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Recent reports suggest dysregulation of the N6-methyladenosine (m6A) RNA modification may contribute to the pathology of neurodegenerative diseases. Herein, we show the m6A methyltransferase complex including METTL3-the catalytic component of the nuclear-localized complex-is robustly upregulated in human microglia and astrocytes exposed to αSyn(f) and Mn. Subcellular localization studies reveal METTL3 was predominantly cytoplasmic following Mn insult but remained nuclear following αSyn(f)...

Parkinson's disease results from degeneration of dopaminergic neurons in the midbrain, but the underlying mechanisms are unclear. Here, we identify novel crosstalk between depolarization-induced entry of Ca2+ and lysosomal cation release in maintaining dopaminergic neuronal function. The common disease-causing G2019S mutation in LRRK2 selectively exaggerated Ca2+ entry in vitro. Chemical and molecular strategies inhibiting the lysosomal ion channel TPC2 reversed this. Using Drosophila, which...

Vorinostat, a pan histone deacetylases (HDACs) inhibitor clinically approved for cutaneous T-cell lymphoma, exerts therapeutic effects by inducing tumor cell death and cycle arrest. Intriguingly, a previously unrecognized hormetic role of low-dose vorinostat in Caenorhabditis elegans. Subtoxic concentrations of vorinostat (1 μM) significantly extended lifespan, enhanced healthspan, and improved resistance to oxidative and heat stress, while ameliorating Aβ-induced paralysis. qPCR analysis...

Microglia are parenchymal brain macrophages that are established during embryogenesis and form a self-containing cellular compartment that resists seeding with cells derived from adult definitive hematopoiesis. We report that monocyte-derived macrophages (MoMΦs) accumulate in the brain of aging mice with distinct topologies, including the nigrostriatum and medulla but not the frontal cortex. Parenchymal MoMΦs adopt bona fide microglia morphology and expression profiles. Due to their...

Aging is a major risk factor for cardiovascular diseases, and the accumulation of DNA damage significantly contributes to the aging process. This study aimed to identify the underlying molecular mechanisms of vascular aging in DNA-repair-deficient progeroid Ercc1^(Δ/-) mice and to explore the therapeutic effect of dietary restriction (DR). RNA sequencing analysis revealed that DR reversed gene expression of vascular aging processes, including extracellular matrix remodeling, in the Ercc1^(Δ/-)...

Cellular senescence, a hallmark of aging, reveals context-dependent phenotypes across multiple biological length scales. Despite its mechanistic importance, identifying and characterizing senescence across cell populations is challenging. Using primary dermal fibroblasts, we combined single-cell imaging, machine learning, several induced senescence conditions, and multiple protein biomarkers to define functional senescence subtypes. Single-cell morphology analysis revealed 11 distinct morphology...

The mitochondrial translocator protein (TSPO) is a biomarker of inflammation associated with neurodegenerative diseases, widely regarded to be upregulated in the aging brain. Here we investigated the interaction between aging and TSPO immunomodulatory function in the mouse hippocampus, a region severely affected in Alzheimer's Disease (AD). Surprisingly, we found that TSPO levels were decreased in brain innate immune populations in aging. Aging resulted in a reversal of TSPO knockout...

Extracellular vesicles (EVs) are secreted by most cell types, transmitting crucial signaling molecules like proteins, small RNAs, and DNA. We previously demonstrated that EVs from murine and human mesenchymal stem cells (MSCs) functioned as senomorphics to suppress markers of senescence and the inflammatory senescence-associated secretory phenotype (SASP) in cell culture and in aged mice. Here we demonstrate that EVs from additional types of human adult stem cells and embryonic progenitor cells...

The mitochondrial translocator protein (TSPO) is a biomarker of inflammation associated with neurodegenerative diseases, widely regarded to be upregulated in the aging brain. Here we investigated the interaction between aging and TSPO immunomodulatory function in the mouse hippocampus, a region severely affected in Alzheimer's Disease (AD). Surprisingly, we found that TSPO levels were decreased in brain innate immune populations in aging. Aging resulted in a reversal of TSPO knockout...

Science, Volume 388, Issue 6745, April 2025.

Science, Volume 388, Issue 6745, April 2025.

Science, Volume 388, Issue 6745, April 2025.

Science, Volume 388, Issue 6745, April 2025.

Science, Volume 388, Issue 6745, April 2025.