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Corticosteroids--secreted after stress--have profound effects on brain and behavior. These effects are mediated by mineralocorticoid and glucocorticoid receptors, which are abundantly expressed in limbic neurons. The role of mineralocorticoid receptors in higher brain functions has never been well understood. Here we argue that the recently discovered low-affinity membrane version of the mineralocorticoid receptor contributes to the initial phase of the stress reaction; this is complemented by the glucocorticoid receptor which terminates the stress response. This concept may explain why human carriers of a mineralocorticoid receptor gene variant display enhanced neuroendocrine and autonomic responsiveness to a psychological stressor.

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[alpha]) 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[alpha] 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[alpha] (NRIH3) 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[alpha] (p = .018), and higher levels of triglycerides (p = .041). Genetic variation in the gene coding for the LXR[alpha] (NR1H3) associates with human life span.