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Boosting blood stem cell housekeeping reversed immunity decline in aging mice

Rejuvenating an important housekeeping process in blood stem cells reversed age-related immune system decline in mice, a path towards potential future treatments in older adults, especially those with leukemia or undergoing cancer treatment. The study, led by NIH supported researchers at the Albert Einstein College of Medicine, was published in Nature.

blood cells grouped togetherOur bone marrow is home to hematopoietic (blood-producing) stem cells (HSCs) that make all of the body’s blood cells, including immune cells that guard against viruses and bacteria. HSCs lose efficiency as we age, producing fewer new healthy cells.

This age-related change is in part linked to drop-offs in a cell housekeeping process known as chaperone-mediated autophagy (CMA). CMA helps clear out waste products like damaged proteins that can reduce or impair blood and immune cells’ natural operations. Build-up of cellular waste products, if allowed to occur, has also been connected to neurodegenerative diseases like Alzheimer’s and Parkinson’s.

In previous studies, the researchers had designed specialized drugs to boost CMA levels in mice. For the current experiment, they tracked mouse CMA to test whether their HSCs lost efficiency as they grew older. The researchers also determined that HSCs depend on CMA to maintain a proper protein equilibrium and to go from a dormant state to switch on and start actively creating new blood cells.

Using specially designed genetic mouse models, the Einstein team then blocked CMA functions in young mice, which made their blood stem cells similar to those of much older mice. They also showed that young mice genetically engineered to avoid age-related CMA drop-offs in their HSCs were capable of restocking their bone marrow’s supply of healthy blood cells well into older age. They found similar success using CMA-boosting drugs, which revitalized HSC levels when injected into older mice.

The research team further confirmed this connection in related lab tests on blood stem cell samples from older adults that had similar dysfunctions to the mouse model cells with blocked CMA. Treating these human cell samples with the CMA boosting drugs triggered a renewal of the stem cells’ ability to produce normal healthy blood cells.

While additional research is needed before the drugs can be tested in human trials, the team is hopeful that this work could someday help prevent common age-related leukemias related to HSC mutations. They also want to explore if these drugs could become part of future treatment regimens for cancer patients whose immune systems are damaged as part of chemotherapy or radiation therapy.

This work was supported by NIH grants AG021904, AG038072, AG031782, DK105134, CA230756, R01HL146442, R01HL149714, R01HL148151, and R21HL150032.

Reference: Dong, Shuxian et al. Chaperone-mediated autophagy sustains haematopoietic stem-cell function. Nature. 2021;591(7848):117-123. doi:10.1038/s41586-020-03129-z.