(Expanded version 5/9/2011)
In animal models of longevity, two interventions have consistently been shown to increase lifespan, caloric restriction and suppression of the GH-IGF1-Insulin axis.
It is not possible to merely dismiss animal studies, saying that humans are somehow different, and therefore the results don’t apply, unless you can provide a convincing explanation of how we are different that makes the results from animal studies inapplicable. Besides, longevity and improved health are also associated with humans who have naturally occurring genetic mutations resulting in suppression of these hormones pathways.
Virtually all mice who lack the IGF1 receptor die at birth; some mice who have the IGF1R, but lack IGF1 survive birth, but these survivors suffer extreme developmental abnormalities, achieving less than half their normal weight: Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 1993. Clearly, both IGF1 and its receptor are necessary for survival and healthy development. The same is true for GH. In a 2002 study, for example, rats who were heterozygous (only had one copy) in an anti-sense GH transgene displayed increased longevity, while homozygous rats (who had two copies of the transgene) showed decreased longevity. An anti-sense gene is one that reduces expression of the target GH gene. (Anti-sense genes work by creating a complementary mRNA that can bind to the target mRNA, effectively canceling it out.) In other words, a mild reduction in GH expression increased lifespan, while a stronger reduction was counterproductive, and actually decreased lifespan. Yes, some GH expression is important, but too much is counterproductive. What is the optimal amount? We have only one way to answer this question, by looking at the relevant studies and examining the data. See Life Span Extension by Reduction in Growth Hormone-Insulin-Like Growth Factor-1 Axis in a Transgenic Rat Model.
The point I wish to convey is that there are no good or bad hormones, it is similarly incorrect to refer to certain kinds of cholesterol as “good” and other kinds as “bad.” More about cholesterol in a future discussion. All compounds and physiological pathways have a function and purpose. However, their effects need to be kept in balance, within certain optimal ranges for improved health outcomes; even though we may not know what those optimal ranges are, and they may vary over the course of the human life cycle.
One interesting study discusses a group of female centenarians with elevated plasma IGF1 levels. However, their increased longevity has nothing to do with their increased IGF1 levels. In fact, they did not have increased IGF1 signaling, at all. They experienced impaired or reduced IGF1 signaling due to a defective IGF1 receptor with decreased ligand binding. This reduced IGF1 signaling resulted in decreased stature as well as increased plasma IGF1 levels. (More IGF1 remained in the plasma, since it could not bind as efficiently to the cellular receptors.) See Functionally significant insulin-like growth factor I receptor mutations in centenarians.
A similar, but even more extreme effect occurred in individuals with a mutation that caused an alteration in the IGF1 protein sequence. This altered IGF1 had a 90% reduced receptor-binding affinity, causing extremely elevated plasma IGF1 levels. This altered IGF1 resulted in pre- and post- natal growth retardation, deafness, and mental retardation, illustrating the importance of IGF1 for normal fetal, as well as postnatal development. (The important role of IGF1, for prenatal development had already been well established, before this study was published.) These examples illustrate that while one mutation resulted in extended lifespan, another mutation with similar, but more extreme effects had very harmful outcome. See Homozygous and Heterozygous Expression of a Novel Insulin-Like Growth Factor-I Mutation.
This body of research focuses on investigating the various health and longevity effects of different, specific, alterations in GH-IGF1-I signaling pathways. Usually the alteration involves an impairment, of varying degree, in signaling; although, in some cases, it involves an over-expression in signaling. In all cases, the results reveal important information about the underlying mechanisms of action of these hormone-receptor signaling pathways, regardless of whether the change is brought about by an alteration in one of the primary hormones, a receptor, or other downstream proteins, i.e. p66, KLOTHO, etc. Some of these studies illustrate important interactions between pathways associated with health and longevity. One, for example, discusses important mechanisms of interaction or interplay between IGF1 signaling and ROS signaling pathways. Radical Oxygen Species have very clear implications for health and aging mechanisms. See Insulin/IGF-1 and ROS signaling pathway cross-talk in aging and longevity determination.
In another interesting study, PAPP-A knockout mice showed dramatically increased healthspan, increased lifespan with a decrease in pathologies such as cancer and heart disease, without any change in circulating GH, IGF1, glucose, or insulin. Loss of pregnancy-associated plasma protein A extends lifespan in mice. See Genetic Deletion of Pregnancy-Associated Plasma Protein-A Is Associated With Resistance to Atherosclerotic Lesion Development. PAPP-A is a protease enzyme that cleaves, or breaks up, IGF1 binding proteins. This is significant because PAPP-A represents a possible way to modify IGF1 signaling, without affecting GH signaling.
