Reactive oxygen species and age-related genes p66shc, Sirtuin, FOX03 and Klotho in senescence

Abstract

Reactive oxygen species (ROS) superoxide and hydrogen peroxide perform important signaling functions in many physiological and pathophysiological processes. Cell senescence and organismal age are not exemptions.Aging-regulating genes p66shc, Sirtuin, FOXO3a and Klotho are new important factors which are stimulated by ROS signaling. It has been shown that ROS participate in initiation and prolongation of gene-dependent aging development.ROS also participate in the activation of protein kinases Akt/PKB and extracellular signal-regulated kinase ERK, which by themselves or through gene activation stimulates or retards cell senescence.Different retarding/stimulating effects of ROS might depend on the nature of signaling species-superoxide or hydrogen peroxide. Importance of radical anion superoxide as a signaling molecule with"super-nucleophilic" properties points to the possibility of the use of superoxide scavengers (SOD mimetics, ubiquinones and flavonoids) for retarding the development of aging.

Figure 1

Different signaling effects of superoxide and hydrogen peroxide on enzymatic processes.

Figure 2

Pinton's mechanism of ROS signaling in the activation of p66shc protein.

Figure 3

Gertz's mechanism of ROS activation of p66shc protein.

Figure 4

(A) Regulation by p66shc of ROS-induced apoptosis (Orsini et al. Trinei et al. and Giorgio et al.14). (B) ROS-mediated phosphorylation of p66shc and ROS signaling pathways of activation of FOXO3a and Akt kinase and suppression of MnSOD (Pinton et al. Cai et al. and Malhotra et al.17).

Figure 5

Forkhead family of transcription factors.

Figure 6

ROS-depended gene/enzyme cascades leading to activation/inactivation FOXO genes (Miyauchi et al., Guo et al. and Purdom and Chen28).

Figure 7

ROS-depended Sitruin pathways (Alcendor et al., Hasegawa et al. and Jacobs et al.41).

Figure 8

Mechanisms of Klotho antiaging effects (Kuro-o, and Yamamoto et al.44).