Aging & Longevity

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...

Understanding cognitive aging requires approaches that capture individual variability while enabling integration across studies. In rodent models, behavioral data are central to this effort, yet cross-laboratory differences in experimental design limit comparability and constrain secondary analysis. To address this gap, we developed the Individual Differences in Cognitive Aging Rodent Datasets (ID-CARD), a first-of-its-kind collaborative repository aggregating trial-level Morris water maze data...

Resilience has become an integral component of theory and research in brain aging. Recent frameworks have provided guidelines for identifying and investigating resilience in the context of diversity (e.g., sex and risk exposure differences). We leverage a multi-factorial longitudinal approach to operationalize and predict pathways of resilience, stability and vulnerability as a function of differential within-person trajectory patterns of hippocampal volume and cognitive change. Participants...

CONCLUSION: Epigenetic clocks may improve the assessment of biological aging in people living with HIV and could support risk stratification, early identification of frailty, and evaluation of interventions. However, longitudinal validation, standardized methods, adjustment for immune-cell composition, and evidence linking clock changes with meaningful clinical outcomes are required before these biomarkers can be used routinely in HIV care.

CONCLUSION: PIS provides a compact, interpretable proteomic measure of inflammaging and captures mortality, multisystem disease burden, and aging-related biology in population-scale cohorts.

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Cellular senescence is a key driver of age-related pathologies. Our study focuses on PTCHD4, a transmembrane protein with previously undefined physiological functions in aging processes. We found that PTCHD4 expression was increased across multiple cellular senescence models and showed an age-associated increase in mouse tissues and human lung transcriptomic datasets. Functionally, PTCHD4 deficiency attenuated senescence progression, whereas its overexpression promoted this process. In vivo,...

As societies age, a deeper understanding of ageing-related factors that contribute to longevity is needed. We therefore investigated possible longevity factors (social, medical, and biological) in relation to parental longevity (PL) and polygenic longevity scores (PGLSs). We examined 1126 70-year-olds from the Swedish population-based Gothenburg H70 Birth Cohort study in 2014-2016 (response rate 72%), with follow-up in 2019-2022 (response rate 77.6%). Comprehensive examinations included...

Long-term humoral immunity relies on long-lived plasma cells in the bone marrow (BM). However, the processes governing plasma cell transport, positioning, and longevity within the BM niche remain poorly understood, especially in humans. Most existing knowledge comes from mouse studies or limited human-based models, which makes translating findings to human biology challenging. Here, we introduce a physiologically relevant human bone marrow-on-a-chip (hBMOC) model to investigate the behavior and...

Ovarian aging leads to permanent reproductive senescence and systemic hormonal changes that predispose women to age-associated comorbidities. Despite these observations, the intrinsic mechanisms driving age-related ovarian decline are poorly defined. Mitochondrial DNA (mtDNA) mutations and instability are strongly associated with aging; however, it remains unknown if naturally occurring mitochondrial genetic variation influences the trajectory of ovarian aging. To address this, we compared two...

Ultraviolet (UV)-induced skin photoaging is driven by cellular senescence and chronic inflammation. Although the secretome (SCT) derived from human umbilical cord mesenchymal stem cells (hUC-MSC SCT) exhibits regenerative potential, its role in combating photoaging remains to be elucidated. In this study, we show that SCT markedly ameliorates photoaging in UV-exposed mice, restoring epidermal barrier function, dermal collagen integrity, senescence-associated markers, and systemic inflammatory...

Ecological theories predict a fundamental trade-off between fast growth and the probability of achieving longevity, with far-reaching consequences for ecosystem resilience and carbon residence time. Tree-ring studies have revealed a globally consistent negative relationship between growth rate and lifespan, yet comparable large-scale evidence for such trade-offs beyond trees remains scarce, largely due to methodological limitations. Here, we exploit annual growth rings formed by secondary...