In some cases, reduced IGF1 signaling does not improve health or increase lifespan. In other cases, increased IGF1 signaling increases healthspan. In one interesting case, for example, tissue-dependent effects are revealed, when over-expression of IGF1 signaling in cardiac tissue increases longevity and cardiac health, even reversing cardiac dysfunction: See CARDIAC-SPECIFIC OVEREXPRESSION OF IGF-1—.
Here is a further sampling of excerpts from some of the relevant literature:
Life span extension by reduction of the growth hormone-insulin-like growth factor-1 axis: relation to caloric restriction: “A reduced growth hormone (GH)-insulin-like growth factor (IGF)-1 axis is associated with an extension of lifespan in laboratory rodents. Several phenotypes of such animal models resemble those induced by caloric restriction (CR). Using a transgenic male Wistar rat model whose GH-IGF-1 axis was moderately suppressed by overexpression of the antisense GH transgene (tg), we elucidated a relationship between the effects of a reduced GH-IGF-1 axis and CR for some biomarkers of aging, lifespan, and pathologies. Heterozygous (tg/-) rats fed ad libitum (AL) had a dwarf phenotype similar to that of control nontransgenic (-/-) rats subjected to 30% CR from 6 wk of age. Both the reduced GH-IGF-1 axis and CR extended lifespan to a similar extent, although the effect of CR seemed to be greater. There was an additive effect of CR to lifespan extension when tg/- rats were subjected to CR. Pathologic analyses indicated that the preventive effect of CR on selected diseases was greater than that of the reduced GH-IGF-1 axis. The present study suggests that CR affects aging and longevity by mechanisms other than suppression of the GH-IGF-1 axis, although CR might exhibit its effects partly through the reduced GH-IGF-1 axis.“
The new biology of ageing“Perhaps the single most important advance in ageing research in recent years has been discovery of mutations in single genes that extend the lifespan of laboratory animals. They first came to light as a result of a systematic chemical mutagenesis screen for lifespan-extending mutations in C. elegans (Klass 1983). Subsequent work with these mutations (Friedman & Johnson 1988), and further screening (Kenyon et al. 1993), revealed that it was possible to double the lifespan of the worm with a mutation in a single gene. Furthermore, rather than solely prolonging the moribund period at the end of the life, the mutations caused the worms to remain healthy and youthful for longer (Kenyon et al. 1993). The mutated genes were discovered to encode components of an invertebrate insulin/insulin-like growth-factor-like signalling (IIS) pathway (Kimura et al. 1997; Lin et al. 1997; Ogg et al. 1997). These findings came as a considerable surprise, because a signalling pathway previously associated with control of growth and metabolism in mammals now turned out to play a role in determination of lifespan in a distantly related invertebrate.”
Role of the GH/IGF-1 axis in lifespan and healthspan: lessons from animal models“Overwhelmingly, the evidence suggests that a reduction in GH/IGF-1 signaling in vertebrates or its homologous pathways in invertebrates extends lifespan as compared to control or normal siblings. . . Insulin and insulin-like growth factor 1 (IGF-1)-like signaling and its downstream intracellular signaling molecules have been shown to be associated with lifespan in fruit flies and nematodes. More recently, mammalian models with reduced growth hormone (GH) and/or IGF-1 signaling have also been shown to have extended lifespans as compared to control siblings. Importantly, this research has also shown that these genetic alterations can keep the animals healthy and disease-free for longer periods and can alleviate specific age-related pathologies similar to what is observed for CR individuals. Thus, these mutations may not only extend lifespan but may also improve healthspan, the general health and quality of life of an organism as it ages. In this review, we will provide an overview of how the manipulation of the GH/IGF-axis influences lifespan, highlight the invertebrate and vertebrate animal models with altered lifespan due to modifications to the GH/IGF-1 signaling cascade or homologous pathways, and discuss the basic phenotypic characteristics and healthspan of these models.“
How does insulin/IGF signalling control lifespan in worms, flies and mice? “Ageing research has been revolutionized by the use of model organisms to discover genetic alterations that can extend lifespan. In the last 5 years alone, it has become apparent that single gene mutations in the insulin and insulin-like growth-factor signalling pathways can lengthen lifespan in worms, flies and mice, implying evolutionary conservation of mechanisms. Importantly, this research has also shown that these mutations can keep the animals healthy and disease-free for longer and can alleviate specific ageing-related pathologies. These findings are striking in view of the negative effects that disruption of these signalling pathways can also produce. Here, we summarize the body of work that has lead to these discoveries and point out areas of interest for future work in characterizing the genetic, molecular and biochemical details of the mechanisms to achieving a longer and healthier life.”
