The PKB/FOXO switch in aging and cancer.

Aging is characterized by the general decline in tissue and body function and the increased susceptibility to age-related pathologies, such as cancer. To maintain optimal tissue and body function, organisms have developed complex mechanisms for tissue homeostasis. Importantly, it is becoming apparent that these same mechanisms when deregulated also result in the development of age-related disease. The build in fail safe mechanisms of homeostasis, which prevent skewing toward disease, themselves contribute to aspects of aging. Thus, longevity is limited by an intrinsic trade-off between optimal tissue function and disease. Consequently, aging and age-related diseases, such as cancer and diabetes are driven by the same genetic determinants. Illustrative in this respect is the insulin/IGF-1 signaling pathway acting through PI3K/PKB and FOXO. Loss of PKB signaling contributes to diabetes, whereas gain of function of PKB drives cancer. Enhanced FOXO activity, at least in model organism contributes to extended lifespan and acts as a tumor suppressive mechanism. Here, we focus on the linkage between PKB and FOXO as a central switch in contributing to tissue homeostasis and age-related diseases in particular cancer. This article is part of a Special Issue entitled: P13K-AKT-FoxO axis in cancer and aging. 2011 Elsevier B.V. All rights reserved.