A new study reveals how aging changes the immune system in complex ways and identifies potential targets for healthier aging.
Why does immunity weaken with age, and does that decline happen the same way throughout the body?
Researchers at USC approached that question by looking across the body rather than focusing on a single organ. Using macrophage data from multiple mouse tissues, including the brain, lungs, liver, and other organs, they found that these immune cells develop some common signs of aging while also changing in ways that depend on the tissue around them. The findings were published in BMC Biology.
“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.”
Macrophages are found in nearly every tissue and play several essential roles in immune defense and tissue maintenance. They fight infections, clear damaged cells, support tissue repair, and help control inflammation. But because the environments surrounding them differ greatly from organ to organ, researchers wanted to know how much those local conditions shape the aging process.
A body-wide view of macrophage aging
Comparing macrophages from younger and older animals revealed a combination of shared and tissue-specific changes.
Across many tissues, older macrophages shifted more of their activity toward responding to cellular stress and damage. At the same time, some molecular programs involved in maintaining healthy tissue structure and communicating with the surrounding environment became less active.
The similarities, however, only went so far. Macrophages in the brain showed age-related changes that differed from those found in the lungs, for example. The researchers also found evidence that macrophage aging can differ between males and females across tissues.
Together, the findings suggest that immune aging reflects both broad biological processes that occur throughout the body and local influences unique to individual organs.
Public datasets made the comparison possible
To build such a wide-ranging picture, the researchers drew heavily on sequencing datasets that had already been made publicly available by other scientists.
Rather than examining one tissue in one experiment, the team integrated data from dozens of previously published studies. That allowed them to compare macrophage aging across tissues and sexes on a scale that would have been difficult for any single study to achieve.
“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 combining those datasets, the researchers produced one of the most comprehensive maps yet of how macrophages change with age across the body.
Immune aging may require tailored treatments
The tissue-specific differences could have implications for efforts to slow or reverse age-related immune decline. If macrophages do not age identically throughout the body, a treatment that works well in one organ may not have the same effect in another. Future approaches may therefore need to account for both the affected tissue and a person’s biological sex.
At the same time, the researchers identified genes and molecular pathways that changed consistently across many macrophage types. Because these recurring changes appeared in multiple tissues, they may represent more fundamental features of immune aging and could provide broader targets for future therapies.
Understanding both kinds of changes is becoming increasingly important as people live longer worldwide. Age-related immune dysfunction is associated with chronic inflammation, greater vulnerability to infection, slower wound healing, and numerous diseases linked to aging.
The researchers hope their body-wide map of macrophage aging will give other scientists a foundation for investigating ways to preserve immune function and promote healthier aging later in life.
Reference: “Shared and niche-specific transcriptional signatures of macrophage aging revealed by a cross-tissue meta-analysis” by Ella Schwab, Eyael Tewelde, Leon Chen and Bérénice A. Benayoun, 15 July 2026, BMC Biology.
DOI: 10.1186/s12915-026-02672-x
This work was supported by Hevolution grant HF-GRO-23–1199072-28 to B.A.B. and USC Leonard Davis School of Gerontology Biology of Aging PhD Research Fellowships to ET.
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