Longevity Papers

Autophagy maintains cellular homeostasis through lysosomal degradation of cytoplasmic components, yet how prolonged autophagy activation reshapes organelle architecture remains poorly understood. Here we identify a previously unrecognized form of endoplasmic reticulum (ER) remodeling induced by chronic mTOR inhibition. This process triggers the formation of autolamellasomes: multilamellar, ER-derived structures that mediate bulk ER degradation. Unlike canonical ER-phagy, autolamellosome biogenesis requires the core autophagy machinery but is independent of known ER-phagy receptors. Cryo-ET, CLEM, and in vitro reconstitution reveal that they arise from autophagy-dependent assembly and compaction of fragmented ER into concentric stacks, which are then engulfed by lysosomes. Autolamellasomes occur at low levels constitutively, but accumulate in senescent cells and HGPS fibroblasts, linking sustained mTOR suppression to aging and ER/lysosomal homeostasis. This work clarifies the origin of intra-lysosomal membrane whorls and introduces a cell-free system for studying autophagy-driven membrane remodeling, connecting nutrient sensing, lipid catabolism, and aging.

Measuring biological age typically requires invasive and costly procedures. To address this, the MoveIt! Age Score was developed: a simple, scalable, and interpretable aging clock that predicts biological age using only wearable-derived steps data. MoveIt! Age was trained on steps data from the United States National Health and Nutrition Examination Survey (NHANES), using chronological age, maximum step count, and step count variability to predict PhenoAge, a blood biochemistry biological age score. MoveIt! Age performance was evaluated in two independent cohorts: Mitochondria and Muscle Health in Elderly (MitoHealth; N = 55; healthy young adults or older adults from the Netherlands) and Restoring Health of Acutely Unwell Adults (RESORT; N = 145; geriatric rehabilitation inpatients from Australia). In RESORT, MoveIt! Age was assessed and compared to SenoClock-BloodAge and PhenoAge (hematological aging clocks). Delta age was the predicted biological age minus chronological age. In the NHANES testing dataset, MoveIt! Age demonstrated high predictive accuracy of chronological age (r = 0.97, RMSE = 5.4 years) and was more significantly associated with mortality than PhenoAge. In MitoHealth, delta MoveIt! Age showed differences between young adults and older adults who were normal, healthy, or health-impaired, with MoveIt! Age more significantly associated with muscle NAD

Alternative splicing is a key mechanism for transcriptomic diversity, but how isoforms map to specific cell types in bulk tissues remains unclear. We present Sciege, a multimodal method that integrates bulk short-read RNA-seq with single-cell and long-read data to estimate cell type-specific isoform distributions. Through simulations, we demonstrate that Sciege accurately estimates isoform abundances and identifies differentially abundant transcripts through statistical tests. Applied to seven tissues in GTEx and brain tissue in ROSMAP datasets, Sciege generates a first-to-date multi-tissue isoform atlas and reveals isoform changes linked to cell types, aging, and Alzheimer\'s disease. Validation with external cohorts and experimental data confirms our findings. Notably, we identify upregulation of the MAPT-010 isoform in AD inhibitory neurons, consistent with known methylation signatures. Our approach demonstrates the value of integrating RNA-seq data to study cell type-specific splicing and provides a foundation for further genetic and functional studies of alternative splicing across biological contexts.

Flavin-Containing Monooxygenases (FMO) are widely conserved, xenobiotic-detoxifying enzymes whose additional endogenous functions have been revealed in recent studies. Those roles include the regulation of longevity in the model nematode Caenorhabditis elegans.

Radiation-induced lung injury (RILI) is a dose-limiting toxicity of thoracic radiotherapy driven by mitochondrial damage-mediated oxidative stress, persistent DNA damage, and senescence, which together destabilize the alveolar-interstitial niche and promote fibrosis. Here, we identify Foenumoside B (FSB), a natural saponin from Lysimachia foenum-graecum, as a dual-action modulator that preserves mitochondrial quality and restores systemic redox homeostasis to attenuate RILI. In a murine total lung irradiation model (20 Gy), oral FSB (10 mg/kg/day) mitigated inflammation and fibrotic remodeling, improved pulmonary mechanics and arterial blood gases, and exhibited no overt hepatorenal toxicity. Mechanistically, FSB activated PINK1/Parkin-dependent mitophagy in alveolar epithelial cells. Pharmacologic autophagy blockade (3-MA) or PINK1 silencing abrogated these benefits, increasing mtROS, γH2AX foci, comet tail moments, and p16/p21 expression, and reducing cell viability, thereby confirming mitophagy as indispensable for FSB's cytoprotection. Molecular docking analysis demonstrates that FSB binds to the catalytic α1 and α2 subunits of AMPK, thereby significantly increasing the p-AMPK/AMPK ratio. Upon pharmacologic inhibition of AMPK, the FSB-mediated improvements in mitophagy, mitochondrial function, redox homeostasis, and tissue protection are markedly attenuated, indicating that FSB's biological effects rely on AMPK activation. FSB also restored Nrf2/HO-1 signaling and antioxidant capacity. Co-IP/ChIP showed AMPK directly associates with Nrf2, enhances its phosphorylation and ARE binding at the HO-1 promoter, and weakens Keap1-mediated degradation. Overall, FSB suppresses reactive oxygen species at their mitochondrial source and, through AMPK-driven mitophagy and Nrf2 activation, enhances endogenous antioxidant defenses, providing a translatable strategy to preserve alveolar architecture during radiotherapy.

The p38 mitogen-activated protein kinase has a well-characterized role in modulation of inflammatory processes throughout the body. In the central nervous system, p38 is primarily studied within neurons and microglia, most commonly in the context of neurological insult. The present study was designed to determine its function in astrocytes during non-pathological aging. We generated a conditional knockout model in which a tamoxifen-inducible Aldh1l1 promoter drives Cre recombinase expression in mice with exon 1 of the p38α gene flanked by loxP sites. Knockout of astrocyte p38α was achieved via tamoxifen administration in young sexually mature mice at 3-4 months old. Animals were subsequently aged to 21-24 months prior to performing electrophysiological, immunohistochemical, and biochemical analyses. We found that early loss of astrocyte p38α was associated with a reduction in hippocampal neuroinflammation and concomitant enhancement of synaptic strength in aged female mice. In subsequent experiments in younger animals, the knockout reduced peripheral GFAP levels and increased non-synaptic mitochondrial uncoupling. These findings indicate that astrocyte p38α has wide-ranging effects on brain metabolism, inflammation, and synaptic function during the course of normal aging, including release of GFAP from the central nervous system to the periphery. Follow-up studies exploring the role of astrocyte p38α in various age-associated neuropathological contexts are warranted.

Short tandem repeats (STRs) are highly abundant in the human genome and their age-related somatic instability is emerging as a pivotal pathomechanism in repeat expansion disorders. Nevertheless, currently no analysis tool exists for genome-wide profiling of STR somatic instability. Here, we present searchSTR, a novel computational framework that enables accurate STR genotyping and somatic instability quantification from both whole-genome and targeted sequencing data. Applying this approach, we analyzed STR variants from whole-genome sequencing data of the 1000 Genomes Project (n=3,202) and targeted deep-sequencing data of the population-based Rhineland Study (n=2,974). We provide a comprehensive multiancestry genome-wide reference panel of STR variants and their somatic instability, covering more than 1.4 million STRs across 26 populations. Remarkably, STR somatic instability at many loci was robustly associated with age, sex, brain morphology and markers of neurodegeneration. These findings reveal a crucial role for STR somatic instability as an age-dependent modifier of brain structure.

