A recent study published in Cellular & Molecular Immunology suggests that a small subset of blood stem cells plays a key role in determining the balance between innate and adaptive immune cells—an important factor in immune system aging. Researchers led by Rong Lu, a scientist at USC Stem Cell, have uncovered how this imbalance may drive age-related diseases and shorten lifespan, offering potential avenues for delaying immune aging.
Innate and Adaptive Immune Systems
The immune system is divided into two major components: the innate immune system, which provides a rapid, non-specific response to infections, and the adaptive immune system, which targets pathogens more specifically through B and T cells, remembering past invaders. A healthy balance between these two arms of the immune system is critical for maintaining overall health and longevity. According to Lu, "When a small subset of blood stem cells overproduces innate immune cells, this drives the aging of the immune system, contributes to disease, and ultimately shortens the lifespan."
Investigating Age-Related Immune Imbalance
First author Anna Nogalska and colleagues found differences in immune aging in mice, even those with the same genetic background raised in identical environments. In particular, they observed that mice who aged more slowly—referred to as "delayed agers"—retained a youthful balance between innate and adaptive immune cells at 30 months of age. Conversely, "early agers" exhibited a pronounced increase in innate immune cells relative to adaptive immune cells.
Through detailed tracking of individual blood stem cells, the researchers identified a small subset of these cells responsible for this imbalance. As mice aged, 30-40% of their blood stem cells shifted production towards innate immune cells. The difference in immune aging between early and delayed agers appeared to stem from how these blood stem cells regulated their response to external signals.
CRISPR Gene Editing to Alter Immune Aging
To explore the genetic basis of this immune aging process, the scientists used CRISPR gene editing to alter the expression of specific genes linked to blood stem cell regulation. In delayed aging mice, certain genes were associated with restrained production of innate immune cells.
When these genes were edited out, blood stem cells began overproducing innate immune cells, mirroring the behavior seen in early agers.
In early aging mice, however, the researchers found that blood stem cells showed increased activity in genes related to the proliferation and differentiation of innate immune cells. When the researchers edited out these genes, the blood stem cells shifted back towards producing more adaptive immune cells, similar to what occurs in delayed agers. As a result, the immune system in early agers became more balanced, closely resembling that of delayed agers.
Potential for Human Application
Nogalska emphasized the relevance of this research to human health: "In the elderly human population, the immune system often tips into producing an overabundance of innate immune cells, which can contribute to diseases such as myeloid leukemia and immune deficiencies." Our study suggests how we might promote a more youthful immune system to combat these common diseases of aging.”
Publication Details
Nogalska, A., Eerdeng, J., Akre, S. et al. Age-associated imbalance in immune cell regeneration varies across individuals and arises from a distinct subset of stem cells. Cell Mol Immunol (2024). https://doi.org/10.1038/s41423-024-01225-y