This paper shows researchers beginning to be able to distinguish between the genetic machinery that causes different parts of the calorie restriction effect on health and longevity: "The FoxO transcription factors may be involved in the antiaging effect of calorie restriction (CR) in mammals. To test the hypothesis, we used FoxO1-knockout heterozygotic (HT) mice, in which the FoxO1 mRNA level was reduced by 50%, or less, 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. ... Several of the selected FoxO1-target genes for cell cycle arrest, DNA repair, apoptosis, and stress resistance, were up-regulated in the WT-CR tissues, [while] the effect was mostly diminished in the HT-CR tissues. Of these gene products, we focused on the nuclear p21 protein level in the liver and confirmed its up-regulation only in the WT-CR mice in response to oxidative stress. The lifespan did not differ significantly between the WT and HT mice in AL or CR conditions. However, the [cancer resistance] effect of CR, as indicated by reduced incidence of tumors at death in the WT-CR mice, was mostly abrogated in the HT-CR mice. The present results suggest a role for FoxO1 in the [anti-cancer] effect of CR through the induction of genes responsible for protection against oxidative and genotoxic stress."