Polymorphism of the angiotensin converting enzyme gene: longevity gene or risk factor in hypertensive disease? In recent decades, the increase in life expectancy stimulated the study of aging processes and the search for candidate genes involved in longevity. The angiotensin converting enzyme (ACE), present in all endothelial cells, plays an essential role in maintaining the homeostasis of blood flow by regulating the production of the vasoconstrictor angiotensin II and inactivating the bradykinin. Some studies reported a possible association between the polymorphism I/D of ACE gene and either hypertension and longevity. The present study was aimed to confirm these data. We studied two large cohorts of nonagenarians and centenarians. One was from Sardinia (200 subjects, 88 males, mean age: 96 years) and their data were compared to a group of 222 subjects (106 males, mean age: 44 years) from the general population of the same geographic area. The latter group of longeve subjects (161 subjects, 71 males, mean age: 97 years) was from Southern Italy. Furthermore, we studied 146 hypertensive patients (98 males, mean age: 51 years) and 172 normotensive subjects (86 males, mean age: 33 years) from Southern Italy. The ACE I/D polymorphism was typed by polymerase chain reaction; the amplified 490 bp (allele I) and 190 bp (allele D) were visualized on 2% agarose gel. Hypertensive subjects had a significantly different distribution of ACE genotypes as compared to normotensive ones (P=0.001) and a higher frequency of the D/D genotype. Long-lived subjects from Sardinia showed a significantly different distribution of ACE genotypes as compared to subjects from the general population of the same geographic area (P <0.001), to long-lived subjects from Southern Italy (P <0.001), to hypertensive patients (P=0.011) and to normotensive subjects from Southern Italy (P <0.001). Surprisingly, they had the highest frequency of the D/D genotype among the compared groups. Our study indicates that: i) centenarians of different ethnic origin have a different genetic background, ii) there is a possible association between longevity and allelic variants of ACE, even if only in specific ethnic groups (i.e., Sardinian) and iii) ACE polymorphisms are a predisposing factor to hypertension.