Chronic activation of AMP-activated kinase as a strategy for slowing aging.
Caloric restriction down-regulates insulin secretion and systemic IGF-I activity, and there is reason to suspect that these effects are key mediators of caloric restriction's favorable impact on longevity. Alternative strategies for down-regulating these hormones are thus of great interest; chronic activation of AMP-activated kinase (AMPK)--clinically achievable with the drug metformin--may have utility in this regard. In the liver, AMPK slows hepatic glucose output by down-regulating expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase; in skeletal muscle, it boosts the efficiency of insulin-stimulated glucose uptake by increasing expression of GLUT-4. These effects evidently mandate a down-regulation of insulin secretion. The resulting reduction of hepatic insulin activity can be expected to suppress hepatic production of IGF-I while boosting that of IGFBP-1, thereby decreasing plasma free IGF-I. AMPK can also directly stimulate IGFBP-1 synthesis in hepatocytes, and interfere with the ras/raf/erk pathway of IGF-I signaling. In non-diabetics, metformin therapy is indeed reported to reduce plasma levels of insulin and of free IGF-I; indeed, this is thought to be the mechanism whereby metformin suppresses excess androgen production in PCOS. A pro-longevity effect of the related biguanide phenformin has already been reported in tumor-prone mice, and mouse longevity studies with metformin are currently in progress. The development of AMPK activators which do not share metformin's modest risk of inducing lactic acidosis--apparently reflecting an inhibition of mitochondrial complex 1 that is not intrinsic to AMPK activity--might aid the practical applicability of this pro-longevity strategy.
McCarty
Mark F
MF
NutriGuard Research, 1051 Hermes Ave., Encinitas, CA 92024, USA. mccarty@pantox.com
D055372:AMP-Activated Protein Kinases; D000375:Aging / Q000187:drug effects* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008687:Metformin / Q000378:metabolism* / Q000494:pharmacology*; D009097:Multienzyme Complexes / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*
D009097:Multienzyme Complexes; D007334:Insulin-Like Growth Factor I; D008687:Metformin; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases