Effects of fasting-mimicking diets with low and high protein content on cardiometabolic health and autophagy: A randomized, parallel group study

Very low-calorie, fasting-mimicking diets (FMD) have been shown to promote cardiometabolic health and autophagy. However, most studies have focused on low protein diets to stimulate autophagy and reduce ageing-related factors. The aim of this study was to investigate the physiological, metabolic and molecular effects of a 7-day plant-based FMD with low protein/high fat (LP) and high protein/low fat content (HP) in healthy humans and compare those responses to a non-intervention comparator control group. Forty six healthy men and women were randomly assigned to one of three groups: CONTROL (isoenergetic diet), n = 16 (mean ± SD age 35.0 ± 9.5 yrs, BMI 23.3 ± 2.7 kg.m-2); LP-FMD (850 Calories per day: 10 % protein/45 % fat), n = 15, (age 38.2 ± 10.7 yrs, BMI 23.4 ± 3.2 kg.m-2); HP-FMD (850 Calories per day: 30 % protein/25 % fat), n = 15, (age 41.4 ± 8.8 yrs, BMI 25.1 ± 3.7 kg.m-2). Blood and faecal sampling, DEXA scans and functional tests of cardiovascular health were performed before and after each 7-day treatment. Both FMDs reduced body weight and fat mass (interaction effects P < 0.0001) but only HP-FMD reduced visceral fat mass relative to CONTROL mean difference (95 % CI): -0.09 (-0.15 to -0.03) kg, P = 0.006. Both FMDs reduced fasting plasma glucose by ∼10 % LP-FMD: -0.41 (-0.80 to -0.02) mmol.L-1, P = 0.038; HP-FMD: [-0.46 (-0.74 to -0.17) mmol.L-1, P = 0.003 and IGF1 by ∼35 % LP=FMD: -9.0 (-12.4 to -5.5) nmol.L-1, P < 0.0001; HP-FMD: -5.4 (-8.6 to -2.1) nmol.L-1, P = 0.024 relative to CONTROL. The increase in serum hydroxybutyrate was higher in the LP- than HP-FMD 0.64 (0.13 to 1.15) mmol.L-1, P = 0.015. Heart rate variability (P < 0.0001), gut microbiome diversity (P = 0.003), circulating triglycerides (P = 0.009) and saturated fatty acids (P = 0.008) were improved in HP-FMD only. Both FMDs induced autophagy at the molecular level. Both FMDs promoted cardiometabolic health and induction of autophagy, with HP-FMD selectively conferring novel benefits in body composition, circulating lipid profiles, heart rate variability and gut microbiome health. These findings suggest that FMDs with varied macronutrient compositions could be customised to better align with individual health goals and preferences. ClinicalTrials.gov Identifier NCT06560996. URL OF REGISTRATION: https://clinicaltrials.gov/study/NCT06560996.