METFORMIN: IS THIS DIABETIC DRUG AIDING LIFE SPAN BY MEANS OTHER THAN JUST GLYCEMIC CONTROL?
Metformin is a hypoglycemia-inducing drug of the biguanide family that has been used to treat the hyperglycemia associated with type 2 diabetes for over 50 years. Indeed, metformin is the most frequently prescribed diabetes treatment drug.
For more information on the effects of metformin go the the Diabetes page of themedicalbiochemistrypage.org
Metformin exerts several effects in several cell types but with respect to overall glucose homeostasis its effects on hepatic metabolism include an induction of glucose metabolism (glycolysis) and repression of glucose synthesis (gluconeogenesis). Combined, these two effects significantly contribute to the promotion of an increase in whole body insulin sensitivity. Over the years studies with metformin have shown that this drug mimics some of the beneﬁts of calorie restriction, such as improved physical performance, increased insulin sensitivity, and reduced low-density lipoprotein (LDL) and cholesterol levels without a decrease in caloric intake. Examination of gene expression profiles demonstrated that metformin induces a gene expression proﬁle highly similar to that induced by calorie restriction. At a molecular level, one of the most important effects of metformin is an increase in AMP-activated protein kinase (AMPK) activity. Increased AMPK activity is associated with increased antioxidant protection, resulting in reductions in both oxidative damage accumulation and chronic inﬂammation, both of which are hallmarks of aging processes. Despite all these important observations there is still controversy regarding whether or not metformin is involved in lifespan extension.
A recent study published in the journal Nature Communications indicates that long-term metformin administration in laboratory animals does indeed lead to increases in lifespan:
In this study adult mice were treated with two different doses of metformin continuously until the mice died naturally. The results demonstrated two critical facts. The first is that too much metformin (the mice treated with the higher of the two doses) was toxic and led to a shortened lifespan compared to control untreated mice. The other observation was that mice given the lower dose of metformin exhibited an extension of their lifespan by 5-6% over that of control mice. Additionally significant findings were that when these mice died (at around 115 weeks of age) they showed no obvious pathology that would account for why they died compared to untreated control mice. Another important finding was that the low dose metformin treated mice were healthier than the untreated mice in the measure of body mass. As humans and animals age there is a progressive change in body mass, and in animal studies the ability to maintain a youthful body mass is associated with healthier parameters. In this study the metformin treated mice maintained a healthy weight even at 124 weeks of age even though they actually ate more calories than untreated mice. This indicated that metformin treatment altered the metabolic profiles of the mice. Indeed, metformin treatment was associated with increased fat oxidation rates and reduced lipid synthesis even though there was no significant increase in the activity level of the treated mice. Similar examinations in short-term metformin studies have shown that the drug partially inhibits mitochondrial functions but this study indicates that long-term there is an adaptation to beneficial metformin effects. Detailed molecular studies in these metformin treated mice showed that the drug inhibited inflammation and preserved mitochondrial functions by inducing a pattern of gene expression that was very similar to that observed in mice on a calorie restricted diet.
The TAKE HOME from this study is that chronic metformin treatment, in type 2 diabetics, may actually have unforeseen benefits unrelated to the prescribed benefit of reduced serum glucose. However, it should be noted although the dose associated with the beneﬁcial effects in the mice was well tolerated, the dose used was an order of magnitude higher than that conventionally used in human patients. Therefore, it is clear that although promising, further studies on the dose and length of metformin treatment in humans is necessary to fully ascertain the effects and potential benefits of chronic exposure to biguanides in health and aging in humans.