Effects of a growth hormone-releasing hormone antagonist on telomerase activity, oxidative stress, longevity, and aging in mice

Abstract

Both deficiency and excess of growth hormone (GH) are associated with increased mortality and morbidity. GH replacement in otherwise healthy subjects leads to complications, whereas individuals with isolated GH deficiency such as Laron dwarfs show increased life span. Here, we determined the effects of treatment with the GH-releasing hormone (GHRH) receptor antagonist MZ-5-156 on aging in SAMP8 mice, a strain that develops with aging cognitive deficits and has a shortened life expectancy. Starting at age 10 mo, mice received daily s.c. injections of 10 μg/mouse of MZ-5-156. Mice treated for 4 mo with MZ-5-156 showed increased telomerase activity, improvement in some measures of oxidative stress in brain, and improved pole balance, but no change in muscle strength. MZ-5-156 improved cognition after 2 mo and 4 mo, but not after 7 mo of treatment (ages 12, 14 mo, and 17 mo, respectively). Mean life expectancy increased by 8 wk with no increase in maximal life span, and tumor incidence decreased from 10 to 1.7%. These results show that treatment with a GHRH antagonist has positive effects on some aspects of aging, including an increase in telomerase activity.Alzheimer's disease | learning | memory | peptide | sarcopenia T he aging process is associated with decreased physical and mental functioning, increased morbidity, and inevitable mortality. Specific neurodegenerative diseases such as Alzheimer's disease lead to decreased learning and memory. The incidence of many benign and malignant tumors clearly increases with aging. Populations show significant variations in the rate at which aging advances and many mechanisms have been proposed to explain aging or were found to be associated with the rate of aging. Oxidative stress, telomerase activity, and variation in hormonal levels are examples of these associations and mechanisms.Among hormones that are implicated in aging is growth hormone (GH). GH levels decrease dramatically with aging (1) and some of the findings in aging, such as thinning of the skin and bones, are the opposite of those found in acromegaly, a condition in which GH is overproduced (2). This has led to the proposal that replacement of GH will reverse or slow the aging process. However, several clinical trials showed that replacement of GH is associated with increased mortality (3, 4). Acromegaly is also linked to many adverse conditions that are associated with aging, including glucose intolerance, heart disease, and an increased cancer incidence (5). Transgenic mice overexpressing GH have a decreased life span and evidence of accelerated aging in several organs and tissues, including the brain (6).Whereas GH replacement and acromegaly are associated with adverse outcomes, GH deficiency or resistance to GH are associated with longer life expectancy. Laron dwarfs show resistance to GH at the receptor level and so do not secrete insulin-like growth factor I (IGF-I) and can live to an advanced age (2). Mouse strains with a deficiency in GH activity because of transcription factor mutations (the Ames m...

Inhibition of GHRH aggravated acetaminophen-induced acute mice liver injury through GH/IGF-I axis

“…Considering that inhibition of GHRH, GH, and IGF-I in the current study reduced the antioxidant system in the liver, it is reasonable to postulate the antioxidative role of GHRH/GH/IGF-I axis in acute liver injury. Two previous studies showed that application of GHRH antagonist attenuated oxidative stress in human cancer cells and aging cognitive deficiency mice, respectively [35,36]. The inconsistency between the current study and these reports is probably from the differences between normal animal and cancer cell line, as well as the differences between the healthy and APAP-induced liver…”

Dietary resveratrol prevents Alzheimer’s markers and increases life span in SAMP8

“…At present, resveratrol was reported to prevent early mortality in mice fed with a high-fat diet ) but failed to affect survival significantly in old mice (Miller et al 2011). A growth hormone releasing hormone antagonist has been shown to extend SAMP8 mice's median life span (Banks et al 2010), which was associated with decreased brain oxidative stress. Melatonin has also been reported to increase life span and longevity in SAMR1 and SAMP8 mice (Rodríguez et al 2008).…”

Antagonist of GH-releasing hormone receptors alleviates experimental ocular inflammation

“…These results agree with earlier findings that GHRH-R antagonists suppress inflammation by reducing the production of inflammatory proteins, such as IL-β, NF-κB/p65, and COX-2, in experimental prostatic hyperplasia and breast cancer (15,18) and alleviate inflammation-triggered oxidative stress by increasing glutathione and decreasing glutathione peroxidase activity (29). The antagonist may alleviate inflammatory responses by acting as a local modulator for the maturation and migration of immune cells, including macrophages, lymphocytes, and other leukocytes (30)(31)(32). Because GH has been shown to target macrophages to trigger various immune responses (15), we argue that the GHRH-R antagonist may block the signaling of GHRH-R on the macrophages residing in the iris-CB and so inhibit synthesis and release of GH, resulting in reduced IGF1 secretion.…”