Cell stem cellNov 25, 2025

Fixing cell recycling problems may restore youthful function in old blood stem cells

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 27, 2026

Abstract

Essence

Suppressing hyperactivated lysosomes restored youthful molecular features and improved function in aged hematopoietic stem cells.

Evidence

This preclinical stem-cell study used single-cell transcriptomics, functional analyses, ex vivo v-ATPase inhibition of old HSCs, and in vivo repopulation assays showing over eightfold increased repopulation capacity.

Caveat

The intervention was tested ex vivo in aged HSCs with experimental repopulation endpoints, not as an in vivo therapy for elderly patients.

Simplified

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.