Despite strong evidence for an association between IL-6 and sIL-6R phenotypes, there was no evidence for an association between IL6R genotype and longevity in CHS or with other systemic markers of inflammation in InCHIANTI (Rafiq et al., 2007). In fact, the IL6R rs8192284 variant allele was recently reported in a genome-wide association study from WHS (Ridker et al., 2008) to be associated with lower CRP levels, which is opposite to its reported effect on IL-6 and sIL-6R levels. Unlike other soluble receptors, sIL-6R is generally thought to act as an agonist of IL-6, thus allowing gp130-mediated IL-6 signaling to occur on cells without a membrane-bound IL-6R (so-called trans-signaling) (Jones et al., 2001; Knpfer and Preiss, 2008). However, the biology of IL-6 signaling is complex and can have both pro- and anti-inflammatory effects (Gabay, 2006; Knpfer and Preiss, 2008). These observations suggest a different mechanism of action of PARP-1 versus soluble IL-6 receptor gene variants on the expression of distinct inflammatory and aging-related phenotypes. Therefore, the association of PARP1 genotype with higher plasma levels of both CRP and IL-6 (two important inflammation/stress-response proteins, each of which predict mortality), as well as the probable influence of PARP-1 as a more global regulator of transcription and other genes related to aging, may account for the apparent association between PARP1 genotype and the more complex clinical outcome of longevity.

Appendix A. Supplementary data

Supplementary data associated with this article can be found in the online version at doi:10.1016/j.exger.2009.02.004.

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