Diet composition, calories, and fasting times contribute to the maintenance of health. However, the impact of very low-calorie intake (VLCI) achieved with either standard laboratory chow (SD) or a plant-based fasting mimicking diet (FMD) is not fully understood. Here, using middle-aged male mice we show that 5 months of short 4:10 VLCI cycles lead to decreases in both fat and lean mass, accompanied by improved physical performance and glucoregulation, and greater metabolic flexibility independent of diet composition. A long-lasting metabolomic reprograming in serum and liver is observed in mice on VLCI cycles with SD, but not FMD. Further, when challenged with an obesogenic diet, cycles of VLCI do not prevent diet-induced obesity nor do they elicit a long-lasting metabolic memory, despite achieving modest metabolic flexibility. Our results highlight the importance of diet composition in mediating the metabolic benefits of short cycles of VLCI.

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).

e14697 Background: Our understanding of immune-related adverse events (irAEs) has evolved rapidly with management guidelines constantly being updated. We aim to explore temporal changes in irAE management at a tertiary cancer care center to identify areas for potential improvement. Methods: This was a single-center, retrospective study including patients who developed a GI, pulmonary, renal, or cardiac irAE between 07/01/2019-10/01/2019 compared to a contemporary cohort from 2021. The follow-up window was for up to a year after diagnosis. Data collected included patient demographics and irAE management and outcomes. Results: Endoscopic evaluation and GI follow-up after discharge for patients with GI irAEs fell over the years. Despite this, there was a decline in symptom duration and steroid taper attempts. The pulmonary service showed improvements in consultation, hospital admission and re-admission, and ICU admission. However, follow up post-hospital discharge were consistently low ( < 50%). Rate of cardiology consultation was consistently high across the years with an equally fast time to consultation, and myocarditis cohort in 2021 had a higher clinical response rate than the 2019 cohort. There were no major differences across the years for renal irAEs. We found that outpatient treatment and earlier GI consult improved outcomes in GI irAEs. For pulmonary irAEs, hospitalization, symptom recurrence, multiple steroid tapering courses, and hospital readmission were associated with less pneumonitis remission. Conclusions: This is one of the few qualitative studies exploring current practice in managing irAEs. We identified areas to improve the management on across all specialties, and found specific factors associated with better outcomes in GI and pulmonary irAEs. Together, these findings can help improve the quality of irAE management algorithms at our institution. [Table: see text]