ROLES FOR FOXO1 AND FOXO3 IN REGULATION OF CANCER AND LIFESPAN IN DIETARY-RESTRICTED MICE

Forkhead box O (Foxo) transcription factors may be involved in the salutary effect of dietary restriction (DR). We investigated roles for Foxo1 and Foxo3 in regulation of cancer and lifespan in mice. The preventive effect of DR on cancer was diminished in Foxo1-knockout heterozygotic (+/–) mice, although the life-extending effect of DR remained in Foxo1 (+/–) mice. By contrast, the life-extending effect of DR was abrogated in Foxo3 (+/–) mice; the incidence of cancer was diminished by DR in Foxo3 (+/–) mice. These findings indicate differential roles for Foxo1 and Foxo3 in regulation of cancer and lifespan in the DR condition. To elucidate a mechanism by which Foxo3 affects the life-extending effect of DR, we analyzed a metabolome in liver tissues and bioenergetics of mitochondria isolated from 24-month-old mouse liver. The metabolome revealed that some metabolites in the glycolysis/ gluconeogenesis were lower; and that the ratio of lactate: pyruvates and the ratio of NADH: NAD+ were greater in Foxo3+/– DR mice, compared to WT DR mice. The findings suggest a peudohypoxic condition in Foxo3+/– DR mouse tissues. The mitochondrial membrane potential was greater in Foxo3+/– DR mice than in WT-DR mice. These findings suggest that Foxo3 is required for metabolic adaptation to DR, and that the impairment diminishes the life-prolonging effect of DR.