Growth Hormone Receptor Deficiency Is Associated with a Major Reduction in Pro-Aging Signaling, Cancer, and Diabetes in Humans

Abstract

Life span extending mutations in growth signaling pathways protect against age-dependent DNA damage in yeast and decrease insulin resistance and cancer in mice. To test their effect in humans, we monitored for 22 years Ecuadorian subjects with mutations in the growth hormone receptor gene leading to severe growth hormone receptor (GHR) and IGF-I deficiencies and combined this information with surveys to identify the cause and age of death for subjects who died before this period. The individuals with GHR deficiency (GHRD) exhibited only one non-lethal malignancy and no cases of diabetes, in contrast to 17% cancer and 5% diabetes prevalence in the controls. A possible explanation for the very low incidence of cancer may be revealed by in vitro studies: serum from GHRD subjects reduced DNA breaks but increased apoptosis in human mammary epithelial cells (HMECs) treated with hydrogen peroxide. We also observed reduced insulin concentrations (1.4 μU/ml vs. 4.4μU/ml in unaffected relatives) and a very low homoeostasis model assessment of insulin resistance (HOMA-IR) index (0.34 vs. 0.96 in unaffected relatives) in GHRD individuals, indicating increased insulin sensitivity, which could explain the absence of diabetes in these subjects. Incubation of HMECs with GHRD serum also resulted in reduced expression of RAS, PKA and TOR, and up-regulation of SOD2, changes that promote cellular protection and life span extension in model organisms. These results provide evidence for a role of evolutionarily conserved pathways in promoting aging and diseases in humans and identify a candidate drug target for healthy life span extension.

FNDC5 (irisin) gene and exceptional longevity: a functional replication study with rs16835198 and rs726344 SNPs

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MicroRNAs are critical regulators of tuberous sclerosis complex and mTORC1 activity in the size control of the Xenopus kidney

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Should animal fats be back on the table? A critical review of the human health effects of animal fat

“…In calorie-restricted individuals, when protein was reduced to maintenance levels and replaced isocalorically with other macronutrients, the level of insulin-like growth factor-1 (IGF-1) dropped substantially (Fontana et al 2008). This longevity marker, which is associated with cancer, diabetes, and dementia, including Alzheimer's disease (Paolisso et al 1997;Arai et al 2001;Carro et al 2002;Trejo et al 2002;Longo and Finch 2003;Pollak et al 2004;Carro and TorresAleman 2006;Fontana et al 2010;Guevara-Aguirre et al 2011;Duron et al 2012;Rajpathak et al 2012), is raised the least by lipids and most by protein consumption (Thissen et al 1994). A study of raw food enthusiasts consuming 40% of calories as lipid and a maintenance level of 0.7 g/kg of protein (Rand et al 2003),~10% of calories, showed similar low levels of IGF-I without apparent calorie restriction (Fontana et al 2008).…”