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Targeting pro-senescent PTGS2(+) macrophages alleviates chondrocyte senescence and osteoarthritis progression

5 days 11 hours ago
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...
Yuhao Jiang

Core activation program and selective regional responsiveness of microglia during aging and parabiosis

5 days 11 hours ago
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...
Huma Naz

Adipose-cartilage communication via EV-Mito-mtDNA signaling promotes osteoarthritis progression

5 days 11 hours ago
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...
Cheng Gu

A New agent in the matrix: PINK1's expanded role in mitochondrial surveillance and Regulation

5 days 11 hours ago
The identification of pathogenic autosomal recessive mutations in the gene encoding the PINK1 kinase provided early evidence linking mitochondrial dysfunction to neurodegeneration - in this case Parkinson's Disease. PINK1 has since become synonymous with mitophagy, with the prevailing model proposing two alternative fates. The first being partial import - inner-membrane penetration of its transmembrane domain (TMD) - followed by PARL-mediated cleavage and degradation. This happens in healthy...
Ian Collinson

A Mechanism-Based Framework for Anti-Aging Strategies: From Metabolic Regulation to Senotherapy and Stem Cell-Based Interventions

5 days 11 hours ago
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...
Feifei Li

Potential effects of beta-hydroxy-beta-methylbutyrate and exercise on brain aging and age-related disorders: implications for immunometabolic regulation and muscle-brain-immune crosstalk

5 days 11 hours ago
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...
Boyuan Shi

Shelterin TPP1 Promotes Hair Regeneration Through Activating Bulge Hair Follicle Stem Cells

5 days 11 hours ago
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,...
Lihui Wang

Oxygenaging: A Physiological Framework for Geroscience

5 days 11 hours ago
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...
Stefano Donega