Researchers at the Icahn School of Medicine at Mount Sinai report that they have reversed key features of blood stem cell aging in mice. The team restored youthful function by correcting defects in tiny cellular structures called lysosomes. They published the findings in Cell Stem Cell.
The scientists found that aging blood forming stem cells develop hyperactive and damaged lysosomes. Additionally, those defects disrupt how the cells manage energy and control inflammation. When the team slowed that overactivity, the old stem cells began behaving like young ones again. They regained the ability to rebuild healthy blood systems.
Lysosomes act as cellular recycling centers. They break down proteins, fats, and genetic material into reusable parts. Additionally, they store nutrients that cells release during stress. Scientists consider them central managers of a cell’s metabolism.
The research focused on hematopoietic stem cells, often called HSCs. These rare cells live in the bone marrow. They continuously generate all blood and immune cells throughout life. However, they lose strength as people age. Older stem cells struggle to renew themselves. Consequently, aging weakens the immune system and slows blood regeneration.
Researchers also link aging to clonal hematopoiesis. This condition allows certain blood cell clones to expand abnormally. Additionally, doctors consider it a premalignant state. It raises the risk of blood cancers and inflammatory diseases.
Cancer risk rises sharply with age. The American Cancer Society identifies aging and smoking as the strongest predictors of five year cancer risk. Meanwhile, data from the National Cancer Institute show the median cancer diagnosis age in the United States is 67. That pattern reflects a tight link between aging cells and disease.
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Cells can rebound when scientists correct lysosomal dysfunction
Dr. Saghi Ghaffari led the Mount Sinai study. Her team discovered that lysosomes in aged stem cells become overly acidic. Additionally, they found that these lysosomes appear depleted and structurally damaged. The cells also showed abnormal activation of internal breakdown pathways. Consequently, the stem cells lost metabolic balance and epigenetic stability. The researchers used single cell transcriptomics to analyze gene activity.
Furthermore, they applied strict functional tests to measure stem cell performance. They then treated old stem cells with a vacuolar ATPase inhibitor. This compound reduced excessive lysosomal acidity. Additionally, it restored lysosomal integrity inside the cells. After treatment, the old stem cells functioned like young cells. They renewed their capacity to regenerate blood.
They also improved mitochondrial performance, which powers cellular energy production. Furthermore, they corrected harmful changes in their epigenome, the system that controls gene activity.
The treated cells reduced inflammatory signals that can damage tissues. Dr. Ghaffari explained that aging does not permanently lock these stem cells into decline. She said the cells can rebound when scientists correct lysosomal dysfunction. Additionally, she described lysosomal hyperactivity as a reversible driver of aging. By reducing acidity and slowing breakdown processes, the team restored healthier blood production.
The scientists tested the therapy outside the body. They removed aged stem cells from mice and treated them in the laboratory. Subsequently, they transplanted the corrected cells back into living animals. The treated cells showed more than an eightfold increase in blood forming capacity. Additionally, they generated balanced immune cell populations.
The intervention also dampened inflammatory pathways. Researchers traced that effect to improved processing of mitochondrial DNA.
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Doctors struggle with aging donor cells
Furthermore, the treatment reduced activation of the cGAS STING pathway. This pathway normally triggers immune alarms when cells detect misplaced DNA. However, chronic activation can fuel inflammation and aging.
By stabilizing lysosomes, the team reduced that harmful signaling. Consequently, the stem cells produced fewer inflammatory molecules. They also maintained healthier metabolic rhythms.
The discovery opens potential therapeutic paths. Additionally, it could improve outcomes for older patients undergoing stem cell transplants. Doctors often struggle with aging donor cells that perform poorly after transplantation. This approach may strengthen those cells before infusion.
Researchers also see implications for gene therapy. In such treatments, doctors remove stem cells, modify them, and return them to patients. Furthermore, improving lysosomal health may enhance how well those engineered cells survive.
Dr. Ghaffari’s team now investigates links between lysosomal dysfunction and leukemia. They suspect that aging stem cells with unstable lysosomes may transform into leukemic stem cells. Additionally, they aim to determine whether correcting lysosomal defects could reduce cancer risk. The researchers continue exploring how cellular recycling systems shape the biology of aging blood.
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