The repressor element 1-silencing transcription factor (REST), or neuron-restrictive silencer factor (NRSF), is crucial for gene regulation since it binds to chromatin and recruits chromatin-modifying enzymes. Acting as a regulatory hub, REST orchestrates neurogenesis, neuronal differentiation, and the preservation of neuronal identity by regulating a broad network of target genes across stem cells, non-neuronal cells, and neurons. These targets influence critical processes such as axonal growth, vesicular transport, neurotransmitter release, and ion conductance. An important feature of normal aging in cortical and hippocampal neurons is REST induction, where it contributes to extended longevity by repressing genes linked to neuronal excitability and stress vulnerability. However, REST's role in neurodegenerative diseases remains complex and context dependent. Variations in its expression and subcellular localization, including cytoplasmic translocation or loss, have been implicated in the pathology of disorders like Alzheimer's disease, Parkinson's disease, Huntington's disease, schizophrenia, and epilepsy. Given its broad regulatory functions, REST has emerged as an attractive therapeutic target. Strategies such as microRNA modulation, small molecule inhibitors, and complex-disrupting compounds have been explored, each offering unique opportunities and challenges. Understanding REST's molecular mechanisms and disease-specific functions is critical for identifying novel therapeutic interventions. This review provides a comprehensive analysis of REST's role in aging and neurodegeneration, highlighting its regulatory networks, disease relevance, and recent therapeutic strategies targeting REST, with an emphasis on their potential for clinical translation.

Accumulated evidence has shown that the antioxidant diet exhibits protective effects on women's reproductive health. The Composite Dietary Antioxidant Index (CDAI) serves as a crucial indicator for assessing antioxidant-rich diets. However, the relationship between CDAI and menopause age as well as reproductive lifespan remains unclear. In this cross-sectional analysis, we investigated these associations using data from 4514 post-menopausal women who participated in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018. Analyses incorporated sampling weights and design variables to address its complex survey structure, ensuring nationally representative results Information on age at menopause and reproductive lifespan was derived from questionnaire data. The CDAI was calculated based on the intake of selenium, zinc, carotenoid, Vitamin A, C and E. Multiple linear regression, smooth curve fitting, threshold effect analysis, and subgroup analysis were used to investigate the association between the CDAI and age at menopause as well as reproductive lifespan. After adjusting for age, race, BMI and other confounding factors, our findings revealed that higher CDAI was associated with a later age at menopause (β = 0.09, 95% CI = 0.02-0.15, P = 0.013) and longer reproductive lifespan (β = 0.11, 95% CI = 0.04-0.18, P = 0.001). A nonlinear threshold effect was identified, with an inflection point at CDAI = 1.05. Below this threshold, each unit increase in CDAI was associated with a 0.24-year delay in menopause (β = 0.24, 95% CI = 0.09-0.39, P = 0.002), but this effect was not observed above this point. Additionally, each standard deviation increase in CDAI was associated with a 4% decrease in early menopause risk (OR = 0.96, 95% CI = 0.92-1.00, P = 0.048). The use of oral contraceptives and female hormones modified these relationships. Our research highlighted a positive non-linear association between CDAI and age at menopause, as well as reproductive lifespan, emphasizing the potential clinical relevance of dietary antioxidant optimization within specific thresholds.

During aging, peripheral nerves undergo structural and cellular changes that trigger loss of function, impair quality of life, and increase disease risk. During peripheral nerve aging there are cellular and molecular changes, such as increased extracellular matrix deposition. The mechanisms behind these aging-induced alterations remain unclear. Here, we profile mouse sciatic nerves using single nucleus transcriptomics and unravel changes in macrophage subtypes during nerve aging. Phagocytic macrophage numbers increase at the onset of aging, followed by higher numbers of chronic inflammatory macrophages. Based on ligand-receptor analysis, we predict that increased fibroblast growth factor (FGF) signaling from adipocytes activates a chondrocyte-like neural fibroblast state during peripheral nerve aging. Finally, we show that FGF2 induces the co-expression of the chondrocyte markers SOX9 and FOXC2 in senescent human perineurial fibroblast, that can be blocked with FGF1. In conclusion, our findings reveal some of the molecular mechanisms of peripheral nerve aging by FGF-regulated induction of a chondrocyte-like fibroblast state.

Homeostatic systems (nervous, immune, and endocrine) are crucial for maintaining health throughout life and, consequently, relevant for the rate of aging and the longevity achieved. In many species, male and female mammals show different lifespans, attributed to distinct redox states, but it is scarcely known whether sex differences in the functioning of these systems are involved. This study investigated, in an integrative view, sex differences in the nervous and immune systems of Swiss strain mice by analyzing behavior, immune function, and redox biomarkers across aging, to determine whether possible sex differences in homeostatic systems affect longevity. A longitudinal study was conducted on 20 female and male Swiss mice. At their young (2 mon), adult (7 mon), and old (18 mon) ages, subjects were subjected to a battery of behavioral tests, and peritoneal leukocytes were extracted to assess immune function and redox biomarkers. The natural deaths of animals were recorded for a longevity study. Our results indicate that sexual differences begin at a young age, and several are maintained until old age. Females, in general, show better behavior, immune function, and redox biomarkers, contributing to their higher longevity compared to males. The enhanced longevity in females may be attributable, in part, to the preservation of robust immune competence, with emphasis on innate immune functions and lower oxidative stress. The integration of behavioral and immunological profiles, together with redox biomarkers, underscores the critical importance of incorporating both sex as a biological variable in the design of aging-related research.

Transcranial photobiomodulation therapy (tPBM) is a promising non-invasive treatment that uses red or near-infrared light to modulate biological functions and elicit therapeutic effects. This systematic review aimed to summarise the evidence on the effectiveness of tPBM in improving cognitive function in older women, in experimental animal models and in humans, by analyzing the optimal tPBM parameters and behavioral and neurobiological outcomes. tPBM offers advantages specific to older women as a non-invasive brain stimulation technique, applied to a sensitive population with increased risk of ageing-related brain dysfunction due to increased life expectancy. A comprehensive literature search was conducted in PubMed, Scopus, and PsycINFO databases, and only seven articles on older women were included in the review. Studies have shown that tPBM significantly improves cognitive impairment in Alzheimer's disease and related dementias, stroke, cognition and Parkinson's disease in older women. Despite the heterogeneity in the application parameters and limited number of studies, tPBM therapy was preliminarily found to be a safe, feasible, and effective non-pharmacological therapy for several neurological and mental health conditions in older women. Further research is required to establish standardized protocols for optimal therapeutic applications.

Direct reprogramming of fibroblasts into induced cardiomyocytes (iCMs) offers a regenerative strategy for heart repair, but efficiency declines in adult and aged cells. Transcriptomic and epigenetic profiling identified cellular senescence as a major barrier limiting cardiac fibroblast (CF) plasticity and cardiogenic conversion. Postneonatal fibroblasts exhibited impaired activation of cardiac gene programs and persistent expression of fibrotic and inflammatory signatures. A loss-of-function screen identified Nr4a3 as a central repressor. Nr4a3 overexpression promoted senescence and suppressed iCM induction, whereas knockdown enhanced reprogramming in murine and human senescent CFs. Mechanistically, Nr4a3 depletion remodeled the chromatin landscape from a fibrotic and inflammatory state to a regenerative cardiac program. Blocking downstream Cxcl14 restored reprogramming in refractory fibroblasts. In vivo, Nr4a3 knockdown improved heart function following myocardial infarction. These findings established cellular senescence as a major barrier to cardiac reprogramming and identified Nr4a3 and its effectors as potential targets to enhance heart regeneration.

Vascular aging accelerates the gradual deterioration of systemic organ function, yet its key driving factors are still largely unexplored. Here, it is demonstrated that lysine-specific demethylase 5A (KDM5A) decreases and histone H3 lysine 4 (H3K4me3) increases in vascular endothelial cells (VECs) isolated from ageing mice and VEC senescence models. KDM5A deficiency exacerbated endothelial cell aging in vitro. Endothelial-specific KDM5A-deficient mice exhibit shortened lifespan and multiple senescent phenotypes, including fat accumulation, reduced thermogenic capacity, skeletal kyphosis, and age-related liver lesions, while maintaining VECs-specific KDM5A levels attenuates these adverse metabolic abnormalities and prolongs lifespan. Mechanistically, endothelial KDM5A deficiency aggravates aging-associated fatty acid (FA) metabolism disorders by enhancing H3K4me3 enrichment at the promoter region of FA-binding protein 4 (FABP4), which leads to active FABP4 transcription. Together, the study reveals the regulatory mechanisms of KDM5A in age-dependent metabolic disorders and identifies KDM5A/FABP4 axis as a potential therapeutic target for vascular aging and related organ dysfunction.

