2025-11-24 マウントサイナイ医療システム(MSHS)
<関連情報>
- https://www.mountsinai.org/about/newsroom/2025/mount-sinai-scientists-reverse-aging-in-blood-stem-cells-by-targeting-lysosomal-dysfunction
- https://www.sciencedirect.com/science/article/pii/S1934590925004059
リソソーム機能不全を逆転させることで、老化した造血幹細胞の若々しい状態を回復できる Reversing lysosomal dysfunction restores youthful state in aged hematopoietic stem cells
Tasleem Arif, Jiajing Qiu, Hossein Khademian, Anusree Lohithakshan, Anagha Menon, Vijay Menon, Mary Slavinsky, Maxime Batignes, Miao Lin, Robert Sebra, Kristin G. Beaumont, Deanna L. Benson, Nikolaos Tzavaras, Mickaël M. Ménager, Saghi Ghaffari
Cell Stem Cell Available online: 24 November 2025
DOI:https://doi.org/10.1016/j.stem.2025.10.012
Graphical abstract
Highlights
- Lysosomes are hyperacidic, damaged, and dysfunctional in old HSCs
- cGAS-STING signaling triggered by misprocessed mtDNA mediates inflammation in old HSCs
- v-ATPase inhibition reduces inflammation and restores metabolic homeostasis in old HSCs
- Lysosomal inhibition improves old HSCs’ transplantation and self-renewal ability
Summary
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.
