Sci. Aging Knowl. Environ., 24 April 2002
Insulin-Like Growth Factor 1 and Mammalian Aging
The author is in the Department of Physiology in the School of Medicine at Southern Illinois University, Carbondale, IL 62901, USA.http://sageke.sciencemag.org/cgi/content/full/sageke;2002/16/vp4
Key Words: insulin-like growth factor 1 IGF-1 growth hormone Snell dwarf Ames dwarf Laron mice Little mice
Insulin-like growth factor 1 (IGF-1) is produced in many organs in response to growth hormone (GH), which is secreted by the pituitary. IGF-1 serves as a key mediator of GH actions (Fig. 1). Studies in genetically altered mice have provided strong evidence that alterations in GH signaling and therefore in the resulting IGF-1 production can delay aging and prolong life. Five genetic alterations--either spontaneous mutations at a single locus or targeted disruption ("knockout") of a single gene--lead to major extensions of life-span in mice (1-4) (Fig. 2). Three of these five types of genetically long-lived mice are GH-deficient [Ames dwarf mice, which carry a mutation in the prop-1 gene (5), Snell dwarf mice, which carry a mutation in the pit-1 gene (6), and Little mice, which carry a mutation in the Ghrhr gene (7)], and one is GH-resistant [GH receptor gene knockout or Laron mice (8)]. All of these defects lead to the profound suppression of IGF-1 concentration in the peripheral circulation (Fig. 1) [for review, see (9, 10)]. The fifth mouse contains a mutation in the p66shc gene. A discussion of this mouse is beyond the scope of this article, but more information can be found in (2).
Studies on the genetics of aging in the nematode worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster suggest an intriguing possibility: that IGF-1 or insulin/IGF-1 signaling might be involved in the control of aging and life-span in a wide range of animals. In this article, I describe the phenotypes of IGF-1-deficient long-lived mice and discuss the possible mechanisms of delayed aging in these animals. I also discuss the characteristics of these mutant mice in light of the actions of aging-related genes in the nematode and fruit fly and the relationships between growth, reproduction, and life-span in various species. Finally, I attempt to place the available information about the function of IGF-1 in aging in the context of the hotly debated use of GH as an anti-aging agent.
IGF-1 Signaling and Life Expectancy in Mice
In Ames dwarf and Snell dwarf mice, a congenital absence of GH-producing cells in the pituitary leads to a lack of GH in the circulation and thus to a profound IGF-1 deficiency. Postnatal growth in both mutants is reduced, and adult body weight is between one-third to one-half of the body weight of normal (wild-type) animals from the same line. Reproductive development varies greatly depending on the genetic background of the mice. Puberty is delayed by at least several weeks, and the reproductive phenotype of adult males ranges from failure to undergo sexual maturation to full fertility. Females can ovulate and mate, but fail to become pregnant, because Ames and Snell dwarf mice are also prolactin (PRL)-deficient. PRL is a hormone produced by the anterior pituitary gland. It affects the gonads (testes and ovaries), and in rodents is absolutely required for maintenance of pregnancy. Female dwarfs treated with PRL can produce live young and raise them to weaning age [for review, see (10, 11)].
In both types of mutant mice, tumor development, renal pathology, and age-related changes in collagen, which provide a biomarker of aging, as well as age-related declines in immune function, locomotor activity, learning, and memory, are either reduced or delayed. Both the average and the maximal life-span are greatly increased. Depending on gender and genetic background, dwarf mice live approximately 40 to 60% longer than their normal siblings (1, 3). Suspected mechanisms of the observed delayed aging include reductions in plasma glucose and insulin concentrations, improved responsiveness to insulin, reduced body temperature, increased activity of antioxidant enzymes, and reduced oxidative damage (10, 11). Some of the characteristics of dwarf mice resemble those of wild-type individuals subjected to caloric restriction (CR). However, recent studies that include the demonstration of further life-span extension in Ames dwarf mice by CR (12) indicate that Ames mutants are not CR mimetics.
Showing that reduced IGF-1 signaling is related to prolonged longevity in Ames and Snell dwarf mice is complicated by the fact that these animals lack not only GH but also PRL and the thyrotropin thyroid-stimulating hormone (TSH). Results obtained in mutant animals with isolated defects in GH release or action (see details below) provide important evidence for the association between reduced IGF-1 signaling and prolonged longevity.
