Caloric restriction prevents radiation-induced myeloid leukemia in C3H/HeMs mice and inversely increases incidence of tumor-free death: implications in changes in number of hemopoietic progenitor cells

Abstract

Previously, we found a clear decrease in the incidence of radiation-induced myeloid leukemia in C3H/HeMs mouse caused by caloric restriction (CalR). In this report, CalR before and after irradiation was examined to determine whether they exert different effects on the prevention of radiation-induced myeloid leukemogenesis and the consequent extension of life span by CalR. The C3H/HeMS strain, which is prone to radiation-induced myeloid leukemia, was used. Groups subjected to different CalR timings, pre- and postirradiation, were compared with groups not subjected to CalR during their lifetime for the incidences of neoplasms, specifically that of myeloid leukemia, and the incidence of tumor-free death. A single dose of 3Gy X-ray was administered to mice at 10 weeks old. Results of colonization assay before and after CalR were compared with the incidence of leukemogenesis among the groups. Irrespective of the CalR timing in terms of irradiation, there was a significant difference in the prevention of myeloid leukemogenesis, and a consequent difference in longevity (731 approximately 805 days for CalR groups vs. 697 days for the group without CalR; Log rank, P<0.03). During CalR, the number of hemopoietic progenitor cells (HPCs), potential leukemogenic targets, significantly decreased (0.4 x 10(4) vs. 4.2 x 10(4) of granulomacrophage colony forming units per spleen; 1.3 x 10(4) vs. 7.6 x 10(4) of the splenic colony forming units per spleen), but this decreased number of HPCs returned to that of the non-CalR control group, when the CalR group was returned to nonrestricted diet (returned to 1.5 x 10(4) granulomacrophage colony-forming units per spleen; returned to 2.8 x 10(4) splenic colony-forming units per spleen). Although preirradiation CalR followed by a conventional non-CalR diet negates the potential preventive effect, prevention conferred by pre-and postirradiation CalR suggests different underlying mechanisms; preirradiation CalR prevents the initiation of direct genotoxic leukemogenesis, while postirradiation CalR the indirect, epigenetic, leukemogenesis. The incidences of tumor-free death significantly increased in all the groups undergoing CalR except for the group subjected to preirradiation CalR, which contributed to the longevity of the groups undergoing CalR.