Aging & Longevity

Non-communicable diseases (NCDs) dominate global mortality yet remain pervasive despite extensive prevention efforts, suggesting current explanatory frameworks may be incomplete. We propose the "Adaptive Cost Hypothesis": many NCDs represent not primarily lifestyle-mismatch diseases but rather inevitable trade-offs inherent in adaptive epigenetic programming optimized for reproductive success within ancestral human lifespans of 40-60 years. Early-life adversity calibrates immune, metabolic, and...

Transcranial direct current stimulation (tDCS) targeting the primary motor cortex (M1) has previously been shown to enhance motor learning in older adults. However, findings across studies are inconsistent, which may be partly due to variability in stimulation parameters and montages across experimental protocols. We aimed to replicate the effect of 1 mA conventional anodal tDCS over the M1 hotspot during one session of motor sequence learning on retention (24 h) compared to sham stimulation in...

CONCLUSION: In male rats, the SHR+BCAS+D-gal composite model recapitulates the multifactorial background, chronic progression, and multimodal neurological impairment of clinical CSVD at behavioral, neuroimaging, histopathological, and molecular levels. This male rat model may provide a useful experimental platform for mechanistic and interventional studies targeting BBB protection, neuroinflammation, oxidative stress, and white matter repair.

CONCLUSION: These findings indicate that CMDT enhances anticipatory control mechanisms linking brain function to behavior, supporting both emotional regulation and executive efficiency in frail older adults. By embedding cognitive demands within motor actions, this approach provides a low-cost and scalable intervention with increased ecological relevance, offering a promising strategy for addressing multidimensional vulnerability in aging.

Stem cell quiescence is a reversible state in which cells temporarily exit the cell cycle but remain poised to re-enter on cue. Robust protection of the balance between stem cell quiescence and proliferation (Q->P) is critical for long-term tissue health. Proliferation without proper resources drives disease states including cancer or birth defects. Conversely, extended periods of quiescence can lead to irreversible senescence, causing stem cell loss, aging symptoms, and vulnerability to...

Aging is fundamentally associated with the gradual accumulation of DNA damage, which is instrumental in the initiation and advancement of age-associated pathologies, including neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease. Recent studies indicate that lifestyle modifications-especially the consumption of functional foods and participation in consistent physical exercise-can influence cellular and molecular processes related to DNA repair, reduction of oxidative...

Comparative genetics aims to resolve the genetic and molecular architecture of complex traits and the evolutionary constraints governing biology. Recent improvements in genome assembly, coupled with population-scale multi-omics, have generated high-resolution maps of genetic and functional variation across species. These advances have been particularly transformative for farmed animals, which have a rich reservoir of genetic diversity and provide an opportunity for systematic, full-lifespan,...

Ovarian aging precedes decline in many organs, but its mechanisms remain unclear. Here we show that aging oocytes accumulate cytoplasmic mitochondrial DNA (mtDNA) through increased mtDNA leakage, activating the cyclic GMP-AMP synthase (cGAS) pathway to produce cGAMP and trigger stimulator of interferon genes (STING) signaling. Notably, oocyte-derived cGAMP can pass through gap junctions to surrounding granulosa cells (GCs), activating STING signaling in GCs as well. To model age-associated...

Early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD) have different clinical and neuroimaging characteristics, and non-cognitive deficits usually observed are suggestive of hypothalamic dysfunctions. Here, we assessed in vivo the hypothalamic volumetry in EOAD and LOAD and explored its association with cognitive and non-cognitive features. The hypothalamus and its subunits were segmented on T1-weighted MRIs from 14 younger and 23 elderly controls (EC), 14 EOAD, and 28...

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...