Longevity Papers

Aging is a complex biological process involving coordinated changes across multiple molecular systems. Traditional reductionist approaches, while valuable, are insufficient to capture the full scope of aging's systemic nature. Multiomics - integrating data from genomics, transcriptomics, epigenomics, proteomics, and metabolomics - provides a comprehensive framework to study aging as an interconnected network. In this Perspective, I explore how multiomic strategies, particularly those leveraging epigenomic and single-cell data, are reshaping our understanding of aging biology. Epigenetic alterations, including DNA methylation and histone modifications, are not only hallmarks but also powerful biomarkers of biological age. I discuss advances in multiomic aging clocks, cross-tissue atlases, and single-cell spatial technologies that decode aging at unprecedented resolution. I also build on a prior review I wrote with colleagues, Epigenomics. 2023;15(14):741-754, which introduced the concept of pathological epigenetic events that are reversible (PEERs) - epigenetic alterations linked to early-life exposures that predispose to aging and disease but may be therapeutically modifiable. This Perspective examines how PEERs and multiomics intersect to inform biomarkers, geroprotective interventions, and personalized aging medicine. Finally, I highlight integration challenges, ethical concerns, and the need for standardization to accelerate clinical translation. Together, these insights position multiomics as a central pillar in the future of aging research.

Aging is associated with a decline in the regenerative capacity of many tissues. Central to this decline is a complex interplay between inflammation and stem cell function. How these two processes are linked and influence regenerative capacity remains unclear. Here, we undertake a comprehensive assessment of age-related changes in the mouse colon at single-cell resolution. A survey of immune and epithelial compartments revealed a hyperactivated inflammatory state in the colon of old mice characterized by the induction of an interferon {gamma} (IFN{gamma}) response signature in immune cells. This does not result in increased inflammation under homeostasis, but triggers a disproportionate inflammatory response, disrupting regeneration after challenge with the enteropathogen Citrobacter rodentium. Colons of old mice exhibit higher production of IFN{gamma} by T and innate lymphoid cells (ILCs) that are associated with reduced Lgr5+ stem cells and decreased epithelial proliferation. Interestingly, we find aged intestinal epithelial cells to be hypersensitive to IFN{gamma} signaling, inducing a regeneration-associated fetal-like gene expression signature that, in turn, renders these cells more sensitive to IFN{gamma}-induced apoptosis. Our findings reveal an age-related imbalance in the interaction between the immune and epithelial compartments in the colon, priming the system for excessive inflammatory responses and the emergence of a hypersensitive epithelial cell state thus derailing proper repair of the intestinal epithelium after injury.

During aging, physical functioning declines, and disability and frailty increase; phenotypes which are bidirectionally linked. MicroRNAs (miRNAs) are epigenetic regulators of various physiological processes and suggested aging biomarkers. Here we investigate the association between circulating plasma miRNAs and hand grip strength, chair stand, (Rockwood) frailty, and activity of daily living (ADL) in 86 monozygotic twins (73-88 years). In cross-sectional analysis, both individual and twin-pair level analyses were performed, the latter controlling genetic confounding. The majority (74-100 %) of miRNAs identified in the individual-level analysis were validated by twin-pair-level analysis, with 14 miRNAs showing significance (p < 0.05) in both. Longitudinal analysis (up to eight years of follow-up) yielded more significant results (75-93 miRNAs), indicating that miRNAs might be more accurate in predicting functional decline over time. Of these miRNAs, seven showed consistent directions of effects across phenotypes. For all analyses, most (65-79 %) of the observed effect sizes were negative, reflecting reduced functionality with increased miRNA levels. Enrichment analyses revealed pathways of gene expression (incl. p53- and FOXO-mediated transcription), signal transduction, the immune system, metabolism of RNA, among others. Of specific miRNAs, miR-1274a demonstrated negative association in both cross-sectional and longitudinal investigations of ADL. These findings support miRNAs as biomarkers of age-related functional decline.

The global population is ageing rapidly. While genetics, lifestyle, and environment are known contributors to healthspan, most insights are drawn from Western cohorts, leaving Asian populations underrepresented despite unique biological, lifestyle, and cultural factors. The SG90 cohort study aimed to fill knowledge gaps in healthy ageing by identifying modifiable medical, biological, lifestyle, psychological, behavioural, and social factors that contribute to longevity in the oldest-old. The study recruited 1,158 participants aged 85 and above from the Singapore Chinese Health Study (SCHS) and Singapore Longitudinal Aging Study (SLAS) between 2015 and 2021. Data collection involved face-to-face interviews to obtain sociodemographic, lifestyle, sleep, functional status, quality of life, medical conditions and healthcare economics information, along with clinical assessments covering physical examinations, anthropometry, physical performance, cognition, and mental health. Biospecimens, including blood, saliva, stool, urine, toenails, hair, and skin tape strips were collected to support extensive multi-omic and cellular analyses. Participants, primarily female (64.5%) and Chinese (97.5%) with a median age of 87 years [interquartile range (IQR): 86-89], were mostly non-smokers (72.1%) and infrequent alcohol consumers (94.9%), with 66.5% exercising regularly. Functional assessments indicate high independence, with median Basic activities of daily living (BADL) and Instrumental ADL (IADL) scores of 20 (IQR: 19-20) and 14 (IQR: 11-16), respectively. 36% of participants rated their self-reported health as good to excellent. The SG90 cohort study offers a comprehensive clinical and biological data resource on healthy ageing among Asia's oldest-old, laying a foundation for targeted interventions to promote healthy longevity and quality of life.

Proteins are essential biomolecules that play indispensable roles in maintaining cellular homeostasis and regulating systemic metabolic processes. Protein deficiency is closely associated with age-related chronic diseases. Our purpose is to reveal the reason of protein deficiency in the elderly and potential treatments. A systematic literature search mainly on human studies addressing gastrointestinal aging and amino acid homeostasis was conducted. This review investigated the effects of aging on protein metabolism and summarized age-related physiological changes that collectively disrupt protein homeostasis. These changes include reduced secretion of gastric acid and digestive enzymes, which impair protein digestion in the stomach and small intestine. Weakened intestinal motility further delays the transit of digested proteins, reducing the efficiency of amino acid absorption. Additionally, decreased function of amino acid transporter proteins in the intestines and muscles limits the availability of amino acids for protein synthesis. Impaired liver and kidney function exacerbates these issues by affecting amino acid catabolism and clearance. Together, these alterations lead to an imbalance in amino acid homeostasis, contributing to protein deficiency, increasing the risk of sarcopenia in the elderly. Overall, we highlight changes in protein digestion, absorption, and amino acid metabolism in the elderly, and gives the possibility of improving amino acid utilization efficiency in the elderly, paving the way for new treatments for age-related protein deficiency in the future.

The increasing prevalence of anemia and cognitive decline among middle-aged and older adults poses significant public health challenges. While most studies have examined the impact of anemia on cognition, the potential for a bidirectional relationship, where cognitive function also influences anemia risk, remains less explored, particularly via longitudinal designs and advanced modeling. Therefore, we utilized data from 4521 participants (women = 2434, men = 2087) from the initial (2011-2012) and subsequent (2015-2016) waves of the China Health and Retirement Longitudinal Study (CHARLS). We measured hemoglobin levels, global cognitive function, and other factors. Linear regression was used to analyze the association between baseline anemia status and follow-up cognitive function in participants free from low cognitive performance at baseline. Binary logistic regression was used to examine the relationship between baseline cognitive function and the risk of having anemia at follow-up in participants without anemia at baseline. Finally, a cross-lagged panel model (CLPM) was used to evaluate the longitudinal bidirectional association between anemia status and cognition. Baseline anemia status was significantly associated with lower follow-up cognitive scores, particularly among women (estimates, 95% confidence interval, - 0.83 (- 1.39, - 0.28)). Higher baseline cognitive function was associated with a lower risk of follow-up anemia among women (OR = 0.97, 95% CI (0.94-0.99)) but not among men (OR = 0.02, 95% CI (0.98-1.06)). The CLPM results confirmed a robust bidirectional relationship: baseline anemia status predicted lower follow-up cognition (β =  - 0.04), and lower baseline cognition predicted a greater risk of having anemia at follow-up (β =  - 0.02). The standardized effect size of baseline anemia status on follow-up cognitive function was greater than that of baseline cognitive function on follow-up anemia status (- 0.04 vs. - 0.02). These findings provide strong evidence for a bidirectional longitudinal association between anemia status and cognitive function in this population, suggesting that interventions targeting either condition may yield reciprocal benefits for healthy aging.

Bone-derived mesenchymal stem cells (BMSCs) are multipotent stem cells capable of differentiating into adipocytes and osteoblasts. Dysfunctional differentiation, characterized by a shift from osteoblastogenesis to adipogenesis, is closely associated with metabolic and senile osteoporosis. The Aldo-keto reductase family 1 member A1 (Akr1A1) enzyme, which utilizes NADPH to reduce aldehyde groups to alcohols, has emerged as a potential regulator. This study investigates the role of reactive oxygen species (ROS) in modulating Akr1A1 expression during the lineage differentiation of human mesenchymal stem cells into osteoblasts and adipocytes.

