Cellular quality control mechanisms such as autophagy are though to be an important part of the metabolic response to calorie restriction (CR), contributing to its ability to slow aging and lengthen life in most species and lineages tested. Here researchers dig into the biochemical details of the calorie restriction response in muscle tissue, and in this context it is interesting to note that calorie restriction has been shown to slow age-related loss of muscle mass and strength in mice:
It has been hypothesized that CR exerts its beneficial effects via a hormetic response that results in activation of protein chaperones, e.g. heat shock proteins (HSF), and autophagy, as well as in the inhibition of inflammation in rodents. However, the hormonal and molecular effects of long-term CR with adequate nutrition on stress-related factors have not been carefully evaluated in humans on long-term severe CR. In this study, we found that serum cortisol concentration, a major stress hormone, was significantly higher in the CR group than in sedentary or exercising subjects eating a Western diet and was notably inversely correlated with serum TNF-α levels. We also found that key stress-induced cytosolic chaperones and autophagic transcript and protein levels were significantly higher and inflammatory factors were lower in the skeletal muscle of CR individuals than in age-matched controls, providing evidence for a CR-induced enhancement of protein quality control and of the ability of cells to eliminate damaged proteins and organelles.
Chronic CR has consistently been shown to cause a dose-dependent moderate elevation (i.e., 30%-50% above baseline) of circulating corticosterone levels in both rats and mice. Data from a recent randomized clinical trial of 2-year mild CR in nonobese humans has shown a small, 7% transient increase of serum cortisol levels. Here, we show that serum cortisol concentration is ∼30% higher in humans practicing long-term severe CR than in age-matched control subjects. Our data suggest that the mechanism responsible for the sustained increase in serum cortisol concentrations induced by CR is likely related to CR itself, rather than changes in body composition, because the equally low body fat and leptin levels of the exercisers were not associated with high cortisol in the exercisers. Elevation of glucocorticoid levels is an essential adaptation required to cope with a variety of stressors, and in CR animals, high corticosterone level has been shown to play a role in inhibiting inflammation and cancer progression.
Whether the increased level of cortisol plays a direct role in upregulating HSPs is unclear. However, it is well known that CR increases HSF1 and HSP70 levels in rodents. Here, we show that long-term CR significantly upregulates transcripts along the HSF/HSP70 pathway and increases HSP70 and GRP78 protein levels in the human skeletal muscle. Because aging is associated with reduced protein folding capacity and ability to maintain homeostasis in response to stress, these data suggest that CR in humans prevents this decrease and may be involved in the slowing of age-dependent accumulation of damaged and dysfunctional proteins. We also found that chronic CR in humans is associated with lower inflammation.