Understanding the biological mechanisms linking genetic variants to disease risk is essential for advancing precision health. We have developed a causal mediation analysis framework, the C-MAPLE (Causal Mediation Analysis of Pathways Linking Exposures) method, to identify disease-causing pathways for which the effect of genetic variants is mediated through metabolites to impact age-related diseases. Unlike Mendelian randomization, our approach is robust to horizontal pleiotropy, and models multiple mediators and interactions between genetic variants and metabolites simultaneously. To ensure robust model selection, we incorporate least absolute shrinkage and selection operator (LASSO) with stability selection, which can effectively select relevant mediators even in the presence of unmeasured confounding. We also introduce a dynamic adjustment to the number of bootstrap trials to reduce computational burden during uncertainty estimation. Applying this novel framework to the Canadian Longitudinal Study on Aging, we identified 190 potential causal links involving 108 genetic variants, 176 metabolites, and 6 age-related diseases. Our method and findings highlight the utility of causal mediation analysis in uncovering metabolite-mediated genetic mechanisms. This method, combined with large-scale population data sets, has the potential to revolutionize the identification of targets for downstream clinical research, and the development of personalized disease prevention, interventions, and therapeutics.

Aging-related cognitive impairment, characterized by DNA damage and mitochondrial dysfunction, still lacks effective treatment strategies. Recent findings suggest that

Spaceflight induces physiological changes that resemble accelerated aging, however, how age influences bone marrow response at the cellular level remains poorly understood. Here, we perform single-cell transcriptomic profiling of murine femur and humerus bone marrow from young (12-week-old) and old (29-week-old) mice that underwent a 32-day spaceflight mission followed by a 24-day Earth recovery, with age-matched ground controls. Our analysis reveals that, compared with young cohorts, old mice exhibit persistent dysregulation after spaceflight, most prominently in erythroid and B cell lineages. In erythroid cells, old flight mice show pronounced aging signatures, characterized by impaired maturation, inhibited mitophagy, and increased oxidative stress. In B cells, old flight mice show dysregulation associated with failure of the AP-1 stress-response pathway and complete collapse of the intercellular CXCL signaling network. Our findings dissect the age-dependent effects of spaceflight on the bone marrow hematopoietic and immune system at single-cell resolution, and demonstrate that spaceflight imposes a disproportionate burden on the aged hematopoietic system and blunts post-flight recovery. These insights provide candidate pathways and biomarkers for health monitoring and countermeasures in long-duration missions.

The existing evidence concerning the association between sleep duration and long-term cognitive trajectories remains inconclusive. This cohort study utilized data from the China Health and Retirement Longitudinal Study (CHARLS) spanning from 2011 to 2020, with biennial surveys conducted. Group-based trajectory modeling identified cognitive trajectories over a 9-year period. Multivariable logistic regression, incorporating multiple imputation techniques to address missing data, assessed the association between sleep duration and long-term cognitive function. The sample comprised 8668 participants with a mean age of 56.3 years, of whom 45.7% were female. Among them, 34.24% exhibited cognitive decline, while 65.76% maintained stable cognition. The odds ratios (OR) for incident cognitive decline were 1.17 (95% CI: 1.04-1.31) for individuals with short sleep duration (< 6 h) and 1.57 (95% CI: 1.31-1.89) for those with long sleep duration (> 8 h). Subsequent analysis revealed a U-shaped relationship between sleep duration and incident cognitive decline (nonlinear, p < 0.001). Specifically, when sleep duration was below 7.23 h, an increase in sleep duration significantly reduced the risk of cognitive decline (OR = 0.90, 95% CI: 0.86-0.95). Conversely, when sleep duration equaled or exceeded 7.23 h, an increase in sleep duration significantly elevated the risk of cognitive decline (OR = 1.31, 95% CI: 1.17-1.46). These findings suggest that sleep duration is independently associated with long-term cognitive decline in a U-shaped manner, with a nadir around 7.23 h. Screening and brief counseling for short (< 6 h) and long (> 8 h) sleep, alongside promotion of sleep hygiene and assessment for treatable sleep disorders, may offer scalable strategies to support healthy cognitive aging.

Depression is a well-established risk factor for impaired cognitive function, but the mechanisms underlying this relationship remain poorly understood. In this study, we utilized data from the 2017-18 Wave 1 of the Longitudinal Aging Study in India to examine the potentially causal association between depressive symptoms and cognitive performance in middle-aged and older adults using alternative estimation methods to account for observed and unobserved confounding. We also investigated the mediating roles of activities of daily living (ADL), instrumental activities of daily living (IADL), and sleep problems in the pathway linking depressive symptoms to cognitive decline. Our findings indicated a significant decline in cognitive function associated with depression, particularly in the domains of language, immediate memory, and orientation. Moreover, we identified substantial mediation effects, with IADL accounting for 26.3%, ADL for 15.5%, and sleep problems for 10.8% of the relationship between depression and cognitive performance. These results suggest that interventions aimed at improving mental health in aging populations could enhance both performance in daily functioning and cognitive outcomes.

Skin photoaging leads to the deterioration of dermal collagen and overall skin integrity, resulting in visible signs of aging, particularly around the eye. Collagen III plays a pivotal role in maintaining skin elasticity and facilitating proper collagen fibril organization. Messenger RNA (mRNA)-based therapeutics present a novel alternative for addressing these limitations by enabling the localized production of full-length, biologically active proteins.

Ethanol generated during yeast fermentation has potential oxidative damaging effects, which can induce yeast aging and death. It has been reported that water extract of Ligusticum chuanxiong Hort (Lch) exhibits antiaging effects on Saccharomyces cerevisiae. However, the role and underlying mechanisms of Lch in S. cerevisiae under ethanol stress remain elusive. Herein, we showed that Lch significantly improves the survival of S. cerevisiae under ethanol stress. Transcriptome analysis revealed that carbohydrate metabolism, amino acid metabolism, and ribosome biogenesis pathways were enriched in ethanol-treated S. cerevisiae. Compared with ethanol treatment, ribosome biogenesis and RNA polymerase pathways were enriched in Lch and ethanol co-treated S. cerevisiae. Additionally, glutathione (GSH) metabolism pathway was exclusively enriched in S. cerevisiae co-treated with Lch and ethanol. Supplementation with GSH significantly enhanced the survival of ethanol-treated S. cerevisiae. Taken together, these results suggest that Lch protects S. cerevisiae against ethanol stress by modulating ribosome biogenesis and GSH metabolism pathways.

Population aging and increasing retirement rates are reshaping physical activity (PA) and health among older adults worldwide. Using the China General Social Survey data (CGSS), this study applies a fuzzy regression discontinuity design to estimate the causal impact of retirement on PA among Chinese older adults. We find that retirement significantly increases PA frequency. The effect is amplified by higher income and better health, but is weakened by psychological stress. Causal forest analysis reveals pronounced heterogeneity: income consistently emerges as the most influential moderator, while the importance of social participation, intergenerational caregiving, and urban-rural residency rises notably once provincial clustering is considered. Regional disparities also persist, with stronger effects in the eastern provinces, contrasted by more mixed and uneven patterns in central and western China. These findings highlight heterogeneous aging trajectories, showing that retirement's impact on PA is context-specific and requires locally adaptive approaches.