Aging is characterized by a progressive decline in organ and tissue structure and function, significantly increasing the risk of many chronic diseases. Developing interventions to delay aging holds the potential to reduce the burden of age-associated diseases and promote healthy longevity. Gene therapy has emerged as a clinically transformable approach, leveraging advanced gene editing and delivery systems to target the molecular underpinnings of aging. This review systematically explores the potential of gene therapy strategies in aging intervention, focusing on approaches that enhance genomic and epigenetic stability, restore metabolic homeostasis, modulate immune responses, and rejuvenate senescent cells. By providing a comprehensive overview and forward-looking insights, this article aims to inform future research directions and translational applications of gene therapy in mitigating aging-related decline.

Age and early life adversity (ELA) are both key determinants of health, but whether they target similar physiological mechanisms across the body is unknown due to limited multi-tissue datasets from well-characterized cohorts. We generated DNA methylation (DNAm) profiles across 14 tissues in 237 semi-free ranging rhesus macaques, with records of naturally occurring ELA. We show that age-associated DNAm variation is predominantly tissue-dependent, yet tissue-specific epigenetic clocks reveal that the pace of epigenetic aging is relatively consistent within individuals. ELA effects on loci are adversity-dependent, but a given ELA has a coordinated impact across tissues. Finally, ELA targeted many of the same loci as age, but the direction of these effects varied, indicating that ELA does not uniformly contribute to accelerated age in the epigenome. ELA thus imprints a coordinated, tissue-spanning epigenetic signature that is both distinct from and intertwined with age-related change, advancing our understanding of how early environments sculpt the molecular foundations of aging and disease.

Cognitive decline is age-specific or related to dementia and Alzheimer's disease (AD), which poses great concern to older adults. Exercise contributes to cognitive gains, with aerobic exercise (AE) being the most commonly studied type. However, other types, such as resistance exercise (RE), have received less attention in exercise-cognition research. This narrative review aims to synthesize evidence addressing the effects of RE, including the influence of its various parameters on cognitive function in older adults. It also examines the adaptations of neurotrophic factors, brain structure, and brain function in response to RE and explores the relationship between these adaptive responses and cognitive function. A comprehensive search of PubMed databases was conducted up to Jan 2025, identifying 41 randomized controlled trials for inclusion. RE may effectively improve executive function, memory function, and global cognition in older adults with and without cognitive impairment. However, optimal exercise parameters, such as intensity, frequency, and length, remain to be established. Evidence suggests that RE may elevate peripheral insulin-like growth factor 1 levels, increase gray matter thickness, mitigate hippocampal atrophy, and enhance brain activation, all of which appear to contribute to cognitive improvements. Collectively, these studies advance our understanding of the potential role of RE in promoting cognitive and brain health during aging.

Here, we present a combination of cell and gene therapy that harnesses the regenerative properties of GDF11 in age-related pulmonary fibrosis. Our genome-edited SafeCell-GDF11 mouse embryonic stem cell line provides controlled proliferation and efficient derivation to lung progenitors while inducibly expressing GDF11. When these cells were transplanted into bleomycin-injured aged mice, they acted as a source of reparative cells, restoring the damaged alveolar epithelium. Furthermore, the transplanted cells acted as an "in situ factory," enabling the production of GDF11 in response to the inducer drug. This approach attenuated age-associated senescence and led to the successful resolution of fibrosis. Our study presents a GDF11-expressing cell-based strategy that demonstrates the feasibility of promoting alveolar regeneration in a mouse model of age-related pulmonary fibrosis. Additionally, this approach offers a versatile tool that can be expanded to incorporate other regenerative and anti-aging factors. This helps overcome limitations such as high production costs and a short half-life of therapeutic factors. One of the strengths of our system is its ability to allow precise regulation of factor expression when needed to address specific aging phenotypes.

Given the growing global elderly population and the accelerating decrease in grey matter volume (GMV) with age, understanding healthy brain aging is increasingly important. This study investigates whether variations in modifiable traits can account for differences in GMV and whether these traits can inform strategies to mitigate risks of future brain disorders. We identified 66 traits significantly associated with total GMV. Further, we examined the joint contributions of different domain traits to the GMV variance, finding that blood biomarkers and physical measurements accounted for the largest proportion of GMV variance. Some traits mediated the relationship between the genetic risk for brain disorders and GMV. Moreover, the identified traits divided the population into two subgroups, with significant differences in GMV and incidences of brain disorders. Our findings underscore the importance of modifiable traits in supporting healthy brain aging and reducing the risk of brain disorders, suggesting potential targets for intervention.

Cardiomyocyte senescence, characterized by elevated cell cycle inhibitor expression, persistent DNA damage response, and mitochondrial dysfunction, contributes to myocardial stiffness and the progression of heart failure with preserved ejection fraction (HFpEF), the most common form of heart failure affecting individuals over 65. In this study, we investigated the role of NAD metabolism in cardiomyocyte senescence and cardiac function. Aged mice exhibited reduced cardiac NAD levels, impaired NAD biosynthesis and mobilization, and increased consumption, leading to suppressed SIRT1/6 activity and accumulation of senescent cardiomyocytes. This was accompanied by diastolic dysfunction consistent with HFpEF. In senescent AC16 cardiomyocytes, NAD depletion promoted senescence, which was reversed by the NAD precursors nicotinamide riboside (NR) and dihydronicotinamide riboside (NRH). In aged mice, two months of NR or NRH treatment improved diastolic function and reduced cardiomyocyte senescence. While NR primarily activated SIRT1 to suppress cell cycle arrest markers, NRH more robustly activated both SIRT1 and SIRT6, enhancing DNA damage repair. Acetylated H2AX, a SIRT6 substrate elevated in aged hearts and senescent cells, was selectively deacetylated by NRH. These findings identify NAD availability as a critical regulator of cardiac senescence and support NAD precursors, particularly NRH, as promising senescence-reducing therapies for treating aging-associated HFpEF.

The nuclear hormone receptor NHR-49, a homolog of mammalian PPAR and HNF4, is a key transcriptional regulator of nutrition sensing and fatty acid metabolism in Caenorhabditis elegans. Here we uncovered a new function of NHR-49 in reproduction - controlling oocyte activation and ovulation. Loss of NHR-49 causes inappropriate oocyte activation and laying of unfertilized oocytes in the absence of sperm, resulting in rapid loss of yolk and stored fat, and drastically shortening of lifespan. We further demonstrated that prevention of yolk transfer into the oocytes largely restore fat storage and partially rescue lifespan in the nhr-49 mutants. Additionally, NHR-49 appears to couple germline proliferation to nutritional status, as evidenced by its requirement for starvation-induced reduction in germline proliferation. Mechanistically, we showed that NHR-49 primarily acts in somatic cells, rather than the germline itself, to regulate oocyte activation and ovulation. We further demonstrated that NHR-49 binds to the promoter of GSA-1 and may stimulate its expression. GSA-1 encodes a G-protein coupled receptor known to act in the gonadal sheath cells to couple sperm sensing and oocyte activation. Our findings therefore suggest a model whereby NHR-49 regulates the expression of GSA-1, which in turn regulates oocyte activation in response to sperm signal. Overall, our findings suggest a mechanistic link between nutrition sensing and fertility and point to regulated retention of reproductive resources to be critical for maintaining longevity.

Stress response pathways are emerging as conserved modulators of lifespan. The prevailing hypothesis is that activation of stress responsive pathways, including the amino acid deprivation arm of the integrated stress response (ISR; the GCN2-ATF4 pathway) is pro-longevity. Activation of ATF4 orthologs extends lifespan in Saccharomyces cerevisiae (yeast) and Caenorhabditis elegans, but its role in other longer-lived organisms remains unclear. We comprehensively tested the role of the GCN2-ATF4 pathway in the fly (Drosophila melanogaster) for the first time. We used conditional genetic manipulation of dGCN2 and its downstream effector Drosophila ATF4 (crc; dATF4). In contrast to previous studies, we show that overexpression of dGCN2 and dATF4 significantly reduces lifespan, while knockdown (in vivo RNAi) of dATF4 extends lifespan. We confirmed dATF4 activity was successfully modulated using a fluorescent dATF4 activation reporter. Borrelidin, a tRNA synthetase inhibitor, significantly reduced lifespan in a both dATF4 and diet-dependent manner, independent of microbial load, showing our modulation of dATF4 altered nutrient to ISR signalling. We further conducted long-read RNA sequencing and found that our manipulation of dATF4 changed global transcription in opposite directions, including known ATF4 target genes. Enrichment analysis revealed that dATF4 overexpression may drive metabolic stress, while dATF4 knockdown upregulates proteostasis and DNA repair pathways. Our work reveals that ATF4 exhibits a dual, dose- and context-dependent role in ageing. Chronic dATF4 activation is detrimental in flies, while chronic suppression is pro-longevity. The GCN2-ATF4 pathway thus qualifies as a modifiable control of lifespan with cross-species relevance.

