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.

Hesperetin promotes longevity and delays aging via activation of Cisd2 in naturally aged mice

“…Insulin promotes glycogen synthesis and inhibits both glycogenolysis and gluconeogenesis via the regulation of multiple pathways downstream of insulin; this includes activation in the liver of PI3K/Akt signaling, inhibition of glycogen synthase kinase 3β (GSK3β) and inhibition of forkhead box protein O1 (Foxo1) [ 46 , 47 ]. Previous studies have revealed that dysregulation of hepatic insulin signaling results in impaired glucose homeostasis and the development of insulin-resistance during aging [ 48 ]. Notably, in the Veh-treated old mice, most of the DEGs related to insulin signaling pathway are significantly increased in the livers; most of these DEGs belong to four major functional groups, namely inhibition of insulin signaling, glucose metabolism, lipid metabolism, and cell proliferation/differentiation (Additional file 1 : Fig.…”

The effect of Astragali Radix-Radix Angelica Sinensis on acute kidney injury: a network pharmacology and molecular docking study

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Changes of Signaling Pathways in Hypothalamic Neurons with Aging

“…In aging, the occurrence of diabetes and obesity is associated with insulin resistance [100], which leads to the downregulation of AKT and upregulation of FOXOs. In addition, AKT demonstrates differential actions in separate organs [101,102].…”