Long-living growth hormone receptor knockout mice: Potential mechanisms of altered stress resistance

Abstract

Endocrine mutant mice have proven invaluable toward the quest to uncover mechanisms underlying longevity. Growth hormone (GH) and insulin like-growth factor (IGF) have been shown to be key players in physiological systems that contribute to aging processes including glucose metabolism, body composition and cellular protection. Examination of these mutant mice across several laboratories has revealed that differences exist in both the direction and magnitude of change, differences that may result in variation in life span. Growth hormone receptor knock out mice lack a functional GH receptor, therefore GH signaling is absent. These mice have been shown to lack the heightened oxidative defense mechanisms observed in other GH mutants yet live significantly longer than wild type mice. In this study, glutathione (GSH) and methionine (MET) metabolism was examined to determine the extent of variation in this mutant in comparison to the Ames dwarf, a mouse that exhibits delayed aging and life span extension of nearly 70%. Components of GSH and MET were altered in GHR KO compared to wild type controls. The results of these experiments suggest that these pathways may be partially responsible for differences observed in stress resistance and the capacity to respond to stressors, that in the long term, affect health and life span.

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).…”

MECHANISMS IN ENDOCRINOLOGY: Lessons from growth hormone receptor gene-disrupted mice: are there benefits of endocrine defects?

“…Additional factors that lead to the GHRKO mice being the longest-lived mouse in the world include the following -(i) increased stress resistance resulting from superior redox homeostasis due to upregulated expression and activity of glutaredoxin and thioredoxin detoxification systems (214,215,216,217) rather than changes in free-radical scavenging(218), (ii) reduced activity of TORC1 kinase complex (219, 220, 221), (iii) resistance to neoplastic incidence and growth(24, 97), (iv) suppressed hypothalamic inflammation(222) -an end-goal of anti-ageing drugs(223), (v) an anti-inflammatory adipokine profile, inverted liver-WAT lipid distribution and reduced senescent cell burden in WAT(62, 68, 70, 72), (vi) increased markers of mitochondrial biogenesis including higher levels of AMPK, SIRT1, and SIRT3 in heart and increased eNOS and PGC1α levels in skeletal muscle and kidney (224), (vii) detrimental effects of GH/IGF axis on very small embryonic-like stem cell pools in adult tissues (225,226) where age-related changes in DNA methylation patterns lead to increased sensitivity to circulating GH, IGF-1 and insulin with age with concomitant depletion of stem-cell pool and impaired tissue regeneration(225), (viii) resistance to diabetogenic effects of a HF diet (14), and (ix) improved insulin sensitivity(15).…”

Effects of insulin-like growth factor 1 on glutathione S-transferases and thioredoxin in growth hormone receptor knockout mice

“…We previously reported that GHRKO mice exhibited elevated levels of general GST activity in liver, kidney, and heart tissues (Brown-Borg et al 2009). In the present study, GHRKO mice exhibited elevated 4-HNE-specific GST activities that were suppressed in the presence of IGF-1.…”

“…Reverse transcription polymerase chain reaction Gene expression was evaluated in liver tissue using reverse transcription polymerase chain reaction (RT-PCR) techniques (Brown-Borg et al 2009). Total RNA was extracted from tissue using Ultraspec RNA (Biotecx, Houston, TX).…”