Secondly, this gene lies on chromosome 21q21, and trisomy 21 (Down syndrome) resembles accelerated aging, with premature age-related changes including in the skin and hair, increased frequency of premature cataracts, hearing loss, menopause, and Alzheimer's disease [28], suggesting that genes in chromosome 21 could affect lifespan. 

Thirdly, among the top genes identified from the preliminary genetic screen, RNA editing represents a general cellular process that might be expected to improve cellular health; and RNA editing activity has been associated with innate immune response [29,30] and age-related syndromes that include dementia and amyotrophic lateral sclerosis (ALS) [31]. 

Reported are summaries of the last contact ages. All subjects were enrolled by studies with Institutional Review Board approval and oversight. 

To further test the generalizability of these results to other independent groups, we evaluated these associations in the AJCS and the JCS using a combination of proxy SNPs typed with Affymetrix platforms and SNPs in Table 3 typed with more traditional techniques (See methods). Table 4 summarizes the results of the replication study of 4 of the 5 SNPs, and one additional proxy SNP is in Table 5. None of these SNPs in ADARB1 replicate the results in the NECS and SICS samples, although the significant association of the SNP rs17004734, which is within 2Kb from rs414743, is consistent with the presence of longevity-associated variants in the region. Because the SNPs used in the NECS and SICS are chosen to best capture the genetic variations of Caucasians from the HapMap, they may not be the correct choice for this founder population. Indeed, Figure 1 shows a different pattern of LD in ADARB1 in the AJCS subjects. All ADARB1 SNPs in Table 3 and two additional proxy SNPs were genotyped in the JCS subjects, and Tables 6 and 7 summarize the results. The last three SNPs in Table 6 show effects that are consistent with those observed in NECS and SICS subjects but do not reach statistical significance, even when data from all three studies are aggregated. Figure 3 shows the posterior densities of ORs for three rare SNPs that are suggestive of association but would require much larger sample sizes to reach statistical significance. The association of two proxy SNPs for rs2838816 in Table 7 is again consistent with the presence of longevity.

We examined the associations of 31 SNPs in ADARB1 in the NECS and SICS samples using recessive and dominant models with Bayesian logistic regression [32]. The details of the statistical analysis are in the Methods, and significant results are summarized in Table 2, which provides the physical positions and allele frequencies derived from the HapMap for these SNPs, and Table 3 (rows 14-15). Five SNPs in ADARB1 are strongly associated with extreme old age in the NECS, and the association of SNP rs414743 remains significant even after imposing stringent corrections for multiple comparisons (Bayesian significance < 0.00035 where 145 is the overall number of SNPs included in this analysis). The five SNPs tag one region of strong linkage disequilibrium (LD) of the gene (Figure 1). None of the SNPs reached statistical significance in the SICS, although the three SNPs rs2838809, rs2838810, and rs2838816 exhibited consistent associations in terms of odds ratios and allele frequencies. When data from both NECS andthe frequency of alleles negatively associated with EL decreases. However, for other SNPs, the pattern was not monotonic, suggesting a more complex relationship between the SNP and EL. Further studies are needed to elucidate the underlying mechanisms. Overall, our findings suggest that ADARB1 and ADARB2 are important candidates for further investigation into the genetic basis of exceptional longevity.Alleles that are negatively associated with EL become less frequent. This pattern has also been observed for ApoE alleles [33] and is consistent with the phenomenon of demographic selection [34]. These increases in allele frequencies with age also illustrate the increasing gain of power conferred by studying centenarians and even more so, subjects aged 105+ years, in genetic studies of exceptional survival. In a previous study, mutations in both adr-1 and adr-2 resulted in increased GFP reporter transgene silencing, suggesting that declines in ADAR function are associated with an increase in RNA interference (RNAi), which would account for the GFP silencing in those experiments. When the argonaute gene rde-1, which is essential for RNA-induced silencing complex (RISC) formation, was introduced into adr-1;adr-2 worms containing the transgenes, the increased GFP silencing due to ADAR knockdown was suppressed [44]. This suggests cross-regulation between RNA editors and RNA interference that is further supported by results from Tonkin et al [45], wherein they demonstrated that a mild chemotaxis defect of the adr-1;adr-2 double mutant could be rescued by an rde-1 mutant. Therefore, to evaluate the potential for cross-regulation between RNA editing and RNA interference in the context of lifespan, we evaluated adr-1;adr-2 mediated declines in lifespan in the presence of the RNAi defective strain, rde-1(ne-219). Remarkably, and consistent with previous results, the loss of rde-1 completely restored lifespan declines associated with adr-1;adr-2 loss-of-function (Figure 6b). We interpret these data as expanding the interaction between these two RNA regulatory pathways to include lifespan determination.