Falling Levels of Immune Protein C3 May Explain Calorie Restriction's Anti-Aging Effect

Reducing calorie intake has extended lifespan in mice, rhesus monkeys and fruit flies, and in some studies kept the animals healthier for longer, but severe restriction carries costs: mice fed 40% fewer calories become more vulnerable to infection, reproduce less successfully and show impaired growth. A new study published in Nature Aging by researchers at Yale School of Medicine points to a way to gain some of those benefits without the harm, involving an immune protein called complement component 3 (C3).

The team, led by senior author Vishwa Deep Dixit, director of the Yale Center for Research on Aging, examined plasma samples from 42 people who took part in CALERIE (Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy), a National Institutes of Health-funded two-year trial in which participants cut calorie intake by 11 to 14% without feeling deprived. Yale researchers had previously shown that this moderate restriction strengthened participants' immune defenses without harming growth or reproduction.

Measuring more than 7,000 proteins in the plasma samples, the researchers found that C3 levels fell significantly after calorie restriction. C3 is part of the complement system, a network of proteins that defends the body against pathogens; its activation has separately been linked to the chronic inflammation considered a major feature of aging. White adipose tissue, the body's main fat tissue, turned out to be the primary source of the age-related rise in C3, a surprise, the researchers said, since such proteins are mainly made in the liver. Single-cell RNA sequencing traced the source further, to age-associated macrophages within the fat tissue.

Most participants lost about 18 pounds over the two years of calorie restriction, but the researchers found no relationship between how much weight a person lost and how much their C3 levels fell, suggesting the effect on C3 is independent of weight loss. When the team used a drug to block C3 activation in mice, mimicking that effect of calorie restriction, the animals developed less age-related inflammation.

Dixit's team described the finding using the concept of antagonistic pleiotropy, proposed by biologist Peter Medawar in 1952, the idea that biological mechanisms useful early in life, such as growth hormone during development, can become harmful later on. The researchers are now studying whether existing FDA-approved drugs that inhibit C3 production could be used to target aspects of aging in humans.