Journal
MEDICAL HYPOTHESES
Volume 63, Issue 2, Pages 334-339Publisher
CHURCHILL LIVINGSTONE
DOI: 10.1016/j.mehy.2004.01.043
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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. (C) 2004 Elsevier Ltd. All rights reserved.
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