Fig. 1.

Pathways involved in aging. There are numerous cellular mechanisms that regulate aging, many of which were first shown to regulate lifespan in C. elegans (see text for details and for names of the genetic homologs in C. elegans). Regarding hormonal signaling, the IIS pathway consists of a phosphorylation cascade triggered by the insulin receptor (IR) or the IGF1 receptor (IGF1R). This cascade prevents the translocation of the FOXO transcription factor to the nucleus. When the pathway is blocked, however, FOXO functions in the nucleus to activate or repress genes important for promoting longevity. FOXO can also be regulated through phosphorylation by AMPK and JNK, and through deacetylation by SIRT1. SIRT1 activation occurs during dietary restriction, as does inhibition of TOR signaling. TOR function can also be inhibited by rapamycin; in either case, this results in an increase in autophagy, as well as a decrease in translation through activation of eIF4EBP and suppression of S6K. The FOXA and NRF transcription factors are also required to extend longevity through dietary restriction. Additionally, factors that monitor components of the mitochondrial electron transport chain and ROS generation function during aging, such as COQ7, which is required for the production of ubiquinone (coenzyme Q).