Blackwell Publishing, Ltd. introduced insulin/IGF-1 signaling and human longevity.

Introduction:
Diana van Heemst, Marian Beekman, Simon P. Mooijaart, Bastiaan T. Heijmans, Bernd W. Brandt, Bas J. Zwaan, P. Eline Slagboom, and Rudi G. J. Westendorp have found evidence that aging is hormonally regulated by an evolutionarily conserved insulin/IGF-1 signaling (IIS) pathway (reviewed in Tatar et al., 2003).

In the hermaphrodite Caenorhabditis elegans, mutations in components of the IIS pathway were first shown to affect dauer formation. In response to adverse conditions such as food limitation, juvenile C. elegans can enter a non-feeding, developmentally arrested, reproductively immature, stress-resistant, and long-lived dauer state. Upon dauer formation, metabolism shifts to the establishment and utilization of fat reserves. Induction of the dauer state allows the animal to postpone development and reproduction until environmental conditions have become more favorable.

Summary:
Evidence is accumulating that aging is hormonally regulated by an evolutionarily conserved insulin/IGF-1 signaling (IIS) pathway. Mutations in IIS components affect lifespan in Caenorhabditis elegans, Drosophila melanogaster, and mice. Most long-lived IIS mutants also show increased resistance to oxidative stress.

In D. melanogaster and mice, the long-lived phenotype of several IIS mutants is restricted to females. Here, we analyzed the relationship between IIS signaling, body height, and longevity in humans in a prospective follow-up study.

Based on the expected effects (increased or decreased signaling) of the selected variants in IIS pathway components (GHRHR, GH1, IGF1, INS, IRS1), we calculated composite IIS scores to estimate IIS pathway activity.

In addition, we analyzed the relative impact on lifespan and body size of the separate variants in multivariate models. In women, lower IIS scores are significantly associated with lower body height and improved old age survival. Multivariate analyses showed that these results were most pronounced for the GH1 SNP, IGF1 CA repeat, and IRS1 SNP.

In females, for variant allele carriers of the GH1 SNP, body height was 2 cm lower (P = 0.007), and mortality was 0.80-fold reduced (P = 0.019) when compared with wild-type allele carriers. Thus, in females, genetic variation causing reduced IIS activation is beneficial for old age survival. This effect was stronger for the GH1 SNP than for variation in the conserved IIS genes that were found to affect longevity in model organisms.

Key words: human, insulin/IGF-1 signaling, longevity,

More recently, subtle mutations in IIS components were found to affect reproduction, metabolism, stress response, and lifespan in adult C. elegans (reviewed by Kenyon, 2001). A reduction in the level of IIS increases the activity of DAF-16, a member of the family of forkhead transcription factors.

Changed DAF-16 activity results in a different transcriptional profile and thus coordinately affects different effector genes and pathways. The classes of genes regulated by DAF-16 include those implicated in the cellular stress response, antimicrobial defense, metabolism, and hormonal signaling (Murphy et al., 2003).

The link between reduced IIS signaling and longevity originally discovered in C. elegans was subsequently also observed in Drosophila melanogaster.

Mutants in the D. melanogaster insulin receptor InR (Tatar et al., 2001) and in the insulin receptor substrate CHICO (Clancy et al., 2001) are both long-lived. Strikingly, however, in both cases, the long-lived phenotype was only observed for females. In addition to being long-lived, these D. melanogaster females are small, obese, and infertile.

The IIS pathway has greatly increased in complexity during evolution, leading to different branches and tissue specificity. The IGF1 and INS genes probably derive from a common ancestor, which first evolved into IGF and INS, after which event the IGF gene further diverged into IGF1 and IGF2 (Patton et al., 1998).

GH control of IGF-1 arose relatively late in evolution within vertebrates. The different branches of the mammalian IIS pathway interact at several levels, for example by using the same receptor substrates, such as IRS1.

Data from mice indicate that the lifespan regulatory elements of the mammalian IIS pathway are not restricted to one particular component or to one. For instance, recent data from FIRKO mice, in which the insulin receptor was specificallymales for the SOD2 exon 16 SNP, UCP2 promoter SNP, or UCP2 45-bp insertion/deletion. The absence of an effect on mortality for these oxidative stress response polymorphisms is consistent with previous studies (Suh et al., 2008). 

To explain the observed sexual dimorphism in the association between reduced IIS activity and longevity, we must consider sex differences in GH/IGF-1 signaling. In mammals, GH/IGF-1 activity is known to differ between sexes, with irregularity being greater in females due to estrogen increasing the irregularity of GH release. Additionally, the growth spurt that occurs at puberty is sex hormone driven in both sexes. When interpreting the effects of GH/IGF-1 signaling on longevity, cumulative exposure to GH/IGF-1 over an individual's lifetime and the effect of GH/IGF-1 at different time points in an individual's life history should be considered. Increased cumulative exposure to GH/IGF-1 has adverse effects in mice and humans, such as reduced lifespan, insulin resistance, and increased risk of cancer.