middle-aged control groups were in Hardy-Weinberg equilibrium. No significant differences were found in ACE1 genotype or allele frequencies between the two groups. In addition, no significant interaction was observed between ACE1 alleles and APOE alleles, which are also linked to longevity.

However, a significant geographical gradient was observed in ACE1 allele frequencies, with decreasing frequencies of the ACE1*I allele and increasing frequencies of the ACE1*D allele (particularly the ACE1*D/*D genotype) from Northern to Southern Europe. These findings suggest that genetic differences, in addition to environmental factors, may play a role in explaining the association between ACE1 polymorphism and longevity.

In conclusion, our study did not support the previously reported association between ACE1 polymorphism and longevity in Southern Italy. However, our findings highlight the importance of considering regional genetic differences when examining associations between genetic polymorphisms and longevity.The control group was in Hardy-Weinberg equilibrium (respectively: x2 = 0.31; p = 0.58; x2 = 0.008; p = 0.93). No statistically significant differences were found in ACE1 genotype frequencies between centenarians and controls in this Southern Italian population (ACE1*I/*I versus ACE1*I/*D and ACE1*D/*D: Pearson x2 = 0.09 F. Panza et al. / Experimental Gerontology 38 (2003) 1015-1020 Table 1 Angiotensin I converting enzyme 1 (ACE1) genotype and allele distributions in European centenarians and middle-aged subjects Mean age at collection Genotypes n frequency (95% CI) Alleles n frequency (95% CI) (SD) (years) ACE1*I/*I ACE1*I/*D ACE1*D/*D ACE1*I ACE1*D Italian centenarians 100 (2) 10 34 38 54 110 n = 82 0.12 (0.21-0.07) 0.42 (0.52-0.31) 0.46 (0.57-0.36) 0.33 (0.40-0.26) 0.67 (0.74-0.60) French centenarians 103.1 103 261 196 467 653 (Blanche et al., 2001) n = 560 0.18 (0.22-0.15) 0.47 (0.51-0.43) 0.35 (0.39-0.31) 0.42 (0.45-0.39) 0.58 (0.61-0.55) Danish centenarians 0.99 41 95 48 177 191 (Bladbjerg et al., 1999) n = 184 0.22 (0.28-0.16) 0.51 (0.59-0.45) 0.27 (0.33-0.20) 0.48 (0.53-0.43) 0.52 (0.57-0.47) Italian middle-aged 50.5 (18.5) 34 118 100 186 318 subjects n = 252 0.13 (0.18-0.10) 0.47 (0.53-0.41) 0.40 (0.46-0.34) 0.37 (0.41-0.33) 0.63 (0.67-0.59) French middle-aged 51.2 101 288 171 490 630 subjects (Blanche et al., 2001) n = 560 0.18 (0.21-0.15) 0.51 (0.56-0.47) 0.31 (0.35-0.27) 0.44 (0.47-0.41) 0.56 (0.59-0.53) Danish middle-aged subjects 42,46,102,51,194,204 (Bladbjerg et al.,1999)n=199, ACE1*I, ACE1*I; D, ACE1*D; II, ACE1*I/*I; DD, ACE1*D/*D; ID, ACE1*I/*D; n; number of individuals genotyped; CI, confidence interval.Bonferroni-p < .05; df =1; ACE1*I/*D versus ACE1*I/*I and ACE1*D/*D: Pearson x2 = 0.72 Bonferroni-p < .05; df = 1; ACE1*D/*D versus ACE1*I/*I and ACE1*I/*D: Pearson x2 =1.13 Bonferroni-p < .05; df = 1). Similarly, the frequency of the ACE1*D allele (or vice versa, ACE1*I allele) was comparable between centenarians and middle-aged control subjects (Pearson x2 = 0.85 Bonferroni-p < .05; df = 1). We also tested the ACE1 against that of APOE in view of our recent findings for APOE 1 4 in our centenarians (9). We did not find statistically significant differences in rates between alleles and centenarians among those stratified for (Table 2). However, we did find a statistically decreasing gradient from Northern to Southern Europe in ACE1*I allele frequency both in and controls (z = 3.31; p = 0.001; z = 3.62;Italy to Southern Italy, which may have implications for the risk of certain diseases in these populations. The results of this study, in combination with previous research, suggest that APOE may play a role in longevity in some populations, but there is currently no evidence to support a similar involvement for the ACE1 gene or an interaction between the two genes. However, the limitations of this study mean that further longitudinal research is needed to draw definitive conclusions about the impact of ACE1 polymorphism on extreme longevity.This study examines the potential impact of migration to Southern Europe, along with other environmental factors such as diet and lifestyle, on variations in human longevity. The Italian Longitudinal Study on Aging (ILSA) and AFORIGE (Associazione per la FOrmazione e la RIcerca in Geriatria) provided support for the study. FP, CC, and AMC received PhD grants in Carcinogenesis, Aging, and Immunoregulation from the European Union. The authors express their gratitude to Ms Damiana Calamita, Ms Nicoletta Lobascio, Dr Giovanni Castellaneta, and Dr Amalia Terralavoro of Pfizer Inc. for their skilled assistance. 

References:

Agerholm-Larsen, B., Nordestgaard, B.G., Steffensen, R., Sorensen, T.I., Jensen, G., Tybjaerg-Hansen, A., ACE gene polymorphism: ischemic heart disease and longevity in individuals. A case-referent and retrospective cohort study based on the Copenhagen City Heart Study. Circulation.

Bladbjerg, E.M., Andersen-Ranberg, K., de Maat, M.P., Kristensen, S.R., Jeune, B., Gram, J., Jespersen, J., Longevity is independent of common variations in genes associated with cardiovascular risk. Thromb. Haemost.

Blanche`, H., Cabanne, L., Sahbatou, M., Thomas, G., A study of French centenarians: are ACE and APOE associated with longevity? C. R. Acad. Sci. III.

MacLachlan D.R., Alberts M.J., Hulette C., Crain B., Goldgaber D., Roses A.D. Association of apolipoprotein E allele e with late-onset familial and sporadic Alzheimer's disease. Neurology.

Rengo, F., Varricchio, M., ACE gene polymorphism and insulin action in older subjects and healthy centenarians. J. Am. Geriatr. Soc.

Rigat, B., Hubert, C., Alhenc-Gelas, F., Cambien, F., Corvol, P., Soubrier, F., An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J. Clin. Invest.