GH and ageing: Pitfalls and new insights

Abstract

Interrelationships of growth hormone (GH) actions and aging are complex and incompletely understood. The very pronounced age-related decline in GH secretion together with benefits of GH therapy in individuals with congenital or adult GH deficiency (GHD) prompted interest in GH as an anti-aging agent. However, the benefits of treatment of normal elderly subjects with GH appear to be marginal and counterbalanced by worrisome side effects. In laboratory mice, genetic GH deficiency or resistance leads to a remarkable extension of longevity accompanied by signs of delayed and/or slower aging. Mechanisms believed to contribute to extended longevity of GH-related mutants include improved anti-oxidant defenses, enhanced insulin sensitivity and reduced insulin levels, reduced inflammation and cell senescence, major shifts in mitochondrial function and energy metabolism and greater stress resistance. Negative association of the somatotropic signaling and GH/insulin-like growth factor 1 (IGF-1)-dependent traits with longevity was also shown in other mammalian species. In humans, syndromes of GH resistance or deficiency have no consistent effect on longevity, but can provide striking protection from cancer, diabetes and atherosclerosis. More subtle variations in various steps of GH and IGF-1 signaling are associated with reduced old-age mortality, particularly in women and with improved chances of attaining extremes of lifespan. Epidemiological studies raise a possibility that the relationship of IGF-1 and perhaps also GH levels with human healthy aging and longevity may be biphasic. However, the impact of somatotropic signaling on neoplastic disease is difficult to separate from its impact on aging and IGF-1 levels exhibit opposite associations with different chronic, age-related diseases.

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

“…In mice and men, the somatotropic axis occupy a central position in the study of ageing, health-span, and longevity (195,196,197,198,199,200,201). GHD mouse models have consistently shown an extended lifespan, while the results are inconsistent in GHD humans (200,202,203).…”

“…This marked protection from cancer was also consistent in the Israeli cohort of LS patients (99) and, therefore, display one of the most prominent factors underlying lifespan extension due to GHR deficiency in humans (227). For now, a conclusive answer to the question whether the link between GHR dysfunction and extended longevity observed in GHRKO mice holds in GH resistant humans (198,201) remains unknown.…”

“…Most recent ageing research in yeast (239,240) and C. elegans (241) are provocative towards inquiring with the GHRKO model into the status of transcription factors like Gcn4 or Atf4 and proteostasis status. (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).…”

The relationship between serum IGF-1, handgrip strength, physical performance and falls in elderly men and women

“…Human aging is accompanied by a decrease in spontaneous growth hormone (GH) secretion and a decline in serum insulin-like growth factor (IGF)-1. The term 'somatopause' is frequently used to refer to this age-related decline in GH secretion (1,2,3,4). Studies indicate a decrease in spontaneous GH secretion of 14% per decade in adults between the third and eight decade, resulting in a state comparable with functional growth hormone deficiency (GHD) in elderly men and women in the lower part of the distribution of GH secretion (1,5,6,7,8).…”

VCAM‐1 upregulation accompanies muscle remodeling following resistance‐type exercise in Snell dwarf (Pit1dw/dw) mice

“…Hypopituitary mutant dwarf mice with combined anterior pituitary hormone deficiencies of growth hormone, thyrotropin, and prolactin are valuable genetic models for the investigation of both congenital hypopituitarism and lifespan extension (Bartke & Darcy, 2017). The Snell dwarf mouse, first described in 1929, is one such genetic model with a recessive mutation in Pit1 (Pou1f1) , an anterior pituitary transcriptional factor (Snell, 1929).…”