How Immune Protein C3 Regulation Slows Aging and Boosts Immune Defense Through Calorie Restriction

A new study published in Nature Aging reveals that regulating the immune protein Complement component 3 (C3) may slow the aging process by reducing chronic inflammation associated with age-related decline. The research, conducted by scientists at Yale University, builds on earlier findings from the CALERIE trial, which showed that moderate calorie restriction in humans can improve immune function without negative side effects on growth or reproduction.

In the latest analysis, researchers examined plasma samples from participants who achieved an average 14% reduction in calorie intake over two years. They identified more than 7,000 proteins in the longitudinal samples and found that calorie restriction led to a significant decrease in the C3a/C3 ratio, indicating reduced activity of the complement system—a key driver of inflammaging, or chronic low-grade inflammation linked to aging.

The study supports the theory of immune antagonistic pleiotropy, where proteins like C3 that evolved to defend the body early in life can become harmful later, contributing to tissue damage and age-related diseases. By lowering C3 activity, calorie restriction appears to inhibit this harmful pathway, thereby reducing inflammation emanating from three canonical complement pathways.

Further analysis revealed that circulating C3a increases with age in both humans and mice, and that a specific non-senescent macrophage subset in visceral fat is the primary source of this age-related elevation. In these macrophages, C3a binds to its receptor C3AR1, triggering extracellular signal-regulated kinase (ERK) signaling, which drives age-related inflammation. Experiments in mice showed that blocking C3a with a neutralizing antibody reduced inflammaging in fat tissue.

The study also found that interventions known to extend lifespan in mice—such as overexpression of fibroblast growth factor 21 (FGF21) or deficiency of phospholipase A2 group VII (PLA2G7)—likewise reduced C3a levels, suggesting that C3a reduction is a metabolically regulated checkpoint that can be targeted to mitigate inflammaging.

Vishwa Deep Dixit, Waldemar Von Zedtwitz Professor of Pathology, professor of immunobiology and of comparative medicine, and director of the Yale Center for Research on Aging (Y-Age) at Yale School of Medicine, emphasized that the findings demonstrate aging is a malleable process that can be targeted through specific molecular interventions.

The research underscores the potential of targeting immune proteins like C3 to develop therapies that extend healthspan—the period of life spent in good health—without relying solely on dietary restriction, which can carry risks when applied too strictly.

While the study provides strong evidence for the role of C3 in aging, researchers note that further investigation is needed to determine whether modulating this protein can safely produce similar benefits in humans over the long term. The findings open new avenues for developing treatments aimed at delaying age-related decline by targeting the immune system’s role in metabolic regulation.