Growth Hormone Deficiency: Health and Longevity

Abstract

The important role of GH in the control of mammalian longevity was first deduced from extended longevity of mice with genetic GH deficiency (GHD) or GH resistance. Mice with isolated GHD (IGHD) due to GHRH or GHRH receptor mutations, combined deficiency of GH, prolactin, and TSH, or global deletion of GH receptors live longer than do their normal siblings. They also exhibit multiple features of delayed and/or slower aging, accompanied by extension of healthspan. The unexpected, remarkable longevity benefit of severe endocrine defects in these animals presumably represents evolutionarily conserved trade-offs among aging, growth, maturation, fecundity, and the underlying anabolic processes. Importantly, the negative association of GH signaling with longevity extends to other mammalian species, apparently including humans. Data obtained in humans with IGHD type 1B, owing to a mutation of the GHRH receptor gene, in the Itabaianinha County, Brazil, provide a unique opportunity to study the impact of severe reduction in GH signaling on age-related characteristics, health, and functionality. Individuals with IGHD are characterized by proportional short stature, doll facies, high-pitched voices, and central obesity. They have delayed puberty but are fertile and generally healthy. Moreover, these IGHD individuals are partially protected from cancer and some of the common effects of aging and can attain extreme longevity, 103 years of age in one case. We think that low, but detectable, residual GH secretion combined with life-long reduction of circulating IGF-1 and with some tissue levels of IGF-1 and/or IGF-2 preserved may account for the normal longevity and apparent extension of healthspan in these individuals.

Figure 1.

In mice, isolated GH deficiency, hypopituitarism, and GH resistance lead to reduced growth, diminutive adult body size, and extended longevity (1, 2, 4, 5).

Figure 2.

Schematic representation of key mechanistic links between reduced GH signaling and extension of healthspan and lifespan in mice. Arrows identify causal relationships and interactions. Additional mechanisms of extended longevity of GH-related mutants are listed in the text along with references. ROS, reactive oxygen species.

Figure 3.

Three elderly IGHD individuals, homozygous for the c.57+1G>A GHRHR mutation. The man (photograph on the left), 123 cm tall (48.4 inches), died at age 94. At the age of 89 years, he suffered traumatic brain injury riding a horse without a harness to aid a cow in labor. Beside him, his sister (photograph in the middle), 116 cm (45.6 inches) tall, died at age 103. Both did not exhibit kyphosis or gray hair, and they died due to natural causes. The other woman (photograph on the right), 107 cm tall (42.1 inches), died at age 65, probably due to stroke. The author M.H.A.-O., who is 174 cm (68.5 inches) tall, is the normal control.