Original Research: Metabolic alterations from early life thyroxine replacement therapy in male Ames dwarf mice are transient

Abstract

Ames dwarf mice are exceptionally long-lived due to a Prop1 loss of function mutation resulting in deficiency of growth hormone, thyroid-stimulating hormone and prolactin. Deficiency in thyroid-stimulating hormone and growth hormone leads to greatly reduced levels of circulating thyroid hormones and insulin-like growth factor 1, as well as a reduction in insulin secretion. Early life growth hormone replacement therapy in Ames dwarf mice significantly shortens their longevity, while early life thyroxine (T4) replacement therapy does not. Possible mechanisms by which early life growth hormone replacement therapy shortens longevity include deleterious effects on glucose homeostasis and energy metabolism, which are long lasting. A mechanism explaining why early life T4 replacement therapy does not shorten longevity remains elusive. Here, we look for a possible explanation as to why early life T4 replacement therapy does not impact longevity of Ames dwarf mice. We found that early life T4 replacement therapy increased body weight and advanced the age of sexual maturation. We also find that early life T4 replacement therapy does not impact glucose tolerance or insulin sensitivity, and any deleterious effects on oxygen consumption, respiratory quotient and heat production are transient. Lastly, we find that early life T4 replacement therapy has long-lasting effects on bone mineral density and bone mineral content. We suggest that the transient effects on energy metabolism and lack of effects on glucose homeostasis are the reasons why there is no shortening of longevity after early life T4 replacement therapy in Ames dwarf mice.

Increased environmental temperature normalizes energy metabolism outputs between normal and Ames dwarf mice

“…Quantative RT-PCR was performed as previously described [ 12 ] using the StepOne System and SYBR Green master mix. In short, tissue was homogenized, RNA was extracted using an RNeasy lipid tissue mini kit following the manufacturer’s instructions, and cDNA was made using an iScript cDNA synthesis kit.…”

Somatic growth, aging, and longevity

“… 97 , 98 However, treatment of dwarf mice with thyroxine limited to the peripubertal period did not alter their longevity. 93 , 99 …”

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).…”