Entropy, a measure of disorder and randomness, is an essential feature of thermodynamics, chemistry, and information theory, but there has been little study of entropy in human aging. Entropy arises from random molecular interactions or other forms of damage and will manifest at all levels of human biology. It should also progress in concert across many systems and increase the risk of numerous aging-related conditions. Illustrating these principles, research by Hong in this issue of Aging Cell applies Mahalanobis distance to quantify entropy in electrocardiograms showing that entropy in one system predicts aging-related outcomes-fracture and mortality-beyond the heart. Important issues for research on entropy and human aging include the best methods for quantifying entropy and whether the development of entropy can be slowed or reversed in humans.

Despite extensive research on life-extending interventions, rigorous statistical techniques to determine their impact on compression of morbidity (CoM) are rarely used. We present a case example of an analytical method for examining the effect of life-extending dietary interventions on CoM by comparing the rates of decline in vitality and survival toward the end of life. Using data from previous experimental studies in mice, we calculated the average rate of vitality decline by fitting exponential decay models to individual vitality trajectories and compared this rate with the rate of survival decline estimated from Cox proportional hazards model. The results showed that, surprisingly, the life-extending interventions failed to compress morbidity. Instead, the models suggested a potential expansion of morbidity with the interventions, particularly for chronic caloric restriction, as evidenced by a greater difference between the rates of vitality decline and survival decline in the intervention group than in the control group. The results further showed age-dependent effects, with interventions likely to demonstrate CoM at very old ages. These findings challenge the assumption that lifespan extension necessarily compresses morbidity, highlighting the need to consider lifespan, healthspan, and CoM as endpoints when evaluating anti-aging interventions. We do not claim that life-extending interventions categorically fail to achieve CoM; rather, we demonstrate how a rigorous statistical approach can be applied to test the CoM hypothesis. Our framework offers a valuable tool for future studies, and further refining this method will be crucial to determine under which circumstances lifespan extension leads to CoM. The potential to choose from multiple analyses of CoM calls for leadership in the geroscience community both to standardize the nomenclature so that different CoM analysis approaches can be communicated clearly and to establish a "default" CoM analysis for everyone to use in addition to their analyses of choice, thus facilitating comparisons and meta-analyses across studies.

While biological age scores have been shown to characterize aging by estimating chronological age based on physiological biomarkers, interactions between different age scores are largely unknown. To study this, large-scale multi-modal data are crucial. However, such data are scarce as population-based cohorts are generally restricted in sharing their data. Here, we employ federated learning to study the relationship between the two types of biological age scores: BrainAge based on brain MRI and MetaboAge based on metabolites. Using three large population-based cohorts, we trained a federated deep learning model to estimate BrainAge and compared its performance to models trained in a single cohort. The federated BrainAge model yielded significantly lower error for age prediction across the cohorts than locally trained models. Harmonizing the age interval between cohorts further improved BrainAge accuracy. Subsequently, we compared BrainAge and MetaboAge by performing association analysis and survival analysis for dementia and mortality prediction to further characterize both scores. The association analysis showed a weak association between BrainAge and MetaboAge, while the survival analysis indicated complementary predictive values for the mortality risk of the two scores. Federated learning has been shown to be a valuable technique for enabling the use of research cohorts that are restricted in data sharing. We conclude that BrainAge and MetaboAge act synergetically for the prediction of time to all-cause mortality, and both aging scores capture different aspects of the aging process.

Aging substantially increases susceptibility to sepsis, yet the underlying mechanisms of immune dysfunction in the elderly remain incompletely understood. Polymicrobial sepsis was induced in young and aged male mice via cecal ligation and puncture (CLP). Bone marrow from four groups (Y-Sham, n = 2; Y-CLP, n = 3; A-Sham, n = 2; A-CLP, n = 3) was analyzed by single-cell RNA sequencing and intercellular communication inferred via CellChat. Age-related immune changes were evaluated, and Transwell assays were used to assess myeloid cell migration. Aged septic mice showed worsened organ damage and systemic inflammation, with reduced adaptive (18.7% vs. 41.3%) and increased innate immunity (58.8% vs. 37.7%, A-CLP vs. Y-CLP). Neutrophil chemotaxis was impaired; monocytes and macrophages adopted a hyperinflammatory yet functionally exhausted phenotype; dendritic cells showed increased antigen presentation with diminished mobility; B cell maturation was disrupted with regression to earlier developmental stages; and T cells shifted toward stress-responsive and regulatory programs. We identified a cluster-specific expansion of HSCs in aged sepsis (39.8% vs. 31.2% in A-CLP vs. Y-CLP) with impaired Lgals9-Cd44-mediated intercellular communication. Myeloid cell migration was impaired in A-CLP but partially restored by Lgals9-Cd44 activation. This study presents a comprehensive single-cell map of bone marrow immune dysfunction in aged sepsis and identifies impaired HSC-myeloid communication as a critical mechanism driving immune failure. Therapeutically targeting the Lgals9-Cd44 axis may restore immune coordination in elderly sepsis, although its clinical feasibility and safety remain to be validated.

Aging encompasses low-level inflammation and motor decline. Astrocytes are neuroregulatory glial cells that change in aging, particularly in the cerebellum, which is essential for movement coordination. Regulation and functionality of cerebellar astrocytes in aging is unknown. We show that antiviral type I Interferons (IFN-I) drive motor deficits and regional astrocyte aging. Transcriptomics reveal that cerebellar astrocytes, but not cortical, exhibit an antiviral state that intensifies with age, with increased expression of Stat1. Aged mice display motor deficits similar to humans that improve after peripheral IFN-I receptor neutralization, whereas astrocyte Stat1 induces motor deficits during chronic inflammation in adults. While strong systemic inflammation induces astrocyte antiviral state, in aging, chromatin de-repression of Stat1 and nucleotide sensors in cerebellar astrocytes amplifies local IFN-I signaling. We identify functional interaction between a classical immune pathway and astrocytes, representing an actionable strategy to preserve motor function in aging.

Healthspan, the disease-free period of life, has become a central focus in aging research. Cuscuta chinensis seed and Eucommia ulmoides bark extracts, two traditional Chinese medicine (TCM) remedies, have shown promising healthspan-extending effects in Caenorhabditis elegans. In this study, RNA-seq analysis of aged worms treated with these extracts revealed significant transcriptomic alterations. Gene ontology and KEGG pathway analyses indicated upregulation of genes involved in immune defense, lysosomal function, and protein homeostasis, which may underlie the shared phenotype of enhanced stress resistance and lifespan extension. Beyond these effects, C. chinensis further improved multiple health parameters. Consistent with its broad spectrum of phenotypes, C. chinensis induced extensive transcriptomic remodeling involving over 3000 differentially expressed genes. Modulating collagen-, unc-, and muscle-related genes may explain improved locomotion, while upregulation of mec genes could contribute to enhanced mechanosensation. Notably, far-3, encoding a fatty acid- and retinol-binding protein, was upregulated more than 150-fold, and RNA interference assays demonstrated that FAR-3 is necessary for C. chinensis-induced healthspan improvement. Furthermore, C. chinensis influenced genes linked to antagonistic pleiotropy and insulin-like signaling, suggesting a systemic, hormesis-driven reprogramming of aging processes. Together, these findings uncover both shared and distinct molecular mechanisms through which C. chinensis and E. ulmoides promote healthspan in C. elegans.

Down syndrome (DS) is a common and recognizable genetic condition. Altered neurodevelopmental programs caused by trisomy 21 lead to the hallmark intellectual disability in early life. The increased lifespan of individuals with DS in the latter half of the twentieth century revealed the emergence of Alzheimer's disease (AD) earlier and with a higher prevalence in individuals with DS than in the general population. Thus, neuropathology in DS progresses along a continuum from prenatal disruptions to the manifestations of age-related conditions and AD. This review discusses our current understanding of the mechanisms of altered neurodevelopment and the precocious onset of AD in DS. We highlight the gaps in our understanding of how neurodevelopment and neurodegeneration are linked and describe how advancements in molecular technology and computational modeling are revealing molecular neuropathology in DS across the lifespan.

The global rise in the aging population, intensified by the COVID-19 pandemic, has increased loneliness, social isolation, and depression among older adults. This review aimed to examine the relationships between these psychological challenges and to assess the effectiveness of Information and Communication Technology (ICT)-based interventions in mitigating them.

