (Z) (r = -0.55, R² = 0.27, p < 0.05). In addition, σ was positively correlated with hand grip strength (HGS) (r = 0.52, R² =0.20, p=0.30), and maximum voluntary muscle contraction (MVC) (r=0.73, R² = 0.49, p<0.001), and negatively correlated with age (r = -0.76, R² = 0.56, p<0.001) and SARC-F scale scores (r = -0.73, R² =0.57, p<0.001). Finally, the KNN-based sarcopenia classification model demonstrated strong performance in classification tasks, as evidenced by an accuracy of 0.89 and an AUC of 0.94. This study demonstrates that the EIT is a portable, wearable, and long-term monitoring tool for assessing and classifying muscle function in sarcopenia. With further clinical validation, it is expected to be used for early screening and rehabilitation monitoring of sarcopenia.

Proteasomes reversibly form foci bodies in a liquid-liquid phase separation (LLPS)-dependent manner upon stress. We previously reported that internalized protein aggregates were targeted by proteasome-dense foci1, and proposed that such transient aggregate-associated droplets (TAADs) may facilitate aggregate removal2. Here we use quantitative imaging to show that TAADs represent a novel type of gel-like proteasome condensate. TAADs are irregular in shape and slow to disperse, sequestering proteasomes in alignment with our observation of confined diffusion3. We demonstrate that TAADs co-localize with cytosolic alpha-synuclein aggregates to facilitate their clearance. Inhibition of proteasome or ubiquitination activity abolish this aggregate clearance. We identify RAD23B necessary for TAAD formation, amid other co-localizing chaperones and (co-)proteins of the ubiquitin-proteasomes system. TAAD formation is associated with higher proteasomal substrate turnover whilst retaining overall catalytic efficiency, suggestive of altered degradation mechanisms upon aggregate engagement. Proteomics analysis show impact on key mitochondrial-associated processes even after apparent clearance of aggregates. Similar TAAD-aggregate co-localizations can be observed in iPSC-differentiated neurons and in disease-relevant samples, with no detection of compromised proteasome activity. Together, our results indicate a model where TAADs concentrate local proteasome activity, which facilitates aggregate clearance in healthy ageing cells. Potentially with persisting pathological aggregates, TAADs may remain engaged and conceivably sequester proteasomes from physiological activities, thus contributing to neurodegenerative disorders.

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders, characterized by a progressive decline in cognitive function. Increasing evidence indicates that alpha-ketoglutarate (AKG), a key metabolite in the tricarboxylic acid (TCA) cycle, can extend lifespan and healthspan across various animal models, raising interest in its potential neuroprotective effects in age-related disorders such as AD. Our previous research found that dietary supplementation with calcium alpha-ketoglutarate (CaAKG), a calcium derivative of AKG, enhances both lifespan and healthspan in mice. However, little is known about the neuroprotective role of AKG/CaAKG in AD. Here, we show that CaAKG could rescue synaptic deficits that are associated with AD. Treatment with AKG or CaAKG ameliorates long-term potentiation (LTP) at hippocampal CA1 synapses in APP/PS1 mice, with a more profound effect in female AD mice than in males. The effects of CaAKG were mediated through an NMDA receptor-independent mechanism involving L-type calcium channels (LTCC) and calcium-permeable AMPA receptors (CP-AMPARs). Analysis of protein expression showed that AD hippocampal slices treated with CaAKG exhibited increased LC3-II levels, indicating enhanced autophagy. Similarly, rapamycin, an mTOR inhibitor, also rescued LTP deficits in AD mice, suggesting that the observed increase in autophagy may contribute to neuroprotection. Interestingly, rapamycin showed differential effects, as it rescued LTP in AD mice but blocked LTP in WT mice. We also observed that CaAKG facilitated synaptic tagging and capture (STC), a widely studied cellular model for associative memory, indicating its potential to facilitate associative memory. Overall, our findings suggest that CaAKG has neuroprotective effects in APP/PS1 mice. We propose CaAKG as a promising therapeutic target not only for aging but also for AD and potentially other age-associated neurodegenerative diseases, highlighting geroprotective strategies as viable alternatives for the prevention and treatment of AD.

