Role of the IGF/insulin system in longevity

Human life expectancy is influenced by multiple determinants, including various environmental and genetic factors. Though the non-genetic factors are important, it is estimated that approximately 25-32% of the overall difference in human lifespan for survival after the age of 60 years depends on for by genetic polymorphisms among individuals. In addition, there are human homologues to many genes that affect lifespan in model organisms. In people, longevity genes might slow the rate of age-related changes in cells, increase resistance to environmental stresses like infection and injury, and reduce the risk of many age-related conditions. The best studied longevity pathway is probably the one involving insulin/IGF-1 signaling. The important role of IGF and insulin-related signaling pathways in the control of longevity of worms and insects is very well documented. In the mouse, several spontaneous or experimentally induced mutations that interfere with GH/IGF axis modulation lead to extended longevity. Increases in the average life span in these mutants range from approximately 20-70% depending on the nature of the endocrine defect, gender, diet, and/or genetic background. All the data in animals models and in the population studies support the evidence that this pathway drives an evolutionarily conserved network that regulates lifespan and affects longevity across species. Results obtained in humans are still controversial and further extensive studies are required to firmly establish a role of the IGF1 axis in modulation of human longevity. A better knowledge of the role of this pathway in humans may assist in the design of improved treatment methods for age-related diseases, delay the aging process and prolong the human lifespan.     

Analysis of growth hormone receptor polymorphism in Japanese semisuper centenarians

Background:   Recent studies have demonstrated a significant association between mutations in genes involved in the GHR/IGF1 signaling pathway and extension of the lifespan of model organisms. Exon 3 insertion or deletion is one common polymorphism in the growth hormone receptor ( GHR ) of humans. The exon 3 deletion allele is reported to have stronger signaling in the GH/GHR pathway, which may correlate to short lifespan.
Methods:   We investigated the common polymorphic variation in 119 Japanese semisuper centenarians (SSC; older than 105) compared with 104 healthy younger controls via the polymorphism-based polymerase chain reaction method.
Results:   The frequency of exon 3 deletion variation of GHR in SSC was found to be higher than controls, although this was not significant statistically. Also, the single nucleotide polymorphism genotype frequency and allele frequency exhibited no differences between SSC and controls.
Conclusions:   These results show that SSC in Japan do not tend to have the allele of GHR, which has a lower signaling capacity.     

The metabolic syndrome, IGF-1, and insulin action

Recent studies have shown that insulin and insulin-like growth factor (IGF)-1 signaling are involved in the control of ageing and longevity in model organisms. Based on these studies, genes involved in the insulin/IGF-1 signaling pathway are believed to play a role in longevity throughout evolution and could also be important in determining human longevity. However, human studies have yielded conflicting and controversial results. In human, defects in insulin receptor signaling cause insulin resistance and diabetes, and IGF-1 deficiency is associated with an increased risk of cardiovascular disease and atherosclerosis. Interestingly, insulin sensitivity normally decreases during aging; however, centenarians were reported to maintain greatly increased insulin sensitivity and had a lower prevalence of the metabolic syndrome as compared to younger subjects. Additionally, a longitudinal study revealed that insulin-sensitizing hormones, including leptin and adiponectin, were significantly associated with the survival of centenarians, indicating that an efficient insulin response may influence human longevity.     

The longevity effect of cranberry extract in Caenorhabditis elegans is modulated by daf-16 and osr-1

Nutraceuticals are known to have numerous health and disease preventing properties. Recent studies suggest that extracts containing cranberry may have anti-aging benefits. However, little is known about whether and how cranberry by itself promotes longevity and healthspan in any organism. Here we examined the effect of a cranberry only extract on lifespan and healthspan in Caenorhabditis elegans. Supplementation of the diet with cranberry extract (CBE) increased the lifespan in C. elegans in a concentration-dependent manner. Cranberry also increased tolerance of C. elegans to heat shock, but not to oxidative stress or ultraviolet irradiation. In addition, we tested the effect of cranberry on brood size and motility and found that cranberry did not influence these behaviors. Our mechanistic studies indicated that lifespan extension induced by CBE requires the insulin/IGF signaling pathway and DAF-16. We also found that cranberry promotes longevity through osmotic stress resistant-1 (OSR-1) and one of its downstream effectors, UNC-43, but not through SEK-1, a component of the p38 MAP kinase pathway. However, SIR-2.1 and JNK signaling pathways are not required for cranberry to promote longevity. Our findings suggest that cranberry supplementation confers increased longevity and stress resistance in C. elegans through pathways modulated by daf-16 and osr-1. This study reveals the anti-aging property of widely consumed cranberry and elucidates the underpinning mechanisms.     