Elderly individuals were disproportionally affected during the COVID-19 pandemic, and more than 80% of the global COVID-19-related deaths between 2020 and 2021 occurred among people aged 60 years or older. Several cellular modifications in aged cells may lead to systemic inflammation and fibrotic responses. Age or exogenous insults induce cellular senescence, further increasing the release of pro-inflammatory mediators, leading to the condition known as inflammaging, that can contribute to disease severity. Older individuals presented signs of systemic hyperinflammation in severe COVID-19, but few studies analyzed the influence of age on lung tissue responses in cases of severe COVID-19. We hypothesized that age related alterations regarding innate/acquired immunity and cellular senescence in lung tissue of individuals without lung diseases could predispose to viral infection. We also aimed to identify how the aged lung responded to severe COVID-19 infection. We studied lung tissues from 19 individuals that died from non-pulmonary causes and 28 adult individuals who died from COVID-19 between March and May of 2020, divided according to their age (> or < 60 years). Tissue sections were stained, via immunohistochemistry, and 19 markers among immune cells, COVID-19 receptors, cytokines and senescence were analyzed in the lung parenchyma of both groups. In the COVID-19 group, the Luminex multiplex assay technique was used to detect a panel of 25 cytokines/chemokines. In control lungs, aged individuals had a lower TLR7 expression, without differences in other markers. Older patients had a shorter time between onset of symptoms and death, with a significant negative correlation with age. Unlike the adult younger group, older COVID - 19 patients presented significant differences in relation to their age matched controls in the expression of CD8 + T cells, IFN-α2, TLR7, pSTAT-3, p21 and p53. They also presented higher protein expression that IFN-α2 and TGF-beta than the adult COVID-19 group, with a trend to decreased CD20 + cell density in the lungs. Taken together, our data show age adversely affects the lung expression of key proteins related to COVID-19 susceptibility and severity, by perpetuating inflammation and increasing pro-fibrotic responses.

Mindfulness cultivates awareness, presence, and non-judgmental acceptance, enhancing overall well-being. Inflammaging, linking age and aged-related diseases, manifests through heightened levels of IL-6, TNF-α, and CRP, impacting aging indicators like TA, TL, PWV, and FMD. To assess how mindfulness-based interventions (MBIs) affect inflammaging, a search was conducted in PubMed, Web of Science, Cochrane Central Register, and ProQuest Dissertation & Theses Global up to March 2024. Criteria included English articles and dissertations with participants over 18. Selected studies were randomized controlled trials (RCTs) and pre-post trials evaluating biomarkers related to inflammaging. Standardized mean differences were calculated using Morris's d

This study examines the associations between sensory responsiveness levels and biological age among midlife adults, providing insights into the aging process. A cross-sectional study was conducted from 2020 to 2021 on a subset of the Jerusalem Perinatal Study in Israel, including 96 midlife adults (aged 45.65 ± 0.66, 49% women). Biological age was estimated using physiological and blood biomarkers, following the Klemera-Doubal method. The Sensory Responsiveness Questionnaire Scale and the Social Engagement and Activities Questionnaire were employed, along with physical capacity measurements such as muscle strength, cardiorespiratory fitness, and gait analysis. The hypothesis suggested that levels of sensory responsiveness (high or low) would be associated with biological age. Results indicated that low sensory responsiveness was positively associated with older biological age (adjusted R²=0.25, p < 0.01), after controlling for age, sex, social engagement, education and physical capacity. Conversely, high sensory responsiveness showed no significant correlation with biological age. These findings suggest that sensory responsiveness may serve as a potential marker for biological age during midlife and should be considered when addressing early signs of aging, thereby contributing to a deeper understanding of the biological mechanisms underlying aging and age-related diseases.

The chemokine CCL11 is negatively correlated with cognitive function and is able to cause dysfunctions of synaptic plasticity. This research investigate whether CCL11 induce microglia senescence to damage synaptic plasticity and the protective role of Qifuyin.

The weight-adjusted waist index (WWI) is a new obesity metric that may better reflect body fat distribution than traditional measures like body mass index (BMI). However, the link between WWI and serum Klotho levels, an aging biomarker, is not well understood. The study involved non-pregnant adults aged 40 to 79 years who had comprehensive data regarding BMI, waist circumference (WC), and serum Klotho levels. We analyzed data from 12,809 participants aged 40 to 79 years from NHANES. WWI was calculated by dividing WC by the square root of body weight. Participants were categorized into quartiles based on WWI values. A multivariate linear regression model assessed the relationship between WWI and serum Klotho levels, with subgroup analyses for demographic consistency. The analysis showed a significant negative correlation between WWI and serum Klotho levels (

During aging and cellular senescence, repetitive elements are frequently transcriptionally derepressed across species and cell types. Among these, the most abundant repeats by copy number in the human genome are Alu retrotransposons. Though Alu elements are often studied for their mutagenic potential, there is increasing appreciation for their contributions to other biological functions, including pro-inflammatory signaling and mitochondrial dysfunction. However, a comprehensive analysis of Alu-driven molecular changes remains to be conducted, and Alu's potential contributions to aging features remain incompletely characterized. Here, we show that overexpression of an AluJb transposon in human primary IMR-90 fibroblasts leads to large-scale alterations across the transcriptome, cellular proteome, and secretome. Functional genomics analyses reveal alterations in aging pathways, broadly, and mitochondrial metabolism, proteostasis, cell cycle, and extracellular matrix pathways, more specifically. Our results demonstrate that Alu transcriptional upregulation is sufficient to drive widespread disruptions to cellular homeostasis that mirror aging-associated alterations.

Aging profoundly reshapes the immune cell landscape, with particularly strong effects on CD8+ T cells, including a marked decline in naive cells and the emergence of age-associated GZMK+ CD8+ T cells (TAA cells). Although TAA cells make up a significant fraction of the aged CD8+ T cell compartment, the pathway underlying their development remains unknown. In this study, we demonstrate that TAA cell development is cell-extrinsic and requires antigen exposure within aged non-lymphoid tissues. Using a novel TNFdAU/+ mouse model, we show that systemic low-grade inflammation, characteristic of inflammaging, accelerates CD8+ T cell aging and promotes early accumulation of TAA cells. Through detailed analysis of TAA cell heterogeneity, we identified a progenitor subpopulation enriched in the aged adipose tissue. Using heterochronic transplantation, we show that adipose tissue acts as a functional niche, supporting progenitor maintenance and driving the conversion of young CD8+ T cells into the aged phenotype. Taken together, our findings reveal how aging of non-lymphoid tissues orchestrates the reorganization of the CD8+ T cell compartment and highlight adipose tissue as a promising target for therapeutic strategies aimed at modulating immune aging.

Aerobic exercise has significant health benefits, including preventing chronic diseases like sarcopenia. It strongly depends on muscle fiber types, with higher oxidative fiber ratios enhancing endurance. However, the molecular mechanisms underlying aerobic exercise capacity remain incompletely understood. In this study, we identified 395 genes associated with muscle fiber types, among which 39 were linked to metabolic pathways. Notably, we focused on aldehyde oxidase 1 (AOX1), a molybdenum flavin enzyme, due to its unique non-mitochondrial localization, suggesting a potential causal role in regulating muscle metabolism. We further revealed a significant downregulation of Aox1 mRNA expression in the skeletal muscle of mice after two weeks of exercise training, indicating its involvement in exercise adaptation. To further explore this link, we generated Aox1 knockout (KO) mice and subjected them to endurance capacity tests. Aox1 KO mice exhibited significantly enhanced exercise endurance compared to wild-type (WT) controls, accompanied by a shift toward a more oxidative muscle phenotype, as indicated by an increased proportion of oxidative fibers. Mechanistically, Aox1 KO mice exhibit increased expression of PGC-1α, enhanced mitochondrial function, and increased capillary density in skeletal muscle, facilitating improved oxygen delivery and utilization during exercise. Additionally, in vitro experiments using C2C12 myotubes revealed that Aox1 knockdown alleviated starvation- and TNF-α-induced muscle atrophy, which partially mimics sarcopenia, highlighting its protective role against aging- and stress-induced muscle damage. These findings identify AOX1 as a negative regulator of aerobic exercise capacity and stress resilience, advancing our understanding of skeletal muscle adaptation and highlighting AOX1 as a potential target for improving exercise performance and mitigating sarcopenia.

Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality, with aging as a critical risk factor. Cellular senescence, marked by irreversible cell cycle arrest and a pro-inflammatory secretory phenotype, drives age-related cardiovascular pathologies, including vascular dysfunction, atherosclerosis, cardiac fibrosis, and metabolic disturbances. Senolytics-agents that selectively eliminate senescent cells-represent a promising therapeutic strategy. This review explores the role of senescence in CVD and evaluates senolytics potential to improve vascular function, reduce fibrosis, and address CVD-related metabolic and immune dysfunctions. Preclinical studies have shown promising results in improving heart function, particularly in the treatment of heart failure, in post-myocardial infarction recovery, and cardiac transplantation. The interplay between senescence and immunosenescence in CVD is also examined, highlighting the potential of senolytics to rejuvenate immune responses and attenuate chronic inflammation. Furthermore, the review discusses the role of senolytics in addressing metabolic syndrome, a significant contributor to CVD, by alleviating systemic inflammation and insulin resistance. While clinical data remain limited, early-phase trials and strong preclinical evidence provide a compelling rationale for further investigating senolytics in cardiovascular contexts. In this light, the review concludes by emphasizing the challenges and the need for extended preclinical and clinical studies to establish the efficacy, safety, dose, and long-term effects of senolytics and to exploit them as a transformative approach in cardiovascular medicine.

The faithful transmission of genomic DNA over succeeding generations is an essential prerequisite for species maintenance. The germplasm theory by August Weismann has been foundational for the current understanding of heredity; it proposed that genetic inheritance is exclusively mediated by germ cells while they are protecting heritable germline genomes from the phylogenetic influences of an individual's life history. However, recent studies on the inheritance of epigenetic variation have challenged the traditional dogma of heredity and opened new perspectives on molecular mechanisms of inheritance. This review highlights the current knowledge about heritable memories of the ancestral lifestyle and discusses emerging frontiers in soma-germline circuits with a focus on the control of the integrity of heritable genomes as well as their implications for somatic and reproductive aging.

Aging is a universal biological phenomenon that affects all biological systems. It is characterized by the inability to remain in a balanced physiological state, leading to a functional decline of the organism and, in metazoa, an increased risk of age-related diseases. Identifying causal drivers of aging is a major challenge at the cellular level, but in the model organism

The biological process of aging is typically associated with a decrease in muscle quantity, muscle performance (primarily strength), bone mass and architecture, functionality and neurological/cognitive function. From a healthy aging perspective, interventions that have the potential to overcome or attenuate these decrements are clinically relevant.

Frailty, a geriatric syndrome linked to adverse outcomes, is a significant public health concern in aging populations. This systematic review synthesizes evidence on the effectiveness of interventions, grouped by their components, to reduce frailty in community-dwelling older adults.

Background and Objectives: Biological age, reflecting the cumulative molecular and cellular damage such as telomere attrition, epigenetic alterations and mitochondrial dysfunction, may better capture age-related decline and Alzheimer's disease (AD) risk than chronological age. Most studies have focused on one measure of biological age and not investigated joint or interactive contributions to AD pathogenesis. Methods: We estimated blood-derived telomere length (TL) via qPCR, epigenetic age (DNAm age) using the CausAge clock, and mitochondrial DNA copy number (mtDNAcn) from whole genome sequencing in 640 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI; Age: 74.91 (SD 7.56), Female: 44.8%, Cognitively Unimpaired: 34.3%, Mild Cognitive Impairment: 52%, AD: 12.9%). Linear mixed-effects models examined the associations and interactions of these markers with cognitive decline for memory, executive function, language ability, visuospatial ability, and global cognition, while linear regression tested associations with cross-sectional AD biomarkers (CSF Ab42, total-tau, pTau181, and meta-ROI for cortical thickness and gray matter volume). Models adjusted for baseline age, sex, clinical dementia rating scale, APOE, blood cell composition, and outcome-specific covariates (education and intracranial volume). Results: Individually, TL and DNAm age, were not associated with cognition, CSF biomarkers, or neuroimaging outcomes, while higher mtDNAcn was associated with lower CSF tau and ptau181. Interaction models revealed that mtDNAcn modified the effects of both TL and DNAm age: at higher mtDNAcn, shorter TL predicted poorer global cognition (b = 0.033, se = 0.014, p = 0.020) and older DNAm age predicted poorer language performance (b = -0.059, se = 0.028, p = 0.038). A significant three-way interaction showed that the combination of higher mtDNAcn, longer TL, and older DNAm age was associated with lower grey-matter volume. Discussion: These findings suggest that increased mtDNAcn may act as a compensatory response to accelerated epigenetic aging and telomere attrition. Our results underscore the importance of evaluating the interplay among multiple biological aging markers when investigating AD pathogenesis.

Gene-environment interactions (GxE) have been shown to explain a non-negligible proportion of variance for a plethora of complex traits in different species, including livestock, plants, and humans. While several studies have shown that including GxE can improve prediction accuracy in agricultural species, no increase in accuracy has been observed in human studies. In this work, we sought to investigate the reasons for the contradictory results between agricultural species and humans. Model organisms are useful for studying GxE, since environments can be controlled and genotypes can be replicated across environments. Thus, we used data from a previous study in Drosophila melanogaster, where the authors measured lifespan in different environments and found evidence of GxE. We devised three different cross-validation (CV) scenarios that mimic the relationships between reference and test populations observed in agriculture and human studies, and fitted a few statistical models with and without including GxE. The results showed that GxE explained 8% of lifespan variance. Despite that, models accounting for GxE improved prediction accuracy only in CV scenarios where the same genotypes are observed in both the reference and test populations. While these scenarios are common in agriculture, where individuals of the same family or variety appear in both populations, they are not encountered in human studies, where individuals are unrelated. Thus, our work clarifies in which prediction scenarios we can expect improvements by incorporating GxE into statistical models, and provides an explanation for previous results found in studies involving human populations.

Aging induces substantial structural and functional decline in the retina, yet the molecular drivers of this process remain elusive. In this study, we used heterochronic parabiosis (HP) combined with single-cell RNA sequencing to generate comprehensive transcriptomic profiles of murine retinas from young, aged, and HP pairs, aiming to identify antiaging targets. Our analysis revealed extensive transcriptional alterations across retinal cell types with aging. HP experiments demonstrated that systemic factors from young mice rejuvenated aged retinas and alleviated senescent phenotypes, while aged blood accelerated aging in young mice. Integrative analysis pinpointed adiponectin receptor 1 (AdipoR1) and the downstream adenosine 5'-monophosphate-activated protein kinase (AMPK) signaling pathway as central to the molecular mechanisms underlying retinal rejuvenation. Treatment with the AdipoR1 agonist AdipoRon reversed retinal aging. Mechanistically, AdipoR1-AMPK activation promoted mitochondrial function, contributing to the restoration of youthful cellular phenotypes. Together, our study identifies AdipoR1 as a therapeutic target for retinal aging and provides insights into the molecular programs driving retinal rejuvenation.

Aging is associated with the accumulation of molecular damage, functional decline, increasing disease prevalence, and ultimately mortality. Although our system-wide understanding of aging has significantly progressed at the genomic and transcriptomic levels, the availability of large-scale proteomic datasets remains limited. To address this gap, we have conducted an unbiased quantitative proteomic analysis in male C57BL/6J mice, examining eight key organs (brain, heart, lung, liver, kidney, spleen, skeletal muscle, and testis) across six life stages (3, 5, 8, 14, 20, and 26-month-old animals). Our results reveal age-associated organ-specific as well as systemic proteomic alterations, with the earliest and most extensive changes observed in the kidney and spleen, followed by liver and lung, while the proteomic profiles of brain, heart, testis, and skeletal muscle remain more stable. Isolation of the non-blood-associated proteome allowed us to identify organ-specific aging processes, including oxidative phosphorylation in the kidney and lipid metabolism in the liver, alongside shared aging signatures. Trajectory and network analyses further reveal key protein hubs linked to age-related proteomic shifts. These results provide a system-level resource of protein changes during aging in mice, and identify potential molecular regulators of age-related decline.

Circulating Growth Differentiation Factors 11 and 8 (GDF11/8) exist in both latent and active forms, and it is unclear if specific forms can predict disease outcomes. Our data suggest that a dual-specific aptamer selectively binds GDF11/8 after prodomain activation. In 11,609 patients at risk for future cardiovascular events, low dual-specific aptamer-detected GDF11/8 levels strongly predicted adverse outcomes, including cardiovascular events (HR = 0.43, p = 9.1 × 10⁻⁶³) and all-cause mortality (HR = 0.33, p = 4.8 × 10⁻⁴⁰). Use of selective aptamers suggested that results observed with the dual-specific aptamer for cardiovascular and mortality risk replicated with a GDF8 aptamer although with a smaller effect size. In a second cohort of 4110 individuals (ARIC), low dual-specific aptamer-detected GDF11/8 levels also predicted increased 8 year dementia risk (HR = 0.66, p = 0.00148). Our findings reveal that activation of GDF11/8 may be a factor in future aging-related cardiovascular and cognitive decline.

