Innate immune cells constitute the body’s first line of defense, mobilizing a rapid and general 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, which rely on their memory of past infections to mount a specific and targeted response. A healthy balance between innate and adaptive immune cells is the hallmark of a youthful immune system – and the key to longevity.

“Our study provides compelling evidence that when a small subset of blood stem cells overproduce innate immune cells, this leads to aging of the immune system, contributes to disease and ultimately shortens lifespan,” said Lu, associate professor of strains. cell biology and regenerative medicine, biomedical engineering, medicine and gerontology at USC, and a fellow of the Leukemia & Lymphoma Society. Lu is also a member of the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, as well as the USC Norris Comprehensive Cancer Center at the Keck School of Medicine of USC. “Our results 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 discovered 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, delayed-aging mice retained a youthful balance of innate and adaptive immune cells. However, early-aging mice showed a large increase in the number of innate immune cells compared to adaptive immune cells.

By tracking individual blood stem cells responsible for producing innate and adaptive immune cells, scientists have discovered the subset of blood stem cells primarily responsible for the immune system imbalance associated with age. Specifically, the scientists observed that thirty to forty percent of blood stem cells significantly changed their preference for producing innate rather than adaptive immune cells as the mice aged.

In retarded individuals, the blood stem cell subset decreased their production of innate immune cells, protecting against the effects of aging. In retarded individuals, there was an increase in gene activity related to the regulation of blood stem cells and response to external signals, which could control their production of innate immune cells. When scientists used CRISPR to delete these genes, the blood stem cells reversed their natural tendency and produced more innate immune cells instead of adaptive immune cells, as in young children.

In contrast, at young ages, the subset of blood stem cells has shifted toward the production of more innate immune cells, which, in excess, leads to many aging-related diseases. As a result, at these young ages, scientists found an increase in gene activity linked to the proliferation of blood stem cells and the differentiation of innate immune cells. When scientists used CRISPR to delete these early aging genes, the blood stem cells produced more adaptive immune cells instead of innate immune cells, becoming more similar to those in retarded older adults.

It is important to note that retarded people tend to live longer than younger people.

“In the elderly human population, the immune system often shifts toward producing an overabundance of innate immune cells, which can contribute to diseases such as myeloid leukemia and immune deficiencies,” said Nogalska, principal scientist and director laboratory at Lu Lab. “Our study suggests how we might promote a younger-looking immune system to fight 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 funding 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 & Lymphoma Society (grant LLS-1370-20).