Predicting human lifespan is a longstanding objective of biomedical research. Traditional statistical models estimate mortality risk or biological age but not lifespan. We propose a two-parameter model based on stochastic fractional harmonic oscillator for neural signals. The model computes maximum human lifespan using 1/f slope, the measure of neural power decay with frequency, which is indicative of neural noise. Using slope rate from electroencephalographic and electrocorticographic datasets, we estimate the mean lifetimes of healthy adults and epileptic patients as 76.9 and 69.7 years, resulting in 89.4% and 96.9% accuracy respectively. Additionally, the present model resolves the inconsistency in age-related changes of fractal dimension (FD) and captures naturally the non-monotonic variation of stimulus-induced gamma power. Thus, the present model provides a simple way to estimate lifespan while explaining age-related changes in slope, FD and power simultaneously, thereby, paving the way for individualized lifetime measurements and unveiling fundamental principles governing life.

Aging is a complex biological process driven by the dynamic interplay among genetic, environmental, and lifestyle factors. Advances in epigenetics have significantly deepened our understanding of the molecular mechanisms underlying aging, underscoring the critical roles of reversible modifications such as DNA methylation, histone modifications, and non-coding RNA regulation. Emerging evidence suggests that exercise is a potent modulator of these epigenetic processes, capable of reshaping the epigenetic landscape to restore cellular homeostasis, modulate gene expression, and enhance physiological resilience. This review systematically synthesizes current knowledge on how exercise modulates epigenetic mechanisms implicated in aging and delineates the distinct epigenetic adaptations induced by variations in exercise modality, intensity, and duration. By integrating these molecular insights, this review provides a comprehensive mechanistic framework linking exercise-induced epigenetic remodeling to healthy aging, and underscores exercise as a promising intervention to counteract aging-related functional decline and disease progression.

Postmenopausal women face an elevated risk of osteoporosis due to decreased estradiol secretion. Obesity is also a prevalent disease during menopause, but the impact on bone health is understudied. Genistein (GEN) is a soy-derived isoflavone that has beneficial effects on a variety of age-related diseases, but the exact role of GEN in bone health in hypoestrogenism and obesity-induced stress remains to be elucidated. This study employed an ovariectomized (OVX) mouse model subjected to a high-fat diet to simulate postmenopausal obesity and investigate the effects of GEN intake on bone metabolism. Bone mass alterations and metabolic function were evaluated using micro-CT imaging, biochemical markers, and histopathological staining. The homeostasis of the bone matrix was further assessed through primary bone marrow cell differentiation assays, western blotting, and quantitative real-time PCR (qRT-PCR). Additionally, intestinal barrier protein expression, 16S rRNA gene sequencing, and untargeted metabolomics were integrated to examine GEN's impact on gut structure, microbiota composition, and fecal metabolic profiles. Our findings indicated that diet-induced obesity (DIO) exacerbated OVX-induced osteopenia in mice, whereas GEN supplementation significantly mitigated bone loss and restored balanced differentiation among osteoblasts, adipocytes, and osteoclasts. Furthermore, GEN improved metabolic abnormalities associated with obesity. It also preserved intestinal barrier integrity by maintaining tight junction proteins and mucus levels, thereby reducing systemic inflammation. The results of 16s rDNA gene sequencing showed that GEN alleviated intestinal microbiota dysbiosis and increased the abundance of beneficial bacteria

