Researchers identify immune protein C3 as a potential shortcut to calorie-restriction benefits
Yale researchers found that moderate calorie restriction lowers the immune protein C3; blocking C3 in mice reduced age‑related inflammation, suggesting a druggable route to some benefits of dieting.
New laboratory and human data suggest that dialing down a single immune protein — complement component 3 (C3) — may reproduce some anti‑aging effects of moderate calorie restriction without requiring severe dieting.
Scientists at Yale analyzed blood samples from participants in the CALERIE trial, a rigorously controlled, National Institutes of Health–funded study in which volunteers reduced calorie intake by about 11–14% for two years. By measuring more than 7,000 plasma proteins, the team found a clear decline in C3 levels after the dietary intervention.
Fat tissue and immune cells implicated
Follow-up work in mice showed that C3 levels rise with age and that visceral white adipose tissue is a major source of the increase. Single‑cell RNA sequencing identified age‑associated macrophages within fat as the specific producers of C3, pointing to a localized, tissue‑level mechanism linking diet, immunity and chronic inflammation.
Although most human participants lost roughly 18 pounds over the two years, changes in body mass index did not correlate with the drop in complement proteins, suggesting the effect on C3 may be independent of weight loss and instead reflect a unique adipose tissue response to calorie restriction.
In mouse experiments, pharmacologic inhibition of C3 activation reduced markers of age‑related inflammation, raising the possibility that targeting this pathway could extend health span without the downsides of severe dietary restriction.
Investigators say the aim is to restore balance in the complement system rather than eliminate it: “The idea is not to remove complement systems that are required for us to fight infections,” one senior researcher noted. Ongoing work is exploring whether existing FDA‑approved inhibitors could be repurposed to safely modulate C3 activity in humans.
The findings, reported in Nature Aging, add to evidence that specific immune pathways in fat tissue help drive “inflammaging” and may be actionable targets to mimic some benefits of calorie restriction. Researchers caution that the complement system remains essential for defense against pathogens and that more studies will be needed to evaluate safety and long‑term effects in people.