We recently reported that lipoprotein particle sizes are increased in centenarians and their offspring and suggested that this trait may increase the likelihood of attaining exceptional longevity [6]. This phenotype was also associated with approximately a three-fold increased frequency of homozygosity (valinevaline [VVassociations with exceptional longevity remained statistically significant. Analysis of the frequency trend with age (in centenarian and control groups combined) for polymorphisms in APOC3 and CETP (Figure 1) revealed a highly significant (p<0.0006; b=1.89 [95% CI, 0.23-6]) monotonically increasing frequency trend for homozygosity for the APOC3 (rs2542052) (641 C allele (CC)) and near-significance (b=3.06 [95% CI, 0.33-5.8, p=0.069]) for homozygosity for the CETP codon 405 valine allele (VV) (rs5882). The CC genotype at position 641 of APOC3 had a prevalence of 25% among the centenarians and 20% in their offspring compared to only 10% in controls (p=0.0001 and p=0.001, respectively). Five additional SNPs in APOC3 and six SNPs in CETP (Figure 2) showed no evidence of association with longevity. Conversely, the prevalence of the APOC3 AA genotype was reduced in both centenarians and their offspring compared to controls (p=0.001 both) (Figure 3A). The lipoprotein metabolism and thus the favorable alleles showing monotonic increases in allele frequencies among older age strata would also be expected to be associated with a favorable lipoprotein profile. Indeed, participants of all groups carrying the APOC3 rs2542052 CC genotype had lower serum levels of APOC3 compared to those carrying either CA or AA (CA/AA) genotype (mean [SE]: 10.1 [1.1] versus 13.2 [1.1] mg/dl, p<0.05). Given the higher prevalence of this genotype in centenarians, it is therefore not surprising that serum levels of APOC3 were lower in centenarians and their offspring than in controls (mean [SE]: 9.8 [0.6], 9.3 [0.5] versus 11.7 [0.7] mg/dl; p<0.05 and p<0.01, respectively) (Figure 3B). Linkage disequilibrium (LD) analysis of the CETP gene revealed that the single nucleotide polymorphism rs1800776 was in LD with rs1800775 just 2 bp apart (D'=0.94; r2=0.20) (Figure 2). Haplotype analysis with these two SNPs revealed that the C-A haplotype was statistically significantly more prevalent among individuals in the control group compared to centenarian probands (0.355 versus 0.278, p<0.004). LD analysis revealed LD across the neighboring apolipoprotein A4 (APOA4) and apolipoprotein C3 (APOC3) genes as previously reported by others (Figure 2) [8]. In haplotype analysis, the prevalence of the A-C haplotype (corresponding to SNP rs675 in APOA4 and rs2542052 in APOC3) was significantly higher among the centenarian probands compared to controls (0.498 versus 0.344, p<10^-8). The prevalence of the A-A haplotype of the same SNPs was significantly higher among controls compared to probands (0.483 versus 0.307, p<10^-10). Association analysis between various haplotypes of the APOC3/APOA4 and lipid profile was not significant, neither when the most prevalent haplotypes in the two groups were compared (CA versus AA) nor the haplotypes that contain the favorable APOC3 allele. The only trend for association (p<0.07) between haplotype and lipoprotein was for LDL. This suggests that the single genotype APOC3 CC is more prominent in the phenotypes. Relationships between other lipoprotein traits and APOC3 rs2542052 CC genotype are shown in Table 1. Due to the dependency of lipoprotein traits on age and their modifiability with medications, we only considered offspring (n=131) and controls (n=126) not using lipid-lowering drugs in this analysis. In females, triglycerides (TG), high-density lipoprotein cholesterol (HDL), and their ratio, as well as low-density lipoprotein cholesterol (LDL) lipoprotein particle size were significantly more favorable among those with the rs2542052 CC genotype than among those with CA/AA genotypes. As shown in Table 1, the combined group also exhibited significant associations with lipoproteinsMice show absent or decreased APOC3 protein with reduced triglyceride (TG) levels [24], even in the presence of streptozotocin-induced diabetes [25]. However, the impact on lifespan has not been determined in these models. Of the 381 participants we have genotyped since 1998, 64 had the CC genotype. To describe the relationship between genotype and death, we plotted the Kaplan-Meier survival function estimates of study participants by APOC3 genotype (Figure 5). Survival was significantly greater among CC genotype carriers (p < 0.0007). We hypothesized that since only one out of 10,000 people in the general population has survived to 100 years, there should be potent enrichment for favorable genotypes in this unique population. The monotonic, progressive over-representation of the APOC3-641 CC genotype with increasing age, from a relatively infrequent 10% at age 60 years to 25% in individuals surviving to age 100 years is statistically robust and provides evidence that this genotype provides a selective advantage for survival to exceptional old age. Underlying population stratification could be responsible for genotypic associations detected in case-control studies, but this is much less likely in this relatively homogeneous Ashkenazi population. Furthermore, we demonstrated association of this same genotype with survival in a prospectively followed cohort. Finally, the prevalence of heterozygosity for recessive disease alleles (nearly) unique to the Ashkenazi population, e.g., breast cancer and Tay-Sachs disease, did not differ significantly between longevity cases and controls, suggesting the lack of population stratification (unpublished data).