Replenishment of myeloid-derived suppressor cells (MDSCs) overrides CR-mediated protection against tumor growth in a murine model of triple-negative breast cancer.

Caloric restriction (CR) is the leading non-pharmacological intervention to delay induced and spontaneous tumors in pre-clinical models. These effects of CR are largely attributed to canonical inhibition of pro-growth pathways. However, our recent data suggest that CR impairs primary tumor growth and cancer progression in the murine 4T1 model of triple negative breast cancer (TNBC), at least in part, through reduced frequency of the myeloid-derived suppressor cells (MDSC). In the present study, we sought to determine whether injection of excess MDSCs could block regression in 4T1 tumor growth and metastatic spread in BALB/cJ female mice undergoing daily CR. Our findings show that MDSC injection impeded CR-mediated protection against tumor growth without increasing lung metastatic burden. Overall, these results reveal that CR can slow cancer progression by affecting immune suppressive cells.Impact statement: Inoculation of MDSCs from donor mice effectively impedes the ability of calorie restriction to protect against primary tumor growth without impacting lung metastatic burden in recipient animals.

Diet composition influences the metabolic benefits of short cycles of very low caloric intake.

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.

Daily caloric restriction limits tumor growth more effectively than caloric cycling regardless of dietary composition.

Cancer incidence increases with age and is a leading cause of death. Caloric restriction (CR) confers benefits on health and survival and delays cancer. However, due to CR's stringency, dietary alternatives offering the same cancer protection have become increasingly attractive. Short cycles of a plant-based diet designed to mimic fasting (FMD) are protective against tumorigenesis without the chronic restriction of calories. Yet, it is unclear whether the fasting time, level of dietary restriction, or nutrient composition is the primary driver behind cancer protection. Using a breast cancer model in mice, we compare the potency of daily CR to that of periodic caloric cycling on FMD or an isocaloric standard laboratory chow against primary tumor growth and metastatic burden. Here, we report that daily CR provides greater protection against tumor growth and metastasis to the lung, which may be in part due to the unique immune signature observed with daily CR.

Intermittent fasting: from calories to time restriction.

The global human population has recently experienced an increase in life expectancy with a mounting concern about the steady rise in the incidence of age-associated chronic diseases and socio-economic burden. Calorie restriction (CR), the reduction of energy intake without malnutrition, is a dietary manipulation that can increase health and longevity in most model organisms. However, the practice of CR in day-to-day life is a challenging long-term goal for human intervention. Recently, daily fasting length and periodicity have emerged as potential drivers behind CR's beneficial health effects. Numerous strategies and eating patterns have been successfully developed to recapitulate many of CR's benefits without its austerity. These novel feeding protocols range from shortened meal timing designed to interact with our circadian system (e.g., daily time-restricted feeding) to more extended fasting regimens known as intermittent fasting. Here, we provide a glimpse of the current status of knowledge on different strategies to reap the benefits of CR on metabolic health in murine models and in humans, without the rigor of continuous reduction in caloric intake as presented at the USU State of the Science Symposium.