That has left scientists with a difficult question: Could humans gain some of the longevity benefits of calorie restriction without experiencing those harmful effects? A new study, published in Nature Aging, points to a possible answer involving an immune protein called complement component 3 (C3).

Yale researchers have previously shown that people who followed moderate calorie restriction, cutting calorie intake by 14% for two years, developed stronger immune defenses without experiencing problems related to growth or reproduction.

“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.

Calorie Restriction Lowers an Inflammation-Linked Protein

For the new study, Dixit and his colleagues at YSM examined plasma samples from 42 people who participated in a National Institutes of Health-funded two-year study 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 reduced their calorie intake by 11 to 14% without feeling deprived.

The researchers measured more than 7,000 proteins across plasma samples collected over time. One stood out: complement component 3 (C3), an immune protein whose levels fell significantly after calorie restriction.

C3 drew particular attention because earlier research has suggested that activation of the complement system, a network of proteins that helps defend the body against pathogens, may contribute to chronic inflammation. That persistent inflammation is considered a major feature of aging and many age-associated 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.

Fat Tissue Emerges as a Key Source of C3

By comparing protein levels before and after two years of calorie restriction, the team found that white adipose tissue, the main form of fat tissue in mammals, appeared to be the primary tissue affected by the dietary change.

The researchers then tested the pattern in animals. As they had seen in human plasma, C3 expression rose with age in mice. Additional biochemical testing showed that visceral white adipose tissue was a major source of the age-related increase in C3.

“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 allowed the researchers to narrow the source further. They found that C3 was being produced by age-associated macrophages, essential white blood cells located within adipose tissue.

“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 are among the immune system’s first responders and are best known for engulfing pathogens. They also play an important role in maintaining normal tissue function, Dixit adds.

Could the Benefits Be Independent of Weight Loss?

The next question was whether reducing C3 could provide benefits even without weight loss.

The researchers initially thought that losing adipose tissue might itself reduce C3 production and contribute to healthier aging. Most participants in the study lost about 18 pounds after two years of moderate calorie restriction.

However, when the researchers compared changes in body mass index with changes in complement protein levels, they found no relationship between the amount of weight lost and the decline in those proteins.

“This suggests that calorie restriction has a beneficial effect that is unique to adipose tissues and is likely independent of weight loss,” Kim says.

That raised the possibility that some of the biological benefits of calorie restriction might be reproduced without requiring people to lose weight.

Blocking C3 Reduces Inflammation in Mice

To test that idea, the researchers used a drug to inhibit C3 activation in mice, mimicking one of the effects of calorie restriction. The animals developed less age-related inflammation.

According to Dixit, the result illustrates how biological systems that are useful earlier in life can become harmful later. This concept, known as antagonistic pleiotropy, was proposed by biologist Peter Medawar in 1952 as an explanation for aspects of aging.

Growth hormone offers one example. It is essential during early development, but later in life it may also contribute to cancer.

C3 and similar proteins evolved to protect the body against infection. But because humans now live far longer than their ancestors, some of those same protective mechanisms may eventually begin contributing to disease. Dixit says reducing excessive C3 activity could potentially help extend health span.

Researchers Explore Existing Drugs as an Aging Target

The team is now studying whether FDA-approved inhibitor drugs could be used to suppress C3 production and potentially slow aspects of aging in humans.

The goal is not to eliminate the complement system entirely, because it remains essential for fighting infections.

“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.”