Calorie restriction has been shown to extend the lifespan of animals, including mice, rhesus macaques, and fruit flies. In some studies, the animals also stayed healthier for longer. However, severe calorie restriction can have serious drawbacks. Mice fed a diet with 40% fewer calories, for example, are more vulnerable to infections, reproduce less successfully, and experience stunted growth.
These findings raise an important question: Can humans gain some of the longevity benefits of calorie restriction without suffering its harmful effects? A new study points to a possible answer involving complement component 3 (C3), an immune protein linked to natural aging and chronic inflammation.
Researchers at Yale University previously showed that people who practiced moderate calorie restriction—reducing their calorie intake by 14% for two years—developed stronger immune defenses without experiencing problems related to growth or reproduction.
“This concept shows that aging is actually a malleable and targetable process,” says lead author Vishwa Deep Dixit, Ph.D., Waldemar von Zettwitz Professor of Pathology, Professor of Immunobiology and Comparative Medicine, and Director of the Center for the Study of Aging (Y-Age) at Yale School of Medicine.
Calorie restriction lowers inflammation-related proteins
For the new study, Dixit and his colleagues at Yale School of Medicine conducted a two-year clinical trial funded by the National Institutes of Health. The trial, known as the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE) study, examined the effects of moderate calorie restriction in humans.
“This is the only study of its kind to be conducted with enough rigor and control to demonstrate a link to human physiology,” Dixit said. During the trial, participants reduced their calorie intake by 11% to 14% without reporting significant feelings of deprivation.
The researchers analyzed more than 7,000 proteins in plasma samples collected throughout the study. One protein stood out: complement component 3, or C3. Levels of this immune protein decreased significantly after participants followed a calorie-restricted diet.
C3 attracted particular attention because previous research has suggested that activation of the complement system—a network of proteins that helps protect the body against pathogens—may contribute to chronic inflammation. Persistent, low-grade inflammation is considered a key characteristic of aging and many age-related diseases.
“However, the causal role of C3 in aging and chronic inflammation had not been determined, so we were very excited to identify it in our study,” says Dr. Hee-Hoon Kim, a postdoctoral fellow in the Dixit laboratory and co-first author of the study.
Adipose tissue emerges as a major source of C3
By comparing protein levels before and after two years of calorie restriction, the researchers found that white adipose tissue—the primary type of body fat in mammals—was significantly affected by the dietary intervention.
The researchers then tested their findings in mice. As observed in human blood samples, C3 expression increased with age in the animals. Additional biochemical analyses showed that visceral white adipose tissue was the primary source of this age-related increase in C3.
“This was unexpected because these proteins are primarily synthesized in the liver,” says Manish Mishra, Ph.D., a postdoctoral fellow in the Dixit laboratory and co-lead author of the study.
Using single-cell RNA sequencing, the researchers narrowed down the cellular source of C3. They found that the protein was produced by age-associated macrophages, immune cells that reside within adipose tissue.
“This whole process was unclear at first,” Mishra said. “Narrowing down the macrophage subtype responsible for producing this complement protein was extremely difficult.”
Macrophages are among the immune system’s first responders and are best known for engulfing pathogens. They also play an important role in maintaining healthy tissue function, Dixit added.
Are the effects independent of weight loss?
The researchers next asked whether lowering C3 could provide health benefits without requiring weight loss.
Initially, they suspected that losing adipose tissue might reduce C3 production and contribute to healthier aging. Most participants in the study lost approximately 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 weight loss and the reduction in C3 or other complement proteins.
“This suggests that calorie restriction has beneficial effects specific to adipose tissue and that these effects are likely independent of weight loss,” Kim says.
The findings raise the possibility that some of the biological benefits of calorie restriction could be replicated without reducing body weight.
Blocking C3 reduces inflammation in mice
To test this possibility, the researchers used a drug that inhibits C3 activation in mice, mimicking one of the effects of calorie restriction. The treated animals developed less age-related inflammation.
Dixit said the results demonstrate how biological systems that are beneficial early in life can become harmful later. This concept, known as antagonistic pleiotropy, was proposed by biologist Peter Medawar in 1952 to explain certain aspects of aging.
Growth hormone is one example. It is essential for early development, but excessive growth hormone activity later in life may also contribute to cancer.
C3 and related complement proteins evolved to protect the body from infections. However, because humans now live much longer than our ancestors, some protective mechanisms may eventually contribute to chronic disease. Dixit says that reducing excessive C3 activity could potentially help extend healthspan—the number of years a person lives in good health.
Researchers investigate existing drugs for healthy aging
The research team is now studying whether FDA-approved inhibitors that suppress C3 production could help slow aspects of aging in humans.
The goal is not to eliminate the complement system completely because it remains essential for fighting infections.
“The idea is not to remove the complement system, which is necessary to fight infections,” Dixit said. “Rather, the goal is to restore balance.”
Source: www.sciencedaily.com