What factors keep some immune systems young and efficient in preventing diseases related to aging? A recent study involving mice published in Cellular & Molecular Immunology by USC Stem Cell scientist Rong Lu and her team highlights a specific small group of blood stem cells that play a significant role in balancing the two main types of immune cells: innate and adaptive. This balance can either be youthful or show signs of aging.
Innate immune cells act as the body’s initial defense mechanism, launching a swift and broad counterattack against invading pathogens. If these germs manage to bypass these defenses, adaptive immune cells — like B cells and T cells — become involved, using their memory of previous infections to mount a precise and targeted response. Maintaining a healthy equilibrium between innate and adaptive immune cells is crucial for a robust and youthful immune system, which is associated with increased longevity.
“We found strong evidence that an overproduction of innate immune cells by a small subgroup of blood stem cells accelerates immune system aging, contributes to disease, and ultimately reduces lifespan,” explained Lu, who is an associate professor in various fields including stem cell biology and regenerative medicine at USC. She is also connected with the USC Norris Comprehensive Cancer Center and is a member of the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC. “Our results indicate that limiting the overactive blood stem cells producing too many innate immune cells could effectively help delay immune system aging.”
In their research, lead author Anna Nogalska and her colleagues noted significant variances in the rate at which the immune system ages, even among lab mice of the same genetic makeup reared under similar conditions. By the time these mice reached 30 months, those with delayed aging exhibited a favorable balance between innate and adaptive immune cells. In contrast, mice showing early signs of aging had a considerable increase in innate immune cells compared to adaptive ones.
By observing the individual blood stem cells that generate innate and adaptive immune cells, the researchers pinpointed the particular blood stem cell subgroup chiefly responsible for the immune system’s age-related imbalance. Specifically, they noted that thirty to forty percent of blood stem cells altered their focus from producing adaptive immune cells to predominantly generating innate immune cells as the mice grew older.
In the mice with delayed aging, this blood stem cell subset reduced its creation of innate immune cells, thereby buffering the effects of aging. These delayed agers exhibited heightened gene activity associated with the governance and responsiveness of blood stem cells to external signals, likely keeping their innate immune cell production under control. When researchers utilized CRISPR to delete these genes, the blood stem cells reverted to generating more innate immune cells instead of adaptive cells, similar to early aging mice.
Conversely, in the early aging mice, the blood stem cell subset leaned more towards manufacturing excess innate immune cells, a situation that can lead to various age-related diseases. Accordingly, increased gene activity related to blood stem cell growth and the maturation of innate immune cells was observed in these early agers. When early aging genes were removed using CRISPR, the blood stem cells shifted to producing more adaptive immune cells, resembling their counterparts in delayed aging.
It’s noteworthy that those with delayed aging generally enjoyed a longer lifespan compared to those showing early aging.
“In older adults, the immune system frequently shifts toward an excessive production of innate immune cells, which can lead to conditions like myeloid leukemia and immune deficiencies,” commented Nogalska, a senior scientist and lab manager in Lu’s lab. “Our research offers insights into how we might encourage a more youthful immune system to address these prevalent age-related diseases.”
Other co-authors include Jiya Eerdeng, Samir Akre, Mary Vergel-Rodriguez, Yeachan Lee, Charles Bramlett, Adnan Y. Chowdhury, Bowen Wang, Colin G. Cess, and Stacey D. Finley from USC.
The project received substantial support primarily from federal funding sources including the National Institutes of Health (grants R00-HL113104, R01HL138225, R35HL150826, and 1F31HL149278-01A1) and the National Cancer Institute (grant P30CA014089). Additional backing came from the California Institute for Regenerative Medicine (grant EDUC4-12756R) and the Leukemia & Lymphoma Society (grant LLS-1370-20).
