FoxO1 is involved in the antineoplastic effect of calorie restriction

The forkhead box O1 (FoxO1) transcription factor may be involved in the antiaging effect of calorie restriction (CR) in mammals. We tested the hypothesis by using FoxO1 knockout heterozygotic (HT) mice, in which the FoxO1 mRNA level was reduced by 50% of that in wild‐type (WT) mouse tissues. The WT and HT mice were fed ad libitum (AL) or 30% CR diets from 12 weeks of age. Aging‐ and CR‐related changes in body weight, food intake, blood glucose, and insulin concentrations were similar between the WT and HT mice in the lifespan study. The lifespan also did not differ between the WT and HT mice in AL or CR conditions. However, the well‐known antineoplastic effect of CR, as indicated by reduced incidence of spontaneous tumors at death in the WT‐CR mice, was mostly abrogated in the HT‐CR mice. To confirm the contribution of FoxO1 to the antineoplastic effect of CR, we conducted an experiment of the two‐step skin tumorigenesis. Six‐month‐old WT and HT mice fed AL or CR diets were treated once with 7,12 dimethylbenz[a]anthracene, followed by 12‐O‐tetradecanoylphorpbol‐13‐acetate two times/week. By 25 weeks, over 80% of the WT‐AL, HT‐AL, and HT‐CR mice presented a skin tumor; only 40% of WT‐CR mice had a tumor at 25 weeks. The present results indicate that FoxO1 is involved in the antineoplastic effect of CR. (The study was supported by Grants‐in‐Aid for Scientific Research from the Japan Society for the Promotion of Science (20790260).