Naked mole-rats (NMR, Heterocephalus glaber) defy Gompertzian rules of mortality and age-dependent senescence to lead healthy lives well into their fourth decade. The NMR immune system likely contributes to this phenotype by protecting against infections, regulating tissue repair, and eradicating neoplastic cells. In keeping with their many other paedomorphic traits, adult NMRs retain functional thymic tissue in the submandibular triangle. Despite this additional thymic tissue, perinatal NMR thymi are half the size of mouse thymi, yet both species show similar thymic involution trajectories. Smaller thymi may indicate less diverse thymocyte clonotypes that need to complete selection before being released as functional, self-tolerant T cells. Transcriptomic studies revealed that when compared with mice, NMRs have a larger myeloid to lymphoid ratio, lack natural killer (NK) cells, and that the αβ clonotypic diversity of NMR CD8 T cells is limited and smaller than that of their CD4 T cells. NMRs, strikingly, have a large circulating population of γδ T cells with two distinct subsets; one with a large diversity of γ and δ TCR loci and the other, a cytotoxic T cell subset with a dominant clonotype. Collectively, these data suggest that NMRs, living in a sealed milieu, rely more upon the innate immune response and have evolved under relaxed viral selective pressure. Rather, they have selected for an atypical myeloid-biased mode of innate immune surveillance and circulating populations of cytotoxic γδ T cells. In summary, the NMR appears to have been optimized to provide better immunosurveillance, tissue homeostasis, and protection against cancer rather than protection against unlikely environmental exposure to viral pathogens. These features likely contribute to their prolonged healthspan and exceptional longevity.

Recent advances in ultra-accurate sequencing technologies have revealed that somatic mutations accumulate across the human lifespan and may contribute to both normal aging and disease. These mutations are highly diverse, often non-recurrent, and functionally heterogeneous, which makes their biological impact difficult to evaluate systematically. Although many studies have profiled somatic mutations in individual tissues or limited cohorts, a centralized and scalable platform that integrates discoveries and supports functional interpretation has been lacking. To address this gap, we present SomaMutDB 2.0 (https://somamutdb.org/SomaMutDB/), a substantially expanded database that catalogs 8.9 million mutations (8.57 million SNVs and 0.29 million INDELs) from 10,852 samples of 607 human subjects across 47 studies. Beyond expanded data coverage, SomaMutDB 2.0 introduces a comprehensive functional annotation framework that applies 22 predictive models, encompassing coding, regulatory, expression-based, and ensemble predictors, to systematically assess mutational impact. Users can browse pre-annotated variants through an interactive interface or upload their own variants for real-time analysis, with results contextualized against all mutations from normal, non-diseased tissues in the database. Together, these advances establish SomaMutDB 2.0 as the most comprehensive resource currently available for characterizing somatic mosaicism and functional interpretation in human health and aging.

Sarcopenia, recognized as an age-related loss of muscle mass and function, is a critical risk for geriatric health. We previously demonstrated that maternal high-fat diet (HFD) suppresses mitochondrial biogenesis during fetal skeletal muscle development, but the longitudinal effect of maternal HFD challenge on offspring muscle sarcopenia and fitness impairment remains unclear. Mitochondrial polymerase γ (PolG) mutation accelerates mitochondrial DNA mutations and leads to premature aging.

This study aims to investigate the effect of inflammation on the senescence phenotype and osteogenic capacity of aged periodontal ligament cells (PDLCs), and to explore the regulatory role of the NF-κB signalling pathway in the osteogenesis of aged PDLCs.

GLP-1-based therapy is highly effective in combating aging-associated metabolic diseases. However, the metabolic effects of frequent withdrawal from this therapy in aged, obese mice have not been previously studied. In this study, aged obese UM-HET3 mice were assigned to three groups: Group 1 received no liraglutide treatment (Lira OFF); Group 2 underwent 3 cycles of treatment followed by withdrawal (Lira ON/OFF); and Group 3 remained on continuous treatment (Lira ON). As expected, mice in Group 3 showed reduced body weight and food intake, along with improved metabolic health. In contrast, mice in Group 2 developed hyperleptinemia and visceral fat expansion, leading to impaired metabolic health. Importantly, although these mice regained their fat mass after each treatment cycle, they failed to restore lean mass, an unfavorable shift in body composition that may increase vulnerability to aging-related sarcopenia. These findings suggest that continuous GLP-1-based therapy is necessary to sustain metabolic benefits, while intermittent use may promote age-associated sarcopenia and metabolic decline.

