3.1.2 Metformin’s effects on tumorigenesis
Reprogrammed energy metabolism is one of the hallmarks of cancer. The IIS and AMPK pathways, which are associated with maintaining energy homeostasis, have thus been seen as dominant factors in how metformin exerts antineoplastic effects. First, metformin can suppress the IIS pathway by reducing circulating insulin and IGF 1 levels. Subsequently, the downstream PI3K-Akt and mTOR signaling pathways are down-regulated, attenuating the proliferation of cancer cells and inducing autophagy. Memmott et al. have demonstrated that metformin inhibits the cellular proliferation in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung cancer in mice by decreasing the levels of circulating insulin and IGF-1 82. Secondly, metformin can inhibit the growth of cancer cells by activating AMPK and inhibiting mTOR directly. Multiple studies have backed this mechanism and shown that various cancers including lung cancer, breast cancer, and colorectal cancer are suppressed by metformin via the AMPK/mTOR pathway83 .
3.2 Effect of metformin on longevity in animals
Numerous in vivo studies have shown that metformin can increase longevity and maintain healthspan in short-lived organisms including flies, roundworms and mice 84-86. Thus, metformin has been shown to extend healthspan and lifespan in the roundwormC. elegans 87. Consistently, metformin has also been shown to retard aging in rodents. For example, low dose (0.1%) of metformin for middle-aged male C57BL/6 mice’s diet lead to a 5.83% extension of mean lifespan, while a higher concentration of the metformin (1%) was shown to be toxic 84. In addition, when supplementing 5mM metformin to the food of D. melanogaster,a rigorous activation of AMPK and suppressed lipid storage were observed. However, metformin treatment did not increase the lifespan in either male or female fruit flies. This could be due to the dosage of metformin that was administered to activate AMPK was high to an extent that it became toxic to fruit flies and reduced their survival85.
In addition to retarding aging, both in vivo and in vitrostudies have shown that metformin has a protective role of attenuating tumorigenesis
88, 89. For example, metformin was shown to delay the first tumor onset by 22% and 25% respectively in female mice at the age of 3 months and 9 months 90.