Central and Peripheral Effects of Insulin/IGF‐1 Signaling in Aging and Cancer: Antidiabetic Drugs as Geroprotectors and Anticarcinogens

Abstract

Studies in mammals have led to the suggestion that hyperglycemia and hyperinsulinemia are important factors both in aging and in the development of cancer. Insulin/insulin-like growth factor 1 (IGF-1) signaling molecules linked to longevity include DAF-2 and insulin receptor (InR) and their homologues in mammals and to inactivation of the corresponding genes followed by increased life span in nematodes, fruit flies, and mice. It is possible that the life-prolonging effect of caloric restriction are due to decreasing IGF-1 levels. A search of pharmacological modulators of life span-extending mutations in the insulin/IGF-1 signaling pathway and mimetics of effects of caloric restriction could be a direction in the regulation of longevity. Some literature and our own observations suggest that antidiabetic drugs could be promising candidates for both life span extension and prevention of cancer.

Metformin in chemically-induced mammary carcinogenesis in rats

“…No changes in tumor incidence and frequency in HER-2/neu transgenic mice after metformin treatment (100 mg/kg b.w. in drinking water) were found by Anisimov et al [17] either; however, the latency of spontaneous mammary tumors was increased as well as overall surviving. Increased life span and spontaneous mammary carcinogenesis inhibition (as seen by 4-fold tumor incidence reduction) was recorded in female C3H/Sn mice after phenformin given in a dose of 2 mg/mouse five times a week orally, the calculated daily dose was in the ranges 60-80 kg/b.w.…”

“…The serum IGF-1 decrease was accompanied with insulin decrease in all experimental groups (non-significant in the control group), glycemia, however, was not changed. Metformin and other biguanides impact on insulin/IGF-1 signaling has been suggested as a mechanism involved both in ageing and carcinogenesis by Anisimov group [30,17,31], the effective dose, however, has to be found by further research.…”

“…Metformin treatment resulted in tumor growth reduction in mice bearing LNCaP xenografts [11] and p53 deficient colon cancer HCT116 xenografts [15], however, the growth of HCT116 p53 +/+ cells was not affected [15]. Metformin inhibited pancreatic tumor growth in hamsters [16] and increased mammary tumor latency and overall surviving in HER-2/neu transgenic mice [17]. On the other hand, a study carried out in athymic nude mice suggested metformin may stimulate angiogenesis [13], therefore the metformin effect in vivo should be further analysed.…”

Rapamycin-induced glucose intolerance: Hunger or starvation diabetes

“…[76][77][78][79] Needless to say, insulin promotes cancer and atherosclerosis. [80][81][82] Also, as discussed recently in reference 83, complications may precede type II diabetes and occur several years before diagnosis of diabetes. 77,[84][85][86] Insulin resistance by itself is a risk factor for neuropathy, retinopathy and renal disease as well as death due to myocardial infarction and stroke.…”

Neurohormetic phytochemicals: An evolutionary–bioenergetic perspective

“…The insulin/IGF-1 signaling pathway is evolutionarily conserved and plays a regulating role in the rate of aging across the organisms from yeast to humans (Barbieri et al, 2003; Dupont and Holzenberger, 2003; Kenyon, 2011; Shimokawa et al, 2003). Calorie restriction and exercise reduce circulating IGF-1 levels (Anisimov et al, 2005), but may increase cellular sensitivity to IGF-1. Indeed, it is well-established that insulin and IGF-1 levels are reduced when insulin sensitivity is increased as occurs during dietary energy restriction and with regular exercise, consistent with a beneficial effect of insulin/IGF-1 signaling in neurons (Stranahan and Mattson, 2008).…”