The most well-studied mouse models of extended life span resulting from disrupted growth hormone signaling involve genetic changes that likely do more than just affect growth hormone metabolism. The usual challenges of cellular biochemistry apply, in that most proteins have more than one function. Here, researchers show that a selective knockout of only growth hormone still extends life, but not to the same extent as is observed in the better known models. Looking at the broader context of the influence of growth hormone metabolism on aging, it is worth recalling that the analogous human loss of function mutants, the condition known as Laron syndrome, do not appear to live notably longer than the rest of the population. As is the case for calorie restriction, effects in short lived species are larger than those in long-lived species such as our own.
The somatotrophic axis, comprised of growth hormone (GH) and GH-releasing hormone (GHRH) secreted from the pituitary or hypothalamus, respectively, is a powerful determinant of laboratory mouse longevity evidenced by the dramatic lifespan extensions that result from genetic interruption at any level of this axis in mice. This body of work suggests that the action of GH is a critical regulator of mammalian lifespan. A crucial limitation of these studies, however, is that mice typically treated as “GH-deficient” display defects in several other genes and hormones which leaves the direct contribution of GH unexplored.
Ames dwarf and Snell dwarf mice, deficient for GH as well as prolactin and thyroid-stimulating hormone, were among the first mice with defective somatotrophic signaling found to be long-lived. Mutant mice lacking a functional GHRH-receptor or functional GHRH also cannot be considered true models of “isolated GH deficiency” as the extrapituitary effects of GHRH, which have gained appreciation as important physiological regulators, could contribute to the lifespan extension reported in these mice. Additionally, mice with a targeted disruption of the GH-receptor (GHR) gene display dramatically elevated levels of GH.
To address this critical gap in knowledge, we carried out the first assessment (to our knowledge) of lifespan in mice with a targeted GH gene knockout in conjunction with metabolic assessment during adulthood. GH knockout (KO) mice maintained under specific pathogen-free conditions with ad-libitum access to standard rodent diet and water displayed a 21% extension in median lifespan over wild type littermates. It is noteworthy that while the differences in lifespan we observed between KO and wild type mice were significant, they are lesser in magnitude than the 40+% extensions reported in other models of somatotrophic disruption. This suggests that while GH deficiency clearly contributes to lifespan extension, an additive effect of additional gene/hormone deficiencies on lifespan may also exist.
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