Researchers have identified an immune protein that may help explain some of the biological effects of calorie restriction. The findings suggest that complement component 3, or C3, could become a target for reproducing certain benefits of calorie restriction without requiring severe reductions in food intake.
Calorie restriction has been shown to extend lifespan or improve health-related outcomes in several animal models. However, substantial long-term calorie restriction can carry risks and is difficult to maintain, prompting researchers to investigate the biological pathways responsible for its effects.
Human trial reveals a potential aging signal
The new study, published in Nature Aging, analyzed data from CALERIE, a National Institutes of Health-supported clinical trial that examined calorie restriction in healthy adults. Participants reduced their calorie intake by approximately 11% to 14% over two years.
Yale researchers analyzed more than 7,000 proteins in plasma samples from 42 participants collected before and after the intervention.
Among the proteins that changed, C3 emerged as an important signal, with levels declining following moderate calorie restriction.
C3 is a central component of the complement system, a group of proteins involved in immune defense and inflammation. While complement activity is essential for protecting against infection, excessive or dysregulated activation has also been implicated in inflammatory processes and several age-related diseases.
Fat tissue emerged as an important source
To investigate the biological origin and significance of the C3 changes, the researchers turned to mouse models.
They found that C3 levels increased with age in mice and identified abdominal white adipose tissue as an important contributor to this age-related increase.
Complement proteins are commonly associated with production in the liver, making the contribution from aging adipose tissue particularly interesting.
Using single-cell RNA sequencing, the researchers traced C3 expression within fat tissue to age-associated macrophages. Macrophages are immune cells involved in functions including pathogen defense, removal of cellular debris and regulation of inflammatory responses.
The findings suggest that changes in immune cells within aging adipose tissue may contribute to increased C3 production and age-associated inflammation.
Changes were not explained by weight loss alone
Participants undergoing calorie restriction lost an average of approximately 18 pounds over the two-year intervention.
However, the researchers did not find a direct association between changes in body mass index and changes in C3 and related complement proteins.
This suggests that the reduction in complement signaling may not simply reflect losing body weight. Calorie restriction may also alter the biological characteristics of adipose tissue and the immune cells within it.
The distinction could be important because it suggests that the health effects associated with calorie restriction cannot necessarily be reproduced simply by achieving the same amount of weight loss.
However, the analysis does not establish that reducing C3 is responsible for the broader health effects of calorie restriction in humans.
Blocking C3 reduced inflammation in mice
The researchers next investigated whether directly interfering with C3 activity could affect age-related inflammation.
In mice, pharmacological inhibition of C3 activation reduced inflammatory changes associated with aging. This provided experimental evidence that C3 is not merely a marker that changes alongside aging, but may participate in inflammatory processes.
The findings are consistent with the broader concept of antagonistic pleiotropy, in which biological mechanisms that are advantageous earlier in life can have less beneficial effects later.
The complement system is essential for immune defense, but persistent or excessive complement activity later in life could potentially contribute to chronic inflammatory states.
That also presents a challenge for potential therapies. Completely suppressing complement activity could interfere with protection against infection, meaning that any future strategy would need to balance reducing harmful inflammation against preserving essential immune functions.
Could existing drugs target this pathway?
The findings raise the possibility that complement-targeting drugs could eventually be investigated for age-related conditions.
Several complement inhibitors are already approved by the U.S. Food and Drug Administration for specific diseases. Their existence provides researchers with established pharmacological approaches for modifying parts of the complement pathway.
However, approval for one disease does not mean these medications are safe or effective as treatments for aging. Complement inhibition can carry significant risks, including increased susceptibility to certain infections.
Clinical studies would therefore be required to determine whether targeting C3 or related pathways can produce meaningful health benefits in older adults and whether those benefits outweigh the risks.
Researchers are also interested in understanding how complement activity interacts with other biological changes associated with aging, including metabolic dysfunction, cellular senescence and changes in immune function.
For now, the study does not provide evidence for an anti-aging drug or demonstrate that C3 inhibition can extend human lifespan. Instead, it identifies a potential biological pathway connecting moderate calorie restriction, adipose-tissue immune activity and age-related inflammation.
The findings suggest that changes occurring within fat tissue may be important to understanding the effects of calorie restriction beyond weight loss alone. If future human studies confirm a causal role for excessive complement activity in age-related disease, selectively modifying this pathway could eventually offer another way to target some of the biological processes associated with aging.