The brain barrier system, including the choroid plexus, meninges and brain vasculature, regulates substrate transport and maintains differential protein concentrations between blood and cerebrospinal fluid (CSF). Aging and neurodegeneration disrupt brain barrier function, but proteomic studies of the effects on blood-CSF protein balance are limited. Here we used SomaScan proteomics to characterize paired CSF and plasma samples from 2,171 healthy or cognitively impaired older individuals from multiple cohorts, including the Global Neurodegeneration Proteomics Consortium. We identified proteins with correlated CSF and plasma levels that are produced primarily outside the brain and are enriched for structural domains that may enable their transport across brain barriers. CSF to plasma ratios of 848 proteins increased with aging in healthy control individuals, including complement and coagulation proteins, chemokines and proteins linked to neurodegeneration, whereas 64 protein ratios decreased with age, suggesting substrate-specific barrier regulation. Notably, elevated CSF to plasma ratios of peripherally derived or vascular-associated proteins, including DCUN1D1, MFGE8 and VEGFA, were associated with preserved cognitive function. Genome-wide association studies identified genetic loci associated with CSF to plasma ratios of 241 proteins, many of which have known disease associations, including FCN2, the collagen-like domain of which may facilitate blood-CSF transport. Overall, this work provides molecular insight into the human brain barrier system and its disruption with age and disease, with implications for the development of brain-permeable therapeutics.

Dibutyl phthalate (DBP), a common plastic additive, is employed extensively to enhance the flexibility of various polymeric materials despite its known toxicity to multiple organ systems. Our previous study found that maternal DBP exposure caused early puberty in male offspring, but the effect on male brain aging was unclear. In this study, pregnant mice were orally administered corn oil (control) or varying doses of DBP via gavage from gestational day 12. The results demonstrated that prenatal DBP exposure induced premature aging in the hippocampus and hypothalamus of male offspring during adolescence and led to a cognitive decline in adulthood. In vitro analyses further showed that monobutyl phthalate (MBP), the principal DBP metabolite, promotes senescence in both HT22 hippocampal and GT1-7 GnRH neuronal cells by activating NF-κB signaling. Notably, the pharmacological inhibition of NF-κB using BAY 11-7082 significantly mitigated this senescence. This study provides the first evidence linking maternal DBP exposure to accelerated brain aging and precocious puberty in offspring, establishing a foundation for investigating DBP's role in aging-related toxicity.

Frailty is a significant clinical syndrome affecting aging populations, leading to increased risks of negative outcomes such as falls, disability, hospitalization, and premature mortality. The concept has evolved from a simplistic view to a complex view that incorporates physical, psychological, cognitive, and social domains. Early intervention is crucial, yet research on the interactions among these domains is limited. This study protocol aims to outline various combinations of biological, psychosocial and nutritional interventions in prefrail older adults to address their effects on frailty status, including physical, psychological, and social functioning, nutritional status, and lifestyle changes over a 9-month intervention and follow-up period.

Intermittent administration of parathyroid hormone (PTH) produces potent anabolic effects on bone. These anabolic effects appear to be mediated by activation of the Gs-cyclic AMP system initiated by the PTH1 receptor (PTHR1) in osteoblast lineage cells. Gs-mediated cyclic AMP production can be inhibited by activation of Gi signaling, and we have previously demonstrated that Gi signaling in osteoblasts suppresses bone formation and thereby plays a prominent role in the bone loss associated with aging in female mice. It is not clear whether this increased Gi signaling with aging dampens the anabolic response to intermittent PTH (iPTH) administration. To address this possibility, we determined the effect of inducible blockade of Gi signaling in osteoblasts on the anabolic response to PTH in 4-month-old female mice. Blockade of Gi signaling was achieved by tetracycline-regulated expression of pertussis toxin (PTX) driven by a Col1(2.3) promoter. We found that the expression of PTX potentiated the anabolic effect of iPTH on the trabecular bone, both at the distal femur and L4 lumbar vertebra. In addition, the ability of PTH to promote cortical bone thickness and strength was evident only in mice expressing PTX. These novel results demonstrate that endogenous Gi signaling in osteoblasts limits the anabolic action of iPTH on the skeleton of adult female mice. Strategies that suppress osteoblast Gi signaling could provide an effective adjunct to iPTH therapy in the treatment of postmenopausal osteoporosis.

Singapore's rapidly aging population and increasing healthcare demands highlight the need for projections to inform policy planning. Here we adapted a previously published dynamic Markov microsimulation model, the Future Elderly Model, to estimate disease trajectories and healthcare expenditure among adults aged 51 years and older in Singapore. The model simulated four long-term lifestyle interventions aligned with the Healthier SG program from 2020 to 2050. Our projections indicate an increasing prevalence of chronic conditions, comorbidities, obesity and disabilities, with ethnic differences. The projected lifetime healthcare expenditure is the highest among Indians (US $93,900; 95% credible interval (CI), US $68,900-119,000), followed by the Chinese (US $75,700; 95% CI, US $57,600-93,800) and Malays (US $70,000; 95% CI, US $52,000-88,000). Despite having a higher chronic disease burden, Malays are expected to incur lower lifetime expenditure due to their shorter life expectancy. Implementing all 4 interventions could save US $505 million (95% CI, US $462-547 million) in healthcare use by 2050. Sustained lifestyle interventions may moderate the increase in future burdens. Policy strategies should prioritize preventive care tailored to the specific needs of diverse population subgroups.

The increasing number of elderly individuals has made age-related disorders a significant health concern. Aging is a natural, progressive and gradual phenomenon that leads to irreversible modifications in all molecules, cells, tissues and organs of an organism. Brain senescence is associated with increased risk of developing various neurological diseases, such as Alzheimer's disease, Parkinson's disease, and stroke. Therefore, finding effective strategies to counteract or delay brain senescence is of great importance for improving the quality of life and health span of the elderly population. Previous studies demonstrated that D-galactose is an appropriate agent to induce aging effects in in vivo and in vitro models.

In several diseases, senescent T lymphocytes increase in number and release a senescence-associated secretory phenotype (SASP) with inflammatory and osteoclastogenic potential, favoring inflammation and bone loss. It is well known that the activation of p38 mitogen-activated protein kinase (p38 MAPK) orchestrates senescence in CD8

The pursuit of understanding early genetic or protein markers for ovarian aging has garnered considerable attention in the realm of reproductive medicine. Sirtuins (SIRTs) are a group of proteins that are NAD

The increase in life expectancy has caused a rise in age-related brain disorders. Although brain rejuvenation is a promising strategy to counteract brain functional decline, systematic discovery methods for efficient interventions are lacking. A computational platform based on a transcriptional brain aging clock capable of detecting age- and neurodegeneration-related changes is developed. Applied to neurodegeneration-positive samples, it reveals that neurodegenerative disease presence and severity significantly increase predicted age. By screening 43840 transcriptional profiles of chemical and genetic perturbations, it identifies 453 unique rejuvenating interventions, several of which are known to extend lifespan in animal models. Additionally, the identified interventions include drugs already used to treat neurological disorders, Alzheimer's disease among them. A combination of compounds predicted by the platform reduced anxiety, improved memory, and rejuvenated the brain cortex transcriptome in aged mice. These results demonstrate the platform's ability to identify brain-rejuvenating interventions, offering potential treatments for neurodegenerative diseases.

Aging is a complex biological process driven by genetic and immune-mediated mechanisms, yet the causal roles of immune-cell-specific gene regulation remain unclear. In this study, we integrate single-cell expression quantitative trait loci (sc-eQTL) data with Mendelian randomization (MR) and colocalization analyses to identify immune-mediated regulatory mechanisms and therapeutic targets for aging. Using data from 14 immune cell types, we systematically evaluated 8733 eGenes for causal effects on telomere length (TL), facial aging (FA), and frailty index (FI). We identified 27 immune-cell-specific eGenes with significant causal associations and strong colocalization evidence (posterior probability for a shared causal variant, PP.H4 > 50 %). Key regulators include FUBP1, TUFM, ATIC, and SLC22A5, with distinct effects across cell types and aging traits. Phenome-wide association studies (PheWAS) demonstrated minimal off-target associations for most genes, supporting their safety as therapeutic targets. Drug repurposing analysis revealed several approved or investigational compounds, such as Irofulven, zinc-based agents, and acetylcarnitine, with potential for aging-related interventions. Our findings provide new insights into the immune-genetic architecture of aging and establish a scalable framework for identifying cell-type-specific causal genes and repurposable drug targets. This approach enhances precision medicine strategies aimed at promoting healthy aging and delaying age-related decline.

