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I.R.F. / Aging news / Diseases / 03071601

Could IGF-I and GH Be the Salvation of Aging?
Posted on: July 16, 2003

Dozens of genes extend adult longevity. Remarkably, many of these genes are involved with hormonal signals, and both these genes and their endocrine systems are conserved among eukaryotes. Thus, insulin-like peptides, insulin-like growth factor (IGF), lipophilic signaling molecules and steroids are all candidate effectors of aging in organisms as diverse as nematode Caenorhabditis elegans, the fly Drosophila melanogaster and mouse Mus musculus. Suppression of these hormones or their receptors can increase life span and delay age-dependent functional decline. This regulation is likely adaptive because, at least among invertebrates, these hormones regulate the organism's capacity to survive during states of reduced metabolism coupled with high stress resistance and arrested development. Mutations that increase life span through hormones are though to initiate elements of this survival program independent of the appropriate environmental cues. Because mechanisms for survival often oppose the progress of aging, they can illuminate the cellular and molecular causes of senescence. The insulin/IGF system and its associated downstream hormones are likely to prove particularly instructive.

Of a number of genetic models that retard aging, several involve deficiency of pituitary endocrine action. Certain mutations impede pituitary production of growth hormone (GH), thyroid stimulating hormone and prolactin; reduce growth rate and adult body size and increase adult life span. Expressed throughout life, these mutations produce many secondary alterations in endocrine system.

Without GH the synthesis of circulating IGF-1 is suppressed. In invertebrates reduced insulin/IGF signaling increases longevity. In rodents as in humans, levels of GH and IGF-1, decline with adult age. Short-term GH supplementation in aged adults restores some aspects of body composition and cognition. Thus, the withdrawal of GH and IGF-1 has been suggested to be a cause of senescence rather than a condition that retards aging. On the other hand, because it stimulates metabolism and cell growth, GH may hasten tissue pathology. High IGF-1 titers in young wild-type animals may produce a trade-off between current benefits to reproduction and later costs in senescence.

Diseases that result in either overproduction or reduction of plasma GH and IGF-1 can be informative for developing therapies that prevent multiple age-related diseases. Human somatotroph adenomas of pituitary gland can cause chronic secretion of excessive GH, resulting in acromegaly, which is associated with a major life shortening from cardiovascular diseases and cancer. Treatment of acromegaly with somatostatin analogs decreases GH and IGF-1, resulting in clinical improvements. Although these studies imply a role for GH and IGF-1 in diseases of aging, the abnormally high GH levels in acromegaly patients provide limited information on the role of normal levels of GH in cancer and cardiovascular diseases.

The dwarf phenotype (side effect of genetic manipulations including fat accumulation) of long-lived yeast, flies and mice suggest that it will be difficult to extend human longevity without causing side effects. In fact, GH deficiency in humans can lead to reduced life expectancy and is associated with increased fat mass, reduced muscle and bone mass, behavioral problems, increased prevalence of hypertension, insulin resistance and premature atherosclerosis. Thus, the changes that accompany fat accumulation may counteract putative beneficial effects of GH/IGF-1 deficiency in humans. The increased mortality is observed in GH deficient hypopituitary patients that, in most cases, also lack adrenocorticotrophic hormone (ACTH). By contrast, human mutations analogous to the prop-1 mutation that extends longevity in rodents cause defects including dwarfism, wrinkled skin and intellectual deficiency but do not appear to shorten life span. Among the rare prop-1 patients for whom life-span data are available, several surpassed the average life-span and one survived to age 91. Unlike most patients with GH deficiency, humans with prop-1 mutation do not lack adrenocorticotrophic hormone (ACTH), raising the possibility that the increased mortality observed in hypopituitary patients is caused by ACTH and not GH deficiency.

The human Laron Syndrome (LS) is caused by a defect in the GH receptor and resembles GH deficiency clinically and biochemically. High GH, but very low plasma IGF-1, very short stature, obesity and impairments in physical and intellectual development characterize Laron Syndrome. Later in life LS causes hypercholesterolemia and glucose intolerance. In summary, GH and IGF-1 deficiencies in humans are associated with major defects and diseases. However, the normal (and possibly longer) life-span of a few individuals with mutation analogous to those that extend longevity in mice suggest that it may be possible to extend human longevity by reducing plasma GH and IGF-1 levels.

Although studies in rodent models point to GH and IGF-1 as promoters of aging and age-related diseases, GH is prescribed extensively as an anti-aging hormone. GH treatment can increase body mass and decrease adipose tissue in 61 to 81-year old men with low plasma IGF-1 concentration, and long-term GH replacement therapy causes some improvements in patients with GH deficiencies. However "anti-aging" effects of GH therapy are typically observed after short-term treatment of patients with low plasma GH. By contrast, chronically high GH levels increase incidence of diseases, including cancer and kidney diseases in rodents, and increase cardiovascular diseases and cancer in human acromegaly patients. GH administration also increases the development of diabetes and glucose intolerance in healthy, older women and men and increases morbidity and mortality in patients that are clinically ill, even after short-term treatment. It is clear that a major and chronic increase in plasma GH/IGF-1 levels increases morbidity and mortality.

Three categories of drugs may have the potential to prevent or postpone multiple age-related diseases: drugs that (i) simulate dwarf mutations and therefore decrease GH production by pituitary cells, (ii) prevent IGF-1 release from the liver, or (iii) decrease IGF-1 signaling.

Dwarf mice eat normally and become obese in old age, yet they live 50% longer. Therefore, the pharmacological simulation of dwarf mutations should also increase obesity and extend longevity in mice. Although we do not know whether the longevity effect of dwarf mutations can be separated from the small body size, preliminary data suggest that it is possible. Dwarf mice treated transiently in early adult life with GH and thyroid hormone become much larger than littermate control mice. Studies in yeast and worms indicate that life span can be extended without causing growth and reproductive defects. Obesity and muscle weakness are other major side effects of GH deficiency that must be prevented before drugs that simulate dwarf mutations can be considered for human studies.

Studies in simple eukaryotes indicate that IGF-1-like factors activate a major pro-senescence pathway. Drugs that prevent IGF-1 generation in response to GH would have the advantage of reducing plasma IGF-1 levels without decreasing GH levels. Because GH can directly stimulate growth, activation and differentiation in cells, e.g., phagocytes and lymphocytes, it is possible that, by reducing IGF-1 but not GH levels, longevity may be extended while reducing side effects. Drugs that block IGF-1 receptor activation may have a similar effect. However, mice with very low plasma IGF-1 and elevated GH have a fourfold increase in insulin levels and muscle-specific insulin resistance, suggesting that reduction of only IGF-1 is also associated with some adverse side effects.

Other drugs can target intracellular mediators of pro-senescence hormone and growth factors. Although a mammalian signal transduction pathway that regulates longevity has not been identified, the increased stress resistance and longevity of mice with certain mutations suggest that a pro-senescence pathway is also present in mammalian cells. The well-characterized yeast and worm longevity pathways should provide templates for the identification of genes and drugs that regulate longevity and diseases in mammals.

Source: V.D. Longo and C.E. Finch. Evolutionary Medicine: From Dwarf Model Systems To Healthy Centenarians? Science, 2003, vol 299, p: 1342-1346.
M. Tatar, A. Bartke, A. Antebi. The Endocrine Regulation of Aging by Insulin-like Signals. Science, 2003, vol 299, p: 13461351.
Figure: Insulin growth factor I structure prediction
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