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The htSNP approach employed here is likely to have captured the common variation present in the SIRT1 genomic region for the samples analyzed in this study. By tagging the common variation (haplotypes) within SIRT1 we implicitly assume that any undetected rare variants will be carried by one or other of the common background haplotypes and hence be statistically detectable; this is the logic of the htSNP approach. It is of course possible, albeit unlikely, that the selected markers might not tag the common variation comprehensively, and that rare SIRT1 polymorphisms, with a weak impact on the longevity phenotype, may exist. Overall however, our findings would suggest that there is no noteworthy influence of SIRT1 gene variation on exceptional human longevity in the German population. The possibility that this negative association finding results from population stratification in our samples is unlikely. The validity and efficacy of our extensive study population for genetic longevity research have recently been demonstrated (Nebel et al., 2005).

The conserved function of SIRT1 in invertebrates and mammals predicts that the up-regulation of the SIRT1 gene and the subsequent increase in levels of the SIRT1 protein would also exert a life-prolonging effect in humans. In this case, potential mutations affecting the transcription of the gene would be of particular interest. Because the htSNPs used in this study, which are in strong LD, also span the promoter of SIRT1, a significant influence of variation in this regulatory region of the gene may be excluded. However, it is possible that allelic variants in direct modulators of SIRT1 may be crucial in regulating SIRT1 protein levels. In addition, variation in the broad array of SIRT1 downstream targets could also play critical roles in extending lifespan.