Metabolic Flexibility: Interplay of Diet Composition and Intermittent Fasting on Healthspan (P08-053-19)

Abstract Objectives 4:10 periodic fasting schedule is proposed to improve biomarkers of healthspan through metabolic flexibility in mice on both standard and high fat diets. Methods Our study adopted the 4:10 fasting schedule using the fasting-mimicking diet (FMD) as our model. FMD is a plant-based, low-protein, and low-sugar diet regime implemented for four days every two-week cycle. Its regenerative effect is observed in the refeeding phase following starvation, allowing for the breakdown of cells via increased autophagy. In comparison to stricter fasting regimes such as intermittent fasting, chronic caloric restriction, and periodic fasting, FMD is well-tolerated in the clinical setting. 74 12-month old C57BL/6 mice were randomized into two diet groups: standard diet or high-fat diet. For 4 days out of every fourteen days, the mice were severely caloric restricted and refed with ad-libitum of either standard or high fat diets for the remaining 10 days, matching the controls who were fixed on the ad-libitum diet. The 4:10 fasting schedule was repeated 11 times before the mice were sacrificed. To measure metabolic flexibility, metabolic cages, ELISA, and glucose meters were used. Results Body weight and composition, metabolic flexibility, and insulin sensitivity indicate differences between fasting on diet composition. Not only did those on the fasting high-fat diet (FHFD) remain overweight, identical to their HFD controls, insulin sensitivity was also attenuated in FHFD groups. Fasting standard diet (FSD) had a reduction of 5% in body weight and 15% in body fat. Carbohydrate and lipid metabolism differences indicated by the respiratory exchange ratio as well as motor function performance differences further support the positive impact of fasting on SD groups, not HFD groups. Characteristic of positive healthspan biomarkers, reduced leptin and improved insulin sensitivity was observed with FSD, not FHFD. Conclusions We found that while the FMD schedule improved healthspan as indicated by biomarkers of healthy aging for mice on the standard diet, it could not counteract the negative health effects of the obesogenic diet. These results demonstrate the importance of not only time of feeding but also diet composition in respect to healthspan. Funding Sources National Institute on Aging (NIA) – National Institutes of Health (NIH).