Aging impairs hematopoietic stem cells (HSCs), driving clonal hematopoiesis, myeloid malignancies, and immune decline. The role of lysosomes in HSC aging-beyond their passive mediation of autophagy-is unclear. We show that lysosomes in aged HSCs are hyperacidic, depleted, damaged, and aberrantly activated. Single-cell transcriptomics and functional analyses reveal that suppression of hyperactivated lysosomes using a vacuolar ATPase (v-ATPase) inhibitor restores lysosomal integrity and metabolic and epigenetic homeostasis in old HSCs. This intervention reduces inflammatory and interferon-driven programs by improving lysosomal processing of mitochondrial DNA and attenuating cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) signaling. Strikingly, ex vivo lysosomal inhibition boosts old HSCs' in vivo repopulation capacity by over eightfold and improves their self-renewal. Thus, lysosomal dysfunction emerges as a key driver of HSC aging. Targeting hyperactivated lysosomes reinstates a youthful state in old HSCs, offering a promising strategy to restore hematopoietic function in the elderly.
Keywords: MMP; aging; cGas-STING; hematopoietic stem cell; inflammation; interferon; lysosomes; mitochondria; mtDNA; quiescence.
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