What keeps some immune systems young and effective at protecting against age-related diseases? In a new article published in cellular and molecular immunology, USC stem cell scientist Rong Lu and her collaborators point the finger at a small subset of blood stem cells, which contribute greatly to maintaining a youthful balance or age-related imbalance of the two main types of immune cells. : innate and adaptive. .
Innate immune cells serve as the body’s first line of defense, mobilizing a rapid, all-out attack against invading germs. For germs that evade the body’s innate immune defenses, the second line of attack consists of adaptive immune cells, such as B cells and T cells, that rely on their memory of past infections to mount a specific, targeted response. A healthy balance between innate and adaptive immune cells is the hallmark of a youthful immune system and a key to longevity.
“Our study provides compelling evidence that when a small subset of blood stem cells overproduce innate immune cells, this drives the aging of the immune system, contributes to disease, and ultimately shortens lifespan,” Lu said, associate professor of mother sciences. cell biology and regenerative medicine, biomedical engineering, medicine and gerontology at USC, and a fellow of the Leukemia and Lymphoma Society. Lu is also a member of the USC Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, and the USC Norris Comprehensive Cancer Center at the Keck School of Medicine of USC. “Our findings suggest that restricting the small subset of blood stem cells that overproduce innate immune cells could be an effective way to delay immune aging.”
In the study, first author Anna Nogalska and her colleagues found striking differences in how quickly the immune system ages, even among laboratory mice with the same genetic background raised under identical conditions. At the advanced age of 30 months, the aging-delayed mice retained a youthful balance of innate and adaptive immune cells. However, early aging mice showed a large increase in innate immune cells relative to adaptive immune cells.
By tracing the individual blood stem cells responsible for producing both innate and adaptive immune cells, scientists discovered the subset of blood stem cells primarily responsible for age-associated immune system imbalance. Specifically, the scientists observed that thirty to forty percent of blood stem cells dramatically changed their preference for producing innate versus adaptive immune cells as the mice aged.
In older people, the blood stem cell subset decreased their production of innate immune cells, protecting against the effects of aging. Among people with delayed aging, there was an increase in gene activity related to the regulation of blood stem cells and response to external signals, which could keep their production of innate immune cells in check. When scientists used CRISPR to edit these genes, blood stem cells reversed their natural tendency and produced more innate immune cells instead of adaptive immune cells, as in early ages.
In contrast, at early ages, the blood stem cell subset began to produce more innate immune cells, which, in excess, lead to many diseases of aging. Thus, at these early ages, scientists found an increase in genetic activity related to the proliferation of blood stem cells and the differentiation of innate immune cells. When scientists used CRISPR to edit these early aging genes, the blood stem cells produced more adaptive immune cells instead of innate immune cells, becoming more similar to those of older people.
Importantly, older people tended to live longer than younger people.
“In the elderly human population, the immune system often produces an overabundance of innate immune cells, which can contribute to diseases such as myeloid leukemia and immune deficiencies,” said Nogalska, senior scientist and laboratory director of the Lu Laboratory. . “Our study suggests how we might promote a younger immune system to combat these common diseases of aging.”
Additional co-authors are Jiya Eerdeng, Samir Akre, Mary Vergel-Rodriguez, Yeachan Lee, Charles Bramlett, Adnan Y. Chowdhury, Bowen Wang, Colin G. Cess, and Stacey D. Finley of USC.
Ninety percent of the project was supported by federal funds from the National Institutes of Health (grants R00-HL113104, R01HL138225, R35HL150826, and 1F31HL149278-01A1) and the National Cancer Institute (grant P30CA014089). Additional funding came from the California Institute for Regenerative Medicine (grant EDUC4-12756R) and the Leukemia and Lymphoma Society (grant LLS-1370-20).