Aging involves complex biological changes that affect disease susceptibility and aging trajectories. Although females typically live longer than males, they have a higher susceptibility to diseases like Alzheimer's, speculated to be influenced by menopause, and reduced ovarian hormone production. Understanding sex-specific differences is crucial for personalized medical interventions and sex equality in health. Our study aims to elucidate sex differences in regional cerebellar structure and connectivity during normal aging by investigating both structural and functional connectivity variations in the context of sex-steroid hormones. The study included 138 participants (mean age = 57 (13.3) years, age range = 35-86 years, 54% women). The cohort was divided into three groups: 38 early middle-aged (EMA) individuals (mean age = 41 (4.7) years), 48 late middle-aged (LMA) individuals (mean age = 58 (4) years), and 42 older adults (OAs) (mean age = 72 (6.3) years). All participants underwent MRI scans, and saliva samples were collected for sex-steroid hormone quantification (17β-estradiol (E), progesterone (P), and testosterone (T)). We found less connectivity in females between Lobules I and IV and the cuneus, and greater connectivity in females between Crus I, Crus II, and the precuneus with increased age. Higher 17β-estradiol levels were linked to greater connectivity in Crus I and Crus II cerebellar subregions. Analyzing all participants together, testosterone was associated with both higher and lower connectivity in Lobules I-IV and Crus I, respectively, while higher progesterone levels were linked to lower connectivity in females. Structural differences were observed, with EMA males having larger volumes compared to LMA and OA groups, particularly in the Right I-IV, Right Crus I, Right V, and Right VI. EMA females showed higher volumes in the Right Lobules V and VI. These results highlight the significant role of sex steroid hormones in modulating cerebellar connectivity and structure across adulthood, emphasizing the need to consider sex and hormonal status in neuroimaging studies to better understand age-related cognitive decline and neurological disorders.

Epigenetic regulation is a key determinant of the aging process, and its dysregulation contributes to cognitive aging and increased vulnerability to Alzheimer's disease (AD). As major regulators of epigenetic processes, histone deacetylases (HDACs) have emerged as potential therapeutic targets for cognitive enhancement in neurodegenerative diseases. However, the distinct roles of individual HDAC isoforms remain to be defined. Here, we report that HDAC9 is specifically expressed in neurons of human and mouse brains, and its expression declines with age. HDAC9 deficiency impairs cognitive function and synaptic plasticity in young mice. Selective deletion of HDAC9 in hippocampal CA1 neurons also induces cognitive impairment. In contrast, overexpression of HDAC9 in forebrain glutamatergic neurons preserves cognitive function in aged mice. Moreover, HDAC9 is also downregulated in the brain of AD mouse models, whereas neuronal overexpression of HDAC9 alleviates AD-related cognitive and synaptic deficits and reduces Aβ deposition. Together, these findings suggest neuronal HDAC9 is necessary and sufficient for maintaining cognitive and synaptic functions in the context of aging and AD.

Intervertebral disc degeneration (IVDD) is a multifactorial pathology primarily driven by the senescence of nucleus pulposus cells (NPC), inflammatory microenvironment of extracellular matrix (ECM), and the resultant decline in NPCs viability. Conventional treatment strategies often fail to address these two interconnected factors simultaneously. To overcome this limitation, a bifunctional anti-swelling hydrogel system encapsulating anti-senescence drugs quercetin (Q) and dasatinib (D), as well as nucleus pulposus-derived exosomes (NP-Exo) is developed. This system is designed to clear senescent NPCs, regulate the inflammatory disc microenvironment, and enhance NPC activity, thereby significantly improving treatment efficacy. Mechanistically, this strategy helps preserve mitochondrial function, maintain mitochondrial membrane potential, and reduce excessive reactive oxygen species production, which collectively contribute to delaying cellular senescence and restoring disc homeostasis. Additionally, the anti-swelling property of the hydrogel can alleviate structural displacement caused by swelling, further optimizing the stability and efficacy of the treatment. The biological efficacy of this system is validated in both rat and goat models. The experimental results demonstrated that this drug delivery system can effectively restore the integrity of the ECM, ultimately promoting the repair of IVDD. These findings highlight the platform's potential for IVDD treatment, offering a novel therapeutic strategy for IVDD repair.

