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What keeps some immune systems youthful and effective in warding off age-related diseases? In a new paper published in Cellular & Molecular Immunology, USC Stem Cell scientist Rong Lu and her collaborators point the finger at a small subset of blood stem cells, which make an outsized contribution to maintaining either a youthful balance or an 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 quick and general attack against invading germs. For germs that evade the body’s innate immune defenses, the second line of attack consists of , such as B cells and T cells that rely on their memory of past infections to craft a specific and 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 overproduces innate immune cells, this drives the aging of the immune system, contributes to disease, and ultimately shortens the lifespan,” said Lu, who is an associate professor of stem cell biology and , , medicine, and gerontology at USC, and a Leukemia & Lymphoma Society Scholar. Lu is also a member of the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, and the USC Norris Comprehensive Cancer Center at the Keck School of Medicine of USC.

The generation and maintenance of protective immunity is a dynamic interplay between host and environment that is impacted by age. Understanding fundamental changes in the healthy immune system that occur over a lifespan is critical in developing interventions for age-related susceptibility to infections and diseases. Here, we use multi-omic profiling (scRNA-seq, proteomics, flow cytometry) to examined human peripheral immunity in over 300 healthy adults, with 96 young and older adults followed over two years with yearly vaccination. The resulting resource includes scRNA-seq datasets of 16 million PBMCs, interrogating 71 immune cell subsets from our new Immune Health Atlas. This study allows unique insights into the composition and transcriptional state of immune cells at homeostasis, with vaccine perturbation, and across age. We find that T cells specifically accumulate age-related transcriptional changes more than other immune cells, independent from inflammation and chronic perturbation. Moreover, impaired memory B cell responses to vaccination are linked to a Th2-like state shift in older adults’ memory CD4 T cells, revealing possible mechanisms of immune dysregulation during healthy human aging. This extensive resource is provided with a suite of exploration tools at https://apps.allenimmunology.org/aifi/insights/dynamics-imm-health-age/ to enhance data accessibility and further the understanding of immune health across age.

A.W.G. serves on the scientific advisory boards of ArsenalBio and Foundery Innovations.

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