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Mitochondrial dysfunction drives scleroderma pathogenesis. The mitochondria-associated endoplasmic reticulum membrane (MAM) regulates mitochondrial function. Parthenolide (PTL) has protective effects on mitochondria. However, its specific role and mechanisms in localized scleroderma (LoS) remain unclear. This study investigates whether PTL reduces senescence and skin fibrosis by stabilizing MAM in LoS and examines the protective effects of a synthesized thermosensitive controlled-release...

Aging is accompanied by progressive immune remodeling and functional decline across multiple organs. However, the role of neutrophils and their heterogeneous states in these processes remains incompletely understood. Here we integrated single-cell RNA sequencing datasets from multiple organs of young and aged mice to characterize aging-associated neutrophil remodeling. We identified organ-dependent changes in neutrophil abundance and state composition, together with neutrophil subsets enriched...

Skeletal muscle aging is increasingly recognized as a failure of tissue-level coordination rather than a consequence of isolated defects in individual cell types. Recent advances in single-cell, spatial, and multimodal omics have revealed that aging remodels the abundance, functional states, and interactions of muscle-resident populations, shifting the tissue from a regenerative niche toward a degenerative niche. In this Review, we summarize current evidence supporting this conceptual transition...

Examination of genetic risk factors associated with neurodegenerative diseases has provided important mechanistic insights into the pathophysiology of these disorders, and it has implicated defects in lysosomal function as a key component of the neurodegenerative process. The lysosome has a primary role in mediating degradation of both intracellular contents and endocytosed material from the extracellular space. Aggregation of misfolded proteins is a pathological mechanism that is observed...

Oligodendrocytes (OLs) are brain cells that make myelin, the insulating sheath that supports nerve signal transmission. Although oligodendrocyte dysfunction is common in the central nervous system (CNS), how these cells respond to injury remains incompletely understood. Here we show, using mouse models and mouse tissue analyses, that OLs respond to demyelinating diseases by increasing the expression and secretion of serine protease inhibitor clade A member 3N (SERPINA3N). This transition of...

Algal-bacterial interactions regulate the production and fate of marine particulate organic carbon (POC), yet their capacity to generate long-lived carbon sinks remains unclear. Using a two-year, nutrient-self-sustaining co-culture of Synechococcus and its mutualistic microbiota, we demonstrate that sustained algal-bacterial interactions promote the progressive accumulation of recalcitrant POC. Continuous release of algal-derived organic substrates, coupled with repeated microbial enzymatic...

Chronic stress-induced osteoporosis is a prevalent yet therapeutically challenging condition, with sympathetic overactivation as a key contributor. The dominant pathological mediator and strategies for its precise, non-invasive modulation remain unclear. Here, we identify sympathetic neuropeptide Y as a critical driver of this pathology. Using an unpredictable chronic mild stress model in male mice, we show that neuropeptide Y directly induces cellular senescence in bone marrow adipocytes,...

Aging paradoxically leads to both a decline in skeletal muscle mitochondrial function and a shift in muscle composition that favors fibers rich in mitochondria. Yet the biological rationale and mechanism underlying this phenomenon remain largely unknown. Here we show that synthesis of the mitochondrial membrane lipid, cardiolipin, causally links mitochondrial dysfunction to fiber-type adaptations in aging mouse and human skeletal muscle. By mimicking the aging decline of skeletal muscle...

Extracellular vesicles (EVs) have been proposed to be mediators of the health-promoting effects of exercise throughout the body, but how EVs communicate these beneficial signals to recipient cells remains unknown. Here we interrogated these mechanisms using articular cartilage as a model. Network propagation of EV microRNA perturbations on a cartilage-specific network identified microRNA-29 as an exercise-responsive regulator of cellular aging. Consistent with this prediction, a 3-month aerobic...

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Evidence suggests that age-associated differences in body composition-bone/muscle/adipose tissue-are nonlinear, but their timing, sex-specific features, and relation to osteosarcopenic adiposity (OSA) phenotype remain poorly defined. OSA is characterized by the coexistence of osteopenia/osteoporosis, sarcopenia, and excess or redistributed adiposity. We examined sex- and age-specific patterns and inflection points for bone, muscle, fat, and intramuscular adipose tissue (IMAT) in cross-sectional...

Meningeal lymphatic vessels drain brain fluid and waste into the cervical lymph nodes, but how removing these nodes during surgery affects brain health is unknown. Retrospective analysis of cancer patients who underwent neck lymphadenectomy without chemo-radiation therapy found that up to 25% developed mild-to-severe cognitive impairment, and neuroimaging showed accelerated temporal horn enlargement after bilateral surgery. To determine mechanistically how cervical lymphadenectomy contributes to...

Circumventricular organs (CVOs) are small brain regions lacking a blood-brain barrier, giving neurons direct access to blood-borne signals, yet how these microenvironments shape the origin and phenotype of local macrophages remains unclear. Using multi-omics, we characterized the immune landscape of two CVOs, the area postrema (AP) and median eminence (ME), revealing brain-border-like environments with a unique macrophage compartment. CVO microglia showed a distinct, heterogeneous phenotype,...

AMP-activated protein kinase (AMPK) is a key evolutionarily conserved sensor of energy homeostasis and plays a central role in metabolic health and disease. AMPK has also been implicated in ageing; however, most in vivo drug studies rely on the use of indirect activators, such as metformin, which have complex modes-of-action, therefore making conclusions on the specific role of AMPK more challenging. Here, we demonstrate that direct activation of AMPK with the compound 991 extends lifespan in...