Human Molecular Genetics Advance Access published online on April 30, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn137
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Evidence that the Gene Encoding Insulin Degrading Enzyme Influences Human Lifespan
1 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77 Stockholm, Sweden 2 Department of Psychology, University of California at Riverside, Riverside, CA 92521, USA 3 Department of Psychology, University of Southern California, Los Angeles, CA 90089-1061, USA 4 Department of Psychology, University of Gothenburg, 405 30 Göteborg, Sweden 5 Department of Clinical Science, University of Bristol, Bristol BS10 5NB, United Kingdom 6 Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 77 Stockholm, Sweden 7 Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, 431 80 Mölndal, Sweden 8 Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden
* Correspondence: Dr. Jonathan A. Prince Department of Medical Epidemiology and Biostatistics Karolinska Institutet Nobels väg 12A / PO Box 281 171 77 Stockholm, Sweden Phone: +46 (0)8 524 86008 Fax: +46 (0)8 31 49 75 E-mail: Jonathan.Prince{at}ki.se
Received March 28, 2008; Revised April 27, 2008; Accepted April 27, 2008
Studies in model organisms have demonstrated that components of insulin and insulin-like signaling pathways are involved in the regulation of lifespan but the relevance of those findings to humans has remained obscure. Here we provide evidence suggesting that variants of the gene encoding insulin-degrading enzyme (IDE) may be influencing human lifespan. We have employed a variety of models and diverse samples that reproducibly indicate the relative change in IDE genotype frequency across the age spectrum as well as allow the detection of association with age-at-death. A tenable molecular basis of this is suggested by the observation of genetic association with both fasting plasma insulin levels and IDE mRNA expression. Across populations the emergent genetic model is indicative of over-dominance, where heterozygotes of critical markers have increased IDE mRNA expression and insulin levels, and this is reflected in diminished heterozygosity at advanced age. A critical and replicating feature of this study is that change in IDE genotype frequency with advancing age appears to only be occurring in men, and this is supported in that insulin levels are only associated with IDE in men. Results suggest a relationship between a gene that is intimately involved in insulin metabolism and the determination of lifespan in humans, but over-dominance and gender specificity will be important parameters to consider towards clarifying the biological importance of these findings.