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. 2025 Dec 4;32(12):1904-1922.e7.
doi: 10.1016/j.stem.2025.10.012. Epub 2025 Nov 24.

Reversing lysosomal dysfunction restores youthful state in aged hematopoietic stem cells

Tasleem Arif  1 , Jiajing Qiu  1 , Hossein Khademian  2 , Anusree Lohithakshan  1 , Anagha Menon  3 , Vijay Menon  1 , Mary Slavinsky  1 , Maxime Batignes  2 , Miao Lin  1 , Robert Sebra  4 , Kristin G Beaumont  5 , Deanna L Benson  6 , Nikolaos Tzavaras  6 , Mickaël M Ménager  7 , Saghi Ghaffari  8
Affiliations

Reversing lysosomal dysfunction restores youthful state in aged hematopoietic stem cells

Tasleem Arif et al. Cell Stem Cell. .

Abstract

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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Conflict of interest statement

Declaration of interests Certain elements of this work (combined with the work in PMID: 32109377, S.G. and R.L.) have been included in a patent application filed with the United States Patent and Trademark Office.

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