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Calorie restriction and human muscle function

The study adds to growing evidence about the health benefits of calorie restriction. KAMPUS / Shutterstock

Calorie restriction reduces total calorie intake while maintaining adequate levels of essential nutrients. In animal models, this approach has been shown to increase lifespan and delay age-related disease. Whether calorie restriction has similar benefits for humans is unclear.

A randomized controlled trial called CALERIE (Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy) studied the health effects of calorie restriction in humans. Participants on calorie-restricted diets were asked to reduce their daily caloric intake by 25%. They were able to achieve an average of 12% calorie reduction and 10% weight reduction, mostly from body fat, over two years. They had minor loss of muscle mass, but without a significant decline in muscle strength. This suggests that calorie restriction may improve muscle quality. But the biological mechanisms behind this effect remained unknown.

A research team led by Dr. Luigi Ferrucci at NIH’s National Institute of Aging sought to understand the mechanisms behind this effect. To do so, they examined gene expression in thigh muscle biopsies from 90 CALERIE participants: 57 in the calorie-restriction group and 33 in the control group. When a gene is expressed, its sequence is transcribed into messenger RNA, or mRNA; this is sometimes called gene activity. Biopsies were taken at the beginning of the study and at one- and two-year follow-ups. Results appeared in Aging Cell on October 12, 2023.

More than 1,000 genes were expressed differently between calorie-restricted and non-calorie restricted participants. Many of these had been found to be affected by calorie restriction in animal models. 

The team grouped the genes according to their biological pathways and identified 53 pathways affected by calorie restriction. Consistent with findings in animal models, expression of most of the affected pathways was activated. These included pathways related to muscle formation and repair, circadian clock regulation, and biological mechanisms tied to aging. Inflammation-related pathways, in contrast, were dampened.

The researchers compared the changes in these pathways to the participants’ changes in muscle quality. Several of the pathway changes were associated with the effects of calorie restriction on muscle quality. Some of them play a similar role in animal models.

The team also examined changes in RNA splicing. After an mRNA is made, it must undergo splicing before it can be translated into protein. By splicing the RNA in different ways, a single gene can produce more than one protein. Calorie restriction led to changes in the splicing variants from many genes. The affected pathways related to muscle physiology and aging. Changes in both expression and splicing often occurred in the same gene.

These findings suggest that moderate calorie restriction likely affects muscle health through similar mechanisms in humans and animal models. Thus, long-term calorie restriction might prevent age-related declines in muscle function in humans.

“A 12% reduction in calorie intake is very modest,” Ferrucci notes. “This kind of small reduction in calorie intake is doable and may make a big difference in your health.”