Aging & Longevity

Gene regulatory networks encode the fundamental logic of cellular functions, but systematic network mapping remains challenging, especially in cell states relevant to human biology and disease. Here, we perturbed all expressed genes across 22 million primary human CD4^(+) T cells from four donors and developed a probe-based perturb-seq platform to measure the transcriptome effects in cells at rest and after stimulation. These data allowed us to map genes regulating immune pathways, including...

Cellular senescence is a state of stable arrest and secretion linked to aging and disease. Here, we identify that senescent cells dispose of large fragments through cell-to-cell adhesion, which we term "senescent-cell adhesion fragments" (SCAFs). Found in many senescent states, including human and mouse cells, and mouse tissues, SCAFs lack nuclear material but contain organelles, including damaged mitochondria. Disrupting adherens junctions decreases SCAF formation but induces senescent-cell...

Reproductive aging in the ovary, endometrium, and testis is characterized by progressive decline in regenerative capacity, yet the upstream mechanisms coordinating stem cell dysfunction across these tissues remain incompletely understood. Emerging evidence suggests that alterations in extracellular matrix (ECM) mechanics, particularly age and disease associated increases in tissue stiffness, may contribute to impaired stem cell function through mechanotransductive signaling pathways. In the...

The planet is experiencing an unprecedented growth in its human population aged 65 years and older, underscoring the urgent need for comprehensive aging-centered biobehavioral data to guide public health interventions. The Arlington Study of Healthy Aging (ASHA) is a multidisciplinary community cohort study designed to investigate the biological, psychological, and social mechanisms underlying age-related functional decline. Here, we present the study's rationale, design, and methodological...

Premature ovarian insufficiency (POI) is a leading cause of female infertility. Its mechanisms are poorly understood, and effective therapies are lacking. In this study, we aimed to identify novel druggable targets and repurposable drugs for POI through an integrated multiomics and computational pharmacology approach. We integrated large-scale proteomic data from two independent cohorts (deCODE, N = 35,559; UK Biobank, N = 54,219) using Mendelian randomization, Bayesian colocalization, and...

Macrophages contribute to osteoarthritis (OA) pathogenesis, but how specific macrophage states influence chondrocyte senescence remains unclear. Using single-cell RNA sequencing of naturally aged mouse joints, we identified a PTGS2-high macrophage subset associated with joint senescence. In a surgically induced OA model, lineage tracing revealed a marked increase of these macrophages, and their selective depletion using a diphtheria toxin receptor-based mouse model attenuated cartilage...

Aging is associated with immune dysregulation in the brain and is the greatest risk factor for many neurodegenerative diseases. Rejuvenation interventions can mediate beneficial effects. Microglia are major contributors to neurodegenerative disease progression; however, the molecular changes underlying brain aging and rejuvenation remain poorly understood at the single-cell level. We identified and benchmarked several reproducible microglial states and a core set of genes that drive microglial...

Obesity is a major risk factor for osteoarthritis (OA), yet the mechanisms linking excess adiposity to joint degeneration remain incompletely understood. Here, we identify adipocyte-derived extracellular vesicles enriched in mitochondrial components (EV-Mito) as pathogenic mediators that transfer mitochondrial DNA (mtDNA) to chondrocytes. The internalized mtDNA activates the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) cytosolic DNA-sensing pathway, inducing inflammatory...

CONCLUSIONS: Multicomponent non-pharmacological interventions may provide cognitive benefits, particularly for memory and executive function, though certainty varied and findings from lower-quality reviews should be interpreted cautiously.

The global prevalence of aging and age-related diseases has increased markedly in recent decades due to extended life expectancy and a growing aging population, posing substantial medical and social burdens. Multiple strategies, including metabolic modulation (e.g., physical exercise, calorie restriction, and calorie restriction mimetics), targeting inflammaging, senotherapy, parabiosis, stem cell-based therapies, and epigenetic rejuvenation, have shown promise in slowing aging and extending...

β-Hydroxy-β-methylbutyrate (HMB), a bioactive leucine metabolite, has emerged as a potentially valuable nutritional compound with effects extending beyond skeletal muscle metabolism toward systemic immunometabolic regulation. This review summarizes evidence from 24 experimental and clinical studies regarding the potential relevance of HMB to brain aging and age-related disorders, with emphasis on mitochondrial regulation, inflammatory signaling, redox homeostasis, and exercise-associated...

Telomere shortening drives hair follicle senescence, yet successful reversal of this aging process has remained elusive. Here, we report that stem cell overexpression of Acd, the gene encoding TPP1 (telomere protection protein 1)-a shelterin component that recruits telomerase-accelerates hair regeneration in mice. Stabilization of TPP1 protein via topical application of TELODIN, a synthetic octapeptide that inhibits TPP1 degradation, similarly promotes hair regeneration. Mechanistically,...

The stepwise movement of oxygen from the atmosphere to the mitochondria, the "oxygen cascade", is one of the most tightly regulated systems in physiology. Despite decades of mechanistic study, it has remained quite unexplored in Geroscience. This oversight should be reconsidered. In young organisms, hypoxic stress (whether environmental or tissue-specific) activates a complex adaptive response to preserve energetic stability via restraining anabolic pathways, optimizing mitochondrial...

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Traumatic brain injury (TBI) is a major cause of mortality and persistent neurological disability and is increasingly recognized as a potential contributor to accelerated brain aging and long-term neurodegenerative processes. Beyond the immediate mechanical insult, TBI initiates dynamic secondary injury cascades involving chronic neuroinflammation, oxidative stress, mitochondrial dysfunction, synaptic and axonal degeneration, metabolic disturbances, and blood-brain barrier disruption. The...

Aging is a major risk factor for the formation, growth, and rupture of intracranial aneurysms, but the underlying biological mechanisms remain incompletely understood. Beyond chronological aging, accumulating evidence suggests that vascular aging is driven by cellular senescence, chronic inflammation, and hemodynamic stress, which together contribute to aneurysm wall degeneration. In this review, we synthesize current evidence on the role of aging in intracranial aneurysm biology, with a...

We are racing towards a time wherein the largest demographic of the population will be comprised of older adults and where it is now also possible to measure, monitor, and diagnose long term risk factors and provide effective and valuable preventative interventions. Thanks to the achievements of modern health care, we have reached a tipping point in the need for a robust geriatric workforce. Through the implementation of thoughtful, deliberate, and collaborative processes, Artificial...

Under-recognition of cognitive impairment remains a major global public health challenge, particularly in low- and middle-income countries. Many cases go unrecognised because conventional cognitive assessment is resource-intensive and difficult to scale across diverse populations. Here we show that easily captured indicators of reduced survey response quality, derived from how older adults answer routine psychosocial questionnaires, can identify cognitive impairment risk across countries. Using...

Aging is accompanied by widespread DNA methylation changes, yet their full genomic scope and parent-of-origin dynamics remain poorly understood. Here, we apply nanopore long-read sequencing to 7,284 whole blood samples enabling methylation measurements of 17,959,684 high-quality CpG units. Over 20% of the measured high quality CpG units undergo age-associated changes, predominantly hypomethylation. From these data, we construct a methylation aging clock from 1,373 high-quality CpG units, with...

The cholinergic system is central to attention, learning, and neuroplasticity and undergoes progressive degeneration with aging. Neuroplasticity-based computerized cognitive training is a scalable, non-pharmacological strategy to support cognitive health in older adults, yet its neurobiological mechanisms remain unclear. [18F]Fluoroethoxybenzovesamicol (FEOBV) positron emission tomography (PET) quantifies presynaptic cholinergic terminals via vesicular acetylcholine transporter (VACht) binding,...