Despite widespread seropositivity, respiratory syncytial virus (RSV) remains a major cause of severe illness in adults aged 60 years and older. This review examines why infection-acquired immunity fails to protect this group, focusing on four key factors: structural lung decline, comorbidities, immunosenescence, and impaired antibody responses. Age-related changes weaken mechanical defenses and antiviral immunity, while chronic diseases amplify RSV risk. Critically, repeated RSV infections may preferentially boost non-neutralizing antibodies targeting the postfusion F protein, limiting protection and possibly enhancing disease. The review also highlights how newly approved vaccines, based on stabilized prefusion F protein, can overcome these barriers by inducing strong neutralizing responses, offering a targeted strategy to reduce RSV burden in older adults.

Ovarian aging is one of the common diseases in the female reproductive system. It is characterized by complex etiologies, involving multiple factors such as genetics, environment, metabolism, and cellular stress. In recent years, autophagy, a crucial cellular self-degradation and repair mechanism, has received substantial attention for its role in maintaining and deteriorating ovarian function. This review systematically summarizes the molecular mechanisms of autophagy and its regulation, as well as the latest research progress of macroautophagy, chaperone-mediated autophagy (CMA) and mitophagy in ovarian aging. Studies have shown that dysregulation of autophagic pathways is closely associated with decreased oocyte quality and reduced ovarian reserve function. Additionally, signaling pathways such as PI3K, AMPK, and mTOR participate in the process of ovarian aging by regulating autophagic activity. Although numerous studies have revealed the critical role of autophagy in ovarian aging, many issues remain to be resolved, such as the crosstalk mechanisms between different autophagic pathways and the precise spatiotemporal dynamics of the autophagic regulatory network. A deep understanding of the regulatory network of multi-pathway autophagy will provide new insights for developing intervention strategies to delay ovarian aging, holding significant scientific and clinical application value.

Long-term hematopoietic stem cells (HSCs) possess the capacity to generate all blood lineages, yet they normally remain quiescent and become activated only in response to acute stress. We previously demonstrated that quiescent HSCs exhibit heterogeneity in intracellular calcium; however the mechanisms that establish this heterogeneity and its physiological relevance remain unclear. Here, we identify phospholipase C like 1 (Plcl1), a non-catalytic protein that binds inositol 1,4,5-trisphosphate (IP), as being specifically enriched in the most quiescent HSC subset. Loss-of-function studies demonstrated that, at steady state, Plcl1 deficiency lowers basal intracellular calcium and shifts the HSC compartment toward CD41 subsets, while preserving overall HSC numbers and long-term reconstitution capacity. Under acute hematopoietic stress, Plcl1 loss accelerated and amplified platelet rebound and expansion of non-canonical megakaryocyte progenitors (ncMkPs), suggestive of activation of the thrombopoietic bypass pathway. In aging HSCs, Plcl1 deficiency exacerbated hallmark features, such as expansion of the phenotypic HSC pool, accumulation of CD41 HSCs and ncMkPs, and myeloid-skewed differentiation with impaired competitive reconstitution. These alterations were accompanied by reduced induction of calcium-responsive immediate-early genes. Collectively, these findings identify Plcl1 as an intrinsic regulator that stabilizes cytosolic calcium dynamics in HSCs, thereby restraining stress- and aging-associated megakaryocytic priming and preserving HSC function.

Photoaging is a widespread skin health concern caused by UV radiation. It significantly contributes to premature wrinkles and exacerbates further skin damage. This study evaluates the enhanced anti-aging efficacy of a nano phytosome incorporating grape seed extract (GSE) as an innovative, naturally driven antiaging formula, demonstrating putative skin permeability. LC-HRMS analysis and molecular docking revealed the potential of GSE components against photoaging targets. A GSE-nano phytosome formula with phosphatidyl choline (PC)/GSE ratio of 50:1 and 10 mg Vitamin E TPGS displayed optimal physicochemical properties, including particle size (195.1 ± 0.4 nm), polydispersity index (0.312 ± 0.015), zeta potential (25.6 ± 0.4 mV), and complexation efficiency (76.2 ± 4.5 %). FTIR analysis confirmed the formation of hybrid phytosomes through complexation with PC and TPGS. ex vivo confocal microscopy displayed enhanced skin permeability. Biochemical studies confirmed the superior antiaging effect of GSE-phytosome(GSE-nanogel) compared to crude GSE in UV-irradiated rats. GSE nanogel promoted anti-aging by suppressing c-Jun N-terminal kinase (JNK) and NF-κB, caspase-3, enhancing GSH-Px level and reducing malondialdehyde level. These effects suppressed elastase and collagenase activity, significantly improving wrinkles and skin redness. Our findings underscore the efficiency of formulating high molecular weight GSE phytoconstituents as phytosomes that mimic the lipophilic nature of cell membranes, improve skin permeability, and therapeutic efficacy.

