protective at very old age, despite its effect on serum LDL-C at middle-age and its association with CDL. These apparently contradictory results give us another “paradox of centenarians” (Forette, 1999) and confirm that genetic risk factors acting at middle-age can be present, and also over-represented, in the centenarians’ gene pool (Mannucci et al. 1997; Baggio et al. 1998; Pepe et al. 1998; Thillet et al. 1998; Rose et al. 2001). On the other hand, it has been suggested that choles- terol metabolism may differ between younger and older populations (Schatz et al. 2001), as revealed by longitu- dinal studies showing that, in very old people, a high serum total cholesterol concentration is associated with increased survival (Weverling-Rijnburger et al. 1997). In line with recently developed mathematical models (Yashin et al. 1997; Yashin et al. 2001), the above find- ings confirm that a genotype can be risky in middle-age but protective at very advanced age, and suggests that the effect of a mutation may depend on the age-related physiological scenario in which the mutation acts. Fur- thermore, since ageing could be viewed as a side-effect of adaptive events that are controlled by genes causing damage (Partridge & Gems, 2002a,b), allele P may be beneficial at very old age by repressing some causes of age-related damage.

Discussion

The most striking result of the present study is that, in males, the APOA1 allele P, which increases serum LDL-C at middle-age and is over-represented in CDL patients, tends to increase its frequency as the cohort selected for best survival emerges from the population (Table 1a). In fact, the frequency of the P allele is al- most the same in CDL patients (0.814 ± 0.047 standard error) as in the oldest healthy subjects (0.817 ± 0.038 standard error). It should be noted that the centenar- ians included in the study belong, as for health status, to the A and B categories defined by Franceschi et al. (2000), and represent therefore a group of people age-

As for the lack of association between the age of the population and APOC3 or APOA4 variability, the neg- ative results may depend on the lack of association be- tween these genes and longevity, or on the history of the population under study. In any case more markers

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Berlin: Springer Verlag. Franceschi, C., Motta, L., Valensin, S. and the Italian Multi- center Study on Centenarians. (

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Friedewald, W.T., Levy, R.I. & Fredrickson, D.S. (

) Es- timation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultra- centrifuge. Clin Chem

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Haase, A. & Stoffel, W. (

) The

-flanking region shared by the human apolipoprotein AI and CIII genes regulates   gene expression in cooperation with

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Hegele, R.A. (

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Ivanova, R., Fhenon, N., Lepage, V., Charron, D., Vicaut, E. & Schachter, F. (

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Genest, J. Jr. (

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Gerdes, L.U., Jeune, B., Ranberg, K.A., Nybo, H. & Vau- pel, J.W. (

) Estimation of apolipoprotein E genotype- specific relative mortality risks from the distribution of genotypes in centenarians and middle-aged men: apolipoprotein E gene is a “frailty gene,” not a “longevity gene.” Genet Epidemiol

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Jian-Gang, Z., Yong-Xing, M., Chuan-Fu, W., Pei-Fang, L., Song-Bai, Z., Nui-Fan, G., Guo-Yin, F. & Lin, H. (

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are needed in order to exclude an association between

From the present study two main conclusions can be drawn. Firstly, the APOA1 allele P, which increases serum LDL-C and is over-represented in CDL patients, is also over-represented in the oldest old people in fairly good health. Secondly, gene-sex interaction seems to be an important phenomenon in the genetic modulation of human lifespan, thus confirming that the effect of a gene on a multifactorial trait depends on the sex-specific physiological scenario in which the gene acts. This anal- ysis of the variability of the APOA1-APOC3-APOA4 gene cluster in a well defined population selected for healthy ageing reveals another paradox of centenarians and confirms the complexity of the human longevity phenotype.

Acknowledgements

Work supported by the Italian Ministry of Health (IRCCS 2000–2002, Marcatori genetici e biologici di invecchiamento nor- male e patologico ) and by the Italian Ministry of University and Scientific & Technological Research (COFIN 2000–2002, Genetic Determinants of Human Longevity ).

References