Lysosomes function as the cell’s internal recycling centers. They break down proteins, nucleic acids, carbohydrates, and lipids, helping cells dispose of waste and reuse materials for essential biological processes. They also store nutrients that can be released when needed. Because of these roles, lysosomes are critical for maintaining cellular metabolism, including both catabolism (breaking down complex molecules to simple ones) and anabolism (building complex molecules from simpler ones).

The research team focused on hematopoietic stem cells (HSCs), which are rare, long-lasting stem cells found in the bone marrow that generate all blood and immune cells in the body. 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.

As people grow older, these stem cells gradually lose their ability to repair and replenish the blood system. This decline weakens immune defenses and contributes to the increased vulnerability to infections seen 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 condition becomes much more common with age.

According to the American Cancer Society, age and smoking are the two strongest risk factors associated with the five-year risk of developing cancer. Data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results report show that the median age at cancer diagnosis is 67.

Restoring Old Stem Cells to a Youthful State

The researchers discovered that lysosomes in aged HSCs become excessively acidic, damaged, depleted, and abnormally active. These changes disrupt both the metabolic balance and epigenetic stability of the stem cells.

Using single-cell transcriptomics and functional testing, the team found that blocking this 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 began behaving 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 that can damage tissues throughout 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.”

Major Increase in Blood-Forming Capacity

The researchers also tested an ex vivo treatment approach (when 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, highlighting the powerful regenerative effects of correcting lysosomal dysfunction.

The improvement also reduced damaging inflammatory and interferon-related pathways. According to the researchers, this occurred because healthier lysosomes improved the processing of mitochondrial DNA and lowered activation of the cGAS-STING immune signaling pathway, which appears to play a major role in stem cell inflammation and aging.

Potential for Anti-Aging and Blood Disorder Therapies

The findings could open the door to new treatments aimed at preventing or reversing age-related blood disorders. 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,” 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.”

The team is now investigating whether lysosomal dysfunction in aging stem cells contributes to the development of leukemic stem cells, potentially connecting normal stem cell aging with cancer formation.

The research involved collaboration with Mickaël Ménager, PhD, and colleagues at the Imagine Institute and INSERM UMR 1163 at Université de Paris Cité in Paris. Funding was provided by the National Institutes of Health, New York State Stem Cell Science, INSERM, and the Agence Nationale de la Recherche.