Researchers at the Icahn School of Medicine at Mount Sinai have discovered how to reverse aging in blood-forming stem cells in mice by correcting defects in the stem cell's lysosomes. The breakthrough, published in Cell Stem Cell , identifies lysosomal hyperactivation and dysfunction as key drivers of stem cell aging and shows that restoring lysosomal slow degradation can revitalize aged stem cells and enhance their regenerative capacity.
Lysosomes are specialized structures that act as the cell's recycling system, breaking down proteins, nucleic acids, carbohydrates, and lipids. Lysosomes accumulate and degrade waste, and eventually recycle it to be reused in biosynthetic processes. Lysosomes can also store nutrients to be released when needed. Lysosomes are recognized as pivotal for regulating metabolism in the cell, both catabolism (breaking down complex molecules to simple ones) and anabolism (building complex molecules from simpler ones).
The study, led by corresponding author 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, focuses on hematopoietic stem cells (HSCs). These are the rare long-lived cells in the bone marrow responsible for generating all blood and immune cells.
As people age, these cells become defective and lose their ability to renew and repair the blood system, decreasing the body's ability to fight infections as seen in older adults. Another example is a condition called clonal hematopoiesis; this asymptomatic condition is considered a premalignant state that increases the risk of developing blood cancers and other inflammatory disorders. Its prevalence increases significantly with age.
According to the American Cancer Society, older age and smoking are the two most important risk factors associated with a relative and absolute five-year risk of developing any cancer. According to the National Cancer Institute's most recent Surveillance, Epidemiology, and End Results report, the median age of a cancer diagnosis is 67 years.
Dr. Ghaffari's team discovered that lysosomes in aged HSCs become hyper-acidic, depleted, damaged, and abnormally activated, disrupting the cells' metabolic and epigenetic stability. Using single-cell transcriptomics and stringent functional assays, the researchers found that suppressing this hyperactivation with a specific vacuolar ATPase inhibitor restored lysosomal integrity and blood-forming stem cell function.
The old stem cells started acting young and healthy once more. Old stem cells regained their regenerative potential and ability to be transplanted and to produce more healthy stem cells and blood that is balanced in immune cells; they renewed their metabolism and mitochondrial function, improved their epigenome, reduced their inflammation, and stopped sending out "inflammation" signals that can cause damage in the body.
"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 Dr. Ghaffari. "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."
Remarkably, ex vivo treatment (when cells are removed from the body, modified in a laboratory, and returned to the body) of old stem cells with the lysosomal inhibitor boosted their in vivo blood-forming capacity more than eightfold, demonstrating that correcting lysosomal dysfunction can restore regenerative potential.
This restoration also dampened harmful inflammatory and interferon-driven pathways by improving lysosomal processing of mitochondrial DNA and reducing activation of the cGAS-STING immune signaling pathway, which they find to be a key driver of inflammation and aging of stem cells.
The discovery opens new therapeutic avenues to prevent or reverse age-related blood disorders and improve the success of stem cell transplants in older patients or their conditioning for gene therapy.
"Lysosomal dysfunction emerges as a central driver of stem cell aging," added Dr. Ghaffari. "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."
Dr. Ghaffari's team is now exploring how lysosomal dysfunction in old stem cells may contribute to the formation of leukemic stem cells, potentially linking normal stem cell aging to cancer development.
Research was conducted in collaboration with Mickaël Ménager, PhD, and his team at the Imagine Institute, and INSERM UMR 1163, Université de Paris Cité, in Paris. With support from the National Institutes of Health, New York State Stem Cell Science, INSERM, and the Agence Nationale de la Recherche.
