Methionine-supplemented longevity diet increases growth hormone, GLP-1, and FGF21; reduces frailty; and promotes healthspan.

Southern European countries have some of the highest life expectancies in the world, yet they display relatively high frailty. We examined different diets to identify compositions that promote both healthspan and strength in mice. The western and ketogenic diets increased fat mass and frailty and increased either cholesterol or insulin resistance, whereas a low-protein longevity diet, modeling the traditional Mediterranean and Okinawan diets but supplemented with methionine (LDMM), reduced fat mass and frailty while improving cardiometabolic markers. LDMM reduced insulin-like growth factor (IGF)-1 while increasing growth hormone, GLP-1, and fibroblast growth factor (FGF)21, which was required for fat loss and insulin sensitivity. Bimonthly cycles of a 4-day fasting-mimicking diet instead improved metabolic markers. A cross-sectional analysis of epidemiological data from over 200,000 men and women indicates that those with the highest animal protein intake tended to have a healthier lifestyle but had approximately double the prevalence of type 2 diabetes compared with those in the lowest intake group. These findings indicate that mostly plant-based low-amino-acid diets have the most potent effects on healthspan but require moderate methionine intake to minimize frailty.