Diverse roles of growth hormone and insulin-like growth factor-1 in mammalian aging: progress and controversies

Abstract

Because the initial reports demonstrating that circulating growth hormone and insulin-like growth factor-1 decrease with age in laboratory animals and humans, there have been numerous studies related to the importance of these hormones for healthy aging. Nevertheless, the role of these potent anabolic hormones in the genesis of the aging phenotype remains controversial. In this chapter, we review the studies demonstrating the beneficial and deleterious effects of growth hormone and insulin-like growth factor-1 deficiency and explore their effects on specific tissues and pathology as well as their potentially unique effects early during development. Based on this review, we conclude that the perceived contradictory roles of growth hormone and insulin-like growth factor-1 in the genesis of the aging phenotype should not be interpreted as a controversy on whether growth hormone or insulin-like growth factor-1 increases or decreases life span but rather as an opportunity to explore the complex roles of these hormones during specific stages of the life span.

Figure 1.

Panel (A): GH/IGF-1 deficiency in ghr−/−, Ames, and Snell dwarf mice is associated with a substantial extension of life span compared with the respective wild-type controls. Relative increases in median life span, based on the data published in references (,–23), are shown. Panel (B): Human GHR-deficient (GHRD) Ecuadorian subjects do not exhibit a longevity phenotype. Median age at 50% survival for the GHRD subjects is indicated based on the survival curve for this population (34). The expected life span for GHRD subjects was calculated by extrapolation of the mouse data. For reference, the life expectancies at birth of the population in Ecuador and the United States are shown. Life-span expectancy data were taken from the Central Intelligence Agency World Factbook (https://www.cia.gov/library/publications/the-world-factbook/rankorder/2102rank.html).

Figure 2.

In male Ames dwarf mice, short-term peripubertal treatment with bovine GH (6 μg/g bw/day injected subcutaneously) between 2 and 8 weeks of age prevents the expression of the longevity phenotype. The median life spans of Ames dwarf mice treated with GH, untreated wild-type controls, and untreated Ames dwarf mice are shown. Data are replotted from (83). *p = .0005.

Figure 3.

In genetically diverse inbred mouse strains, IGF-1 levels measured at 6 months of age are negatively correlated with median life span both in males (A) and females (B). Panels (C and D): No correlation exists between IGF-1 levels measured at 18 months of age and median life span of the mouse strains in either sex. These findings indicate that only levels of circulating IGF-1 early during the life span are predictive of life span. The data are derived from life-span studies conducted at the Jackson Aging Center. Data are replotted from previously published work of Yuan et al. (84,85).

Figure 4.

In genetically diverse inbred mouse strains, larger age-related declines in circulating IGF-1 levels (defined as the difference between IGF-1 levels measured at 18 months of age and 6 months of age) tend to be associated with shorter life span. The hypothesis that low IGF-1 levels in the postdevelopmental period delay aging would predict the opposite. The data are derived from life-span studies conducted in mice housed in a specific pathogen-free facility at the Jackson Aging Center. Data are replotted from previously published work of Yuan et al. (84,85).