Signal pathway of insulin and insulin-like growth factor 1 (IGF-1) as a potential regulator of lifespan: “The experimental material accumulated for two decades allows concluding that regulation of lifespan has hormonal control based on the evolutionary conservative insulin/IGF-1 receptor signal pathway. Data obtained on the commonly accepted models of longevity – nematode Caenorhabditis elegans, Drosophila Drosophila melanogaster, and rodents – demonstrate that reduction of the insulin/IGF- 1 signal pathway leads to an increase of the lifespan. There is shown involvement of the longevity mechanism of a large group of genes whose products perform control of metabolism, alimentary behavior, reproduction, resistance to oxidative stress. Discussed in this review are current concepts of the insulin/IGF-1 signal system as a regulatory “longevity module” and of its possible role in prolongation of life in the higher vertebrates, including human.”
Single-gene mutations and healthy ageing in mammals: “Studies of the effects of single-gene mutations on longevity in Caenorhabditis elegans, Drosophila melanogaster and Mus musculus identified homologous, highly conserved signalling pathways that influence ageing. In each of these very distantly related species, single mutations which lead-directly or indirectly-to reduced insulin, insulin-like growth factor (IGF) or insulin/IGF-like signalling (IIS) can produce significant increases in both average and maximal lifespan. In mice, most of the life-extending mutations described to date reduce somatotropic (growth hormone (GH) and IGF-1) signalling. The reported extensions of longevity are most robust in GH-deficient and GH-resistant mice, while suppression of somatotropic signalling ‘downstream’ of the GH receptor produces effects that are generally smaller and often limited to female animals. This could be due to GH influencing ageing by both IGF-1-mediated and IGF-1-independent mechanisms. In mutants that have been examined in some detail, increased longevity is associated with various indices of delayed ageing and extended ‘healthspan’. The mechanisms that probably underlie the extension of both lifespan and healthspan of these animals include increased stress resistance, improved antioxidant defences, alterations in insulin signalling (e.g. hypoinsulinaemia combined with improved insulin sensitivity in some mutants and insulin resistance in others), a shift from pro- to anti-inflammatory profile of circulating adipokines, reduced mammalian target of rapamycin-mediated translation and altered mitochondrial function including greater utilization of lipids when compared with carbohydrates.”
Mammalian models of extended healthy lifespan“Specific mutations in the insulin/insulin-like growth factor (IGF) signalling (IIS) pathway extend lifespan in model organisms [7–9,13,16–19]. Polymorphisms in several IIS and growth hormone (GH)-related genes correlate with human longevity [20–22], and attenuated IIS may underlie the long life of GH/GH receptor-deficient dwarf mice (e.g. Ames (Prop1df/df), Snell (Pit1dw/dw), Little (Ghrhrlit/lit), growth hormone receptor knockout (GHR-KO) ). The target of rapamycin (TOR) pathway also plays a key and conserved role in longevity control [24–29]. It is clear that understanding how exactly the IIS, GH and mTOR signalling pathways interact with one another to increase lifespan and healthspan is a key challenge to future research.”
Replication of Extended Lifespan Phenotype in Mice with Deletion of Insulin Receptor Substrate 1: “We previously reported that global deletion of insulin receptor substrate protein 1 (Irs1) extends lifespan and increases resistance to several age-related pathologies in female mice. However, no effect on lifespan was observed in male Irs1 null mice. We suggested at the time that the lack of any effect in males might have been due to a sample size issue. While such lifespan studies are essential to our understanding of the aging process, they are generally based on survival curves derived from single experiments, primarily due to time and economic constraints. Consequently, the robustness of such findings as a basis for further investigation has been questioned. We have therefore measured lifespan in a second, separate cohort of Irs1 null female mice, and show that, consistent with our previous finding, global deletion of Irs1 significantly extends lifespan in female mice. In addition, an augmented and completed study demonstrates lifespan extension in male Irs1 null mice. Therefore, we show that reduced IRS1-dependent signalling is a robust mechanism through which mammalian lifespan can be modulated.”
Effects of a growth hormone-releasing hormone antagonist on telomerase activity, oxidative stress, longevity, and aging in mice: “Here, we determined the effects of treatment with the GH-releasing hormone (GHRH) receptor antagonist MZ-5-156 on aging in SAMP8 mice, a strain that develops with aging cognitive deficits and has a shortened life expectancy. Starting at age 10 mo, mice received daily s.c. injections of 10 Î¼g/mouse of MZ-5-156. Mice treated for 4 mo with MZ-5-156 showed increased telomerase activity, improvement in some measures of oxidative stress in brain, and improved pole balance, but no change in muscle strength. MZ-5-156 improved cognition after 2 mo and 4 mo, but not after 7 mo of treatment (ages 12, 14 mo, and 17 mo, respectively). Mean life expectancy increased by 8 wk with no increase in maximal life span, and tumor incidence decreased from 10 to 1.7%. These results show that treatment with a GHRH antagonist has positive effects on some aspects of aging, including an increase in telomerase activity.”