Mount Sinai Scientists Reverse Aging in Blood Stem Cells by Targeting Lysosomal Dysfunction
Study published in Cell Stem Cell reveals a technique that renews aged blood-forming stem cells and may help prevent age-related blood disorders
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 Stem Cell Biology and Regenerative Medicine 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.
About the Icahn School of Medicine at Mount Sinai
The Icahn School of Medicine at Mount Sinai is internationally renowned for its outstanding research, educational, and clinical care programs. It is the sole academic partner for the seven member hospitals* of the Mount Sinai Health System, one of the largest academic health systems in the United States, providing care to New York City’s large and diverse patient population.
The Icahn School of Medicine at Mount Sinai offers highly competitive MD, PhD, MD-PhD, and master’s degree programs, with enrollment of more than 1,200 students. It has the largest graduate medical education program in the country, with more than 2,700 clinical residents and fellows training throughout the Health System. Its Graduate School of Biomedical Sciences offers 13 degree-granting programs, conducts innovative basic and translational research, and trains more than 560 postdoctoral research fellows.
Ranked 11th nationwide in National Institutes of Health (NIH) funding, the Icahn School of Medicine at Mount Sinai is among the 99th percentile in research dollars per investigator according to the Association of American Medical Colleges. More than 4,500 scientists, educators, and clinicians work within and across dozens of academic departments and multidisciplinary institutes with an emphasis on translational research and therapeutics. Through Mount Sinai Innovation Partners (MSIP), the Health System facilitates the real-world application and commercialization of medical breakthroughs made at Mount Sinai.
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* Mount Sinai Health System member hospitals: The Mount Sinai Hospital; Mount Sinai Brooklyn; Mount Sinai Morningside; Mount Sinai Queens; Mount Sinai South Nassau; Mount Sinai West; and New York Eye and Ear Infirmary of Mount Sinai.
About the Mount Sinai Health System
Mount Sinai Health System is one of the largest academic medical systems in the New York metro area, with 48,000 employees working across seven hospitals, more than 400 outpatient practices, more than 600 research and clinical labs, a school of nursing, and a leading school of medicine and graduate education. Mount Sinai advances health for all people, everywhere, by taking on the most complex health care challenges of our time—discovering and applying new scientific learning and knowledge; developing safer, more effective treatments; educating the next generation of medical leaders and innovators; and supporting local communities by delivering high-quality care to all who need it.
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