Why does the immune system become less effective as we age? A new USC study published in BMC Biology offers fresh insights by examining a key immune cell type across tissues: macrophages.
Macrophages act as the body's cleanup and maintenance crew. Found in nearly every tissue, they help fight infections, remove damaged cells, repair tissues, and keep inflammation under control – acting as a first line of defense for the immune system. But like many cells in the body, macrophages change as we get older.
In this new study, researchers analyzed data from macrophages collected from different mouse tissues, including the brain, lungs, liver, and other organs. By comparing younger and older animals, they uncovered common patterns of aging shared across many macrophage populations, as well as important differences depending on where the cells come from.
"We know that aging affects immune cells like macrophages, but most studies focus on a single tissue or organ, so there is little known on how local tissue environment can impact immune cell aging" said USC Leonard Davis School of Gerontology Associate Professor Bérénice Benayoun , the study's senior author. "We wanted to understand whether immune cells age in the same way throughout the body or whether each tissue has its own aging story."
The answer turned out to be both. The researchers found that aging macrophages across many tissues become more focused on responding to stress and cellular damage. At the same time, they appear to lose some of the molecular programs involved in maintaining healthy tissue structure and communication with their surroundings.
However, the study also revealed that macrophages in different organs age differently. For example, brain macrophages showed distinct age-related changes compared with those in the lungs. The researchers also found evidence that aging can affect macrophages differently in males and females across tissues.
These findings suggest that there may not be a one-size-fits-all solution for reversing immune aging. Instead, future therapeutic development may need to account for both the tissue involved and a person's biological sex.
However, the study also identified a set of genes and molecular pathways that changed consistently across many types of macrophages. Because these changes appeared repeatedly in different tissues, they could represent core features of immune aging and potential targets for future treatments designed to promote healthier aging.
As life expectancy continues to increase worldwide, understanding how the immune system changes over time has become an urgent scientific challenge. Age-related immune dysfunction contributes to a wide range of conditions, including chronic inflammation, increased susceptibility to infection, impaired wound healing, and many diseases associated with aging.
Importantly, this study leveraged a wealth of pre-existing datasets made publicly available after the original studies they were part of were published – giving these datasets a second life and extracting more information.
"There's an incredible wealth of publicly available, underutilized sequencing data for studying immune aging," said Ella Schwab, the study's lead author, Benayoun lab member and PhD student at the USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences. "By analyzing data from dozens of pre-existing studies, we could examine how macrophages age across tissues and between sexes - something no single study had the power to do alone."
By creating one of the most comprehensive maps to date of how macrophages age across the body, the researchers hope their work will provide a valuable resource for scientists seeking ways to maintain immune health later in life.
About the study
"Shared and niche-specific transcriptional signatures of macrophage aging revealed by a cross-tissue meta-analysis" appeared in BMC Biology on July 15th, 2026. Along with Schwab and Benayoun, co-authors included Eyael Tewelde and Leon Chen of USC. The study was funded by a grant from the Hevolution Foundation.
