Life Extension via Calorie Restriction Requires FOXO3

The forkhead box (FOX) family of proteins includes members such as FOXO3 that seem to be important in longevity and regeneration in a variety of very different species. Here researchers show that FOXO3 is required for the additional longevity created by the practice of calorie restriction:

Forkhead box O (Foxo) transcription factors may be involved in the salutary effect of dietary restriction (DR). This study examined the role of Foxo3 in lifespan extension and cancer suppression in DR mice. Wild-type (WT) and Foxo3-knockout heterozygous (+/-) and homozygous (-/-) mice were subjected to a 30% DR regimen initiated at 12 weeks of age. Control mice were fed ad libitum (AL) throughout the study. The food intake by Foxo3+/- and Foxo3-/- mice was similar to those by WT mice under the AL condition, and thus, the daily allotments for each DR group were almost the same during the lifespan study. The average body weights of WT, Foxo3+/-, and Foxo3-/- mice were also similar under AL and DR conditions.

In contrast to WT mice, DR did not significantly extend the lifespan of Foxo3+/- or Foxo3-/- mice. However, DR reduced the prevalence of tumors at death in WT, Foxo3+/-, and Foxo3-/- mice. These results indicate the necessity of Foxo3 for lifespan extension but not cancer suppression by DR. The findings in Foxo3+/- mice contrast with those in Foxo1+/- mice reported previously by our laboratory and suggest differential regulation of cancer and lifespan by DR via Foxo1 and Foxo3.



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