Aging is an inevitable biological process in living species characterized by the continuous deterioration of physiological, molecular, cellular, biochemical, and functional changes. While people living with human immunodeficiency virus (HIV) infection (PLWH) are experiencing improved life expectancy due to advancements in the combinatorial antiretroviral therapy (cART) paradigms, they continue to face a higher burden of aging-associated comorbidities like diabetes, cancer, frailty, and pulmonary, liver, cardiovascular, and neurological disorders. Aging and HIV infection have been shown to have negative impacts on the form and function of the central nervous system (CNS). Whether HIV alone or cART alone or both HIV and cART acting synergistically contribute more to the aging-associated perturbations is not well studied because of limitations regarding longitudinal clinical sample availability and suitable human-aging mimicking animal models. With the current knowledge relying heavily on noninvasive approaches or postmortem specimens, gaps persist in understanding how latent HIV infection and chronic ART intake interact with the biological processes of aging in the CNS. In this article, we discussed the advantages and limitations of the models available to study aging and aim to focus on CNS-associated aging in a long-term human immune system carrying rodent model, which could not only advance the development of adjunctive therapies, when combined with cART but may also mitigate or slow the "accelerated" aging observed in older HIV-positive populations.

Sarcopenia has become an urgent socioeconomic problem in rapidly aging societies. The pathogenesis of age-associated sarcopenia is not fully understood and no effective therapeutic strategies have been developed to date. Recent studies have suggested the importance of the functional linkage between the brain and skeletal muscles in the pathogenesis of sarcopenia. However, the functional connections between the brain and skeletal muscles, particularly between the hypothalamus and skeletal muscles, remain unclear. In this study, we focused on the importance of nicotinamide adenine dinucleotide (NAD

Hypertension is a complex, age-related condition that markedly elevates the risk of cardiovascular problems and mortality globally. With the aging global population, understanding the molecular foundations of hypertension is essential. Emerging evidence highlights the essential roles of non-coding RNAs, particularly Long non-coding RNAs and microRNAs, in regulating gene expression linked to vascular health and blood pressure control. This review examines the impact of aging on the expression and synthesis of key ncRNAs, which leads to malfunction in three pivotal systems: vascular smooth muscle cells, the renin-angiotensin-aldosterone system, and endothelial cells. Dysregulated ncRNAs impair nitric oxide bioavailability, enhance inflammation, and modify vascular tone, resulting in arterial stiffness and increased blood pressure. Crosstalk between lncRNAs and miRNAs, as exemplified by MALAT1-miR-145 and H19-let-7b, reveals a complex regulatory network that affects vascular remodeling and homeostasis. This review highlights new molecular targets for early diagnosis and therapeutic treatment of age-related hypertension, incorporating recent findings on miRNA and lncRNA interactions.

The intestine is a vital organ of the digestive system, with its function largely reliant on the continuous regeneration of mucosal epithelial cells by healthy intestinal stem cells (ISCs). However, as we age, the regenerative potential of ISCs declines, primarily due to deleterious aging processes, such as cellular senescence, which contribute to the development of various chronic gut diseases. A growing body of evidence indicates that both healthy ISCs, which maintain intestinal homeostasis, and aging-associated senescent ISCs are profoundly influenced by epigenetic mechanisms. At the molecular level, dynamic and often reversible epigenetic modifications including chromatin remodeling, histone modifications, DNA methylation, N6-methyladenosine (m

