A new study published in Nature Aging suggests that calorie restriction may provide longevity benefits through a mechanism involving an immune protein called complement component 3 (C3). Researchers at Yale School of Medicine examined plasma samples from participants in a rigorous, NIH-funded clinical trial where individuals reduced calorie intake by 11 to 14% over two years. The study identified C3 as a protein whose levels declined significantly following moderate calorie restriction.
C3 is part of the complement system, a network of immune proteins that defend against pathogens. Earlier research has linked activation of this system to chronic inflammation, which is considered a hallmark of aging and age-related diseases. By analyzing more than 7,000 proteins in plasma samples collected over time, researchers determined that C3 was a key factor. They found that white adipose tissue, the primary form of fat tissue in mammals, was the main tissue affected by the dietary intervention. Further investigation using single-cell sequencing revealed that age-associated macrophages within adipose tissue were producing the C3.
A notable finding was that the reduction in C3 appeared independent of weight loss. Despite most study participants losing approximately 18 pounds, researchers found no correlation between the amount of weight lost and the decline in complement proteins. This suggests that calorie restriction may have beneficial effects specific to how adipose tissue functions, potentially separate from weight reduction itself. The discovery raises the possibility that some anti-aging benefits could potentially be achieved through other means without requiring significant weight loss.
To test whether lowering C3 alone could confer benefits, researchers used a drug to inhibit C3 activation in mice. The treated animals developed less age-related inflammation compared to controls. The researchers are now investigating whether FDA-approved C3 inhibitor drugs could be applied in humans to slow aspects of aging. The goal would be to modulate rather than eliminate the complement system, since it remains essential for fighting infections and protecting health.
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