The 438 A allele of the TAFI gene promoter has been associated with decreased circulating levels of TAFI anti- gen in the current study sample of older adults [12] and in other population samples [21]. We similarly observed that in men, but not in women, TAFI antigen levels in the low- est quartile were associated with greater number of years, or healthy years, lived during follow-up (unpublished observa- − tions). The 438 A allele also is in strong linkage disequi- librium with a common Thr325Ile substitution that increases the thermal stability and anti-fibrinolytic activity of activated TAFI [22]. Therefore, the apparent beneficial association of − TAFI 438 A/A genotype on longevity might result from increased fibrinolytic activity due to lower circulating TAFI levels, increased anti-inflammatory activity due to enhanced TAFI proteolysis of inflammatory substrates, or both.

smoking status or obesity with inflammation genotypes in predicting longevity phenotypes. A possible drug–gene in- teraction was observed for the interleukin-6 promoter poly- morphism and inflammation-modulating medication use on all-cause mortality (P-value for interaction = 0.02) and years of healthy life (P-value for interaction = 0.06). After adjust- ing for baseline cardiovascular disease and risk factors, anti- inflammatory medication use was associated with reduced all-cause mortality (HR = 0.68, 95% CI 0.42–1.10) and in- creased years of healthy life (+0.5 years, 95% CI +0.2 to +1.2 years) among subjects with the − 174 C/C genotype. In contrast, among carriers of the common − 174 G allele, anti- inflammatory medication use appeared to be associated with increased all-cause mortality (HR = 1.20, 95% CI 0.98–1.47) and fewer years of healthy life (− 0.5 years, 95% CI − 0.1 to − 0.9 years).

Evolutionarily, inflammation and tissue repair are likely to protect against infectious diseases and promote wound heal- ing, thereby ensuring reproductive fitness. Both TAFI and PAI-1 genotype affect survival in children with meningo- coccal infection [23,24]. Thus, common variants of genes that regulate inflammation or fibrin deposition may repre- sent an example of ‘antagonistic pleiotropy’, in which an attribute that is beneficial during childhood and the repro- ductive years (such as a robust inflammatory or hemostatic

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interleukin-6 [42], but also with a greater than average fall in C-reactive protein and low-density lipoprotein cholesterol levels in response to anti-inflammatory drugs [43]. Confir- mation of our findings would have important implications for variability in the inter-individual response to drug ther- apy among older adults.

response) subsequently reduces the length or quality of life in older adults. During the 19th and 20th centuries, advances in medicine and public health and improved living standards led to greatly improved childhood health and survival along with reduced chronic infections and inflammation. On the basis of cohort-specific adult mortality trends, along with the association of early-age mortality and subsequent mortality, it has been hypothesized that reduction in lifetime exposure to infectious diseases and other sources of inflammation may have contributed to the historical decline in old-age mortal- ity [25]. Sex-related differences in immune function and in- fectious disease susceptibility may also explain in part the shorter life span of men compared to women [26].

In summary, a common promoter variant of the TAFI gene, and perhaps also the PAI-1 gene, may be associated with longevity in older men. These findings suggest that modu- lators of fibrinolytic activity or proteolysis may have a gen- eralized influence on aging or age-related disease, and merit further investigation in studies of genetic determinants of hu- man longevity. Examination of additional TAFI gene vari- ants, such as Thr325Ile, or multi-locus haplotypes, may be required to define more precisely the location of any func- tional longevity-associated allele(s). Interactions with addi- tional life style factors and interventions, as well as other gene pathways related to vascular disease and aging (oxida- tive and metabolic responses, insulin signaling) also may be appropriate for future study.

Our results for the PAI-1 promoter polymorphism were confusing, and may just be due to chance. The 4G/4G geno- type appeared to be associated with lower non-cardiovascular mortality in men, but with greater cardiovascular mortality in women. Smaller population studies examining the PAI-1 pro- moter polymorphism have also showed conflicting results. The 4G allele was associated with increased longevity in an Italian centenarian case–control study, but a gender-specific was not noted [3]. There was no association between PAI-1 genotype in Danish centenarians [27], nor in a German oc- togenarian cohort [28]. The PAI-1 4G/5G variant has been shown to be functional in vitro [29,30]. The 4G sequence abolishes a binding site for a transcription repressor, thereby resulting in higher promoter activity and increased plasma levels of PAI-1 in vivo. In rodent models, the induction of PAI-1 expression in response to stress, and the age-related increase in magnitude of this response, influences the occur- rence of vascular and tissue thrombosis [31,32]. These ex- perimental findings might explain the trend toward increased cardiovascular mortality associated with the 4G/4G genotype observed here and by others [33,34].

Acknowledgements

The research reported in this article was supported by contracts N01-HC-85079 through N01-HC-85086, N01-HC- 35129, and N01-HC-15103 from the National Heart, Lung, and Blood Institute. WSB is supported by a grant from the National Institute of Health (AG 05407). SEH is supported by grants from the British Heart Foundation (RG2000/15).

Appendix A