BRlackwell Pueblishing, Ltdd. uced insulin/IGF-1 signalling and human longevity

Introduction

Diana van Heemst, Marian Beekman, 1 2 Simon P. Mooijaart, Bastiaan T. Heijmans, 2 3 2 Bernd W. Brandt, Bas J. Zwaan, P. Eline Slagboom 1 and Rudi G. J. Westendorp

Evidence has accumulated that in model organisms aging is hor- monally regulated by an evolutionarily conserved insulin/IGF-1 signalling (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 lim- itation, juvenile C. elegans can enter a non-feeding, develop- mentally 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 favourable.

Summary

Evidence is accumulating that aging is hormonally regulated by an evolutionarily conserved insulin/IGF-1 signalling (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 analysed the relationship between IIS signalling, body height and longevity in humans in a pro- spective follow-up study. Based on the expected effects (increased or decreased signalling) 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 analysed the relative impact on lifespan and body size of the separate variants in multi- variate 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 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 signalling, longevity,

More recently, subtle mutations in IIS components were found to affect also 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 defence, metabo- lism and hormonal signalling (Murphy et al., 2003).

The link between reduced IIS signalling and longevity origi- nally 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 recep- tor 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 ances- tor, 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 path- way are not restricted to one particular component or to one

For instance, recent data from FIRKO mice, in which the insulin receptor was specifically deleted in fat tissue, provide evidence for a link between longevity and the insulin branch (Bluher et al., 2003). In addition to being long-lived, FIRKO mice exhibit a reduction in fat mass and lessened age-related loss in insulin sensitivity (Bluher et al., 2002).

Correspondence

Diana van Heemst, Section of Gerontology and Geriatrics, Department of General Internal Medicine, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, The Netherlands. Tel.: +31 71 526 6640; fax: +31 71 524 8159; e-mail: D.van_Heemst@lumc.nl

e-mail: D.van_Heemst@lumc.nl

Accepted for publication 19 January 2005