These tools will no longer be maintained as of December 31, 2024. Archived website can be found here. PubMed4Hh GitHub repository can be found here. Contact NLM Customer Service if you have questions.
Pubmed for Handhelds
PUBMED FOR HANDHELDS
Search MEDLINE/PubMed
Title: Chronic activation of AMP-activated kinase as a strategy for slowing aging. Author: McCarty MF. Journal: Med Hypotheses; 2004; 63(2):334-9. PubMed ID: 15236799. Abstract: 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.[Abstract] [Full Text] [Related] [New Search]