Abstract
The Keap1-Nrf2 signal transduction pathway plays a major role in oxidant and electrophile induction of adaptive homeostasis that transiently and reversibly increases cellular and organismal protection from stress. By expanding (and then contracting) the normal homeostatic range of expression of stress-protective genes, Nrf2 allows us to cope with fluctuations in stress levels. Two major inhibitors of Nrf2 are Bach1 and c-Myc which normally serve the important function of turning off adaptation when appropriate. We have found, however, that both Bach1 and c-Myc levels increase substantially with age and that older human cells, worms, flies, and mice loose Nrf2-dependent signaling and adaptive homeostasis. Nrf2 has also been linked with increased risk of cancers, and cancer incidence certainly increases with age. Here we propose that the age-dependent increase in Bach1 and c-Myc may actually cause the age-dependent decline in Nrf2 signaling and adaptive homeostasis, and that this is a coordinated attempt to minimize the age-dependent increase in cancer incidence. In other words, we may trade off adaptive homeostasis for a lower risk of cancer by increasing Bach1 and c-Myc in ageing.