Organ-differential Roles of Akt/FoxOs Axis as a Key Metabolic Modulator during Aging

Abstract

FoxOs and their post-translational modification by phosphorylation, acetylation, and methylation can affect epigenetic modifications and promote the expression of downstream target genes. Therefore, they ultimately affect cellular and biological functions during aging or occurrence of age-related diseases including cancer, diabetes, and kidney diseases. As known for its key role in aging, FoxOs play various biological roles in the aging process by regulating reactive oxygen species, lipid accumulation, and inflammation. FoxOs regulated by PI3K/Akt pathway modulate the expression of various target genes encoding MnSOD, catalases, PPARγ, and IL-1β during aging, which are associated with age-related diseases. This review highlights the age-dependent differential regulatory mechanism of Akt/FoxOs axis in metabolic and non-metabolic organs. We demonstrated that age-dependent suppression of Akt increases the activity of FoxOs (Akt/FoxOs axis upregulation) in metabolic organs such as liver and muscle. This Akt/FoxOs axis could be modulated and reversed by antiaging paradigm calorie restriction (CR). In contrast, hyperinsulinemia-mediated PI3K/Akt activation inhibited FoxOs activity (Akt/FoxOs axis downregulation) leading to decrease of antioxidant genes expression in non-metabolic organs such as kidneys and lungs during aging. These phenomena are reversed by CR. The results of studies on the process of aging and CR indicate that the Akt/FoxOs axis plays a critical role in regulating metabolic homeostasis, redox stress, and inflammation in various organs during aging process. The benefical actions of CR on the Akt/FoxOs axis in metabolic and non-metabolic organs provide further insights into the molecular mechanisms of organ-differential roles of Akt/FoxOs axis during aging.

Keywords: Aging; Akt/FoxOs axis; CR; inflammation; metabolic organs; non-metabolic organs.

Figure 1.

Organ responses based on the Akt/FoxOs axis during aging. Impaired insulin signaling, insulin resistance induces metabolic changes called “aging metabolism” in metabolic organs during aging. The insulin resistance in metabolic organs and tissues such as the liver, muscles, and adipose tissues causes hyperinsulinemia accompanied by Akt inactivation, which increases FoxOs activity (Akt/FoxOs/PPARγ axis upregulation) leading to lipid accumulation. In contrast, the hyperinsulinemia induces Akt activation and inhibits FoxOs activity (Akt/FoxOs/MnSOD axis downregulation) leading to decreases the expression of FoxOs-dependent antioxidant genes such as MnSOD and catalase in non-metabolic organs including the kidneys and the lungs failing to suppress oxidative stress and age-related inflammation. However, CR modulates insulin resistance and hyperinsulinemia, and alleviates age-related inflammation. CR, Calorie restriction; MTP, Microsomal triacylglycerol transfer protein; SOD, Superoxide dismutase; ROS, Reactive oxygen species.