3 Mb from the top linkage result. However, there is no extensive LD between SNPs in the linkage region and the FRA6E region, indicating that these asso- ciation signals might be independent. FRA6E has not been previously implicated with SA, although some studies have proposed PARK2, located with the FRA6E region, as a putative candidate for longevity and aging (Lunetta et al. 2007). The nearest neighboring genes to these markers in the FRA6E region were PLG and MAP3K4. PLG is a circulating zymogen with the primary function of dissolving fibrin (OMIM #173350). PLG is not an established candidate gene for SA but has been suggested to be involved with wasting (weight loss and poor wound healing) and decreased longevity due to disseminated fibrin deposition in animal model studies (Cheng et al. 2005). There is no established biological evidence implicating MAP3K4 with longevity or aging.

necessary to fully understand the significance of these findings.

A potential limitation to our study was the inability of MQLS to allow for covariate adjust- ment, and as a result we were unable to adjust for heterogeneity in study findings across ascertain- ment center (Ohio and Indiana). However, our linkage analyses should implicitly take care of confounding through pedigree structure. Since we looked at a consensus of results across linkage and association analyses, we believe that the results are not likely confounded by ascertainment center and merit further follow-up.

SA to chromosomes 6, 7, and 14 in a smaller subset of the sample (48 SA cases) used here (Velez Edwards et al. 2011). In the current sample of 74 SA cases, genotyped for a much denser map of markers, the strongest evidence for linkage was obtained in a different area of chromosome 6. This region, near FRA6E, did provide modest evidence 0 – for linkage (MHLOD 1.10 2.09) in our original study, indicating that the expanded sample im- proved power to detect linkage (Velez Edwards et al. 2011). The difference in evidence for linkage across the three models considered (dominant, re- cessive, and nonparametric allele-sharing) may re- flect differences in the goodness of fit for each model given different modes of inheritance. While evidence for linkage maximizes under different models for chromosome 6 (dominant), 16 (reces- sive), and 10, 17 and 20 (nonparametric), the linkage curves for the other models follow a sim- ilar pattern (nonparametric model reaches 2.5 on chromosomes 6 and 16, the dominant model peaks just under 3 on chromosome 10, and the recessive model just over 2 on chromosome 17), suggesting that these findings are fairly robust to the specifi- cation of a genetic model. A notable exception is chromosome 20, which generates much stronger linkage under nonparametric analysis than the oth- er two models (maximum MHLOD ~1 under a dominant model). We note, however, that given relatively small sample size from an isolated pop- ulation and differences in results from our previous study in this population, further replication of these results in an independent cohort is desirable. The correlation between linkage and association on chromosome 6 establishes a priority area for

We observed a higher rate of SA in males relative to females in our cohort, results that have not been observed consistently in previous litera- ture. Studies in the MacArthur Studies of Success- ful Aging observed that males were more likely to have better physical performance at baseline in a – cohort of 70 79-year olds with high function, con- sistent with our observations (Seeman et al. 1994). The studies by McLaughlin et al. of adults aged 65 and older, however observed the opposite asso- ciation between SA and gender (McLaughlin et al. 2010). A possible explanation for these differences is the definition of SA used. We attempted to use a definition as comprehensive as possible, integrat- ing factors pertaining to physical and cognitive function, social engagement, and health, whereas other studies often used only one or two of these components. Another possible explanation for the larger number of SA males relative to females could be the effect of marital status on successful aging which previously has been indicated (Li et al. 2006). Our sample also had a greater propor- tion of successfully aged men (52 % of men SA vs. 17 % of women SA) who were currently married (78 % of men currently married vs. 45 % of women currently married). The relation- ship between gender, marriage, and SA has not been consistent across studies, with the majority finding no association; however, it merits further

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