Reduced insulin/IGF-1 signalling and human longevity.
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 prospective 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 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 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.
van Heemst
Diana
D
Section of Gerontology and Geriatrics, Department of General Internal Medicine, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, The Netherlands. D.van_Heemst@lumc.nl
Beekman
Marian
M
Mooijaart
Simon P
SP
Heijmans
Bastiaan T
BT
Brandt
Bernd W
BW
Zwaan
Bas J
BJ
Slagboom
P Eline
PE
Westendorp
Rudi G J
RG
D000368:Aged; D000369:Aged, 80 and over; D001827:Body Height / Q000235:genetics / Q000502:physiology; D005260:Female; D019382:Human Growth Hormone / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000235:genetics* / Q000502:physiology; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000502:physiology; D015810:Linkage Disequilibrium; D008136:Longevity / Q000235:genetics* / Q000502:physiology; D008297:Male; D015999:Multivariate Analysis; D010750:Phosphoproteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D018013:Receptors, Neuropeptide / Q000235:genetics; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000235:genetics
C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; C048250:somatotropin releasing hormone receptor