The key role of growth hormone–insulin–IGF-1 signaling in aging and cancer

Abstract

Studies in mammals have led to the suggestion that hyperglycemia and hyperinsulinemia are important factors in aging. GH/Insulin/insulin-like growth factor 1 (IGF-1) signaling molecules that have been linked to longevity include daf-2 and InR and their homologues in mammals, and inactivation of the corresponding genes increases lifespan in nematodes, fruit flies and mice. The life-prolonging effects of caloric restriction are likely related to decreasing IGF-1 levels. Evidence has emerged that antidiabetic drugs are promising candidates for both lifespan extension and prevention of cancer. Thus, antidiabetic drugs postpone spontaneous carcinogenesis in mice and rats, as well as chemical and radiation carcinogenesis in mice, rats and hamsters. Furthermore, metformin seems to decrease the risk for cancer in diabetic patients.

An increased need for dietary cysteine in support of glutathione synthesis may underlie the increased risk for mortality associated with low protein intake in the elderly

“…These effects are similar to those evoked by calorie restriction and by germline mutations that compromise GH/IGF-I signaling-which typically slow aging, prevent cancer, and boost maximal lifespan (Bartke 2008;Brown-Borg et al 2009;Anisimov and Bartke 2013).…”

Sex differences in aging, life span and spontaneous tumorigenesis in 129/Sv mice neonatally exposed to metformin

“…13 In a number of studies it was shown that administration of antidiabetic biguanides (phenformin, buformin and metformin) started at adult age increased life span and suppressed spontaneous and induced tumorigenesis. 2,[34][35][36][37][38] It is worthy to note that male and female adult 129/Sv mice demonstrated divergent reaction to the same dose of metformin. Metformin failed to increase life span of male F344 rats.…”

“…1,2 This leads to a conclusion that the normal levels and physiological actions of GH are not optimal for disease-free survival or for longevity. Since GH is key determinant of circulating levels of insulin-like growth hormone-1 (IGF-1) and it also increases insulin levels as a secondary consequence of its anti-insulinemic actions, conclusions concerning GH and normal aging extend to the roles of IGF-1 and insulin in this process.…”

“…Growth rate and adult body size, key markers of GH and IGF-1 actions, as well as plasma IGF-1 levels are negatively correlated with lifespan in comparisons with mice from different stocks or inbred strains, as well as with individual animals from a genetically heterogeneous population. 2,3 However, even with this evidence it may be difficult to envisage how physiological effects of hormones within normal ranges of their concentration can be detrimental for something as fundamental as longevity. The most likely explanation for this paradox can be found in the concept of antagonistic pleiotropy which emerged from analysis of genetic control of aging.…”

“…Somatotropic signaling would not have been suppressed or eliminated by natural selection on the basis of these detrimental effects because the force of natural selection declines with age and is presumably negligible during the post-reproductive period, and in the sense of evolutionary fitness promotion of growth, development and fertility far outweigh the risks of late life disease including cancer. 2 It have been shown that perinatal (prenatal and early neonatal) period is a critical stage for sexual dimorphism differentiation as well as for the development of energy balance and metabolic circuit. [5][6][7] Barker's hypothesis of links between poor perinatal environment such as undernutrition, and increased susceptibility to diseases has attracted substantial attention during the last years.…”