American descent found that the heritability of human longevity is estimated at 20-30%, and that specific genetic variants may have non-linear effects on different human phenotypes (2,3). However, the molecular genetics of human longevity is largely unexplored in Latin America and other developing regions, despite the fact that life expectancy is increasing in these areas (6). Genetic explorations of human longevity may shed light on molecular factors associated with resistance to several common age-related diseases (1,2). 

To explore the possibility of an association between common polymorphisms in two candidate genes and longevity in Colombia, we analyzed two polymorphisms in apolipoprotein E (APOE) and angiotensin-converting enzyme (ACE) genes in a sample of 538 Colombian subjects aged 18-106 years using previously validated PCR-based methods (13,17). We found a significant decrease in ACE DD genotype (24% vs. 16%) between young and old subject groups (mean age: 45 vs. 77 years) (p=0.03). The ACE DD genotype and D allele decrease was significant only in women. There were no differences for APOE polymorphism between young and old subjects.

Our results are compatible with the expected age-related decrease of ACE DD genotype. Future studies examining functional single nucleotide polymorphisms (SNPs) in the ACE gene and its correlation with serum ACE activity in the older subjects and their younger relatives in this sample are warranted. Because cardiovascular disease is one of the main causes of death worldwide, polymorphisms in genes involved in vascular dysfunction such as apolipoprotein E (APOE) and angiotensin-converting enzyme (ACE) have been posited as strong candidates for longevity in different studies searching for age-related differences in the frequency of alleles and genotypes related to cardiovascular risk in Caucasian and Asian populations (2,7).Differential values of heritability were observed among Latin American populations (3). Colombia is expected to be greatly impacted by human aging; life expectancy was only 40.7 years in 1930 but is estimated to be 74 years in 2015 (6,19). The Colombian population has distinct genetic and environmental features, including a mixture of Caucasian and Native American genetic backgrounds in the population living in Bogota (20), which make an analysis of candidate genetic polymorphisms for human longevity in this population interesting. In this study, we found no significant differences in the frequency of APOE polymorphism (allele or genotype) between different age groups in a large Colombian sample (538 subjects). However, we did find a significant decrease in the frequency of the ACE DD genotype in the older group sample compared to the younger sample (24 vs. 16%), particularly among women. A lack of statistical power due to the smaller size of the subsample of men may have prevented us from detecting an association between ACE DD and longevity in male subjects. Sex-dependent genetic associations with human longevity have been reported with several polymorphisms (7). Preliminary data from an ongoing analysis of selected demographic and environmental variables for a subset of the sample of older subjects (206 individuals) showed higher values for BMI and serum total cholesterol and lower rates of smoking in women (unpublished results). Consistent with these demographic variables and a non-linear effect of specific polymorphisms on human longevity, there is a possibility that other unknown environmental and genetic variables accounted for the earlier death of men (in comparison to women) in this sample. The interaction of specific genetic variants (ACE DD genotype) with some female-specific environmental characteristics found in this population (higher serum cholesterol, for example) may account for an earlier death among ACE DD carriers and the decreased frequency of this genotype seen in older women in this study. The mean age of the older subjects (77 years) was 30 years more than the estimated life expectancy of their birth year cohort (40.7 years) (19). 

Previously, we found a highly significant association in our population between several SNPs in the APOE gene and Alzheimer's disease (16,37), but not with ACE or A2M genes (17). A future analysis in the present population of other promising candidate genes for human longevity (MTP, WRN, among others) (2,38), together with the analysis of additional SNPs in the ACE I gene having a possible functional effect (39) and analysis of ACE serum levels (26) in older subjects and their younger relatives (40), will be important. 

Although previous reports in Europe and Asia showed that there were no differences in ACE genotypes with age or a paradoxical decrease in ACE II genotype (23-33), a recent report showed a decrease of ACE DD genotype (34) (60 vs. 70 years, 45 vs. 42%) in a smaller sample of older subjects of mixed descent living in Brazil. The age-dependent decrease and negative selection of ACE DD genotype carriers is compatible with its associated risk for cardiovascular diseases in Caucasian populations (10). Results of prospective studies analyzing mortality in small time windows (2-10 years) are also inconclusive regarding effects of ACE and APOE polymorphisms (35,36).