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Caloric restriction in humans reveals immunometabolic regulators of health span

O. Spadaro,Y. Youm,I. Shchukina,S. Ryu,S. Sidorov,A. Ravussin,K. Nguyen,E. Aladyeva,A. Predeus,S. Smith,E. Ravussin,C. Galbán,M. Artyomov,V. Dixit

Published 2022 in Science

ABSTRACT

The extension of life span driven by 40% caloric restriction (CR) in rodents causes trade-offs in growth, reproduction, and immune defense that make it difficult to identify therapeutically relevant CR-mimetic targets. We report that about 14% CR for 2 years in healthy humans improved thymopoiesis and was correlated with mobilization of intrathymic ectopic lipid. CR-induced transcriptional reprogramming in adipose tissue implicated pathways regulating mitochondrial bioenergetics, anti-inflammatory responses, and longevity. Expression of the gene Pla2g7 encoding platelet activating factor acetyl hydrolase (PLA2G7) is inhibited in humans undergoing CR. Deletion of Pla2g7 in mice showed decreased thymic lipoatrophy, protection against age-related inflammation, lowered NLRP3 inflammasome activation, and improved metabolic health. Therefore, the reduction of PLA2G7 may mediate the immunometabolic effects of CR and could potentially be harnessed to lower inflammation and extend the health span. Description Searching for caloric restriction mimetics Moderately decreased food intake that does not cause malnutrition (caloric restriction) has beneficial effects on health span and life span in model organisms. Spadaro et al. examined measures of immune function in humans who restricted caloric intake by about 14% over 2 years and in mice under a more severe 40% restriction (see the Perspective by Rhoads and Anderson). Cellular analyses and transcriptional surveys showed marks of improved thymic function under caloric restriction. Expression of the gene encoding platelet activating factor acetylhydrolase (PLA2G7) was decreased in humans undergoing caloric restriction. Inactivation of the gene in mice decreased inflammation and improved markers of thymic function and some metabolic functions in aging mice. Thus, decreased expression of PLA2G7 might mediate some beneficial effects of caloric restriction. —LBR A gene knockout in mice partially mimics the benefits of caloric restriction observed in humans.

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