estra, M., Donazzan, S., Sangiorgi, G.B., Barbagallo, M., Frada, G., Passeri, M., Fagnoni, F., Sansoni, P., Senin, U., Cherubini, A., Polidori, M.C., Marigliano, V., Bauco, C., Cacciafesta, M., Forconi, S., Guerrini, M., Boschi, S., Fabris, F., Cappa, G., Ferrario, E., Giarelli, L., Cavalieri, F., Stanta, G.,

Epidemiological and socioeconomic aspects of Italian centenarians. Arch. Gerontol. Geriatr.

,

–

Costerousse, O., Jaspard, E., Wei, L., Corvol, P., Alhenc-Gelas, F.,

The angiotensin I-converting enzyme (kininase II): molecular organ- ization and regulation of its expression in humans. J. Cardiovasc. Pharmacol.

(Suppl.

), S

–S

Davignon, J., Gregg, R.E., Sing, C.F.,

Apolipoprotein E polymorph- ism and atherosclerosis. Arteriosclerosis

,

–

Eisenlohr, L.C., Bacik, I., Bennink, J.R., Bernstein, K., Yewdell, J.W.,

Expression of a membrane protease enhances presentation of endogenous antigens to MHC class I-restricted T lymphocytes. Cell

,

–

Evans, A.E., Poirier, O., Kee, F., Lecerf, L., M

rum, E., Falconer, T., Crane, J., O’Rourke, D.F., Cambien, F.,

Polymorphisms of the angiotensin-converting-enzyme gene in subjects who die from coronary heart disease. Q. J. Med.

,

–

Frisoni, G.B., Louhija, J., Geroldi, C., Trabucchi, M.,

Longevity and the epsilon

allele of apolipoprotein E: the Finnish Centenarians Study. J. Gerontol. A Biol. Sci. Med. Sci.

, M

–M

Galinsky, D., Tysoe, C., Brayne, C.E., Easton, D.F., Huppert, F.A., Dening, T.R., Paykel, E.S., Rubinsztein, D.C.,

Analysis of the apo E/apo C-I, angiotensin converting enzyme and methylenetetrahydrofolate reductase genes as candidates affecting human longevity. Athero- sclerosis

,

–

Lindpaintner, K., Pfeffer, M.A., Kreutz, R., Stampfer, M.J., Grodstein, F., L

otte, F., Buring, J., Hennekens, C.H.,

A prospective evaluation of an angiotensin converting-enzyme gene polymorphism and the risk of ischemic heart disease. N. Eng. J. Med.

,

–

Louhija, J., Miettinen, H.E., Kontula, K., Tikkanen, M.J., Miettinen, T.A., Tilvis, R.S.,

Aging and genetic variation of plasma apolipopro- teins. Relative loss of the apolipoprotein E

phenotype in centenarians. Arterioscl. Thromb.

,

–

Kehoe, P.G., Russ, C., M

lory, S., Williams, H., Holmans, P., Holmes, C., Liolitsa, D., Vahidassr, D., Powell, J., M

leenon, B., Liddell, M., Plomin, R., Dynan, K., Williams, N., Neal, J., Cairns, N.J., Wilcock, G., Passmore, P., Lovestone, S., Williams, J., Owen, M.J.,

Variation in DCP

, encoding ACE, is associated with susceptibility to Alzheimer disease. Nat. Genet.

,

–

Panza, F., Solfrizzi, V., Torres, F., Mastroianni, F., Del Parigi, A., Colacicco, A.M., Basile, A.M., Capurso, C., Noya, R., Capurso, A.,

Decreased frequency of apolipoprotein E epsilon

allele from Northern to Southern Europe in Alzheimer’s disease patients and centenarians. Neurosci. Lett.

,

–

Panza, F., Solfrizzi, V., D’Introno, A., Colacicco, A.M., Capurso, C., Kehoe, P.G., Capurso, A.,

Shifts in angiotensin I converting enzyme insertion allele frequency across Europe: implications for Alzheimer’s disease risk. J. Neurol. Neurosurg. Psychiatry

, (in press) http://jnnp.bmjjournals.com/future/preview.shtml. Paolisso, G., Manzella, D., Ferrara, N., Gambardella, A., Abete, P., Tagliamonte, M.R., De Lucia, D., Furgi, G., Picone, C., Gentile, S.,

While it appears that APOE may play a role in longevity in centenarians in Southern Italy (Panza et al., 1999) and other populations (Schachter et al., 1994; Louhija et al., 1994; Frisoni et al., 2001), the current evidence in conjunction with previous work (Bladbjerg et al., 1999; Blanche` et al., 2001) does not support a similar involvement for the ACE1 gene, nor of an interaction between the alleles of both genes. We must however, also acknowledge that the cross-sectional design and a relatively small number of centenarians of the present study are limited in their statistical power and thus we cannot make definitive conclusions. Only longitudinal studies specifically designed for addressing the impact of the ACE1 polymorphism on extreme longevity could provide more robust evidence. In conclusion, in the present study no association between ACE1 polymorphism and longevity was found for Southern Italy populations, however, it is interesting that there are significant geographical differences in ACE1 allele fre- quencies, decreasing in a gradient-like fashion from North- ern to Southern Europe, that could impact, with other environmental factors (e.g. differing diet, lifestyle), on variation in human longevity.

Acknowledgements

This study was supported by Italian Longitudinal Study on Aging (ILSA) (Italian National Research Council— CNR-Targeted Project on Aging—Grants 9400419PF40 and 95973PF40), and by AFORIGE (‘Associazione per la FOrmazione e la RIcerca in Geriatria’). FP, CC, and AMC were supported by a PhD grant in ‘Carcinogenesis, Aging, and Immunoregulation’ from the European Union. The authors wish to thank Ms Damiana Calamita, Ms Nicoletta Lobascio, Dr Giovanni Castellaneta, and Dr Amalia Terralavoro, Pfizer Inc., for skilful 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

,

–

F. Panza et al. / Experimental Gerontology 38 (2003)

Ma

achlan, D.R., Alberts, M.J., Hulette, C., Crain, B., Goldgaber, D., Roses, A.D.,

Association of apolipoprotein E allele e