UV induced skin aging also known photo-aging generally occurred due to accumulation of cellular damage brought on by external causes. Photoaging is the prime consequence of the repeated exposure of UVB. We focused on the isolation and identification of the UVB photo-protective metabolites from bamboo shoot (Phyllostachys pubescens). As the edible part, bamboo shoot is widely recognized and has been studied to evaluate different biological activities but evaluation of the UVB photo-protective activity on skin fibroblast is not done yet. Isolation of UVB photo-protective metabolites on human dermal fibroblast cells (NHDF-Ad) of bamboo shoot methanolic extract yields three compounds. The structure of these three compounds was determined by using NMR and HR-ESI-MS as 2,3-dihydroxypropyl 9-octadecenoate (1) 2,3-dihydroxypropyl tridecanoate (2) and 2,3-dihydroxypropyl undecanoate (3). These isolated compounds were also tested for the UVB photo-protection. Isolated compounds showed no obvious cytotoxicity until the concentration 10 μg/mL. Among all isolated compounds, compound-1 showed the strongest photo-protective activity. All these isolated compounds at different concentrations, increased the cell viability of UVB irradiated NHDF-Ad cells without any cytotoxicity. The crude extract and the isolated compounds were tested for anti-inflammatory activity in mouse leukemic monocyte (RAW 264) cells and all of them reduced NO production at non-cytotoxic concentration and reduced the expression of the inflammatory genes cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). The present study is the first to explore the isolation and identification of UVB photo-protective metabolites from bamboo shoot and the contributory compounds to be further utilized in the cosmeceutical industry.

Biological aging varies across individuals and tissues, influencing chronic diseases, including heart failure (HF). Emerging proteome techniques enable quantification of organ-specific aging acceleration (OAA), but whether OAA relates to HF severity and differs by sex remains unclear. We aim to assess the sex-related association between OAA of heart, artery and kidneys and HF severity, and to investigate relevant cardiometabolic risk factors of organ aging.

Functional independence is the basis for healthy ageing and quality of late life. However, evidence on how healthy lifestyle factors and social determinants of health affect longevity in independence remains limited, particularly regarding sex differences. We aimed to examine the associations of these factors with life expectancy with and without dependency, and to assess whether such effects differ by sex.

Hemokinin-1 (HK-1) regulates several processes in the central and peripheral nervous systems, including musculoskeletal functions; however, its involvement in age-related motor coordination and muscle strength remains unknown. Therefore, these were investigated here with HK-1-deficient mice together with the expression patterns in the mouse and human motor coordination centers. Tac4 gene expression, encoding HK-1, was detected by RNAscope, and its age-dependent changes in the cerebellum and soleus muscle were analyzed by qPCR. The rotarod and static rod tests were used to measure motor coordination, while the horizontal bar and grid tests assessed muscle strength in 3-4 (young), 12 (middle-aged), and 18-month-old (old) C57BL/6 wildtype (WT) and HK-1-deficient male and female mice. HK-1 mRNA was abundant in motor cortices, basal ganglia, and cerebellum, showing a significant increase with age. Motor coordination gradually declined with aging in WT mice of both sexes. This age-dependent reduction in motor coordination was significantly enhanced by HK-1 deficiency in middle-aged males but not females. Additionally, muscle strength was also remarkably worse in old WT mice, with a significantly greater decline in males. HK-1 deletion resulted in improved muscle strength in middle-aged male mice, but interestingly worsened function in the old groups of both sexes. HK-1 exerts age- and sex-dependent effects on motor coordination with a predominantly protective action on aging-induced decline in males. This might be explained by its high expression in all motor regions of the brain. Meanwhile, its function in regulating muscle strength is more complex, with a protective role only evident in old age.

Telomerase, crucial for maintaining telomere integrity and genomic stability, is typically silenced in somatic cells with advancing age. In this study, we identify circHERC1 as a regulator of telomerase reverse transcriptase (TERT) transcription. Specifically, circHERC1 binds to the TERT promoter, facilitating the recruitment of RNA polymerase II and c-Fos, thereby activating TERT expression. Notably, circHERC1 expression exhibits a decline with age, which correlates with reduced telomerase activity. Restoration of circHERC1 expression enhances telomerase activity, promotes telomere elongation, and reverses aging-associated phenotypes. Furthermore, delivery of circHERC1 using adeno-associated virus vectors or extracellular vesicles effectively restores telomerase activity, preserves telomere integrity, and mitigates senescence. This intervention leads to improvements in cognitive function, physical performance, and a reduction in inflammation. These findings highlight the important role of circHERC1 in telomerase regulation and the aging process, positioning it as a potential therapeutic target for antiaging interventions.

Global population aging highlights frailty as a critical health concern, yet its genetic basis remains poorly understood. We employed Mendelian randomization (MR) and National Health and Nutrition Examination Survey (NHANES) to examine causal relationships between frailty index (FI) and 36 urological diseases, investigating shared genetic mechanisms. The FI was calculated using genome-wide association data, and bidirectional MR analysis with multiple statistical methods was applied to investigate causal links between FI and 36 urological diseases. Complementary observational analyses using NHANES and generalized summary MR validation were conducted, followed by genetic correlation assessments, genome annotation, and metabolomic explorations to identify mediating pathways. MR analysis identified a significant causal association between FI and renal tubule-interstitial disease, chronic kidney diseases (CKDs), diabetes with renal complications, renal failure, and acute kidney injury. Reverse MR analysis indicated a bidirectional causal relationship between FI and acute renal failure, as well as CKD and type 1 diabetic kidney disease. NHANES data confirmed FI as an independent risk factor for CKD and renal failure. Genetic linkage analyses identified strong regional correlations between FI and CKD/renal failure within the chromosome 6 locus (31,571,218-32,682,664). Genome-wide analyses uncovered 103 novel single-nucleotide polymorphism with pleiotropic effects on the frailty-urinary disease relationship. Mediation analyses implicated the complement pathway (C2), SLITRK1, and 4-methylhexanoylglutamine as putative mediators of FI effects on CKD and kidney failure. This study elucidates the bidirectional causal relationship between frailty and CKD, while identifying novel genetic variants and metabolic pathways. These findings provide a molecular basis for developing personalized therapeutic strategies targeting both frailty and urological disorders.

Aging profoundly compromises immune homeostasis, leaving elderly individuals highly vulnerable to inflammatory diseases. Central to this process is macrophage dysfunction, as macrophages progressively shift toward a pro-inflammatory M1 phenotype with excessive inflammation and impaired phagocytosis. This diminished phagocytic capacity not only weakens host defense but also limits the therapeutic efficacy of nanoparticle (NP)-based antisenescence interventions due to the reduced cellular uptake. Therefore, reversing cellular inflammation and restoring the function of senescent macrophages are crucial in treating inflammatory diseases in the elderly. This article presents an M1-targeted NP to rejuvenate aged macrophages and restore their phagocytosis. Gold nanocages (AuNCs) were camouflaged with

Porphyromonas gingivalis (P. gingivalis) functions as a catalyst bacterium in the development of periodontitis, and the serum antibody level against P. gingivalis is considered a surrogate marker for the activity level of periodontopathic microbiota. The chronic systemic inflammation induced by P. gingivalis elevates the risk of various systemic and neurodegenerative disorders, including atherosclerosis, diabetes, and Alzheimer's disease. Although the connection between human microbiota and age-related macular degeneration (AMD) remains relatively unexplored, it is noteworthy that AMD shares risk factors and etiological mechanisms with diseases related to P. gingivalis. To investigate the potential association between periodontopathic microbiota and AMD occurrence, we conducted a candidate microbe approach case-control study in the Third National Health and Nutrition Examination Survey (NHANES-III). Our hypothesis was tested by examining the correlation between serum P. gingivalis immunoglobulin G (IgG) levels and AMD. Comparing the lowest IgG category (≤ 57 enzyme-linked immunosorbent assay units (EU)) with higher categories revealed escalating risks: the second higher category (58-65 EU) conferred almost a 30% increased risk (odds ratio (OR) = 1.28, 95% confidence interval (CI): 1.17 to 1.4), the third higher category (66-119 EU) conferred nearly a 60% increase (OR = 1.58, 95% CI: 1.46 to 1.72), and the highest category (> 119 EU) conveyed over a two-fold risk (OR = 2.04, 95% CI: 1.62 to 2.58) of early AMD. Consistent with current evidence that host nutritional status critically modulates immune responses to the microbiota and influences human health, our analysis indicates that sustaining elevated serum levels of lutein/zeaxanthin (≥ 0.35 µmol/L or ≥ 20 µg/dL) might potentially mitigate the P. gingivalis-related AMD risk by as much as 35% (P for interaction < 0.0001). Although the precise mechanism requires additional exploration, these findings suggest a connection between nutrients related to eye health and humoral response to P. gingivalis.Significance statement: While humoral response to P. gingivalis indicates an impact on age-related macular degeneration, nutritional factors may modulate the associated risk.

