Blood stem cell aging: scientists reverse cellular decline by targeting lysosomal dysfunction

BAVIDA Overview

• Mount Sinai researchers reversed aging in blood stem cells by targeting lysosomal dysfunction with a specific inhibitor
• Treatment restored regenerative capacity more than eightfold in aged hematopoietic stem cells
• The discovery may lead to therapies preventing age-related blood disorders and improving transplant success in elderly patients

The study, published in Cell Stem Cell, identifies malfunctioning lysosomes as central drivers of stem cell aging and demonstrates that correcting these defects can restore aged cells to a youthful, functional state. The findings open potential therapeutic pathways for age-related blood disorders and could improve outcomes for stem cell transplants in older patients.

Understanding lysosomes and their role in cellular health

Lysosomes function as the cell's recycling system, breaking down proteins, nucleic acids, carbohydrates, and lipids. These specialized structures accumulate and degrade cellular waste, eventually recycling materials for reuse in biosynthetic processes. Lysosomes also store nutrients for release when the body requires them.

Beyond waste management, lysosomes regulate cellular metabolism in both directions. They control catabolism, the breakdown of complex molecules into simpler ones, and anabolism, the construction of complex molecules from simpler components. This dual regulatory function makes lysosomes pivotal for maintaining cellular equilibrium and overall health and wellbeing.

Hematopoietic stem cells and the aging process

The study, led by corresponding author Saghi Ghaffari, MD, PhD, Professor of Cell, Developmental, and Regenerative Biology at Mount Sinai and member of the Black Family Stem Cell Institute, focuses on hematopoietic stem cells. These rare, long-lived cells reside in bone marrow and bear responsibility for generating all blood and immune cells throughout a person's lifetime.

Age-related decline in stem cell function

As people age, hematopoietic stem cells become increasingly defective, losing their capacity for self-renewal and repair of the blood system. This decline directly reduces the body's ability to fight infections, a vulnerability frequently observed in older adults. The deterioration also contributes to a condition called clonal hematopoiesis, an asymptomatic state considered premalignant that elevates the risk of developing blood cancers and other inflammatory disorders.

According to the American Cancer Society, older age and smoking represent the two most significant risk factors associated with cancer development. The National Cancer Institute's most recent Surveillance, Epidemiology, and End Results report indicates that the median age of cancer diagnosis stands at 67 years.

The mechanism of lysosomal dysfunction

Dr. Ghaffari's research team discovered that lysosomes in aged hematopoietic stem cells undergo several damaging changes. They become hyper-acidic, depleted, damaged, and abnormally activated. This cascade of dysfunction disrupts the cells' metabolic stability and epigenetic integrity, undermining their fundamental capacity to function properly.

Using single-cell transcriptomics and stringent functional assays, the researchers identified that suppressing this hyperactivation with a specific vacuolar ATPase inhibitor could restore lysosomal integrity. The treatment effectively normalized the overactive lysosomes and returned blood-forming stem cell function to healthier parameters.

Reversing cellular aging

The intervention produced remarkable results in aged stem cells. Following treatment, old stem cells began functioning with the characteristics of young, healthy cells. The restoration encompassed multiple dimensions of cellular health.

Comprehensive cellular rejuvenation

Treated cells regained their regenerative potential and ability to be transplanted successfully. They produced more healthy stem cells and generated balanced blood with proper immune cell composition. The cells renewed their metabolism and mitochondrial function, improved their epigenome, reduced inflammation markers, and ceased transmitting inflammatory signals that cause systemic damage.

The restoration also dampened harmful inflammatory pathways and interferon-driven signaling. This improvement occurred through enhanced lysosomal processing of mitochondrial DNA and reduced activation of the cGAS-STING immune signaling pathway, which the researchers identified as a key driver of inflammation and stem cell aging.

Quantifying the regenerative improvement

The research team conducted ex vivo treatment, removing cells from the body, modifying them in laboratory conditions, and assessing their capacity upon return. Treatment of old stem cells with the lysosomal inhibitor boosted their in vivo blood-forming capacity more than eightfold. This dramatic improvement demonstrates that correcting lysosomal dysfunction can substantially restore regenerative potential in aged cells.

Implications for medicine and aging

The discovery establishes new therapeutic avenues for preventing or reversing age-related blood disorders. It may also improve the success rate of stem cell transplants in older patients and enhance their conditioning for gene therapy applications.

Dr. Ghaffari emphasized the significance of the findings, noting that aging in blood stem cells does not represent an irreversible fate. Old blood stem cells retain the capacity to revert to a youthful state when the underlying lysosomal dysfunction receives appropriate intervention.

Future research directions

Dr. Ghaffari's team is now exploring how lysosomal dysfunction in old stem cells may contribute to the formation of leukemic stem cells. This investigation could potentially establish links between normal stem cell aging and cancer development, opening further research pathways into age-related malignancies.

The researchers suggest that targeting the lysosomal pathway may eventually help maintain healthy blood and immune systems in elderly populations, improve their stem cells for transplantation procedures, and reduce the risk of age-associated blood disorders. Such interventions might also influence overall aging processes throughout the body.

The BAVIDA Community invites readers to share their perspectives on stem cell research and regenerative medicine. What aspects of aging reversal research interest you most, and how do you see these findings influencing future healthcare approaches for older adults?