When a Calorie Is Not a Calorie: Metabolic and Molecular Effects of Intermittent Fasting in Humans; Exploratory Outcomes of a Randomized Clinical Trial.

Intermittent fasting (IF) extends healthspan and lifespan in rodents and has been associated with metabolic benefits in humans, yet results so far have been inconsistent. In this study, we tested the effects of IF-induced weight loss on metabolic and molecular determinants of healthy aging. We performed a randomized clinical trial with a partial cross-over design in overweight men and women (30-65 y, average 49.3 ± 8.2 y) to test the effects of six-month IF (NCT01964118). Fifty participants were randomized to the IF (n = 28) or usual diet (n = 22) group. The primary outcome was the assessment of change in serum C-reactive protein levels from baseline to six months; secondary outcomes were changes in insulin sensitivity using oral glucose tolerance test (OGTT)-based indexes, and plasma metabolomics and gene expression changes in colon mucosa. No difference in serum levels of C-reactive protein or multiple cytokines and chemokines was observed over this period, despite a significant IF-induced 8% weight loss. IF caused a statistically significant but clinically irrelevant small improvement in OGTT-derived insulin sensitivity indexes. Preliminary multi-omic data analysis suggests that a nonlinear relationship exists between IF-induced weight loss and inhibition of multiple key nutrient-sensing aging pathways. More trials are needed to understand the impact of different degrees of energy restriction on metabolic and molecular health in humans, and how fasting should be complemented with diet quality changes during feast days to maximize clinical and longevity outcomes.