Association of the insulin-like growth factor binding protein 3 (IGFBP-3) polymorphism with longevity in Chinese nonagenarians and centenarians

Human lifespan is determined greatly by genetic factors and some investigations have identified putative genes implicated in human longevity. Although some genetic loci have been associated with longevity, most of them are difficult to replicate due to ethnic differences. In this study, we analyzed the association of 18 reported gene single nucleotide polymorphisms (SNPs) with longevity in 1075 samples consisting of 567 nonagenarians/centenarians and 508 younger controls using the GenomeLab SNPstream Genotyping System. Our results confirm the association of the forkhead box O3 (FOXO3) variant (rs13217795) and the ATM serine/threonine kinase (ATM) variant (rs189037) genotypes with longevity (p=0.0075 and p=0.026, using the codominant model and recessive model, respectively). Of note is that we first revealed the association of insulin-like growth factor binding protein 3 (IGFBP-3) gene polymorphism rs11977526 with longevity in Chinese nonagenarians/centenarians (p=0.033 using the dominant model and p=0.035 using the overdominant model). The FOXO3 and IGFBP-3 form important parts of the insulin/insulin-like growth factor-1 signaling pathway (IGF-1) implicated in human longevity, and the ATM gene is involved in sensing DNA damage and reducing oxidative stress, therefore our results highlight the important roles of insulin pathway and oxidative stress in the longevity in the Chinese population.     

Genetic analysis of insulin signaling in Drosophila.

Studies in the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans have revealed that components of the insulin signaling pathway have been highly conserved during evolution. Genetic analysis in Drosophila suggests that structural conservation also extends to the functional level. Flies carrying mutations that reduce insulin signaling have a growth deficiency phenotype similar to that seen in mice with disruptions of genes encoding insulin-like growth factors (IGFs) or the IGF-I receptor. Recent studies in flies have demonstrated a role for the insulin signaling pathway in the regulation of metabolism, reproduction and lifespan via modulation of central neuroendocrine pathways. Similarly, mice with loss of brain insulin receptors or insulin receptor substrate 2 deficiency exhibit neuroendocrine defects and female infertility. These parallels suggest that the insulin system has multiple conserved roles, acting directly to modulate growth and indirectly, via the neuroendocrine system, to modulate peripheral physiology in response to changes in nutrient availability.     

Association analysis between longevity in the Japanese population and polymorphic variants of genes involved in insulin and insulin-like growth factor 1 signaling pathways

Recent studies have demonstrated a significant association between mutations in genes involved in the insulin/IGF1 signaling pathway and extension of the life span of model organisms. In this study which compared 122 Japanese semisupercentenarians (older than 105) with 122 healthy younger controls, we examined polymorphic variations of six genes which are involved in insulin/IGF1 signaling. These genes were FOXO1A, INSR, IRS1, PIK3CB, PIK3CG, and PPARGC1A. We investigated the possible association of each gene locus and longevity by haplotype-based association analyses using 18 SNPs from public databases and the published literature. One INSR haplotype, which was comprised of 2 SNPs in linkage disequilibrium, was more frequent in semisupercentenarians than in younger controls.     

The GH/IGF-I axis and longevity

Several converging lines of evidence obtained over the last years in a wide variety of experimental model organisms suggest that the ageing process is regulated by genes that encode proteins from the somatotroph axis: longevity genes like daf-2, which were identified using mutant Caenorhabditis elegans strains, turned out to be orthologues of the mammalian genes encoding insulin-like signalling cascade proteins. Transgenic flies with mutations in the corresponding insect genes showed a similar pattern of increased lifespan. Finally, mice with spontaneous mutations leading to pituitary hormone deficiency significantly outlived controls. While these and other genetic models suggest that the downregulation of the somatotroph axis can slow the ageing process, other results from studies using pharmacological administration of growth hormone suggest that such stimulating treatment can restore some of the phenotypic traits associated with youth. To better understand the role of the insulin-like receptors in mammalian lifespan regulation and ageing, we explored the phenotype of heterozygous IGF-I receptor (IGF1R) knockout mice. Compared with control littermates these mutants live longer without any obvious impairment of their health and physiology, except a reduced glucose tolerance that we observed in males. These IGF1R(+/-) mutants were also more resistant to oxidative stress in vivo, and we identified a possible molecular pathway linking underphosphorylation of IGF-I receptors to the lack of activation of p66Shc, a protein capable of increasing resistance to oxidative stress through regulation of a set of downstream genes. These and other results suggest that in mammals too, lifespan can be increased by continuous, long-term downregulation of IGF signalling. Since growth hormone administration normally stimulates IGF production in tissues, the question arises whether the beneficial effects of GH, as reported by others, could be IGF independent. This hypothesis can be addressed, for example, by adequately combining existing transgenic mouse models.     

The frontal cortex IGF system is down regulated in the term,intrauterine growth restricted fetal baboon

ObjectiveThe IGF system exerts systemic and local actions during development. We previously demonstrated that fetal cerebral cortical IGF1 is reduced at 0.5 gestation in our IUGR baboon nonhuman primate model. We hypothesized that by term protein expression of several key IGF system stimulatory peptide pathway components and downstream nutrient signaling effectors of IGF, mammalian target of rapamycin (mTOR) and S6, would decrease, indicating reduced cellular nutrient uptake and protein synthesis.DesignWe fed 7 control baboons ad libitum while 6 baboons ate a globally reduced diet (70% of feed eaten by controls) from 0.16 gestation through pregnancy that produces IUGR. Fetuses were removed at Cesarean section at 0.9 gestation. Frontal cortex sections were stained for IGFI, IGFII, IGFRI, IGFR2, IGFBP2, 3, 5 and 6, and mTOR and ribosomal protein S6 and double stained with NeuN a neuron-specific nuclear antigen.ResultsAll proteins stained neuronal cytoplasm except IGFRI which showed only glial cell cytoplasmic and blood vessel staining. IUGR fetuses showed decreased frontal cortical immunoreactive IGFI, IGFII, IGFRI, IGFBP2, 5 and 6, and mTOR and S6 (p < 0.05). IGFBP3 increased (p < 0.05) and IGFR2 was unchanged (p > 0.05). There were no differences between male and female fetal brains.ConclusionsWhen fetal nutrient availability is decreased, IUGR down regulates the IGF system and its mTOR signaling pathway in the fetal frontal cortex coincident with slowed growth. These findings emphasize the importance of the local tissue IGF system in fetal primate brain development.     

Metabolic syndrome in the offspring of centenarians: focus on prevalence,components, and adipokines

With aging, an increased prevalence of a clustering of metabolic abnormalities has been observed. These abnormalities include obesity, dyslipidemia, hypertension, and insulin resistance and are collectively known as metabolic syndrome (MetS), a low-grade, systemic, inflammatory condition associated with an increased risk of cardiovascular disease, diabetes, and other adverse health outcomes. A number of studies have demonstrated that centenarians’ offspring have a significant survival advantage and a lower risk of developing the most important age-related diseases. They therefore represent one of the best models with which to study the familiar component of human longevity. The aim of this study was to determine if the offspring of centenarians (n = 265 subjects) showed a different prevalence of MetS in comparison to the offspring of non-long-lived parents (controls, n = 101 subjects). In addition, we assessed whether centenarians’ offspring showed particular features of MetS and a distinct regulation of circulating adipokines, cytokines, and metabolic mediators. Although the prevalence of MetS was quite similar both in the offspring of centenarians and the controls, MetS-affected centenarians’ offspring seemed healthier, more functionally fit, and had lower resistin levels. MetS prevalence did not change in centenarians’ offspring across resistin, IGF-1, and resistin/IGF-1 ratio tertiles. On the other hand, in controls, MetS prevalence strongly increased across resistin tertiles and in the third resistin/IGF-1 ratio tertile, indicating a dramatic increase in MetS prevalence when the ratio between these two factors is unbalanced, with high levels of resistin and low levels of IGF-1.     

