Reducing calorie intake has extended the lifespan of animals such as mice, rhesus monkeys, and fruit flies. In some studies, animals also stayed healthier for longer. But severe calorie restriction can come with significant costs. Mice placed on a diet with 40% fewer calories, for example, become more vulnerable to infections, reproduce less successfully, and show poor growth.
This 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 agingpoints to a possible response involving an immune protein called complement component 3 (C3).
Yale researchers have shown above that people who followed moderate calorie restriction, reducing calorie intake by 14% over two years, developed stronger immune defenses without experiencing problems related to growth or reproduction.
“This concept demonstrates that aging is actually malleable and a steerable process,” says senior author Vishwa Deep Dixit, PhD, Waldemar Von Zedtwitz Professor of Pathology, professor of immunobiology and comparative medicine, and director of the Yale Center for Research on Aging (Y-Age) at Yale School of Medicine.
Caloric restriction reduces a protein linked to inflammation
For the new study, Dixit and his YSM colleagues examined plasma samples from 42 people who participated in a two-year study funded by the National Institutes of Health called Comprehensive assessment of the long-term effects of reducing energy consumption or CALERÍA.
“It is the only trial of its kind that has been performed with such rigor and control and demonstrates relevance to human physiology,” says Dixit. During the test, participants reduced their calorie intake by 11 to 14% without feeling deprived.
The researchers measured more than 7,000 proteins in plasma samples collected over time. One stood out: complement component 3 (C3), an immune protein whose levels dropped significantly after calorie restriction.
C3 drew particular attention because previous 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. Such persistent inflammation is considered an important characteristic of aging and many age-related diseases.
“But the causal effects of C3 on aging and chronic inflammation have not been identified. Therefore, we were very excited to discover it in our study,” says Hee-Hoon Kim, PhD, a postdoctoral associate in the Dixit lab and co-senior 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 fatty tissue in mammals, appeared to be the main tissue affected by the change in diet.
The researchers then tested the pattern on animals. As they had observed in human plasma, C3 expression increased with age in mice. Additional biochemical testing showed that visceral white adipose tissue was an important source of the age-related increase in C3.
“We didn’t expect that because these proteins are primarily synthesized in the liver,” says Manish Mishra, PhD, a postdoctoral associate in the Dixit lab and co-first author of the study.
Single-cell RNA sequencing allowed the researchers to further narrow down the source. They found that C3 was produced by age-associated macrophages, essential white blood cells located within adipose tissue.
“At first this whole process was unknown,” says Mishra. “Just narrowing it down to the macrophage subtypes responsible for the production of this complement protein was a big challenge.”
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, adds Dixit.
Could the benefits be independent of weight loss?
The next question was whether reducing C3 could provide benefits even without losing weight.
Initially, researchers thought that loss of adipose tissue could reduce C3 production and contribute to healthier aging. Most study participants 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 decrease in those proteins.
“This suggests that caloric restriction has a beneficial effect that is unique to adipose tissues and is likely independent of weight loss,” says Kim.
This raised the possibility that some of the biological benefits of calorie restriction could be replicated without the need for weight loss.
C3 blockade 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 early in life can become harmful later on. This concept, known as antagonistic pleiotropy, was proposed by biologist Peter Medawar in 1952 as an explanation of aspects of aging.
Growth hormone offers an example. It is essential during the early stages of development, but later in life it can also contribute to cancer.
C3 and similar proteins evolved to protect the body against infections. But because humans now live much longer than their ancestors, some of those same protective mechanisms may eventually begin to contribute to disease. Dixit says reducing excessive C3 activity could help extend lifespan.
Researchers explore existing drugs to target aging
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 completely eliminate the complement system, because it is still essential for fighting infections.
“The idea is not to eliminate the complement systems that we need to fight infections,” Dixit says. “Instead, the goal is to restore balance.”