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

Abstract

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.

Short-Term Fasting Synergizes with Solid Cancer Therapy by Boosting Antitumor Immunity

“…Low glucose conditions are linked to increased transcription of genes that render T cells dysfunctional [42]. Nevertheless, T cells with increased glycolytic activity characterized by heightened mTOR pathway signaling can show low persistence, antigen recall response, and proliferative capacity [39][40][41]. Conversely, inhibiting mTOR signaling with rapamycin was shown to increase T cell persistence [43].…”

“…In contrast, the tumor promoting myeloid derived suppressor cells (MDSCs) do not benefit from hematopoietic regeneration [40]. One study showed that the MDSC (CD11b+, Gr1+) frequency was similar in peripheral blood mononuclear cells (PBMCs) but reduced in the spleen after two cycles of 4-day FMD (with 50% or 70% calorie restriction) followed by a 10-day ad libitum diet in a 4T1 breast cancer mouse model [40]. Moreover a significant reduction of tumor-resident MDSCs and an increased T cell to MDSC ratio in PBMCs was detected [53].…”

Role of Diet in Stem and Cancer Stem Cells

“…These molecular events ultimately impact SC “performance” and prevent SC transformation into CSCs. Accordingly, mTOR, AMPK and SIRT1 have been found deregulated in tumors [ 58 , 64 , 65 ] and in correlation with lifestyle factors lowering ATP, such as CR and exercise, which activate AMPK and are associated with lower cancer risk [ 6 ].…”

“…Dietary patterns, foods and bioactive food compounds have been found to significantly modify lifespan and health in diverse organisms such as yeast, worms, flies, and mammals [ 5 ] and to affect cancer risk and tumor growth, directly or indirectly participating in the cancer process with a profound impact on all cancer’s hallmarks [ 5 , 6 , 7 , 8 , 9 ]. Food quality (what we eat), food quantity (how much we eat) and meal frequency (when we eat) are all aspects that weigh in on the impact of diet on our health system.…”

Boosting the immunotherapy response by nutritional interventions

“…In obese patients, caloric restriction–induced weight loss is not further improved by time-restricted feeding (eating only between 8:00 am and 4:00 pm), suggesting that global caloric intake is the most important determinant of the metabolic consequence of fasting ( 3 ). However, when applied to mice, continuous caloric restriction appears to be more efficient in reducing the development and progression of cancer than intermittent fasting ( 4 ). Of note, a single fasting cycle of 48 hours administered together with immunogenic chemotherapeutics (such as anthracyclines or oxaliplatin) alone or together with PD-1 blockade improves tumor growth reduction ( 5 – 7 ).…”