In Little (GHRHRlit) (7) mice, a profound but incomplete GH deficiency leads to an approximately 50% reduction in the body weight of young adults as compared to wild-type mice. In Little mice with a C57BL/6 genetic background, aging is associated with a pronounced increase in fat deposition. If obesity is prevented by a low-fat diet, Little mice live 23 to 25% longer than their normal siblings (3).
In GH receptor knockout (GHR-KO-/- or Laron) mice, targeted disruption of the gene that encodes the GH receptor/GH-binding protein produces a syndrome of complete GH deficiency analogous to Laron dwarfism in humans (8). In these animals, plasma IGF-1 concentrations are extremely low or nondetectable, depending on the assay system used; postnatal growth is reduced; and adult body weight is approximately 50% of normal. Plasma GH concentrations are elevated because of the lack of negative feedback on the hypothalamus and pituitary; this negative feedback "tells" the organs that continued production of GH is not needed. PRL concentrations are increased, perhaps representing a compensatory adjustment to the absence of GH signaling. Plasma insulin concentrations are profoundly suppressed, plasma glucose concentration is reduced or normal, and responsiveness to insulin is increased. Unexpectedly, glucose tolerance (the ability to control blood glucose concentrations after glucose administration) is reduced rather than increased. This aspect of the animal's physiology is presumably due to a reduced ability to release insulin. Thyroid hormone concentrations are low, presumably as a consequence of diminished IGF-1 action on the thyroid, and body core temperature is slightly lower than normal.
Sexual maturation is delayed, which is consistent with the physiological role of IGF-1 in the control of puberty. Most of the GHR-KO-/- animals are fertile, but exhibit quantitative deficits in female and male reproductive function and in endocrine signaling that involves control of the gonads [(4, 8) and reviewed in (10)]. The GHR-KO-/- mice are healthy, maintain excellent cognitive function into advanced age (as measured by performance in the passive avoidance task, a commonly used test of learning and memory) (10, 13), and live 37 to 55% longer than phenotypically normal GHR-KO+/+ or GHR-KO+/- animals from the same line (4). Both mean and maximal life-span are increased in GHR-KO-/- mice (14), which suggests that the genetic alteration yields a true delay of aging.
Taken together, the data from Snell dwarf, Ames dwarf, Little, and GHR-KO-/- mice suggest that reduced IGF-1 signaling in these animals is associated with delayed aging and prolonged longevity. This conclusion and the possible existence of a cause/effect relationship between IGF-1 and aging are consistent with the reliable negative correlation of adult body weight and longevity in genetically normal mice and by the dramatically reduced life-span of giant transgenic mice that overexpress GH [reviewed in (9, 10)]. Also consistent with this concept is the finding that small breeds of domestic dogs have lower plasma IGF-1 concentrations and live longer than do larger breeds [see references in (9, 11)]. Finally, there are numerous reports that in humans, height is negatively associated with life expectancy [reviewed in (15)]. Thus the correlative evidence for the importance of IGF signaling in the control of mammalian aging is compelling and consistent with results obtained in invertebrates. However, the proposed cause:effect relationship between IGF-1 and longevity will remain a working hypothesis until formal proof is obtained from replacement studies or genetic rescue experiments.
IGF-1/Insulin Signaling As a Fundamental Mechanism for Controlling Aging in Animals
Recently, an elegant series of studies was conducted in C. elegans and D. melanogaster that resulted in the identification of a number of genes with major effects on longevity. The signaling pathway controlled by the products of these genes exhibits extensive homology to the IGF-1 and insulin signaling pathways in mammals. Particularly striking were the following findings: (i) daf-2, a key longevity-related gene in C. elegans, exhibits homology to mammalian insulin and IGF receptors (16); (ii) the human gene FKHRL1, which encodes a protein implicated in insulin and IGF signaling pathways, can substitute for daf-16, another longevity-related gene in C. elegans that encodes a member of the forkhead family of transcription factors (17); and (iii) knocking out the insulin receptor-like or insulin receptor substrate (chico) genes can prolong life in D. melanogaster (18, 19).
