Thyroxine modifies the effects of growth hormone in Ames dwarf mice.

Andrew Do,Michal M Masternak,Liou Sun,Andrzej Bartke,Vinal Menon,Xu Zhi,Adam Spong,Adam Gesing,Denise S Wiesenborn

doi:10.18632/aging.100739

Abstract

Ames dwarf (df/df) mice lack growth hormone (GH), thyroid stimulating hormone and prolactin. Treatment of juvenile df/df mice with GH alone stimulates somatic growth, reduces insulin sensitivity and shortens lifespan. Early-life treatment with thyroxine (T4) alone produces modest growth stimulation but does not affect longevity. In this study, we examined the effects of treatment of juvenile Ames dwarf mice with a combination of GH + T4 and compared them to the effects of GH alone. Treatment of female and male dwarfs with GH + T4 between the ages of 2 and 8 weeks rescued somatic growth yet did not reduce lifespan to match normal controls, thus contrasting with the previously reported effects of GH alone. While the male dwarf GH + T4 treatment group had no significant effect on lifespan, the female dwarfs undergoing treatment showed a decrease in maximal longevity. Expression of genes related to GH and insulin signaling in the skeletal muscle and white adipose tissue (WAT) of female dwarfs was differentially affected by treatment with GH + T4 vs. GH alone. Differences in the effects of GH + T4 vs. GH alone on insulin target tissues may contribute to the differential effects of these treatments on longevity.

Highlights

Ames dwarf mice have underdeveloped anterior pituitary glands due to a homozygous recessive deletion at the Prop1 locus
Average longevity of female and male Ames dwarf mice that had been treated with growth hormone (GH) + T4 between 2 and 8 weeks of age did not differ from the longevity of dwarf mice of the same sex that had been injected with saline
Reduction of maximal longevity was detected only in females. These findings contrast with the ability of treatment with GH alone during the same period of development to reduce longevity in both female and male dwarfs from the same breeding colony ([6]; Hill Arum & Bartke, unpublished observations). This difference between the effects of treating juvenile Ames dwarf mice with GH + T4 vs. GH -only treatment was unexpected, because both treatments produced a major increase in somatic growth

Summary

Introduction

Ames dwarf mice (df/df) have underdeveloped anterior pituitary glands due to a homozygous recessive deletion at the Prop locus. This loss of function mutation leads to primary hormonal deficiencies in growth hormone (GH), thyroid stimulating hormone (TSH), and prolactin (PRL) [1,2,3]. Ames dwarf mice show a delayed aging process, demonstrated by enhancements in lifespan and healthspan including maintenance of higher insulin sensitivity and glucose tolerance throughout life, preservation of cognitive and neuromuscular function, and decreased occurrence of cancer [6, 8,9,10,11,12]. Mechanisms of the 40-60% increase in lifespan of df/df mice most likely include the interruption in somatotropic (GH/IGF-1) signaling and enhanced www.impactaging.com

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