Biological age (BA) and its residual relative to chronological age are popularly used to quantify individual aging. Although these residuals independently predict age-related health outcomes, conventional BA measures often lack robustness in heterogeneous populations, and their residuals are not directly derivable in clinical practice. To address these limitations, we introduce the Gompertz law-based residual (GOLD-R) framework, a method designed to directly estimate BA residuals and optimized for cross-sectional data. We demonstrated the applicability and robustness of GOLD-R across multiple data types and populations. First, training on DNA methylation data from the EWAS Data Hub, the framework outperformed established epigenetic clocks in predicting mortality in a pan-cancer dataset. Then, applied to UK Biobank proteomics data, GOLD-R generated organismal and organ-specific aging measures that proved more robust than conventional age-prediction approaches in forecasting incident diseases and mortality. Finally, extending the analysis to clinical biomarkers using the NHANES and HRS, we found that GOLD-R residuals, derived from clinical biomarkers, surpassed those from both epigenetic and phenotypic clocks in performance. In summary, our findings establish GOLD-R as a robust algorithm for biological age estimation, providing a practical tool for both research and clinical applications.

Circulating non-cellular factors, such as plasma proteins, contribute to various features of aging. To determine the impacts of endogenous circulating factors on human age-related bioenergetic decline, we treated primary human fibroblasts with serum samples representing the adult life-course. Our results demonstrate that the maximal mitochondrial bioenergetic capacity of fibroblasts treated with serum is negatively correlated with the chronological and epigenetic age of the serum donor. Using targeted proteomics, we identified plasma proteins associated with the bioenergetic effects of serum. We then utilized elastic net, a linear regression modeling technique, to derive a novel proteomic signature of age-related mitochondrial differences. MitoAge is a 25-protein signature of age-related mitochondrial health that predicts the systemic bioenergetic effects of circulating factors and is related to differences in physical function across human aging. Signatures that report on cellular hallmarks of aging, such as mitochondrial function, represent a new generation of mechanistically-informed biomarkers of biological aging.

Microbiota-derived metabolites have emerged as key regulators of longevity. The metabolic activity of the gut microbiota, influenced by dietary components and ingested chemical compounds, profoundly impacts host fitness. While the benefits of dietary prebiotics are well-known, chemically targeting the gut microbiota to enhance host fitness remains largely unexplored. Here, we report a novel chemical approach to induce a pro-longevity bacterial metabolite in the host gut. We discovered that wild-type Escherichia coli strains overproduce colanic acids (CAs) when exposed to a low dose of cephaloridine, leading to an increased life span in the host organism Caenorhabditis elegans. In the mouse gut, oral administration of low-dose cephaloridine induced transcription of the capsular polysaccharide synthesis (cps) operon responsible for CA biosynthesis in commensal E. coli at 37 °C, and attenuated age-related metabolic changes. We also found that low-dose cephaloridine overcomes the temperature-dependent inhibition of CA biosynthesis and promotes its induction through a mechanism mediated by the membrane-bound histidine kinase ZraS, independently of cephaloridine's known antibiotic properties. Our work lays a foundation for microbiota-based therapeutics through chemical modulation of bacterial metabolism and highlights the promising potential of leveraging bacteria-targeting drugs in promoting host longevity.

Early-life psychosocial stress is increasingly recognized as a contributor to accelerated biological aging and health disparities, yet its impact during young adulthood remains underexplored. Existing studies often focus on one or two dimensions of stress exposure and rely on retrospective assessments. Utilizing data from a longitudinal cohort initiated in 1989, we aim to examine the impact of early life psychosocial stress on accelerated aging in young adulthood, as well as its potential contribution to health disparities between Black and White Americans. Participants included 470 individuals (223 Black and 247 White Americans) with DNA samples collected at age > 20 years. Psychosocial stress exposures in the first 20 years of life were assessed prospectively using validated instruments across individual, family, and neighborhood domains. DunedinPACE, a novel biomarker of the pace of aging, was calculated from DNA methylation data generated from peripheral blood using the Illumina 450K array. The joint effect of early life psychosocial factors on DunedinPACE and the relative importance of each stressor were estimated using the Weighted Quantile Sum (WQS) approach. Mediation analysis was conducted to evaluate the contribution of early life stress to racial disparities in aging.

The mechanisms underlying skeletal muscle ageing, whilst poorly understood, are thought to involve dysregulated micro (mi)RNA expression. Using young and aged rat skeletal muscle tissue, we applied high-throughput RNA sequencing to comprehensively study alterations in miRNA expression occurring with age, as well as the impact of caloric restriction (CR) on these changes. Furthermore, the function of the proteins targeted by these age- and CR-associated miRNAs was ascertained. Numerous known and novel age-associated miRNAs were identified of which CR normalised > 35% to youthful levels. Our results suggest miRNAs upregulated with age to downregulate proteins involved in muscle tissue development and metabolism, as well as longevity pathways, such as AMPK and autophagy. Furthermore, our results suggest miRNAs downregulated with age to upregulate pro-inflammatory proteins, particularly those involved in innate immunity as well as the complement and coagulation cascades. Interestingly, CR was particularly effective at normalising miRNAs upregulated with age, rescuing their associated protein-coding genes but was less effective at rescuing anti-inflammatory miRNAs downregulated with age. Lastly, the effects of a specific miRNA, miR-96-5p, identified by our analysis to be upregulated with age, were studied in cultured C2C12 myoblasts. We demonstrated miR-96-5p to decrease cell viability and markers of mitochondrial biogenesis, myogenic differentiation and autophagy. Overall, our results provide novel information regarding how miRNA expression changes in skeletal muscle, as well as the potential functional consequences of these changes and how they are ameliorated by CR.

Brain aging is characterized by progressive structural and functional deterioration, leading to cognitive decline and impaired social functioning. A key factor in this process is the age-related decline in adult neurogenesis, particularly in the hippocampal dentate gyrus, which is linked to deficits in learning, memory, and increased social anxiety. Oxytocin, a neuropeptide synthesized in the hypothalamus, regulates social behavior, cognition, and emotion by acting on brain regions including the hippocampus. Importantly, oxytocin levels decrease with age, potentially contributing to cognitive impairment. Here, we examined whether chronic intraperitoneal oxytocin administration could attenuate cognitive decline in aged mice. Twelve-month-old mice received oxytocin injections (0.5 mg/kg) five times weekly for 13 weeks. Behavioral testing at 12 weeks of treatment using the object-place recognition task showed enhanced spatial learning and recognition memory in oxytocin-treated mice compared with saline controls. Immunohistochemistry revealed significantly increased doublecortin (DCX)-positive cells in the hippocampus, indicating enhanced neurogenesis. Furthermore, oxytocin treatment upregulated the expression of glutamate receptor 1 (GluR1) and N-methyl-D-aspartate receptor subunit 2B (NMDAR2B), which are markers of synaptic plasticity. These findings suggest that chronic oxytocin treatment is associated with enhanced neurogenesis and synaptic plasticity, which may contribute to improved cognition in aged mice. Our results support oxytocin as a potential therapeutic agent for age-related cognitive decline.

