A team of researchers from Mount Sinai Health System has pinpointed a mechanism that facilitates the reversal of aging in hematopoietic stem cells. They determined that lysosomal dysfunction, which involves the cellular components responsible for breaking down and recycling molecules, plays a critical part in this process. The findings of their study have been featured in the journal Cell Stem Cell.
The specialists clarified that as organisms age, the lysosomes within stem cells either sustain damage or become overly active, disrupting the cells’ metabolic and epigenetic stability. This degradation leads to pathologies in the hematopoietic stem cells; they lose their regenerative capacity, resulting in poorer blood system renewal, and the cells exhibit increased susceptibility to clonal hematopoiesis—a precursor condition to cancer associated with aging.
Employing advanced analytical techniques, the experts found a way to curb this lysosomal hyperactivity in mice using a vacuolar ATPase inhibitor. Following treatment with this compound, the lysosomes regained their potential for regeneration: the cells demonstrated improved engraftment after transplantation, generated more balanced populations of immune cells, and stabilized both their metabolism and mitochondrial function. A reduction in inflammatory signaling was another observed outcome.
The impact was particularly pronounced when the cells were treated ex vivo (outside the body): the hematopoietic potential of aged stem cells increased by more than eightfold. Furthermore, the restoration of normal lysosomal function was shown to suppress the pathological activation of the cGAS-STING pathway, which is implicated in both inflammation and aging, by enhancing the clearance of mitochondrial DNA.
These outcomes strongly suggest that lysosomes represent a highly promising primary target for rejuvenating the blood-forming system. The authors anticipate that correcting lysosomal dysfunction could form the foundation for novel therapeutic strategies against age-related blood disorders and for substantially improving the success rates of stem cell transplantation.
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