Signaling pathways that involve the products of longevity genes in worms and flies and their homology to mammalian IGF-1 and insulin signaling pathways were discussed in recent publications (20, 21). It appears that in the course of evolution, the common IGF-1/insulin signaling pathway has diverged into two similar but clearly discernible pathways in mammals, with the IGF-1 pathway regulating primarily cell division and growth, and the insulin pathway controlling carbohydrate metabolism and the partitioning of energy resources. In both invertebrates and mammals, these signaling pathways might serve the purpose of adjusting energy partitioning, reproductive activity, and life cycle to environmental conditions and especially to food availability. Simply put, when food is plentiful, organisms tend to channel the available energy toward growth, sexual maturation, and reproduction. This strategy appears to be associated with the relative "neglect" of stress resistance and repair mechanisms and thus is associated with early and/or accelerated aging and reduced life-span. On the other hand, when food is scarce, energy resources might be channeled toward mechanisms that favor survival and away from growth and reproduction, thus leading to delayed aging and prolonged longevity. The biological validity of this hypothesis and its applicability to mammals are strongly supported by studies of the effects of caloric restriction in many organisms, including laboratory mice and rats. Limiting food intake prevents age-related deterioration and disease and prolongs life, but reduces growth, adult body size, and fertility.
This view of the fundamental and evolutionarily conserved mechanisms of adjusting reproductive strategies and life histories to environmental opportunities and limitations fits well with the proposed role of IGF-1 signaling in the control of aging. It is known that plasma concentrations of IGF-1 are suppressed by caloric restriction (22). In addition, IGF-1 serves as an important signal for sexual maturation and exerts numerous stimulatory, synergistic, and/or permissive effects on the reproductive system and fertility (23, 24).
Interpretation of the available data on resource allocation for repair and survival versus growth and reproduction has some important practical implications. For example, it allows a prediction that any intervention that effectively prolongs life is likely to achieve this at the expense of mechanisms related to growth, adult stature, and reproductive function. Such costs of life extension correspond to the observed phenotypes of long-lived genetically altered organisms and to the characteristics of calorie-restricted animals.
"Anti-Aging" Effects of GH Versus the Role of IGF-1 Signaling in the Control of Aging
Human recombinant GH, GH-releasing compounds, and various other GH-related products are marketed to the public as substances that control and/or reverse the various symptoms of aging. The rationale for this approach is based primarily on the following observations: (i) GH release declines significantly with age in human as in other species (the so-called somatopause); (ii) symptoms of adult GH deficiency (GHD), which include an increased deposition of fat, primarily in the trunk, and loss of muscle mass, resemble symptoms of aging; (iii) in GHD patients, these symptoms can be reversed and the quality of life greatly improved by GH replacement therapy; and (iv) treatment of a group of elderly people with GH reversed or reduced age-related changes in lean body mass, adiposity, and bone mineral density (25).
At first glance, claims of anti-aging effects of GH therapy appear incompatible with the evidence that it is the reduction, rather than the enhancement, of IGF signaling that prolongs life in animals. However, it is important to note that there is no evidence that GH therapy in adult or elderly individuals has any effect (positive or negative) on aging per se or on life expectancy. Arguments used by both proponents and opponents of the use of GH in this context focus on issues of frailty, functionality, and risk factors for cardiovascular disease and diabetes rather than on observed effects on the mechanisms of aging per se. In contrast, the pathological excess of GH release in acromegaly--a chronic metabolic disorder caused by a GH-producing anterior pituitary tumor--leads to increased IGF-1 concentrations in plasma and a significant reduction in life expectancy (26) [see also references in (9, 10)]. In both situations, it is difficult to separate the effects of GH and IGF-1 on age-related diseases from their effects on aging.
Detailed discussion of the complex and controversial issues surrounding the potential utility of GH therapy in geriatrics is outside the scope of this brief Viewpoint. Therefore, I will limit my commentary to the following observation. The available evidence is compatible with the view that reduced IGF-1 signaling during growth, early adulthood, and middle age mediates the action of several mammalian aging-related genes, retards aging, and increases life expectancy, whereas the age-related declines in GH and IGF-1 concentrations contribute to destructive changes in body composition and perhaps also a decrease in functionality in the elderly.
Questions That Remain To Be Explored
The suspected importance of IGF-1 in the control of mammalian and especially human longevity remains to be rigorously tested. Acceptance or rejection of this hypothesis and a description of the mechanisms by which genes that promote longevity act will require further studies, probably including the following: (i) silencing or overexpression of genes that control the IGF-1 signaling pathway; (ii) altering IGF production and the responsiveness of target cells to IGF-1 through nongenetic (pharmacological or dietary) interventions; (iii) studying human populations through genetic, demographic, and prospective clinical studies designed to test the relationships between IGF-1 signaling and aging; and (iv) screening for additional genes, proteins, and protein modifications present in the tissues of long-lived mutant animals to discover new and perhaps unsuspected mechanisms of delayed aging and prolonged longevity.
April 24, 2002
Science of Aging Knowledge Environment. ISSN 1539-6150