Mice overexpressing Sirt6 or fed a caloric restriction (CR) diet live longer with improved health. CR increases Sirt6 levels, and its beneficial effects are mediated by the gasotransmitter H

Aging challenges healthcare globally. Fish and shellfish (fish-shellfish) are substantial providers of omega-3 fatty acids, which may mitigate multiple aging-related diseases. However, the relationship between fish-shellfish consumption and biological aging (BA) remains incompletely elucidated.

Epigenetic clocks are increasingly proposed as surrogate endpoints in aging trials, yet their short-term behavior in healthy older adults is not well characterized. We analyzed DNA methylation at baseline, year 1, and year 2 in 899 COSMOS-Blood participants (mean age 70.0; 50% women), deriving Horvath, Hannum, PhenoAge, and GrimAge clocks (original and principal component [PC] versions) and DunedinPACE. Epigenetic age acceleration was computed by regressing each clock on chronological age. Chronological age was independent of epigenetic age acceleration and DunedinPACE. PC clocks exhibited substantially smaller 2-year change variance than original clocks, indicating greater measurement stability. Linear mixed-effects models showed statistically detectable but numerically small annual epigenetic age acceleration increases for several PC clocks (e.g., PC Horvath + 0.14 year/year; PC GrimAge + 0.16 year/year), whereas DunedinPACE did not change significantly. Baseline values strongly predicted the same measure at years 1 and 2 (R

Background: A growing body of research has found that neural representations of task stimuli are less distinctive in older adults relative to younger adults, a phenomenon known as age-related neural dedifferentiation. The original funding period of the Michigan Neural Distinctiveness (MiND) study aimed to investigate the scope, causes, and consequences of neural dedifferentiation. We recruited a sample of healthy older adults (aged 65+ years) and younger adults (aged 18-29) and administered fMRI (to measure neural distinctiveness), MRS (to measure GABA), and substantial behavioral testing (to measure cognitive, motor, and sensory functions). We found that neural distinctiveness was lower in older vs. younger adults, that reduced GABA was associated with this neural dedifferentiation, and that behavioral performance was associated with both neural dedifferentiation and reduced GABA. In this current paper, we describe the rationale and methods for the second phase of the MiND study, in which we: 1) investigate age-related trajectories of change in neural distinctiveness, GABA, and behavior longitudinally; and 2) explore how neural differentiation is related to Alzheimer's disease pathology. Methods: In the longitudinal aim, we are re-contacting participants from the original MiND funding period. We aim to test participants at two additional time points approximately 3-5 years apart using the same assessments (fMRI, MRS, and behavioral tests). We plan to have approximately 150 participants with two time points and 100 participants with three time points. We will also recruit new participants who will be tested twice, approximately 3-5 years apart in order to further increase our sample size and power. We predict to have approximately 250 new participants with one time point. We will then test whether neural distinctiveness, GABA, and behavioral performance decline longitudinally with age. To explore neural dedifferentiation in Alzheimer's disease pathology, we plan to recruit 100 MCI participants who are already undergoing PET imaging to determine amyloid beta and tau burden. These patients are then completing our fMRI, MRS and behavioral testing sessions so that we can examine associations between Alzheimer's pathology and our measures of neural distinctiveness, GABA, and behavior. Discussion: This line of research has the potential to lead to new insights into how aging affects the mind. In particular, it could shed light on the role that neural dedifferentiation, GABA, and Alzheimer's disease pathology play in age-related behavioral declines. Trial Registration: This study was registered with the ISRCTN registry on November 11, 2024. The registration number is ISRCTN16528440. Keywords: aging, neural distinctiveness, GABA, Alzheimer's disease, functional MRI, MR spectroscopy, cognition

Aging trajectories are influenced by modifiable risk factors, and prior evidence has hinted that multilingualism may have protective potential. However, reliance on suboptimal health markers, small samples, inadequate confounder control and a focus on clinical cohorts led to mixed findings and limited applicability to healthy populations. Here, we developed biobehavioral age gaps, quantifying delayed or accelerated aging in 86,149 participants across 27 European countries. National surveys provided individual-level positive (functional ability, education, cognition) and adverse (cardiometabolic conditions, female sex, sensory impairments) factors, while country-level multilingualism served as an aggregate exposure. Biobehavioral factors predicted age (R

Aging is a complex biological process marked by progressive physiological decline and increased disease vulnerability. Single-cell RNA sequencing offers unprecedented resolution for studying aging, yet isolating aging-related signatures remains challenging because gene expression is primarily shaped by other factors such as cell type, tissue, and sex. We present ACE (Aging Cell Embeddings), an explainable deep generative framework that disentangles aging-related gene expression changes from background biological variation. ACE employs two latent representations: one capturing aging-related signatures and another representing non-aging-related variation in the data. Through explainable AI, ACE identifies key genes and pathways associated with aging amid dominant non-aging-related variations. Applied to large-scale mouse, fly, and human datasets, ACE uncovers aging signatures both within specific tissue-cell-type contexts and across all tissues and cell types, enabling accurate prediction of biological age. Moreover, ACE identifies aging genes conserved across species, highlighting its ability to reveal shared biological mechanisms of aging. Experimental RNAi knockdowns in C. elegans validate ACE\'s findings, confirming its ability to prioritize novel aging genes affecting lifespan. ACE reveals key pathways involved in proteostasis, immune regulation, and extracellular matrix remodeling, and identifies Uba52 through the cross-species model as an important aging gene, whose knockdown in C. elegans significantly shortens lifespan. By providing interpretable and generalizable aging embeddings, ACE establishes a foundation for cross-species single-cell aging studies and translational geroscience.

Injuries characterizing recent military service, such as traumatic brain injury and posttraumatic stress disorder, are linked to accelerated biological aging. If recent veterans have accelerated aging, they might also show early onset of aging-related phenotypes, such as frailty. In this study, we examined the prevalence of frailty and associations with biological aging using data from 1,654 post-9/11 veterans, who were followed for an average of 12.6 years. Biological aging was assessed using DunedinPACE and frailty was assessed using 11 years of Jen Frailty Index scores from electronic health records. We found a high proportion of frailty-25.5% of the post-9/11 veterans met criteria for frailty during the study. This is roughly double the prevalence among community-dwelling older adults, despite the cohort's average age of 50.2 years at study end. Veterans with faster aging had higher initial frailty scores (β, 0.21; 95% CI, 0.15-0.27), higher peak frailty scores (β, 0.24; 95% CI, 0.18-0.30), and larger increases in frailty scores over time (β, 0.15; 95% CI, 0.09-0.21, all ps < .001). Faster aging was associated with a 62% (95% CI, 44%-82%) greater rate of incident frailty over the follow up while accounting for demographics, baseline health, and smoking. These results suggest post-9/11 veterans are at risk of early onset frailty and this increased risk could be explained by accelerated rates of biological aging. Future research should replicate these results in nationally representative samples of post-9/11 veterans and explore whether screening for frailty should be implemented at younger ages for veterans.

The biological aging process exhibits heterogeneous effects on different tissues, manifesting as tissue-specific variations in structural integrity and functional decline. Previously developed models are able to predict age from DNA methylation in the blood and the difference between estimated epigenetic age and chronological age is suggested to reflect accelerated or decelerated biological aging. While most prior studies have focused on the association between epigenetic age acceleration and global cortical thickness, it remains to be determined whether biological aging varies across specific cortical regions. This study aimed to assess associations between epigenetic age acceleration and regional cortical thickness, brain age gaps, as well as intra- and interindividual neuroanatomical heterogeneity in 756 participants of the BiDirect Study, including 430 participants from the general population and a cohort of 326 individuals with depression. Epigenetic age was estimated from whole blood DNA methylation data using the GrimAge algorithm. We observed an association of epigenetic age acceleration with cortical thinning across almost all cortical regions, suggesting a global association without regional confinement. This result was additionally underpinned by showing that accelerated epigenetic aging was also associated with increased interindividual neuroanatomical heterogeneity in contrast to a lack of association between epigenetic aging acceleration and intraindividual neuroanatomical heterogeneity. Accelerated epigenetic aging was furthermore paralleled by higher neuroimaging-based brain age gaps, suggesting at least partly shared aging processes. Together, these findings highlight that accelerated epigenetic aging reflects a global rather than region-specific neuroanatomical aging process, linking molecular and structural markers of brain aging and underscoring the potential of epigenetic clocks as biomarkers for brain health and neurodegenerative risk.

