Pleiotropic effects of growth hormone signaling in aging

Abstract

Summary Growth hormone (GH) affects somatic growth, sexual maturation, body composition and metabolism, as well as aging and longevity. Mice lacking GH or GH receptor outlive their normal siblings and exhibit symptoms of delayed aging associated with improved insulin signaling and increased stress resistance. Beneficial effects of eliminating the actions of GH are counterintuitive but conform to the concept of antagonistic pleiotropy. Evolutionary selection for traits promoting early life fitness and reproductive success may account for detrimental effects post-reproductively. Reciprocal relationships between GH signaling and longevity discovered in mutant mice apply also to normal mice, other mammalian species, and perhaps humans. This review summarizes the present understanding of the multifaceted relationship between somatotropic signaling and mammalian aging.

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

“…Decades of research has documented a pleiotropic role of GH/IGF-1 in human ageing and disease (16). In mice and humans, the global absence of GH action leads to improved glucose homeostasis, cognition, better memory, possibly a longer than normal lifespan, and substantial protection from incidence of diabetes, cancer, as well as neuropathologies.…”

“…Laron's seminal work with the Israeli cohort of LS patients (3,4,9,10) and Guevara's subsequent 22-year follow-up study on the Ecuadorian cohort (11,12) of LS patients along with extensive work with GHR knock-out (GHRKO) mice developed 25 years ago in our laboratory (13) have been instrumental in helping to define GH and insulin-like growth factor-1 (IGF-1) activities. Both human LS patients and GHRKO mice share several physical, metabolic, and cognitive similarities that will be described below (14,15,16,17).…”

Peroxiredoxins, gerontogenes linking aging to genome instability and cancer

“…Specifically, aging is decelerated by mutations reducing signaling through nutrient-responsive pathways, including insulin/insulin-like growth factor, mTOR, and RAS-PKA signaling (Cohen and Dillin 2008;Kenyon 2010;Bartke 2011;McCormick et al 2011). Such a reduced activity in nutrient-responsive pathways results in the altered expression of a large number of genes, and it is presently not clear which of all of these genes are the most crucial targets responsible for life span extension.…”

Dissociation of somatic growth, time of sexual maturity, and life expectancy by overexpression of an RGD ‐deficient IGFBP ‐2 variant in female transgenic mice

“…This implicates, at least to some extent, that an uncoupling of pleiotropic IGFBP‐2 effects is possible in the current experimental system. The concept of antagonistic pleiotropy has been discussed extensively in the context of the GH/IGF‐system before (Bartke, 2011). …”