Sulfur Amino Acid Supplementation Abrogates Protective Effects of Caloric Restriction for Enhancing Bone Marrow Regrowth Following Ionizing Radiation

Abstract

Radiation therapy damages and depletes total bone marrow (BM) cellularity, compromising safety and limiting effective dosing. Aging also strains total BM and BM hematopoietic stem and progenitor cell (HSPC) renewal and function, resulting in multi-system defects. Interventions that preserve BM and BM HSPC homeostasis thus have potential clinical significance. Here, we report that 50% calorie restriction (CR) for 7-days or fasting for 3-days prior to irradiation improved mouse BM regrowth in the days and weeks post irradiation. Specifically, one week of 50% CR ameliorated loss of total BM cellularity post irradiation compared to ad libitum-fed controls. CR-mediated BM protection was abrogated by dietary sulfur amino acid (i.e., cysteine, methionine) supplementation or pharmacological inhibition of sulfur amino acid metabolizing and hydrogen sulfide (H2S) producing enzymes. Up to 2-fold increased proliferative capacity of ex vivo-irradiated BM isolated from food restricted mice relative to control mice indicates cell autonomy of the protective effect. Pretreatment with H2S in vitro was sufficient to preserve proliferative capacity by over 50% compared to non-treated cells in ex vivo-irradiated BM and BM HSPCs. The exogenous addition of H2S inhibited Ten eleven translocation 2 (TET2) activity in vitro, thus providing a potential mechanism of action. Short-term CR or fasting therefore offers BM radioprotection and promotes regrowth in part via altered sulfur amino acid metabolism and H2S generation, with translational implications for radiation treatment and aging.

Caloric restriction and fasting-mimicking diets in the treatment of cancer patients

“…This effect was abolished in animals with intestinal epithelial-specific deletion of autophagy gene Atg7 , supporting the assumption that caloric restriction confers a regenerative benefit, which is dependent on functional autophagy [10 ▪ ]. Similarly, regrowth of bone marrow after cellular depletion by irradiation was improved by caloric restriction (50% for 7 days or fasting for 3 days) prior to the injury [11]. Further analyses revealed that intestinal radioprotection was associated with lowering of luminal glycocholic acid [10 ▪ ], while in bone marrow, an increase in H 2 S generation was involved [11].…”

“…Similarly, regrowth of bone marrow after cellular depletion by irradiation was improved by caloric restriction (50% for 7 days or fasting for 3 days) prior to the injury [11]. Further analyses revealed that intestinal radioprotection was associated with lowering of luminal glycocholic acid [10 ▪ ], while in bone marrow, an increase in H 2 S generation was involved [11].…”