In a recent study, scientists have demonstrated that lysosomal dysfunction actively decreases the potency of hematopoietic stem cells. Calming lysosomes reversed this process, opening avenues for new treatments [1].
Few and far between
Hematopoietic stem cells (HSCs) are rare and precious: they produce blood progenitor cells, which, in turn, produce all differentiated blood cells. With age, HSC function gets increasingly dysregulated, which has been linked to immune decline, increased inflammation and atherosclerosis, and higher cancer risk [2].
One particular consequence is clonal hematopoiesis, which occurs when some HSCs acquire mutations that make them more reproductive. However, their progeny, which overwhelms the blood cell pool, is usually of lesser quality. Clonal hematopoiesis is increasingly recognized as an important driver of aging and mortality [3], especially in the oldest people.
Lysosomes are the cell’s recycling plants: they break down worn-out proteins, lipids, and even whole organelles into reusable building blocks, keeping the cell clean, fueled, and functional. Scientists have been unsure whether lysosomal dysfunction, which worsens with age, is a causal driver of HSC aging. A new study from the Icahn School of Medicine at Mount Sinai, published in Cell Stem Cell, asks the question: do lysosome changes in old HSCs actively cause dysfunction, and if so, can reversing these changes restore youthful HSC function?
The lysosome connection
The team took mouse HSCs from young (8-week) and old (22- to 24-month) mice. First, they sorted the cells into more quiescent/potent and more activated/less potent subsets. The researchers then analyzed lysosomes and found that lysosomal function was markedly dysregulated in aged cells and present across both subsets, pointing to a general aging-related decline.
Old HSCs showed reduced lysosomal mass and had lysosomes with a lower pH than normal (hyperacidification). The older lysosomes overall had leakier, compromised membranes. Surprisingly, they were also more active compared to lysosomes in young cells, like older, more polluting engines operating at higher speeds.
Inhibiting the enzyme v-ATPase, a proton pump that acidifies lysosomes, with a compound called ConA dampened lysosomal activity and normalized pH levels. Markers of lysosomal integrity bounced back as well. This showed that lysosomal defects in old HSCs are at least partly driven by v-ATPase and can be reversed.
Old HSCs had higher levels of mTORC1, a nutrient-sensing kinase that pushes cells toward growth and cycling. Essentially, hyperactive lysosomes helped keep old HSCs metabolically active. Inhibiting v-ATPase reduced mTORC1 expression and its lysosomal colocalization back toward young levels associated with a restrained, quiescent metabolism.
The researchers also found that lysosomes in old HSCs mis-process damaged mitochondria. As a result, mitochondrial DNA (mtDNA) escapes into the cytosol. Cells mistake cytosolic mtDNA for foreign (such as viral) DNA and activate the cGAS-STING inflammatory pathway. ConA reduced extramitochondrial mtDNA and suppressed cGAS-STING activation.
Rebuilding the blood system
For their in vivo experiments, the scientists took HSCs out of mice and cultured them with ConA for four days. Mice were then irradiated to wipe out their bone marrow – much like after high-dose chemotherapy – so transplanted stem cells had to rebuild the entire blood system from scratch.
A small number of treated old HSCs were transplanted back into these mice, together with a much larger number of ordinary bone-marrow cells from a healthy mouse. The ability of HSCs to produce substantial progeny despite the competition would indicate success. Another group received sham-treated HSCs.
ConA pretreatment boosted old HSC output up to 16-fold compared to sham-treated cells over the 21-week follow-up, showing that the cells regained the ability to sustain blood production long-term, not just transiently. Several recipients of sham-treated old HSCs died by 21 weeks, while survival in the ConA group was higher. ConA also increased lymphoid compared to myeloid output from old HSCs, reversing this hallmark of clonal hematopoiesis, and significantly increased the number of donor-derived T and B cells.
“Our findings reveal that aging in blood stem cells is not an irreversible fate. Old blood stem cells have the capacity to revert to a youthful state; they can bounce back,” said Saghi Ghaffari, MD, Ph.D., Professor of Cell, Developmental, and Regenerative Biology at the Icahn School of Medicine. “By slowing down the lysosomes and reducing their acidity, stem cells became healthier and could make new balanced blood cells and new stem cells much more effectively. By targeting lysosomal hyperactivity, we were able to reset aged stem cells to a younger, healthier state, improving their ability to regenerate blood and immune cells.”
“Lysosomal dysfunction emerges as a central driver of stem cell aging,” he added. “Targeting this pathway may one day help maintain healthy blood and immune systems in the elderly, improve their stem cells for transplantation, and reduce the risk of age-associated blood disorders and perhaps have an effect on overall aging.”
Literature
[1] 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. (2025). Reversing lysosomal dysfunction restores youthful state in aged hematopoietic stem cells, Cell Stem Cell
[2] Kasbekar, M., Mitchell, C. A., Proven, M. A., & Passegué, E. (2023). Hematopoietic stem cells through the ages: A lifetime of adaptation to organismal demands. Cell Stem Cell, 30(11), 1403-1420.
[3] Jaiswal, S., & Ebert, B. L. (2019). Clonal hematopoiesis in human aging and disease. Science, 366(6465), eaan4673.
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