Aging & Longevity

Interest in fasting-based diets to improve metabolic health is growing. Caloric restriction (CR) with one meal per day includes an extended fasting component that contributes to its metabolic and longevity benefits, yet the role of fasting within CR remains unclear. Here, we compare CR with a fasting-refeeding-fasting (FRF) regimen while controlling food intake and fasting duration. Changes in plasma insulin and free fatty acids, hepatic mTOR signaling and ketogenesis, metabolic rhythms, and...

Individuals of the same chronological age differ in biological aging, and scalable, noninvasive markers are needed. The deep learning-derived retinal age gap (RAG) is a promising measure of retinal aging, but its associations with real-world health determinants remain unclear. We developed a multi-task model to predict retinal age using 29,530 fundus images from 7535 participants in a health screening cohort and evaluated RAG in cohort A for lifestyle, socioeconomic, and systemic factors (n =...

Aging in mammals is characterized by widespread yet coordinated epigenetic alterations. However, integrative analyses of DNA methylation and gene expression in dogs remain largely unexplored, particularly within genetically homogeneous single-breed populations. To elucidate the molecular signatures of canine aging, we profiled the genome-wide methylome and transcriptome of clinically healthy beagle dogs representing three distinct age groups. Global methylation levels were highly conserved...

Pigeons (Columba livia) rely heavily on spatial cognition for navigation. As such, this species is commonly used to investigate the neural correlates of spatial behaviours in birds, particularly the hippocampus and septum. As this species can live for decades when housed in the laboratory, several studies have recently used pigeons to examine long-term effects of aging on the brain, a concept that is less well-understood in birds compared to mammals. Studies assessing age-related structural...

Over the past two decades, human aging has been characterized across DNA methylation, transcriptomic, proteomic, and clinical modalities, yet no benchmark evaluates whether AI systems can interpret these heterogeneous data types in the context of aging biology. We introduce LongevityBench, an open suite of 17 tasks spanning five biodata domains, and use it to assess 18 frontier AI systems from six developer teams. Despite recent advances in AI, no single model dominates all tasks, with...

CONCLUSIONS: Hearing loss was associated with adverse cognitive trajectory membership and modified the association between baseline cognitive function and moderate decline. The association with rapid decline was particularly consistent across sensitivity analyses. These findings support considering hearing status when assessing cognitive aging risk, while further studies should determine whether hearing interventions alter cognitive trajectories.

Skin ageing is a multidimensional process driven by the convergence of intrinsic biological changes and cumulative environmental stressors. These alterations progressively disrupt epidermal barrier integrity, compromise extracellular matrix (ECM) homeostasis, and establish a chronic low-grade inflammatory state that significantly impairs tissue repair. Consequently, aged skin represents a particularly vulnerable substrate for delayed or chronic wound healing, a condition that disproportionately...

CONCLUSIONS: The majority of the 5Ms are covered in the curriculum, though notable gaps remain in several subcategories. Recommendations include strengthening preclinical exposure to concepts students will encounter in clinicals, such as pharmacology and delirium. This is the first known published study to explicitly identify how the 5Ms are covered in a U.S. undergraduate medical school curriculum.

ObjectiveThis study examines associations between neighborhood socioeconomic disadvantage during adolescence and early adulthood and chronic disease accumulation in mid- to late life.MethodsUsing Panel Study of Income Dynamics data linked to U.S. Census and American Community Survey data, we identify four trajectories of neighborhood disadvantage, namely persistent disadvantage, increasing disadvantage, decreasing disadvantage, and persistent advantage, and estimate their associations with...

Hutchinson‑Gilford progeria syndrome (HGPS) is a rare premature aging disorder caused by mutations in the LMNA gene. High mobility group A1 (HMGA1) exhibits differential expression patterns across aging models. However, its roles and mechanisms in aging remain unclear. Here, we show a positive correlation between HMGA1 and the heterochromatin protein HP1β in multiple tissues of Lmna^(G609G/G609G), a classic genetic mouse model of HGPS to recapitulate typical premature aging features, and...

Intracellular pathogens are ideal candidates for modelling the pathophysiology of chronic infection, as they hide within host cells and avoid immune clearance by reshaping cellular fate. This study unveils how the intracellular pathogen Mycobacterium abscessus (Mab) reprograms alveolar macrophages towards a senescent state -a multifaced phenotype marked by proliferative arrest, distinctive morphological shifts, activation of DNA damage signalling cascade, and secretion of senescence-associated...

Chronic activation of the cGAS-STING pathway drives inflammaging and cellular senescence. Although nuclear envelope (NE) barrier failure leading to cytoplasmic chromatin leakage is a key trigger, the molecular mechanisms governing STING activity at the NE during aging remain poorly understood. Here, we identify lamin A/C (LMNA) as a critical NE scaffold that orchestrates STING regulation by recruiting both STING and Casein Kinase 2 (CK2α). We demonstrate that LMNA facilitates the phosphorylation...

Cellular senescence is a state of irreversible cell cycle arrest triggered by telomere erosion, persistent DNA damage or chronic stress. The accumulation of senescent cells disrupts tissue function and contributes to aging and disease. Here, we employ mass spectrometry-based proteomics to systematically interrogate dynamic proteome changes at multiple levels during the progression of replicative cellular senescence. We demonstrate that proteome changes during senescence occur in a coordinated...

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Sex differentially shapes aging, neurodevelopment and neurodegenerative diseases such as Alzheimer's disease (AD). However, most biological aging clocks (artificial intelligence-predicted age minus chronological age) were trained on sex-pooled samples and implicitly assume sex invariance.Here we developed 38 sex-specific biological aging clocks across 15 organ systems. We first demonstrate the importance of sex-stratified training for constructing sex-specific healthy normative references and...

Age-related neurodegenerative diseases are characterized by progressive DNA damage in post-mitotic neurons against a backdrop of deteriorating circadian rhythms, yet the molecular link between these conjoined features of brain aging remains unclear. We propose the TyrRS cascade as that link: a signaling architecture in which the noncanonical nuclear functions of tyrosyl-tRNA synthetase (TyrRS/YARS1) schedule neuronal genome maintenance across the day through three coregulated streams,...

The accumulation of lipid droplets in microglia has been reported to increase in response to ageing and age-related diseases like Alzheimer's disease. The present study investigates changes in lipid droplet dynamics with increasing age in the mouse and the similarly sized long-lived rodent, the naked mole rat (Heterocephalus glaber). We show that the naked mole rat contains large amounts of microglial lipid droplets in the CA1 and CA3 region of the hippocampus with an age-dependent increase in...

Apolipoprotein E (APOE) genotype is the strongest genetic determinant of late-onset Alzheimer's disease (AD) risk. Of its three common isoforms, E4 increases AD risk and promotes inflammatory and metabolic dysregulation, whereas E2 is protective and is associated with altered lipid handling and immune function. Microglia express APOE in response to stress or injury and exhibit isoform-dependent transcriptional profiles, but the specific contribution of microglial APOE to these phenotypes remains...

N-terminal acetylation (NTA) is a ubiquitous eukaryotic post-translational modification catalyzed by Nα-acetyltransferases (NATs). Among the eight NAT families, the NatA complex-composed of the catalytic subunit NAA10 and auxiliary subunit NAA15-mediates N-terminal acetylation of ~40% of mammalian proteins. Pathogenic mutations in NAA10 or NAA15 disrupt NatA complex integrity or enzymatic activity, resulting in NAA10- or NAA15-related syndromes. Both disorders share overlapping clinical...