Aging & Longevity

Understanding the molecular basis of neurodegeneration requires a comprehensive map of the genome's protein-coding output. Although thousands of small open reading frames (ORFs) are translated in the human brain, proteomic evidence for their encoded microproteins (MPs) (≤150 amino acids (aa)) remains limited. Here, we present a brain MP atlas that integrates transcriptomics, mass spectrometry and deep-learning-predicted spectra across more than 600 postmortem frontal cortex samples with and...

Somatic mosaicism is increasingly recognized as a pervasive feature of the human brain and a potential contributor to neurological disease across the lifespan. Unlike germline variants, somatic variants arise post-zygotically and are unevenly distributed across regions, cell types and even individual neurons, enabling focal biological effects that can scale to network-level dysfunction. In this Review, we synthesize current evidence that developmental timing, clonal architecture and...

Sleep is increasingly recognised as a potentially modifiable factor in cognitive ageing, but evidence is often limited by cross-sectional designs, single sleep measures and global cognitive outcomes. This study examined whether multiple sleep characteristics (device-based and self-report) were associated with domain-specific cognitive function across repeated observations in community-dwelling adults aged 55 years and older. Adults aged ≥ 55 years were assessed at three time points over 2 years...

Tobacco smoking is a critical modifiable risk factor for age-related diseases and mortality. Although smoking cessation is known to improve health outcomes, whether smoking-induced biological aging is reversible upon cessation remains unclear. We investigated the associations of smoking status and cessation duration with epigenetic age acceleration (EAA) using multi-generational DNA methylation clocks. We analyzed data from 1,911 adults aged 50-84 years in the National Health and Nutrition...

Chronic occupational stress is increasingly recognized as a modifiable accelerator of biological aging, yet it remains underappreciated as a target of geroscience-informed public health intervention. This review reframes workplace stress as a life-course determinant of aging trajectories and introduces a translational framework that positions occupational environments as platforms for promoting healthy aging. Drawing on insights from the Semmelweis Study, a large longitudinal occupational...

Rapid population aging has markedly increased the exposure of elder humans to invasive mechanical ventilation (MV). Mounting evidence suggests that aging fundamentally alters pulmonary structure and stress responses, predisposing the aged lung to ventilator-induced lung injury (VILI). However, the biological basis of this heightened vulnerability remains insufficiently synthesized. The review was conducted in accordance with the PRISMA 2020 guidelines. To this end, PubMed, Web of Science, and...

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce major adverse cardiovascular events, all-cause mortality, and systemic inflammation in randomized controlled trials, with effect sizes exceeding those predicted from glycemic and weight-related improvements alone. The convergence of these findings with a maturing body of evidence linking metabolic dysfunction to accelerated epigenetic aging has prompted renewed interest in GLP-1 RAs as candidate gerotherapeutic agents. The present...

Physical multimorbidity and loneliness are increasingly recognised as public health concerns, but the nature of their potential relationships remains unclear. Here we report bidirectional associations between physical multimorbidity and loneliness in middle-aged and older adults and the mediating role of social inactivity. Longitudinal data from adults aged ≥45 years are analysed across 19 countries from five prospective cohorts: US Health and Retirement Study; English Longitudinal Study on...

This study investigated environmental justice by developing and comparing four contemporary urban segregation typologies (persistent exclusivity, persistent disadvantage, recent gentrification, and recent displacement-hosting) with historical Homeowners' Loan Corporation (HOLC) zones and 104 variables spanning the natural and built environments, pollution, environmental hazards, health, and disability. We applied principal component analysis to the 2010 and 2020 American Community Survey and the...

Aging is associated with impairments in cognitive flexibility, a key executive function supported by the medial prefrontal cortex (mPFC), yet the biological mechanisms underlying individual variability in age-related decline remain poorly understood. Here we investigated behavioral, ultrastructural, and proteomic correlates of cognitive inflexibility in mice across aging. Using a touchscreen-based attentional set-shifting task, we observed substantial individual variability in cognitive...

CONCLUSION: This study developed an explainable ML-based prediction model for functional disability trajectories in older patients with CLBP and preliminarily explored a trajectory-based risk stratification pathway. The findings provide an interpretable, data-driven approach for estimating trajectory-specific risk within this dataset and may help inform future research on early risk identification. Further external validation, recalibration, and impact analyses are required before clinical...

Alzheimer's disease (AD) is conventionally framed as a consequence of progressive amyloid-β and tau pathology, yet substantial heterogeneity in cognitive outcome at any given level of pathological burden indicates that cognitive resilience constitutes a parallel determinant of disease risk. Here we test whether pathology and resilience function as independent and synergistic dimensions of incident AD dementia. In 3,119 older adults from the China Cognition and Aging Study, followed for a median...

Aging epithelial tissues, including the esophagus, are colonized by somatic mutant clones under strong competitive selection. The effect of cancer treatment on mutant selection in normal epithelium is unknown. We hypothesized that some mutant clones may be selectively expanded during treatment. To test this, we sequenced normal esophageal epithelium removed from 70 patients after therapy for esophageal cancer. Patients received either no treatment, combination chemotherapy (FLOT, ECX or EOX) or...

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The accumulation of somatic mitochondrial DNA (mtDNA) mutations across life is among the oldest and most debated proposed drivers of aging. A defining, counter-intuitive feature is that individual mutant molecules, although vanishingly rare when they arise, can come to dominate a cell's multi-copy mtDNA population through intracellular clonal expansion, producing a mosaic of respiratory-deficient cells across aging tissues. Here we synthesize current evidence to argue that clonal mosaicism of...

CONCLUSION: AS-IV alleviates HR-induced endothelial senescence by modulating the Notch1/VCAM-1 axis. Our data suggest that AS-IV does not merely inhibit Notch1 but acts by modulating its signaling toward a protective equilibrium, thereby attenuating endothelial senescence and inflammation associated with the restoration of Notch1/VCAM-1 signaling balance. These findings highlight the potential of AS-IV as a therapeutic candidate for AD vascular pathology.

Cellular senescence is increasingly recognized as a fundamental driver of aging and age-related diseases. Studies in peripheral tissues have revealed that senescence is not a uniform cellular state, but a highly heterogeneous phenotype shaped by distinct combinations of DNA damage, mitochondrial dysfunction, chromatin remodeling, impaired proteostasis, and diverse senescence-associated secretory phenotype. This heterogeneity critically influences both the identification and therapeutic targeting...

CONCLUSIONS: CSF TIMP2 levels primarily reflect ageing-related processes associated with neurodegeneration rather than disease-specific effects. Genetic variation in TIMP2 may contribute to clinical heterogeneity. These findings support a role of extracellular matrix-related ageing mechanisms in PD and related disorders.

Caloric restriction (CR) extends lifespan and delays age-related diseases in model organisms, yet its effects on biological aging in humans remain unclear. We pooled data from seven randomized CR trials (n = 829) and examined randomization to CR and change in weight with a biomarker index composed of CRP, IL-6, cystatin C, insulin, GDF-15, and TNF-R1. CR improved the composite biomarker index. The effect of CR decreased from -2.2 to -1.2 (95% CI -2.0 to -0.3) after adjustment for weight, while...