Nutrient surplus sensing through PI3K (phosphoinositide-3-kinase) and mTOR (mechanistic target of rapamycin) stimulates anabolism to expand cellular mass, whereas nutrient and energy deprivation sensing through SIRT1 (sirtuin-1) and AMPK (adenosine monophosphate-activated protein kinase) promotes catabolism to support cytoprotective quiescence. By signaling through downstream effectors (PGC-1α [peroxisome proliferator-activated receptor gamma coactivator 1-alpha], PPARα/PPARγ, FoxO1 [forkhead box protein family O1], NRF2 [nuclear factor erythroid-derived factor 2], HIF-1α [hypoxia-inducible factor-1α], and HO-1 [heme oxygenase-1]), environmental nutrients, growth factors, and cellular stress influence mitochondrial biogenesis, autophagic flux, cardiac hypertrophy, and cardiomyocyte senescence and apoptosis. Despite these canonical descriptions, the actual response to each effector is determined by the intensity and duration of signaling. Typically, transient and measured signaling produces adaptive effects, whereas continuous heightened activity yields maladaptive responses. The effects of signaling are also influenced by context; ie, the nature and intermittency of the external stress and the characteristics of the underlying substrate (eg, cardiomyopathy, obesity, or aging). PI3K signaling promotes physiological hypertrophy and is cardioprotective during abrupt cardiac stress, but its sustained activation accelerates pathological hypertrophy related to obesity and aging. Signaling through SIRT1/AMPK (and upregulation of autophagic flux) exerts favorable effects during exercise training and in chronic cardiomyopathy, obesity, and aging, but it undermines the cardiac response to abrupt stress. Intermittent FoxO1 upregulation may promote physiological hypertrophy while antagonizing pathological hypertrophy, but prolonged activation leads to cardiomyocyte apoptosis. NRF2 exerts antioxidant effects when background autophagic flux is vigorous but aggravates cellular stress when autophagy is suppressed (as in pathological hypertrophy). Sustained activation of PPARγ, NRF2, and HIF-1α in nutrient surplus states can lead to maladaptive ventricular remodeling, thus explaining the results of clinical trials with thiazolidinediones, bardoxolone, and prolyl hydroxylase inhibitors. The influence of duration, intensity, and context may be mediated (in part) by the activation or suppression of counterregulatory mechanisms, by the selective recruitment of corepressors, and by posttranslational protein modifications. These observations, considered collectively, suggest that no protein or cellular process viewed in isolation can be regarded as cardioprotective or maladaptive. Cell signals operate usefully if they are delivered as part of an orchestrated program of compartmentalized nuanced bursts, acting as elements of multifaceted oscillating systems whose periodicity is determined by the need to achieve homeostasis.

Brain aging is accompanied by progressive cognitive decline and increased risk of neurodegenerative diseases, with adult hippocampal neurogenesis (AHN) playing a pivotal role in maintaining cognitive resilience. Selenium, an essential trace element, exerts significant neuroprotective and neurogenic effects predominantly through its incorporation into selenoproteins, which regulate oxidative stress, neuroinflammation, and synaptic plasticity. This review synthesizes recent advances delineating selenium's metabolism, bioavailability, and its multifaceted roles in brain development, function, and aging, emphasizing mechanisms underpinning hippocampal neurogenesis. Key molecular pathways influenced by selenium include phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/Wingless/Integrated (Wnt) and brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling pathways that promote neural progenitor cell proliferation and differentiation. Selenium transport via selenoprotein P and its receptor low-density lipoprotein receptor-related protein 8 (LRP8) is critical for adequate selenium delivery to the hippocampus to support neurogenesis, with exercise demonstrated to potentiate this axis. Selenium also mitigates ferroptosis, preserves mitochondrial integrity, and modulates neuroimmune interactions by attenuating microglial activation and inflammasome signaling, fostering a neurogenic environment. Emerging evidence highlights selenium's regulatory effects on RNA expression, including microRNAs modifications, further influencing neuronal health. Despite promising preclinical and observational data, clinical translation remains limited by heterogeneous and short-term studies. Future research priorities include multi-omics investigations, longitudinal cohorts, and addressing global selenium intake disparities through policy initiatives and precision nutrition. By consolidating mechanistic insights with clinical perspectives, this review underscores selenium's potential as a modifiable factor to enhance AHN and cognitive health, advocating for integrated translational strategies to combat brain aging and neurodegeneration.

To determine if physical activity increase at midlife is associated with less cognitive decline over time.