AMPK

AMP-activated protein kinase (AMPK) plays a major role in regulating cellular energy balance, being activated by an increase in AMP or ADP relative to ATP. ^[1] AMPK is an evolutionarily conserved serine/threonine kinase originally identified as the key player in maintaining cellular energy homeostasis. ^[2] Homologs of AMPK are found in all eukaryotic species and serve as an ancient sensor of conditions of low cellular energy. ^[3]

Activation of AMPK increases the rate of catabolic ATP-generating pathways and decreases the rate of anabolic ATP-utilising pathways, and beyond intracellular energy balance it regulates whole-body energy metabolism. ^[1] At the cellular level AMPK supports numerous processes required for energy and redox homeostasis, including mitochondrial biogenesis, autophagy, and glucose and lipid metabolism. ^[4] AMPK acts as an energy sensor and key regulator of mitochondrial biogenesis, in part through PGC-1alpha, whose activity is directly affected by AMPK through phosphorylation. ^{[5] [6]} AMPK and the TOR pathway are interlinked, opposing signaling pathways, with AMPK switched on by lack of energy or nutrients to inhibit cell growth while TOR is switched on by nutrient availability to promote cell growth. ^[7]

AMPK activity has been shown to decrease with age, which may contribute to decreased mitochondrial biogenesis and function with aging. ^[5] AMPK, SIRT1 and PGC-1alpha act as an orchestrated network that explains many of the beneficial effects of physical activity and dietary interventions against type 2 diabetes and related metabolic disorders. ^[6] Dietary restriction and different forms of fasting and protein restriction promote healthy longevity in part by acting on key nutrient-sensing geroprotective pathways including AMPK, mTOR, sirtuins and NAD+. ^[8] AMPK plays a key role in orchestrating aging and aging-related disorders including cardiovascular diseases, osteoarthritis and diabetes. ^[9]

Given its key role in controlling energy homeostasis, AMPK has attracted widespread interest as a potential therapeutic target for metabolic diseases including type 2 diabetes and cancer. ^[1] Exercise, caloric restriction, metformin and many natural products increase AMPK activity and exert a multitude of health benefits, though developing direct activators of AMPK has been challenging. ^[10] As calorie restriction mimetics, the AMPK activator metformin and the mTOR inhibitor rapamycin are being explored among anti-aging pharmaceutical strategies. ^[11] Exercise-induced activation of AMPK promotes physiological adaptations such as mitochondrial biogenesis