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.