The above critique of the application of models of GH/IGF-1 deficiency to aging research indicates that the precise roles of GH and IGF-1 in regulation of lifespan are uncertain.
It has been recognized for some time that IGF-1 is an important mitogen that has the potential to contribute to neoplasia and potentially age-related pathogenesis in humans and rodents.
Some studies also indicates that lower levels of IGF-1 could contribute to the protective effect of moderate caloric restriction against age-related pathology.
It was demonstrated that calorically restricted rats have low levels of IGF-1 and are resistant to p-cristine-induced bladder cancer.
Furthermore, the replacement of IGF-1 restored the incidence of bladder cancer to that of ad libitum-fed animals.
Furthermore, studies in Ames dwarf mice have shown that whereas there is no difference in numbers of tumors between dwarf and wild-type mice there is an extended latency for the tumors to form.
Although a complete analysis of these findings has yet to be conducted, they suggest that IGF-1 is required for some types of chemically induced pathogenesis.
Unfortunately, more detailed pathological analyses have yet to be performed in any of the dwarf models discussed here.
Without this information, our ability to reach a conclusion concerning the effects of GH deficiency on age-related pathologies is clearly impaired.
However, it has been suggested that the primary result of GH/IGF-1 deficiency is the slowing of a central "biological clock", an effect dissociable from the simple reduction in age-related pathology proposed by others.
In support of this view, it has been argued that robust changes associated with biological aging (reduced immune function and increased collagen crosslinking) and behavioral aging (reduced cognitive ability as measured by passive avoidance tasks) are ameliorated in the Ames and Snell dwarfs, effects that are inconsistent with the known actions of GH and IGF-1 (see box 1 for regulation pattern).
Regardless of the parameters measured, the aforementioned concerns with these models persist, and thus, the consequences of GH/IGF-1 deficiency on aging remain unresolved.
In addition, any evidence that GH/IGF-1 deficiency delays biological aging must be reconciled with a substantial body of the literature demonstrating beneficial actions of these hormones in young and old animals.
Box 1. The action of growth hormone and insulin-like growth factor-1
Growth hormone (GH), produced in the anterior pituitary, is modulated by two hypothalamic hormones, growth hormone-releasing hormone (GHRH), which stimulates both the synthesis and secretion of GH; and somatostatin (SS), which inhibits GH release in response to GHRH.
GH also feeds back to inhibit GHRH secretion and probably has a direct inhibitory effect on secretion from the somatotroph (GH-producing cells).
Basal concentrations of GH in blood are very low.
In mammals, GH is secreted in pulsatile bursts from the anterior pituitary gland, a pattern that is necessary to achieve full biological activity.
GH binds with high affinity to its receptor, found in tissues throughout the body, and activation of this receptor stimulates the synthesis and secretion of insulin-like growth factor 1 (IGP-1) [a].
Although 90% of circulating IGF-1 is synthesized and secreted by the liver, many types of cells, including some found in the brain and vasculature, are capable of IGF-1 production [b,c].
Binding of the hormone to the IGP-1 receptor causes potent mitogenic effects, including increases in DNA.RNA and protein synthesis [d].
Although heterogeneity exists in the processing of IGF-1 mRNA.
These transcripts appear to produce a single peptide that is homologous to the structure of proinsulin.
Blood and tissue levels as well as activity of the peptide are regulated by IGF-1 binding proteins (IGFBP) [d].
Although it was initially proposed that all of the actions of GH were mediated through IGF-1, data from several studies support direct roles for GH in the regulation of lipolysis and insulin sensitivity that are independent of IGF-1 [e.f].
References to box 1.
a. LeKoith, D. el at. (2001) The somatomedin hypothesis. Endocr. Rev. 22, 23-74.
b. Lopez-Fernandez, J. et al. (1996) Growth hormone induces somatostatin and insulin-like growth factor I gene expression in the cerebral hemispheres of aging rats. Endocrinology 137, 4384-4391.
c. Yamamoto, H. and Murphy, L.J. (1995) Enzymatic conversion of IGF-1 to des(l-3)IGF-I in rat serum and tissues: a further potential site of growth hormone regulation of IGF-1 action. J. Endocrinol. 146, 141-148.
d. Cohick, W.S. and Clemmons, D.R. (1993) The insulin-like growth factors. Annu. Rev, Physiol. 55, 131-153.
e. Daughaday, W.H. (1989) A personal history of the origin of the somatomedin hypothesis and recent challenges to its validity. Perspect. Biol. Med. 32, 194-211.
f. Isaksson, O.G. e( al. (1988) Action of growth hormone: current reviews. Acta Paediatr. Scand. (Suppl. 343), 12-18.