Calorie restriction in humans: results after 2-years CALORIE study

Caloric restriction (CR) is a term used to describe moderately decreased food intake that does not cause malnutrition. In model organisms, CR was proven to have beneficial effects on health- and lifespan. In rodents, 40% CR leads to an extension of lifespan combined with changes in growth, reproduction, and immune defense. The CALORIE (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy) clinical trial was created to test the long-term effects of 2 years of moderate CR on physiology, aging biomarkers, and predictors of healthspan and longevity in healthy volunteers.

Spadaro et al. studied measures of immune function in CALORIE participants with about 14% voluntary CR and in mice under more severe 40% CR. As the level of CR in human participants was lower than the forced CR in laboratory animals, the researchers hypothesized that it may engage unique homeostasis-regulating mechanisms. 

The thymus is a specialized organ of the immune system within which the T-cells mature. Aging of the thymus precedes aging of other organs and is accompanied by loss of T cell production. The study showed that the CR improves thymic function including thymopoiesis (creation of mature T cells). Through adipose tissue reprogramming, CR influenced multiple pathways involved in mitochondrial bioenergetics, anti-inflammatory responses, and longevity. Mice on CR maintained thymopoiesis late in life, whereas in humans, CR led to the reduction in the number of circulating lymphocytes and pro-inflammatory cytokines in the blood. Compared with baseline, 2-years CR led to a significant increase in thymic mass as well as total volume in study participants.

Analysis of gene expression in the human adipose tissues identified the top 20 up- and down-regulated genes previously not highlighted in rodent studies. Changes were similar to those observed after bariatric surgery. Two years of CR in humans increased mitochondrial biogenesis and expression of insulin signaling components, suggesting enhanced insulin sensitivity. CR also induced the BMAL1 (brain-muscle-ARNT-like protein 1) clock pathway in human adipose tissue, implicated in mediating some of CR’s pro-longevity effects. Other discovered effects included decreased expression of components of innate immune activation and increased gene expression of FMO-2 (flavin-containing dimethylaniline monooxygenase 2). FMO-2 is an enzyme for which increased activity is associated with enhanced life span in Caenorhabditis elegans, whose relevance to human physiology is unclear.  

PLA2G7 (platelet-activating factor acetylhydrolase) gene was found to play a particularly important role regarding immune function and CR. Inactivation of the gene in mice decreased inflammation, improved thymic function, and some metabolic functions in aging mice. This deletion in mice showed decreased thymic atrophy, protection against age-related inflammation, and improved metabolic health. In humans undergoing CR, PLA2G7 was also inhibited. Thus, the reduction of PLA2G7 may mediate the immunometabolic effects of CR and could potentially be used in the creation of CR mimetics able to lower inflammation and extend the healthspan.

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