Insulin-like growth factor system on adrenocortical tumorigenesis

The insulin-like growth factor (IGF) signaling pathway has many important roles in normal cell growth and development. Remarkably, all of the components of this system (IGFs, receptors, and binding proteins) are expressed in human fetal adrenals. Beckwith-Wiedemann syndrome, a congenital overgrowth disorder characterized by a high risk of development of childhood tumors, is also distinguished by a high incidence of adrenocortical carcinomas. This disease has been associated with structural abnormalities at the 11p15 locus, which harbors the IGF2 gene as well as the genes coding for insulin, H19, and p57kip2. Notably, rearrangements at the 11p15 locus and overexpression of IGF2 were also described in sporadic adrenocortical tumors. In addition, the IGF2 overexpression was exclusively demonstrated in adults with adrenocortical tumors as a frequent feature of the malignant state. More recent studies demonstrated that the interaction of IGF-2 with IGF receptor type 1 (IGF-1R) plays also a pivotal role in adrenocortical tumorigenesis. IGF1R expression levels were significantly higher in pediatric adrenocortical carcinomas, suggesting that IGF1R expression represents a potential prognostic marker in this group of patients. These findings indicate that the IGF system is an important pathway for autonomous growth of adrenocortical cells and potential inhibitors of this system could be a rational therapeutic target for adrenocortical tumors.     

Genetic variation for stress-response hormesis in C. elegans lifespan

Increased lifespan can be associated with greater resistance to many different stressors, most notably thermal stress. Such hormetic effects have also been found in C. elegans where short-term exposure to heat lengthens the lifespan. Genetic investigations have been carried out using mutation perturbations in a single genotype, the wild type Bristol N2. Yet, induced mutations do not yield insight regarding the natural genetic variation of thermal tolerance and lifespan. We investigated the genetic variation of heat-shock recovery, i.e. hormetic effects on lifespan and associated quantitative trait loci (QTL) in C. elegans. Heat-shock resulted in an 18% lifespan increase in wild type CB4856 whereas N2 did not show a lifespan elongation. Using recombinant inbred lines (RILs) derived from a cross between wild types N2 and CB4856 we found natural variation in stress-response hormesis in lifespan. Approx. 28% of the RILs displayed a hormesis effect in lifespan. We did not find any hormesis effects for total offspring. Across the RILs there was no relation between lifespan and offspring. The ability to recover from heat-shock mapped to a significant QTL on chromosome II which overlapped with a QTL for offspring under heat-shock conditions. The QTL was confirmed by introgressing relatively small CB4856 regions into chromosome II of N2. Our observations show that there is natural variation in hormetic effects on C. elegans lifespan for heat-shock and that this variation is genetically determined.     

Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features

Inwardly rectifying potassium channels (Kir channels) control cell membrane K(+) fluxes and electrical signaling in diverse cell types. Heterozygous mutations in the human Kir6.2 gene (KCNJ11), the pore-forming subunit of the ATP-sensitive (K(ATP)) channel, cause permanent neonatal diabetes mellitus (PNDM). For some mutations, PNDM is accompanied by marked developmental delay, muscle weakness, and epilepsy (severe disease). To determine the molecular basis of these different phenotypes, we expressed wild-type or mutant (R201C, Q52R, or V59G) Kir6.2/sulfonylurea receptor 1 channels in Xenopus oocytes. All mutations increased resting whole-cell K(ATP) currents by reducing channel inhibition by ATP, but, in the simulated heterozygous state, mutations causing PNDM alone (R201C) produced smaller K(ATP) currents and less change in ATP sensitivity than mutations associated with severe disease (Q52R and V59G). This finding suggests that increased K(ATP) currents hyperpolarize pancreatic beta cells and impair insulin secretion, whereas larger K(ATP) currents are required to influence extrapancreatic cell function. We found that mutations causing PNDM alone impair ATP sensitivity directly (at the binding site), whereas those associated with severe disease act indirectly by biasing the channel conformation toward the open state. The effect of the mutation on ATP sensitivity in the heterozygous state reflects the different contributions of a single subunit in the Kir6.2 tetramer to ATP inhibition and to the energy of the open state. Our results also show that mutations in the slide helix of Kir6.2 (V59G) influence the channel kinetics, providing evidence that this domain is involved in Kir channel gating, and suggest that the efficacy of sulfonylurea therapy in PNDM may vary with genotype.     

