Acknowledgments: This study was funded by the Fondo de Investigaciones Sanitarias (FIS, refs. # PI12/00914, PI10/00036, and PI12/00788) and supported in part by grants from the program A Grant-in-Aid for Challenging Exploratory Research (24650414 to N. Fuku) from the Ministry of Education, Culture, Sports, Science and Technology and by a Grant-in-Aid for Scientific Research from the Ministry of Health, Labor, and Welfare of Japan (to M. Miyachi).

The genotype distribution of Spanish centenarians vs. their healthy (CAD-free) controls suggests that the potential influence of the rs1333049 SNP on exceptional longevity goes beyond its documented influence on CAD. With regards to this, although the functional significance of the rs1333049 SNP remains unclear, and the 9p21.3 locus does not contain any known expressed gene products, it lies adjacent to CDKN2A and CDKN2B, two important cell cycle regulators that are cyclin-dependent kinase inhibitor genes regulating the G1 phase of the cell cycle by inhibiting cyclin/cyclin-dependent kinases. This raises the possibility that rs1333049 may modulate the rate of cellular aging (Emanuele et al., 2010). In fact, recent genomewide scanning has suggested an association between CDKN2A/CDKN2B and extreme longevity, and CDKN2A performs a key step in the p53 pathway, which plays a crucial role in inducing cellular senescence (Sebastiani et al., 2012).