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Evidence that the gene encoding insulin degrading enzyme influences human lifespan.

Artikel i vetenskaplig tidskrift
Författare Mun-Gwan Hong
Chandra Reynolds
Margaret Gatz
Boo Johansson
Jennifer C Palmer
Harvest F Gu
Kaj Blennow
Patrick G Kehoe
Ulf De Faire
Nancy L Pedersen
Jonathan A Prince
Publicerad i Human molecular genetics
Volym 17
Nummer/häfte 15
Sidor 2370-8
ISSN 1460-2083
Publiceringsår 2008
Publicerad vid Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi
Psykologiska institutionen
Sidor 2370-8
Språk en
Länkar dx.doi.org/10.1093/hmg/ddn137
Ämnesord Aged, Aged, 80 and over, Alternative Splicing, Female, Gene Expression, Genotype, Humans, Insulin, metabolism, Insulysin, genetics, physiology, Linkage Disequilibrium, Longevity, genetics, Male, Middle Aged, RNA, Messenger, biosynthesis
Ämneskategorier Medicin och Hälsovetenskap

Sammanfattning

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 be occurring only 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 clarifying the biological importance of these findings.

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