Pleiotropic effects of growth hormone signaling in aging

Abstract

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 could account for post-reproductive deficits. 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.

Figure 1. Effects of growth hormone (GH) during different life stages

Stimulation of growth, maturation and fertility by growth hormone (GH) apparently involves ‘costs’ of accelerated aging and increased susceptibility to age-related disease. Current understanding of the evolution of aging suggests that the detrimental GH actions late in life have not been eliminated because of beneficial effects of GH on early reproductive fitness.

Figure 2. Mechanisms linking reduced GH signaling with extended longevity in GH-resistant or GH-deficient mice

Simplified outline of mechanisms of GH effects on longevity. Interactions and reciprocal relationships omitted for clarity. = increase; = decrease This diagram lists consequences of GH deficiency or resistance that constitute likely mechanisms of extended longevity. The Specific Effects listed in the first column include those detected in long-lived mutants, and most have been linked to GH actions by evidence from other experimental systems. The More Global Effects listed in the second column represent broader functional consequences of these changes known to be involved in the control of aging and longevity. The diagram is not intended to be comprehensive or all-inclusive. For example, plausible mechanisms of extended longevity that have been demonstrated in only one mutant have not been included.