Somatotropic signaling: trade-offs between growth, reproductive development, and longevity

Abstract

Growth hormone (GH) is a key determinant of postnatal growth and plays an important role in the control of metabolism and body composition. Surprisingly, deficiency in GH signaling delays aging and remarkably extends longevity in laboratory mice. In GH-deficient and GH-resistant animals, the "healthspan" is also extended with delays in cognitive decline and in the onset of age-related disease. The role of hormones homologous to insulin-like growth factor (IGF, an important mediator of GH actions) in the control of aging and lifespan is evolutionarily conserved from worms to mammals with some homologies extending to unicellular yeast. The combination of reduced GH, IGF-I, and insulin signaling likely contributes to extended longevity in GH or GH receptor-deficient organisms. Diminutive body size and reduced fecundity of GH-deficient and GH-resistant mice can be viewed as trade-offs for extended longevity. Mechanisms responsible for delayed aging of GH-related mutants include enhanced stress resistance and xenobiotic metabolism, reduced inflammation, improved insulin signaling, and various metabolic adjustments. Pathological excess of GH reduces life expectancy in men as well as in mice, and GH resistance or deficiency provides protection from major age-related diseases, including diabetes and cancer, in both species. However, there is yet no evidence of increased longevity in GH-resistant or GH-deficient humans, possibly due to non-age-related deaths. Results obtained in GH-related mutant mice provide striking examples of mutations of a single gene delaying aging, reducing age-related disease, and extending lifespan in a mammal and providing novel experimental systems for the study of mechanisms of aging.

Figure 1.

Age-related decline in circulating levels of human growth hormone (GH) and insulin-like growth factor I (IGF-I).[From Corpas et al. (69) and Zadik et al. (335), with permission from The Endocrine Society.]

Figure 2.

Schematic representation of key mechanisms of growth hormone (GH) signaling. GH binds to two transmembrane GH receptors and alters expression of numerous genes via activation of STAT and ERK; details and references are in the text.

Figure 3.

The somatotropic axis. This diagram contrasts endocrine, primarily hepatic IGF-I that acts as a mediator of GH actions with partially or completely GH-independent IGF-1 produced by other organs that can act locally in paracrine or autocrine fashion.

Figure 4.

Key mechanisms linking GH signaling with adiposity, insulin resistance, and cardiovascular disease (CVD). Details and additional mechanisms are in the text.

Figure 5.

Mechanisms believed to be involved in linking GH signaling with healthspan and lifespan. Details and references are in the text and in TABLE 2.