Insulin growth factor adjustment in preimplantation rabbit blastocysts and uterine tissues in response to maternal type 1 diabetes

Insulin-like growth factors (IGFs) are well-known regulators of embryonic growth and differentiation. IGF function is closely related to insulin action. IGFs are available to the preimplantation embryo through maternal blood (endocrine action), uterine secretions (paracrine action) and by the embryo itself (autocrine action). In rabbit blastocysts, embryonic IGF1 and IGF2 are specifically strong in the embryoblast (ICM). Signalling of IGFs and insulin in blastocysts follows the classical pathway with Erk1/2 and Akt kinase activation. The aim of this study was to analyse signalling of IGFs in experimental insulin dependent diabetes (exp IDD) in pregnancy, employing a diabetic rabbit model with uterine hypoinsulinemia and hyperglycaemia. Exp IDD was induced in female rabbits by alloxan treatment prior to mating. At 6 days p.c., the maternal and embryonic IGFs were quantified by RT-PCR and ELISA. In pregnant females, hepatic IGF1 expression and IGF1 serum levels were decreased while IGF1 and IGF2 were increased in endometrium. In blastocysts, IGF1 RNA and protein was approx. 7.5-fold and 2-fold higher, respectively, than in controls from normoglycemic females. In cultured control blastocysts supplemented with IGF1 or insulin in vitro for 1 or 12 h, IGF1 and insulin receptors as well as IGF1 and IGF2 were downregulated. In cultured T1D blastocysts activation of Akt and Erk1/2 was impaired with lower amounts of total Akt and Erk1/2 protein and a reduced phosphorylation capacity after IGF1 supplementation. Our data show that the IGF axis is severely altered in embryo-maternal interactions in exp IDD pregnancy. Both, the endometrium and the blastocyst produce more IGF1 and IGF2. The increased endogenous IGF1 and IGF2 expression by the blastocyst compensates for the loss of systemic insulin and IGF. However, this counterbalance does not fill the gap of the reduced insulin/IGF sensitivity, leading to a developmental delay of blastocysts in exp IDD pregnancy.     

Insulin and its analogues and their affinities for the IGF1 receptor

Insulin analogues have been developed in an attempt to achieve a more physiological replacement of insulin and thereby a better glycaemic control. However, structural modification of the insulin molecule may result in altered binding affinities and activities to the IGF1 receptor (IGF1R). As a consequence, insulin analogues may theoretically have an increased mitogenic action compared to human insulin. In view of the lifelong exposure and large patient populations involved, insulin analogues with an increased mitogenic effect in comparison to human insulin may potentially constitute a major health problem, since these analogues may possibly induce the growth of pre-existing neoplasms. This hypothesis has been evaluated extensively in vitro and also in vivo by using animal models. In vitro, all at present commercially available insulin analogues have lower affinities for the insulin receptor (IR). Although it has been suggested that especially insulin analogues with an increased affinity for the IGF1R (such as insulin glargine) are more mitogenic when tested in vitro in cells expressing a high proportion of IGF1R, the question remains whether this has any clinical consequences. At present, there are several uncertainties which make it very difficult to answer this question decisively. In addition, recent data suggest that insulin (or insulin analogues)-mediated stimulation of IRs may play a key role in the progression of human cancer. More detailed information is required to elucidate the exact mechanisms as to how insulin analogues may activate the IR and IGF1R and how this activation may be linked to mitogenesis.