To Grow or to Age: New Research in Growth Hormone

Abstract

GH is a hormone with diverse actions. As the name implies, GH plays a critical role in body growth. At the onset of puberty, GH reaches its peak level, leading to the elongation of the long bones and rapid linear growth. GH induces the expression of insulinlike growth factor-1 (IGF-1) in the liver, which mediates part of the growth-promoting action of GH. GH and IGF-1 both decline rapidly from early teens and decline thereafter as a function of age. Another well-known action of GH is the anabolic effect in the skeletal muscle, resulting in enhanced protein synthesis and increased muscle mass. In contrast, GH induces a catabolic effect in the adipose tissue, resulting in fat loss [3]. Because of these effects in the muscle and fat, GH is often abused and mis-used by athletes. In addition to these classical actions of GH, other documented although less-well studied effects of GH include fluid retention, reproduction and immunity. GH acts on the renin-angiotensin-aldosterone system to promote fluid retention [4]. In this regard, both extracellular volume and plasma volume are decreased in GH deficient patients and normalized after GH replacement therapy [4]. GH also regulates reproduction. Normal GH signaling is needed for folliculogenesis, ovarian maturation, ovulation, and pregnancy in females and for spermatogenesis and the Leydig cell function in males [5]. Adding to its diverse physiological effects, GH also plays an important role in immune modulation. It stimulates T and B cells proliferation and immunoglobulin synthesis, promoting the differentiation of myeloid progenitor cells and modulates cytokine response [6]. These physiological effects of GH warrant further study to understand the related health issues and potential applications in therapeutics. In recent years, GH has been shown to regulate aging. Animal studies have demonstrated that disrupted GH signaling results in increased longevity [7], whereas increased GH signaling leads to premature aging [8,9]. Thus GH shows a pleiotropic effect- beneficial at early age for fitness and reproduction while detrimental at old age [10]. The mechanism for the aging promoting effect is not completely understood, but may involve increased insulin resistance and cancer incidence, and reduced stress defense and mitochondria functions associated with prolonged increase of GH signaling [10]. In humans, acromegaly, a disorder of excess GH secretion, is known to be associated with hypertension, cardiovascular anomaly, diabetes, respiratory problems and increased mortality if untreated [11], which is consistent with studies of GH transgenic mice. However, increased lifespan has not been observed in Laron Syndrome subjects, who have mutations in their GH receptor (GHR) gene therefore no GH signaling. This is in contrast to GHR null mice which show a 50% increase in lifespan compared to control mice. Interestingly though, Laron subjects have a decreased incidence of cancer and diabetes [12], thus supporting the