Calorie restriction lowers C3, an immune protein tied to aging and inflammation, improving health without requiring weight loss.
Cutting calories has long been linked to longer life—but there’s a catch. In animals, dialing back food intake can delay disease and extend lifespan, yet pushing it too far begins to backfire, weakening immunity and disrupting basic biology.
Now, scientists think they may be closing in on why. A study published in Nature Aging highlights an unexpected player, an immune protein called complement component 3 (C3), that could help explain how modest calorie reduction delivers benefits without the risks.
Earlier work from Yale found that people who reduced calorie intake by about 14% over two years showed stronger immune function without negative effects on growth or reproduction.
Aging as a Modifiable Process
“This concept demonstrates that aging is actually malleable and a process that can be targeted,” says senior author Vishwa Deep Dixit, PhD, 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.
In the latest study, Dixit and colleagues analyzed plasma samples from 42 participants in a National Institutes of Health-funded two-year trial called the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy, or CALERIE.
“It’s the only trial of its kind that has been done with such rigor and control and demonstrates relevance to human physiology,” Dixit says. During the trial, participants were able to reduce their calorie intake by 11 to 14% without feeling deprived.
Discovery of C3 and Inflammation Link
The team identified more than 7,000 proteins in the samples. One protein, complement component 3 (C3), dropped significantly after calorie restriction. This protein drew attention because earlier research linked activation of the complement system, a group of proteins that help fight infections, to chronic inflammation, a key feature of aging and age-related diseases.
“But the causal effects of C3 in aging and chronic inflammation have not been identified. So, we were very excited to find that in our study,” says Hee-Hoon Kim, PhD, a postdoctoral associate in the Dixit lab and a co-first author of the paper.
Comparing protein levels before and after two years of calorie restriction showed that white adipose tissue, the body’s main fat storage tissue, was the primary site affected.
Adipose Tissue and Aging Mechanisms
The researchers confirmed these results in animals. In mice, C3 levels increased with age, and further analysis indicated that visceral white adipose tissue drove this rise.
“We were not expecting that because these proteins are mainly synthesized in the liver,” says Manish Mishra, PhD, a postdoctoral associate in the Dixit lab and a co-first author of the study.
Single-cell RNA sequencing revealed that age-associated macrophages, a type of immune cell found in fat tissue, produce this protein.
Role of Macrophages in Immune Function
“This whole process was unknown in the beginning,” Mishra says. “Just to narrow it down to the subtypes of macrophages responsible for this complement protein production was very challenging.”
Macrophages serve as a first line of defense by engulfing pathogens. They also help maintain tissue balance, Dixit explains.
Researchers then asked whether lowering C3 could provide benefits without weight loss.
Weight Loss vs. Biological Effects
At first, they thought fat loss itself might reduce C3 and slow aging, since participants lost about 18 pounds over two years of moderate calorie restriction.
However, body mass index data showed no link between weight loss and reduced complement protein levels.
“This suggests that calorie restriction has a beneficial effect that is unique to adipose tissues and is likely independent of weight loss,” Kim says.
Targeting C3 and Aging Theory
When researchers blocked C3 activation in mice using a drug that mimics calorie restriction, the animals showed lower levels of age-related inflammation.
The results support the idea that processes helpful early in life can become harmful later, a concept known as antagonistic pleiotropy. First proposed by biologist Peter Medawar in 1952, this theory explains aging by highlighting trade-offs such as growth hormone, which supports development but may also increase cancer risk later.
Proteins like C3 evolved to protect against infection, but as humans live longer, they may contribute to disease. Lowering C3 levels could help improve health span, Dixit says.
Researchers are now exploring whether FDA approved drugs can safely reduce C3 activity to slow aging in humans. “The idea is not to remove complement systems that are required for us to fight infections,” Dixit says. “Instead, the goal is to restore the balance.”
Reference: “Exoproteome of calorie-restricted humans identifies complement deactivation as an immunometabolic checkpoint reducing inflammaging” by Manish Mishra, Hee-Hoon Kim, Yun-Hee Youm, Elsie Gonzalez-Hurtado, Konstantin Zaitsev, Tamara Dlugos, Irina Shchukina, Christy Gliniak, Eric Ravussin, Subhasis Mohanty, Albert C. Shaw, Philipp E. Scherer, Maxim N. Artyomov and Vishwa Deep Dixit, 13 April 2026, Nature Aging.
DOI: 10.1038/s43587-026-01107-0
The research in this article was supported by the National Institutes of Health (awards AG073969, P01AG051459, and U54AG079759) and Yale University.
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