Calorie Restriction Lowers C3 Protein Linked to Aging Inflammation

Study Links Calorie Restriction to Lower C3 Protein Levels

Researchers at Yale School of Medicine have found that moderate calorie restriction in humans leads to a significant drop in the immune protein complement component 3 (C3), which is associated with chronic inflammation as people age.

The study, published in Nature Aging, analyzed plasma samples from 42 participants in a two-year National Institutes of Health-funded trial, where calorie intake was reduced by 11 to 14%.

Evidence from Human and Animal Research

The human study, known as CALERIE, is the only trial of its kind to rigorously test the effects of calorie restriction on human physiology over two years. Participants did not report feeling deprived, and the intervention did not cause problems with growth or reproduction.

Researchers also studied mice and found that C3 levels increased with age, particularly in visceral white adipose tissue. Blocking C3 in mice reduced age-related inflammation, suggesting a possible mechanism behind calorie restriction's benefits.

Fat Tissue and Immune Cells as Key Sources of C3

The team discovered that white adipose tissue, especially visceral fat, was a main source of increased C3 with age. This was unexpected, as C3 is usually synthesized in the liver.

Single-cell RNA sequencing identified age-associated macrophages—immune cells in fat tissue—as the producers of C3. This finding highlights a new connection between immune function, fat tissue, and aging-related inflammation.

Implications for Metabolic Health and Aging

The results suggest that targeting C3 could potentially mimic some anti-aging effects of calorie restriction without requiring severe dietary changes. This could be relevant for people seeking to manage inflammation and metabolic health as they age.

However, the study does not show whether reducing C3 provides benefits independent of weight loss, and further research is needed to determine if these findings translate into practical treatments for humans.

Limitations and Next Steps

The study involved a small group of human participants and relied on animal models to test the effects of blocking C3. The long-term safety and effectiveness of targeting C3 in humans are not yet known.

Researchers note that while calorie restriction lowered C3 and inflammation, severe restriction can have negative effects, such as increased infection risk and impaired growth in animals. More research is needed to find safe ways to achieve similar benefits.