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Liver X Receptor Alpha Associates With Human Life Span

¹ Department of Gerontology and Geriatrics, ² Department of Medical Statistics and Bioinformatics, ³ Section of Molecular Epidemiology, and ⁴ Department of General Internal Medicine, Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands.
⁵ Department of Biotechnology, Institute of Molecular and Cell Biology, Tartu University, Tartu, Estonia.

Address correspondence to Simon P. Mooijaart, MD, Department of Gerontology and Geriatrics, C-2-R Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands. E-mail: s.p.mooijaart{at}lumc.nl

In the nematode Caenorhabditis elegans, nuclear hormone receptor DAF-12 regulates the decision to go into a resistant dauer diapause, in which the worm exhibits a decreased rate of aging. Using sequence similarity searches, we previously identified the liver X receptor alpha (LXR) as one of the human nuclear hormone receptors the protein sequence of which is most similar to C. elegans DAF-12. Here, we studied whether variation in the gene encoding LXR associates with human life span. In the Leiden 85-Plus Study, a population-based prospective follow-up study, we genotyped four polymorphisms spanning the gene coding for LXR (NR1H3) and tagged four common haplotypes. Among 563 participants, haplotype 2 associated with reduced mortality during the 7-year follow-up (hazard ratio 0.78; p =.015), predominantly caused by reduced mortality from infectious disease (hazard ratio 0.31; p =.023). Haplotype 2 also associated with higher levels of plasma apolipoprotein E, a target gene of the LXR (p =.018), and higher levels of triglycerides (p =.041). Genetic variation in the gene coding for the LXR (NR1H3) associates with human life span.