Old blood stem cells might not be stuck acting their age after all.
Scientists at the Icahn School of Medicine at Mount Sinai say they reversed aging in blood-forming stem cells in mice by repairing defects in lysosomes, structures that act as the cell’s recycling centres. The findings were published in Cell Stem Cell.
The team found lysosomal dysfunction and overactivity are major causes of stem cell aging, and that restoring proper lysosomal activity can rejuvenate old stem cells and improve their ability to regenerate blood and immune cells.
The research focused on hematopoietic stem cells, or HSCs, rare long-lasting stem cells in the bone marrow that generate all blood and immune cells in the body.
As people age, these stem cells gradually lose their ability to repair and replenish the blood system. The decline weakens immune defences and contributes to greater vulnerability to infections in older adults. Aging HSCs are also linked to clonal hematopoiesis, an asymptomatic condition considered a premalignant state that raises the risk of blood cancers and inflammatory diseases.
The study was led by Saghi Ghaffari, MD, PhD, professor of Cell, Developmental, and Regenerative Biology at the Icahn School of Medicine and a member of the Black Family Stem Cell Institute.
Researchers found that lysosomes in aged HSCs become excessively acidic, damaged, depleted and abnormally active. Those changes disrupt the cells’ metabolic balance and epigenetic stability.
Using single-cell transcriptomics and functional testing, the team found that blocking excessive lysosomal activity with a vacuolar ATPase inhibitor restored lysosomal health and improved the function of aging blood stem cells.
After treatment, the old stem cells behaved more like young, healthy cells again. They regained the ability to regenerate effectively, produce balanced blood and immune cells, and generate additional healthy stem cells.
The treated cells also showed improved metabolism and mitochondrial performance, healthier epigenetic patterns, reduced inflammation, and fewer harmful inflammatory signals.
“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,” Dr Ghaffari said.
“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.”
The researchers also tested an ex vivo treatment approach, where cells are removed from the body, modified in a laboratory and returned to the body.
Treating old stem cells with the lysosomal inhibitor increased their blood-forming ability in living animals by more than eightfold, according to the researchers.
The improvement also reduced damaging inflammatory and interferon-related pathways. The researchers said this happened because healthier lysosomes improved the processing of mitochondrial DNA and lowered activation of the cGAS-STING immune signalling pathway, which appears to play a major role in stem cell inflammation and aging.
The findings could lead to new treatments aimed at preventing or reversing age-related blood disorders. The researchers said they may also improve stem cell transplantation outcomes in older patients and enhance conditioning methods used in gene therapy.
“Lysosomal dysfunction emerges as a central driver of stem cell aging,” Dr Ghaffari said.
“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.”
The team is now investigating if lysosomal dysfunction in aging stem cells contributes to the development of leukemic stem cells, potentially linking normal stem cell aging with cancer formation.
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