Epigenetic Clocks have been trained to predict chronological age, healthspan and lifespan. Such clocks are often analysed in relation to disease outcomes - typically using small datasets and a limited number of clocks. Here, we present the first large-scale (n=18,849), unbiased comparison of 14 widely used clocks as predictors of 174 incident disease outcomes and all-cause mortality. Second-generation clocks significantly outperformed first-generation clocks, which have limited applications in disease settings. Of the 176 Bonferroni significant (P<0.05/174) associations, there were 27 diseases (including primary lung cancer and diabetes) where the hazard ratio for the clock exceeded the clock's association with all-cause mortality. Furthermore, there were 35 instances where adding a clock to a null classification model with traditional risk factors increased the classification accuracy by >1% with an AUCfull > 0.80. Second-generation epigenetic clocks show promise for disease risk prediction, particularly in relation to respiratory and liver-based conditions.

Antler blastema progenitor cells (ABPCs) are a distinct population of skeletal mesenchymal stem cells found in regenerating deer antlers, with strong stemness and renewal capacity in vitro. Stem cell-derived extracellular vesicles (EVs) are emerging as potential therapeutic candidates that can mediate donor cells' beneficial effects. Here, we tested the effects of ABPC-derived EVs (EVs

The aryl hydrocarbon receptor (AhR) is proposed to mediate the frailty-promoting effects of the tryptophan metabolite kynurenine (Kyn), which increases with age in mice and humans. The goal of the current study was to test whether administration of pharmacological AhR inhibitors, BAY2416964 and CH-223191, could abrogate musculoskeletal decline in aging mice. Female C57BL/6 mice (18 months old) were treated with vehicle (VEH) or BAY2416964 (30 mg/kg) via daily oral gavage 5 days/week for 8 weeks. A second AhR antagonist, CH-223191, was administered to 16-month-old male and female C57BL/6 mice via intraperitoneal injections (3.3 mg/kg) 3 days/week for 12 weeks. While grip strength declined over time in VEH-treated mice, BAY2416964 preserved grip strength in part by improving integrity of neuromuscular junctions, an effect replicated during in vitro studies with siRNA against AhR. Cortical bone mass was also greater in BAY2416964- than VEH-treated mice. Similarly, CH-223191 treatment improved cortical bone and showed beneficial effects in skeletal muscle, including reducing oxidative stress as compared to VEH-treated animals. Transcriptomic and proteomic data from BAY2416964-treated mice supported a positive impact of BAY2416964 on molecular targets that affect neuromuscular junction function. Taken together, these data support AhR as a therapeutic target for improving musculoskeletal health during aging.

Attenuating protein synthesis promotes longevity in multiple species. However, numerous studies indicate that aging drives a decrease in protein synthetic capacity. These observations hint at potential, unexplored benefits of stimulating protein synthesis in old age. In this work, we focus on Maf1, a repressor of protein synthesis genes transcribed by RNA Polymerase (Pol) III, such as the 5S rRNA and tRNAs, and its role in aging. We show that the knockdown of Maf1 extends lifespan in Drosophila. Maf1 limits longevity specifically from adult neurons in both female and male fruit flies. In older females, adult neuron-specific knockdown of Maf1 improves neuromuscular function as well as the function of a distal organ, the gut. We find that the extension of female lifespan upon Maf1 knockdown requires Pol III initiation on the 5S rRNA. Indeed, reducing neuronal Maf1 activity rescues the age-related decline in 5S expression and protein synthesis in the brain of female flies. Hence, our findings show that stimulating neuronal protein synthesis can promote healthy aging.

Aging is associated with immune dysfunction, but long-term endurance training may confer protective effects on immune cell function. This study investigates how natural killer (NK) cell phenotypes, functional markers, and metabolism differ between endurance-trained and untrained older adults. Ex vivo expanded NK cells from endurance-trained (63.6 ± 2.1 years) and untrained (64.3 ± 3.3 years) males were exposed to adrenergic blockade (propranolol; 0-200 ng/mL) or mTOR inhibition (rapamycin; 10-100 ng/mL), both with or without PMA-induced inflammatory stimulation. Flow cytometry assessed NK subsets, activation (CD38, CD57, CD107a, NKG2D), senescence (KLRG1), and inhibitory markers (PD-1, LAG-3, TIM-3, NKG2A). Seahorse analysis measured metabolic parameters. Trained participants displayed healthier immune profiles (lower NLR, SII) and higher effector NK cells with lower cytotoxic subsets. Propranolol at 100 ng/mL blunted PMA-driven increases in CD57, CD107a, and NKG2D, while potentiating regulatory markers KLRG1, LAG-3, and PD-1 in the trained group, indicating stronger immunoregulation. With rapamycin, trained NK cells preserved NKG2D and CD107a at 10 ng/mL, maintaining cytotoxicity and degranulation. In contrast, at 100 ng/mL rapamycin plus PMA, trained NK cells shifted toward an effector phenotype with higher CD57 and CD107a, yet a blunted PMA-increased LAG-3 and TIM-3, suggesting resistance to exhaustion. PD-1 and KLRG1 remained elevated, reflecting balanced immune control. Mitochondrial analysis revealed that trained NK cells exhibited higher basal and maximal OCR, greater spare respiratory capacity, and OCR/ECAR ratio, reflecting superior metabolic fitness. These findings indicate that endurance-trained older adults have NK cells with greater functional adaptability, reduced senescence, and enhanced metabolism under inflammatory and pharmacological stress.

In this work, we proposed a multiband dual-VENC 2D PC-MRI technique termed MB-DV PC-MRI to simultaneously measure arterial pulsatility across multiple cerebral arterial segments, including both proximal greater and distal smaller arteries. A multiband SINC RF pulse was designed to simultaneously excite multiple slices with varied gaps between adjacent slices in MB-DV PC-MRI. A retrospectively gated MB-DV PC-MRI sequence was performed on 11 young (29.9 ± 7.3 years) and nine elderly (68.3 ± 11.1 years) to measure pulsatility indices (PIs) of multiple cerebral arterial segments. A test-retest study and a comparison study with conventional single-band 2D PC-MRI demonstrated MB-DV PC-MRI provides good reproducibility and reliability in cerebral PI measurements. Additionally, the damping factor (DF) was calculated as the ratio of PIs between proximal and distal vessel segments, showing good reproducibility. Compared to younger adults, elderly adults exhibited overall higher PI values across cerebral arterial segments and varied damping along ICA-MCA. This study demonstrates that MB-DV PC-MRI is a reliable technique for the assessment of arterial pulsatility along the cerebrovascular tree, which could be a useful imaging tool in studying the role of cerebrovascular dysfunction in aging and neurodegenerative diseases.

Intervertebral disc degeneration (IVDD) is a significant contributor to chronic low back pain and disability worldwide, yet effective treatment options remain limited. Through integrative analysis of single-cell RNA-seq data from intervertebral discs (IVDs), we have firstly uncovered that the aberrant accumulation of R-Loops-a type of triple-stranded nucleic acid structure-can result in the cytoplasmic accumulation of double-stranded DNA (dsDNA) and activate cGAS/STING signaling and induce cellular senescence in nucleus pulposus cells (NPCs) during IVDD. Restoring the R-Loop state significantly mitigated both the activation of the cGAS/STING pathway and NPC senescence. Additionally, we identified ERCC5 as a critical regulator of the R-Loop state and cellular senescence. Thus, we developed an NPC-targeting nano-delivery platform (CTP-PEG-PAMAM) to deliver si-Ercc5 to the NP region of the IVDD. This approach aims to modulate the abnormal R-Loop state and inhibit the activation of cGAS/STING signaling in NPCs for IVDD treatment. CTP-PEG-PAMAM demonstrated excellent targeting capability towards NPCs and NP tissue, and achieved effective silencing of the Ercc5 gene without causing systemic organ complications. Both in vitro and in vivo experiments revealed that CTP-PEG-PAMAM-siERCC5 significantly inhibited cGAS/STING signaling activated by aberrant R-Loops, alleviated cellular senescence and promoting cell proliferation, thereby delayed IVDD in a puncture-induced rat model. In conclusion, the ERCC5-R-Loop-cGAS/STING axis in NPCs represents a promising therapeutic target for delaying IVDD, and the designed CTP-PEG-PAMAM/siRNA complex holds great potential for clinical application in the treatment of IVDD.

The Rab3 protein family is composed of a series of small GTP-binding proteins, including Rab3a, Rab3b, Rab3c, and Rab3d, termed Rab3s. They play crucial roles in health, including in brain function, such as through the regulation of synaptic transmission and neuronal activities. In the high-energy-demanding and high-traffic neurons, the Rab3s regulate essential cellular processes, including trafficking of synaptic vesicles and lysosomal positioning, which are pivotal for the maintenance of synaptic integrity and neuronal physiology. Emerging findings suggest that alterations in Rab3s expression are associated with age-related neurodegenerative pathologies, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, among others. Here, we provide an overview of how Rab3s dysregulation disrupts neuronal homeostasis, contributing to impaired autophagy, synaptic dysfunction, and eventually leading to neuronal death. We highlight emerging questions on how Rab3s safeguards the brain and how their dysfunction contributes to the different neurodegenerative diseases. We propose fine-tuning the Rab3s signaling directly or indirectly, such as via targeting their upstream protein AMPK, holding therapeutic potential.

