Methionine-supplemented Longevity diet increases GLP-1 and FGF21 to reduce frailty and promote healthspan

Southern European countries have some of the highest life expectancies in the world, yet they display high frailty. Here, we examined different diets to identify compositions that promote both healthspan and strength. In genetically diverse mice, the western and ketogenic diets increased fat mass, insulin resistance, and cholesterol levels. In contrast, a low-protein pescatarian Longevity Diet (LD), combining traditional Mediterranean and Okinawan features with moderate methionine supplementation (LDMM) or a fasting-mimicking diet (FMD), reduced fat mass and frailty while improving cardiometabolic markers. The normocaloric LDMM reduced IGF-1 while increasing growth hormone, GLP-1, and FGF21, which was crucial for diet-induced fat loss and improved insulin sensitivity. These findings indicate that high methionine intake may partially explain the major increase in overweight and diabetes in epidemiological studies of subjects who maintain a healthy lifestyle but consume a high animal protein diet, but not in those consuming a high plant protein diet.