Caloric restriction in humans reveals immunometabolic regulators of health span

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.

Sulfur Amino Acid Supplementation Abrogates Protective Effects of Caloric Restriction for Enhancing Bone Marrow Regrowth Following Ionizing Radiation

“…Although therapeutic DR is safe and effective in animal models and in humans under closely supervised conditions [ 74 , 75 ], the extent of 50% daily restriction utilized in this study may be difficult for the majority of individuals and/or potentially dangerous for those with certain underlying metabolic disorders and nutritional requirements [ 76 , 77 ]. However, it was recently reported that reducing daily caloric intake by just 14% in humans over a 2 year span was sufficient to drive CR-induced transcriptional reprogramming related to bioenergetics, anti-inflammatory responses, and longevity [ 78 ]. Thus, such severe restriction of total food intakes by 50% may not be necessary to drive radioresistance in humans.…”

Epigenome-wide association study analysis of calorie restriction in humans, CALERIE™ Trial analysis

“…The goal of the CALERIE™ Trial was to identify effects of CR on predictors of longevity, disease risk factors and quality of life. Published analyses of CALERIE™ data establish that the intervention improved cardiometabolic health and suggest it may have slowed or reversed aging-related biological changes (15–19,36). In this study, we tested whether the intervention altered whole-blood DNAm.…”

“…The intervention yielded substantial and sustained weight loss and signs of improved cardiometabolic health, reduced inflammation, and slowed biological aging, as measured by physiology-based algorithms (16,17). In ancillary studies in subsets of CALERIE TM participants, CR induced signs of metabolic slowing and reversal of markers of immune-system aging (18,19).…”

Nonresolving inflammation redux

“…Caloric restriction, which counteracts some effects of aging, reduced the expression of the platelet activating factor acetylhydrolase PLA2G7 in human and mouse myeloid cells, leading to decreased ceramide-dependent NLRP3 activation ( Spadaro et al., 2022 ). Deletion of PLA2G7 led to lower amounts of circulating TNF-α and IL-1β in 2-year-old mice, implicating PLA2G7 as a mediator of inflammatory aging ( Spadaro et al., 2022 ). Age-related de-repression of retrotransposable elements promotes type I IFN secretion ( De Cecco et al., 2019 ).…”