Numerous factors, including some modifiable factors as well as demographic factors, are associated with risk for age-related cognitive impairment. Evaluating the complex interaction of these factors and their trajectories across the adult lifespan requires large sample sizes with diverse cohorts. Online research has the potential to overcome barriers to research participation and provide the statistical power required to examine individual differences in cognitive functions. Understanding the complexity of cognitive aging is critical for developing individualized interventions aimed at promoting brain and cognitive health across the lifespan.

To understand observed spatial distributions of white-matter (WM) aging, developmentally driven theories termed "retrogenesis" have gained traction, positing that WM tract development order predicts order of declines, with later developing regions expected to deteriorate first, i.e., "last-in-first-out." Alternatively, regions that develop most rapidly may decline most rapidly in aging, i.e., "gains-predict-loss." The validity of such theories remains uncertain, partly due to lack of clarity in defining developmental order. Recent findings suggest that WM aging is also associated with physiological parameters such as perfusion and fiber size. Here, we address the extent to which degrees of WM aging are determined by development trajectory (i.e., retrogenesis) and/or physiological states. We obtained microstructural and perfusion data from the Human Connectome Project in Aging (HCP-A), complemented by a meta-analysis involving maps of fiber calibre and macrovascular volume. Our results suggest (1) myelination development order explains more associations with WM health than prenatal emergence order; (2) earlier-myelinating tracts exhibit higher microstructural integrity and less susceptibility to microstructural deterioration in aging but lower perfusion and longer arterial-transit times (ATT), suggestive of collateral blood supply; (3) earlier-emerging tracts show longest ATT and greatest ATT increase across aging; (4) tracts with larger axons and higher macrovascular density in young adulthood show longer ATT and less susceptibility to microstructure/perfusion degeneration irrespective of developmental order; and (5) negligible support for "gains-predict-loss." These findings were sex-dependent in a tract-specific manner. Future work will investigate the role of macrovascular collateral flow and tract-wise influences of metabolic demand.

Adaptive modulation of physiological traits in response to environmental variability, particularly dietary fluctuations, is essential for organismal fitness. Such adaptability is governed by complex gene-diet interactions, yet the molecular circuits integrating microbe-derived metabolites with host metabolic and stress response pathways remain less explored. Here, we identify the conserved mechanistic target of rapamycin complex 2 (mTORC2) component, RICTOR, as a critical regulator of dietary plasticity in Caenorhabditis elegans, specifically in response to bacterially derived vitamin B12 (B12). Loss of rict-1, the C. elegans ortholog of RICTOR, confers enhanced osmotic stress tolerance and longevity on B12-rich bacterial diets. These phenotypic adaptations require two B12-dependent enzymes: methionine synthase (METR-1), functioning in the folate-methionine cycle (Met-C), and methylmalonyl-CoA mutase (MMCM-1), a mitochondrial enzyme essential for propionate catabolism. The latter catalyzes the formation of succinyl-CoA, subsequently converted to succinate via the tricarboxylic acid (TCA) cycle. Elevated succinate levels were found to induce mitochondrial fragmentation, thereby activating mitophagy, an autophagic process indispensable for the increased stress resilience and longevity observed in the rict-1 mutants. Crucially, this Met-C-mitophagy axis is modulated by microbial inputs, with B12 and methionine acting as proximal dietary signals. Our findings delineate a mechanistic framework through which RICTOR restrains host sensitivity to microbial-derived metabolites, thus maintaining mitochondrial homeostasis and regulating lifespan. This work reveals a pivotal role for RICTOR in insulating host physiology from environmental nutrient-driven perturbations by modulating organellar quality control pathways.

Wound healing in old mice is characterized by disturbed tissue homeostasis, manifested by delayed immune cell infiltration and reduced growth factor secretion, leading to a delayed onset and prolonged duration of the inflammatory phase. The endocannabinoid system (ECS) is an important regulator of tissue homeostasis and cell migration and is also considered to be subject to aging processes, which may contribute to observable aging phenomena. Therefore, stimulating the aged ECS could represent a therapeutic option to support tissue regeneration in aging. Female old mice received a low-dose of medical THC daily for 3 weeks, before four excisional full skin wounds were created. At day 1, 3 and 7 post-surgery, the wound closure rate was analyzed and wound samples were examined immunohistochemically for the numbers of granulocytes, M1-macrophages and mesenchymal stem cells (MSCs). The concentrations of inflammatory cytokines and regenerative growth factors were determined by ELISA. Administration of THC improved the wound healing rate of old mice between day 1 and 7, which was associated with an altered timing and quantity of infiltrating immune cells and decreased levels of inflammatory cytokines in wound tissue on days 1 and 3 post-injury. THC treatment significantly increased MSC infiltration but had no effect on the growth factor release. The present study confirmed the anti-inflammatory activity of THC in vivo. The THC-treatment improved wound healing in old mice by coordinating the temporal sequence of immune cell infiltration and cytokine release. Thus, restoration of ECS signaling could be an effective strategy to support age-related skin regeneration.

Background: Aging and male sex are major risk factors for abdominal aortic aneurysm (AAA), a disease characterized by vascular cell phenotypic switching and aortic wall remodeling. Mitochondrial oxidative stress (mtOS) has been implicated in these changes. We previously demonstrated that NOX4 expression and activity increase with age in cardiovascular cells, promoting mtOS and vascular dysfunction. This study investigates whether NOX4-driven mtOS and DNA damage promote AAA development through vascular cell reprogramming. Methods: We used mitochondria-targeted Nox4-overexpressing (Nox4TG) mice with an Apoe-/- background to model Angiotensin II (Ang II)-induced AAA. AAA incidence, aortic morphology, reactive oxygen species (ROS) levels, DNA damage markers, and wall remodeling parameters were assessed in Apoe-/-, Apoe-/-/Nox4TG, and Apoe-/-/Nox4-/- mice. Vascular cell populations were analyzed by spectral flow cytometry and gene expression profiling. In vitro, Ang II-treated SMCs from wild-type, Nox4TG, and Nox4-/- mice were evaluated for mtROS, DNA damage, and activation of inflammatory pathways. Results: Apoe-/-/Nox4TG mice exhibited the highest AAA incidence, aortic dilation, ROS levels, DNA damage, and inflammation, while Apoe-/-/Nox4-/- mice were most protected. Macrophage-like SMCs increased, while contractile SMCs decreased in Nox4TG aortas. Ang II-treated Nox4TG SMCs showed elevated mtROS, DNA damage, and cGAS-STING activation. Flow cytometry analysis confirmed the presence of aneurysmal SMC with reduced ACTA2, MYH11, TAGLN and increased CD68, CD11b, LGALS3 expression. Conclusions: NOX4-dependent mitochondrial DNA damage and activation of DNA-sensing pathways promote SMC phenotypic switching, inflammation, and aortic wall remodeling in AAA. Targeting NOX4 and enhancing mitochondrial function may offer therapeutic strategies for AAA prevention.

Epigenetic clocks have been widely applied to assess biological ageing, with Age Acceleration (AA) serving as a key metric linked to adverse health outcomes, including mortality. However, the comparative predictive value of AAs derived from different epigenetic clocks for mortality risk has not been systematically evaluated. In this retrospective cohort study based on 1,942 NHANES participants (median age 65 years; 944 women), we examined the associations between AAs from multiple epigenetic clocks and the risks of all-cause, cancer-specific, and cardiac mortality. Restricted cubic spline models were used to assess the shape of these associations, and Cox proportional hazards regression was employed to quantify risk estimates. Model performance was compared using the Akaike Information Criterion (AIC) and concordance index (C-index). Our findings revealed that only GrimAge AA and GrimAge2 AA demonstrated approximately linear and positive associations with all three mortality outcomes. Both were significantly associated with increased risks of death, and these associations were consistent across most subgroups. GrimAge and GrimAge2 AAs showed very similar performance in predicting all-cause, cancer and cardiac mortality, with only small differences in AIC values and C-index scores. These findings suggest that both GrimAge and GrimAge2 are effective epigenetic biomarkers for mortality risk prediction and may be valuable tools in future ageing-related research.