Metabolic rewiring helps to construct efficient microbial cell factories; however, these cells suffer from metabolic stress during long-term fed-batch fermentation. Thus, the construction of robust cells is vital for industrial application of microbial cell factories at the laboratory scale. Here, we systematically characterized longevity factors and pathways for biosynthesis of the diterpenoid sclareol and found that weakening nutrient-sensing pathways and enhancing mitophagy synergistically improved sclareol production by 70.3% (20.1 g/L with a yield of 0.046 g/g glucose). Further enhancing central metabolism improved sclareol production to 25.9 g/L with a yield of 0.051 g/g glucose, the highest production achieved in microbes. Omics data demonstrated that the extension of chronological lifespan by upregulating the expression of lifespan-related genes automatically remodeled the cellular metabolism and improved overall cellular robustness for efficient chemical biosynthesis. We also showed that our strategy significantly improved the biosynthesis of other products such as sesquiterpene β-elemene and phenolic acids. Therefore, this study may provide metabolic connections between cell aging and biosynthetic capacity.

Biological age, which may be older or younger than chronological age due to factors such as genetic predisposition, environmental exposures, serves as a meaningful biomarker of aging processes and can inform risk stratification, treatment planning, and survivorship care in cancer patients. We propose EpiCAge, a multimodal framework that integrates epigenetic and phenotypic data to improve biological age prediction. Evaluated on eight internal and four external cancer cohorts, EpiCAge consistently outperforms existing epigenetic and phenotypic age clocks. Our analyses show that EpiCAge identifies biologically relevant markers, and its derived age acceleration is significantly associated with mortality risk. These results highlight EpiCAge as a promising multimodal machine learning tool for biological age assessment in oncology.

Peripheral artery disease (PAD) has historically been regarded as an age-related vascular disorder; however, recent attention has shifted toward the myopathic components of the disease. Conventional interventions, such as revascularization, have had limited success in reversing muscle pathology or preventing adverse outcomes like amputation. Hypoxia-inducible factors (HIFs) are key regulators of cellular responses to ischemia, including the promotion of angiogenesis and glycolysis. While pharmacological stabilization of HIF proteins represents a promising therapeutic strategy, its efficacy is diminished in aged muscles due to their intrinsically low basal HIF expression. We hypothesized that long noncoding RNAs (lncRNAs) might enhance the hypoxic response in aged muscle through post-transcriptional regulation of HIF expression. Our study identified Neat1, a long noncoding RNA, as a critical mediator of the hypoxia-induced stress response, including upregulation of Hif1alpha;. In a murine hindlimb ischemia model, Neat1 knockout mice exhibited extensive necrosis following femoral artery ligation, whereas Neat1 overexpression conferred protection against ischemic injury. Mechanistically, we found that Neat1 regulates the stability of Hif1a mRNA, as Hif1a transcript levels were significantly reduced in Neat1-deficient muscle cells. Importantly, aged muscles displayed a blunted hypoxic response due to diminished Hif1a expression, an effect that was reversed through Neat1 overexpression, resulting in improved resistance to ischemic damage. In summary, our findings highlight Neat1 as a novel regulator of muscle adaptation to hypoxia in aging. Enhancing Neat1 expression may represent a promising therapeutic strategy for improving ischemic outcomes in patients with peripheral artery disease.

Aging ovaries exhibit increased oxidative stress, contributing to infertility through cellular and hormonal changes. Nuclear factor E2-related factor 2 (NRF2), a key transcription factor, regulates antioxidant responses. This study investigates NRF2 in dormant (primordial) ovarian follicles to determine if NRF2 activation accounts for primordial follicle activation. We show that trigonelline (TRG) transiently activates NRF2, promoting primordial follicle activation in the non-hormonal phase of follicle development. Indeed, TRG enhances egg quality in aged mice. In human ovarian tissues, TRG increased activation of primordial follicles, resulting in more primary and secondary follicles. Mechanistically, TRG induces NRF2 nuclear translocation and upregulates NRF2-responsive genes, including

Sarcopenia (SP) is an age-related disorder characterized by progressive loss of muscle strength, mass, and limb dysfunction, severely compromising the quality of life and life safety in older adults. With the global aging population, the incidence of this disease has been escalating, posing a significant public health challenge. Preclinical studies have demonstrated that acupuncture effectively mitigates muscle loss in rats; however, the field currently lacks robust randomized controlled trials (RCTs), marked by limitations such as the absence of sham acupuncture controls, multicenter designs, and standardized outcome metrics. Therefore, this study integrates acupuncture with exercise therapy, incorporating the following design highlights: A multicenter approach to enhance research reliability; A control group receiving sham acupuncture combined with exercise to eliminate the placebo effect; The most comprehensive and validated set of outcome measures to ensure study rigor and expand the conceptual framework for sarcopenia assessment. This research aims to provide robust evidence for acupuncture as an effective adjuvant therapy for SP. The study has been registered with the International Traditional Medicine Clinical Trials Registry Platform (ITMCTR2024000374).

Klotho (Kl) is an anti-aging protein primarily produced in the kidney and the choroid plexus (CP, where it regulates cerebrospinal fluid composition and exerts neuroprotective effects. Here, we investigated the age-dependent consequences of a CP-specific Kl deletion on CP structure and function using mice lacking KL exclusively in CP epithelial cells (Kl{Delta}CP). In control mice, aging markedly disrupted CP architecture and cilia organization both in the lateral (LV-CP) and fourth ventricle (FV-CP). While CP-specific Kl deletion alone caused no major structural changes it induced region- and age-dependent calcification: FV-CP calcification increased in both aged and young Kl{Delta}CP mice, whereas LV-CP calcification emerged only in older Kl{Delta}CP mice. Proteomic analysis of the CP and hippocampus revealed mild molecular alterations, suggesting compensatory mechanisms that preserve structural and functional stability despite calcium dysregulation. Consistently, Kl{Delta}CP mice exhibited no significant behavioral or cognitive deficits. Overall, Kl deficiency sensitizes the CP to age-related calcification prior to overt structural decline, revealing a region-specific and functional link between Klotho, calcium imbalance, and brain aging.

Osteoporosis (OP), characterized by progressive bone loss, is closely linked to ferroptosis-induced senescence of bone marrow mesenchymal stem cells (BMSCs). N6-methyladenosine (m

The world population is aging at an alarming rate, which is an amalgamation of various causative factors. A significant factor contributing to this phenomenon is the dramatic change in the social conditions of the people such as the life style behavioral change, a sedentary pattern of living and a huge dependence on food lacking substantiated nutrition. It has become important to understand the intricate relationship between aging, epigenetics, and nutrition in order to sustain the best possible health and well-being. Aging encompasses numerous molecular, cellular, and systemic changes and is a multifaceted process that involves altered nutrition sensing. Epigenetic factors influence aging. These epigenetic changes affect genes linked to aging and age-related illnesses. A significant obstacle is the identification of key epigenetic markers that can predict health and aging rate. This could help in the prevention of age-related illness and slow the aging process. The precise biochemical mechanisms underlying the interplay between diet and nutrition in epigenetics are still unknown. It is therefore necessary to determine the best food regimens which would lead to epigenetic changes that would help in age gracefully. This research aims to identify a few selected nutrients and their possible effects on epigenetic modulations that might lead to delayed aging.