Reversing lysosomal dysfunction restores youthful state in aged hematopoietic stem cells

Area of Science:

• Gerontology
• Cell Biology
• Hematology

Background:

• Aging hematopoietic stem cells (HSCs) exhibit impaired function, contributing to clonal hematopoiesis, myeloid malignancies, and immune decline.
• The specific role of lysosomes in HSC aging, beyond autophagy, remains largely undefined.

Purpose of the Study:

• To investigate the role of lysosomes in HSC aging.
• To determine if targeting lysosomal dysfunction can restore aged HSC function.

Main Methods:

• Single-cell transcriptomics and functional analyses were performed on aged HSCs.
• Vacuolar ATPase (v-ATPase) inhibitors were used to suppress hyperactivated lysosomes.

Main Results:

• Aged HSCs possess hyperacidic, damaged, and aberrantly activated lysosomes.
• Inhibiting lysosomes restored lysosomal integrity, metabolic, and epigenetic homeostasis in aged HSCs.
• Lysosomal inhibition reduced inflammatory signaling by improving mitochondrial DNA processing and attenuating cGAS-STING pathway activation.
• Ex vivo lysosomal inhibition increased aged HSCs' in vivo repopulation capacity eightfold and improved self-renewal.

Conclusions:

• Lysosomal dysfunction is a key driver of HSC aging.
• Targeting hyperactivated lysosomes rejuvenates aged HSCs, presenting a promising strategy for restoring hematopoietic function in elderly individuals.