Cellular senescence is defined as a stable state of cell cycle arrest, characterized by the loss of proliferative capacity. This process can be triggered by diverse intracellular and extracellular stimuli. Senescent cells exhibit multiple hallmark features, including upregulation of cell cycle inhibitory proteins p16INK4a and p21Cip1, activation of DNA damage response, alterations in cellular architecture, and metabolic reprogramming. A prominent characteristic of senescent cells is their ability to secrete a heterogeneous array of bioactive molecules, collectively termed the senescence-associated secretory phenotype (SASP). These SASP components encompass cytokines, chemokines, growth factors, proteases, and other signaling mediators that exert biological functions through autocrine and paracrine mechanisms.With global population aging, osteoporosis has emerged as a critical public health challenge worldwide. Emerging evidence underscores the close association between osteoporosis and cellular senescence. During aging, the accumulation of senescent cells leads to enhanced SASP production, which contains pro-inflammatory cytokines, chemokines, and other mediators. These SASP factors not only propagate the senescence phenotype but also disrupt bone homeostasis by impairing the functionality of bone tissue cells, thereby accelerating skeletal aging. Recent advances highlight SASP as a promising therapeutic target for bone metabolic disorders such as osteoporosis. However, the precise molecular mechanisms through which SASP regulates bone cell populations remain incompletely elucidated.Addressing this knowledge gap, the present study aims to investigate the regulatory mechanisms of SASP in bone tissue cells, with the ultimate goal of providing mechanistic insights for developing novel strategies against age-related bone metabolic diseases.

Retinoic acid receptor-related orphan receptor beta (RORβ) is a ligand-dependent transcription factor essential for bone metabolism. While RORβ negatively regulates osteoblast differentiation and contributes to age-related or postmenopausal osteoporosis, its role in early skeletal development remains unclear. This study developed a Rorβ gene knockout (KO) mouse model using CRISPR/Cas9 to investigate its effects on endochondral ossification. At 4 weeks, Rorβ KO mice exhibited dwarfism and early-onset osteoporosis, with reduced femur length (-8.84%), lower cortical and trabecular bone mass, and impaired bone quality. The trabecular bone was fragile, with reduced surface osteoblasts and impaired osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Chondrogenesis was also disrupted, evidenced by a thinner growth plate, fewer chondrocytes, and a disorganized hypertrophic zone (HZ). The expressions of proliferation (Ki67) and hypertrophic differentiation (Collagen X) markers were significantly reduced. Mechanistically, RORβ deficiency downregulated hypoxia-inducible factor 1-alpha (HIF-1α) and its downstream target vascular endothelial growth factor A (VEGFA) in both the pre-hypertrophic zone (PHZ) of the growth plate and BMSCs. These findings identify RORβ as a critical regulator of endochondral ossification, linking its loss to skeletal defects via impaired HIF-1α/VEGFA signaling. This study provides insights into potential therapeutic strategies for skeletal diseases such as skeletal dysplasia.

Oocyt e development from non-growing to metaphase II (MII) stages is largely dependent on timely and correctly controlling gene expression. During the process of biological or postovulatory aging, the epigenetic mechanisms, particularly DNA methylation, histone methylation, and acetylation, exhibit notable changes in oocytes at various stages of development. These changes mainly result from altered expression of the related catalytic enzymes. In this review, changes in DNA methylation, histone methylation, and acetylation marks and expression of the acting enzymes in aging mammalian oocytes have been comprehensively evaluated in the light of existing studies. Potential interactions between these epigenetic mechanisms are also discussed. Finally, possible interventions to regulate them in order to mitigate the loss of female fertility in the later periods of the reproductive lifespan are reviewed.

Ovulated oocytes deteriorate rapidly if not fertilized within the optimal timeframe, known as postovulatory aging. Astragaloside IV (AS-IV), an active ingredient of Astragalus membranaceus, has been demonstrated to have anti-aging and antioxidant effects. However, it has not been elucidated whether AS-IV mitigates in vitro postovulatory oocyte aging. Here, AS-IV was administered into the in vitro culture buffer, and we found that its addition could improve the quality of in vitro postovulatory aged oocytes in mice. Specifically, AS-IV treatment enhanced morphological integrity, preserved spindle/chromosome structure, stabilized actin cytoskeleton, maintained centromere cohesion, and improved ovastacin dynamics in aging oocytes. These improvements collectively enhanced sperm binding capacity and subsequent developmental competence following parthenogenetic activation. Mechanistically, AS-IV appears to inhibit mRNA degradation of antioxidant enzymes and sustain mitochondrial function, thereby preventing reactive oxygen species (ROS) accumulation during in vitro oocyte aging. Meanwhile, reduced oxidative stress in AS-IV-treated oocytes may counteract apoptosis-related mRNA accumulation, delaying apoptotic initiation. Taken together, our findings demonstrate that AS-IV supplementation effectively improves the quality of in vitro-aged postovulatory oocytes. This provides a valuable reference and evidence base for its potential application in human-assisted reproductive technology and livestock embryo production.

Obesity constitutes a growing global health concern, affecting individuals during the aging process. Flavonoids that increase tissue NAD+ levels, such as apigenin (Api), are proposed for the treatment of obesity and age-related diseases. Thus, this study aimed to provide initial preclinical evidence of Api in this setting using middle-aged rats induced to obesity by a high-calorie diet (HCD). Forty-seven 15-month-old male Wistar rats were assigned to five groups: standard diet (SD) or HCD, each with (Api at 50 mg/kg) or without treatment (vehicle), plus vehicle control group. Obesity induction and therapeutic intervention were conducted concurrently for 88 days. Biometric, cardiac, adiposity, muscular, and blood biochemical parameters were analyzed. Eighty-eight days post HCD rats had hyperglycemia, hypertriglyceridemia, increased visceral and subcutaneous fat, and heart hypertrophy, indicating obesity and related disorders (p < 0.05 for all). The gastrocnemius of these rats exhibits reduced mass, smaller myocytes, and fibrosis (p < 0.05), indicating sarcopenia, likely caused or worsened by obesity. In parallel, preemptive Api treatment failed to prevent obesity and did not affect key adipose tissue browning genes, cardiac oxidative stress markers, or sirtuin and CD38 levels. However, it mitigated muscle loss and hypotrophy, in addition to elevating p70S6K levels in HCD-fed rats (p < 0.05 for both). These preclinical results suggest that although Api may not prevent some HCD-induced disturbances, it may attenuate age- and obesity-related atrophy via p70S6K anabolic signaling in middle-aged rats. To support clinical translation, particularly in sarcopenia subtypes, further mechanistic and therapeutic investigations on Api are required to elucidate its effects on skeletal muscle.

As a biologically intricate process, aging entails functional impairment and predisposes individuals to chronic conditions. Medicine-food homology (MFH) plants, deeply rooted in traditional Chinese medicine, are increasingly recognized for their potential to delay aging through natural bioactive compounds.

Age-related retinal degeneration, such as diabetic retinopathy and age-related macular degeneration, are major causes of blindness in modern society. Recent studies suggest that dysbiosis and intraocular translocation of bacteria from the blood circulation are critically involved in retinal degeneration. We hypothesise that the blood-retinal barrier (BRB) cells can protect the neuroretina from blood-borne pathogens by producing antimicrobial peptides (AMPs). The antimicrobial activity may decline during ageing, putting the retina at risk of low-degree chronic inflammation and degeneration. Here, we found that the retinal pigment epithelial (RPE) cells, which form the outer BRB, express a variety of AMPs/AMP precursors, including APP, RARRES2, FAM3A, HAMP, CAMP, GNLY, and PI3. Senescent RPE cells expressed lower levels of APP and RARRES2 mRNA, accompanied by increased intracellular retention of E. coli in a bactericidal assay. Silencing APP, not RARRES2, with shRNA reduced the antibacterial activity of RPE cells. Senescent RPE cells had lower levels of α-secretase and higher levels of β-secretase (BACE1) and γ-secretase (PS1), accompanied by reduced soluble APPα and increased amyloid beta (Aβ) production, particularly the Aβ42 isoform. Eyes from aged donors showed a higher Aβ accumulation within RPE cells. Our results suggest that while RPE cells possess antimicrobial activity, this ability declines with age and is impaired in senescent cells. The impaired antimicrobial activity and augmented Aβ deposition in senescent RPE cells may contribute to age-related retinal para-inflammation and neurodegeneration.

Population aging presents significant health challenges and socioeconomic burdens globally, driving an increased demand for precision health management. In the era of big data, the exponential growth of health information is accelerating advances in precision health strategies for older adults. For this population, effective strategies can be achieved by the integration of wearable devices, nanosensors, and machine learning. Wearable devices enable continuous monitoring of diverse, real-time health metrics, serving as vital tools for collecting comprehensive health data. Nanosensors can be loaded into wearable devices to enhance their performance by significantly improving detection sensitivity and specificity, thereby increasing the accuracy and reliability of the data collected. Meanwhile, machine learning provides powerful methods for rapid and efficient analysis of large-scale health data, driving the optimization of nanosensors as well as wearable devices. This review examines the synergistic roles of wearable devices, nanosensors, and machine learning in the precision health management field, focusing on the value of big health data (i.e., big data in health care). We begin by exploring wearable devices as critical tools for gathering extensive health information, followed by an in-depth discussion of how nanosensors enhance data quality. Subsequently, we highlight the contributions of machine learning algorithms to the precise analysis of big health data and propose several proactive health management strategies from the perspective of "diagnosis-analysis-prevention". Finally, we present perspectives on the future integration of these technologies to advance comprehensive health management, precision diagnostics, and personalized medicine for older individuals.