2.2 AMPK Signaling
AMPK, the upstream controller of the mTOR pathway, exists among many mammalian species, functioning as an exquisite cellular energy sensor and regulator of nutrient and energy homeostasis. AMPK contains a catalytic α subunit, a regulatory β subunit, and a regulatory γ subunit50. On the contrary to the mTOR pathway, the activation of the AMPK pathway under energy deficiency drives catabolic processes and induces autophagy. Numerous studies have indicated that the activating capacity of the AMPK signaling pathway declines with aging, and its decline disturbs autophagy, increases cellular stress, and promotes inflammation, which further provoke many age-associated diseases, such as cardiovascular disease, diabetes, and cancer38, 51. Correspondingly, increased activation of the AMPK pathway has been shown to extend lifespan in lower organisms in response to CR and pharmaceutical agents, such as metformin52. Aside from promoting autophagy by activating the TSC1-TSC2 complex and inhibiting the Raptor component of mTORC1, AMPK can independently phosphorylate and activate ULK1 of the ULK complex40. AMPK also activates the FOXO transcription factors, which transactivate the genes involved in detoxification, autophagy, tumorigenesis suppression, and energy homeostasis40.
Furthermore, AMPK activation attenuates the aging process by inhibiting NF-κB, the major regulator of innate and adaptive immunity. Inflammation is a crucial step for the immune system to defend against pathogens. Nonetheless, chronic inflammation that is harmful for the host can be triggered by endoplasmic reticulum (ER) stress and oxidative stress. ER stress and oxidative stress are caused by nutrition overload, the aging process, and the production of reactive oxygen species (ROS). Those stresses are implicated in many metabolic disorders, such as obesity and type II diabetes 53. AMPK inhibits NF-κB indirectly via several downstream targets, including SIRT1, PGC-1α, p53, and FOXO. It can also relieve ER stress and oxidative stress by promoting the expression of the mitochondrial uncoupling protein 2 (UCP-2), which inhibits the production of ROS in mitochondria, suppressing the ROS produced by the NAD(P)H oxidase, and inducing the expression of thioredoxin (Trx) by activating FOXO3. The reduction of oxidative stress improves homeostasis in ER and relieves ER stress 53.
Nutrient scarcity and energy depletion are detected by several upstream sensors of AMPK. AMPK can be activated by increasing AMP:ATP and ADP:ATP ratios as well as by directly AMP binding 38. Moreover, the AMPK pathway can be activated by two adipokines, which are cytokines secreted by adipocytes, leptin and adiponectin (ADIPOQ), whose quantities positively and negatively correlate with lipid storage40. Leptin stimulates phosphorylation and activation of the α subunit of AMPK. It can also activate AMPK via the hypothalamic and sympathetic nervous system 54. ADIPOQ binds the adiponectin receptor 1 (AdipoR1) and initiate a cascade to activate AMPK and sirtuin 1 (SIRT1) 55.
The AMPK pathway may also be activated by Sestrins, which is a family of proteins that is activated responding to genotoxic stress, hypoxia, and oxidative stress. Genotoxic stress, defined by the accumulation of compounds that are harmful to the DNA, induces p53 and stimulates the Sestrin genes. Hypoxia causes energy deprivation and the activation of the Sestrin genes as well. Oxidative stress induces Sestrins in different ways for different Sestrins family member56. Once activated by Sestrins, the AMPK pathway drives autophagy to clear the cell of the harmful compounds such as ROS.