Thyroxine modifies the effects of growth hormone in Ames dwarf mice

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.

The somatotropic axis and longevity in mice

“…When DR is applied to the GHRKO, no additional insulin sensitivity is observed, nor is there an extension of lifespan in contrast to the Ames dwarf. However, when GH is combined with thyroxine treatment for 6 wk in juvenile Ames mice, no effect on longevity is observed (31). Treatment with growth hormone in vitro and in vivo decreases antioxidative enzyme activities and glutathione and methionine metabolism in Ames mice (21,59).…”

“…However, lifelong treatment of Snell dwarf mice with thyroxine shortened lifespan such that treated mice lived 83% of the untreated-dwarf lifespan (110). A more recent report indicated that Ames mice treated with GH and thyroxine between the ages of 2 and 8 wk did not reduce lifespan to match wild-type controls yet increased body weights of the dwarf mice to that of untreated wild-type mice (ϳ18 g) (31). Mutations that impact GH status, both spontaneous and engineered, strongly support a major role for GH in lifespan regulation.…”

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

“…(ii) Bartke and colleagues, have dealt intensively into various conditions of GH deficit and ageing (198,242) and recently reported that a short (6 weeks) phase of early exposure to GH (starting at 2 weeks age) reduced lifespan and cellular stress resistance in Ames dwarf mice (243). A parallel thyroxine treatment had no effect on lifespan (243,244,245) whereas thyroxine and GH combined treatment reduced maximal lifespan in only female Ames mice (246). (iii) Extensive work by Brown-Borg and colleagues have described epigenetic signatures in DNA methylation patterns in Ames mice compared to their WT littermates (247,248).…”

Growth hormone actions during development influence adult phenotype and longevity

“…Unexpectedly, concomitant treatment of juvenile Ames dwarf mice with thyroxine severely reduced (in females) or eliminated (in males) the effect of early GH treatment on longevity [42]. Treatment with thyroxine alone during the same period (between 2 and 8 weeks or age) had no significant impact on longevity [42] and 11 weeks of treatment of Snell dwarfs starting at 4 weeks of age similarly failed to affect their longevity [24].…”

“…Treatment with thyroxine alone during the same period (between 2 and 8 weeks or age) had no significant impact on longevity [42] and 11 weeks of treatment of Snell dwarfs starting at 4 weeks of age similarly failed to affect their longevity [24]. These findings were counterintuitive.…”