Is the ACE I/D polymorphism associated with extreme longevity? A study on a Spanish cohort


Rate of ageing and survival are partly heritable traits, with some alleles contributing to exceptional lifespan. One possible approach for identifying those gene variants that are associated with ‘longevity assurance’ is to study the genotype of centenarians.1 These people are the survival tail of the population since they escaped diseases of the pre-antibiotic era, and have avoided or postponed age-related diseases and their fatal consequences2.

The renin–angiotensin–aldosterone system (RAAS) plays a critical role in the maintenance of cardiovascular homeostasis. One important gene of the RAAS that has received attention with regards to its possible role in longevity is the gene encoding the angiotensin-converting enzyme (ACE). The 287 bp Ins(I)/Del(D) polymorphism [rs1799752] in intron 16 of the ACE gene is associated with coronary artery disease (CAD). For instance, a recent meta-analysis on 118 studies (involving 43,733 cases with CAD and 82,606 controls) showed that, compared with II individuals, the DD genotype is associated with an increased risk for CAD in most ethnic groups worldwide (odds ratio (OR), 1.25; 95% confidence intervals (CI), 1.16–1.35).3 The DD genotype is also a risk factor for ischaemic stroke,4 and the D allele is associated with a 14% increased risk of type II diabetes relative to the I variant (OR, 1.14; 95% CI, 1.04–1.24).5 Paradoxically, the same (D) allele which predisposes to CAD has been reported to be more frequent insome cohorts of European centenarians, including from France,6 the United Kingdom,7 and Italy,8 as well as in nonagenarians and centenarians from the Uighur population in China,9,10 compared with their younger ethnically matched referents. However, the association between the D allele and increased longevity has not been replicated in other studies on centenarians from Denmark,11 France,12 Italy,13,14 Korea15 or China (Han population).16 To further complicate the issue, Forero et al.17 recently reported an age-related decrease of the D allele in a Latin-American population (Colombia). Controversy between studies can arise from different factors, including homogeneity of cohorts within a given report or geographic differences between studies. For instance, the frequency of the I allele decreases from Northern to Southern Europe.14

In view of (i) the well-documented association between the ACE I/D polymorphism and important disease phenotypes, notably CAD, (ii) the potential role of this polymorphism as a candidate to explain, at least partly, individual differences in longevity, (iii) the aforementioned controversy in the literature (with both negative and positive results), and (iv) the fact that the question has not been studied in other cohorts from Europe (for example, in the Spanish population), the purpose of this study was to compare the allelic and genotypic frequency of the ACE I/D polymorphism in a group of Spanish centenarians and a cohort of healthy young adults (aged < 40 years) of the same ethnic origin. To increase the statistical power of comparisons, we also studied a group of nonagenarians together with the centenarians.


Carmen Fiuza-Luces1, Jonatan R Ruiz2, Gabriel Rodríguez-Romo3, Catalina Santiago1, Félix Gómez-Gallego1, Amalia Cano-Nieto4, Nuria Garatachea5, Inmaculada Rodríguez-Moreno6, María Morán7* and Alejandro Lucia1*

  • 1 Universidad Europea de Madrid, Spain
  • 2 Department of Biosciences and Nutrition at NOVUM, Unit for Preventive Nutrition, Karolinska Institutet, Stockholm, Sweden
  • 3 INEF, Universidad Politécnica de Madrid, Spain
  • 4 SUAP Archena, Hospital Morales Meseguer, Murcia
  • 5 Faculty of Health and Sport Science, University of Zaragoza, Huesca, Spain.
  • 6 Residencia AMMA de Valdebernardo, Madrid, Spain
  • 7 Centro de Investigación Hospital 12 de Octubre and CIBERER, Madrid, Spain
  • * These authors contributed equally


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