In our opinion, the major findings concern the LDL- C and Lp(a) concentrations.

The mean concentration of LDL-C in centenarians is low, very close to that considered as the optimal cut-off level in CAD secondary prevention, 100 mg:dl [38]. This probably makes it one of the major factors which confer protection against this disease in such individu- als, thus representing a possible selective feature for longevity. The concentration of apo B is almost the

* Lp(a) values expressed as medians.

INDIVIDUALS (%)2Soayoa°oaoaowoSonDSo>o P<0.005No. 13(+13)HAPLOTYPES@CentenariansWAdults  

Fig. 2. Frequencies of the ((cid:27)13:(cid:27)13) and ((cid:27)14:(cid:27)14) genotypes in the centenarians and adults having Lp(a) concentration \20 Number of individuals is shown above the bar for each genotype.

thrombotic mechanisms in very old age, rather appear- ing as a positive survival factor. This hypothesis is supported by another paradoxical feature, the apparent hypercoagulability of centenarians, who surprisingly do not undergo thrombosis [41]. The above unexpected observation on Lp(a) in centenarians motivated our interest in the apo(a) isoforms. The preliminary results indicate that S2 and S3 are the most frequent isoforms in centenarians with almost equal frequencies, which are similar to those reported for Caucasian populations [7,28]. Both isoforms have high incidence in centenari- ans with higher Lp(a) values and ((cid:27)13) genotype. The association of the small S2 isoform with the high Lp(a) concentration is in agreement with the general observa- tion that apo(a) size and Lp(a) concentration are in- versely related [28], whereas the association of the larger S3 isoform with the high Lp(a) concentration is quite unusual and appears to be another peculiar fea- ture of centenarians. A more detailed analysis is now in progress to elucidate this point. Data from other au- thors report an inverse relationship between Lp(a) con- centration and age [42], or even the absence of association between Lp(a) level, apo(a) isoforms, and longevity [43]. Such discrepancies could, in our opinion, derive from differences in the sex ratio and age range of the groups observed. Thus, any new investigation in this field is worthwhile.

same in adults and centenarians and the higher B:L ratio in the latter is due to their LDL-C lower concen- tration. Our data could suggest the presence of smaller and denser LDL particles in centenarians, compared with adults. However, no final conclusion can be reached to confirm such a feature, usually associated to a lipoprotein atherogenic phenotype [39], as direct mea- surements of the LDLs diameter are not yet available.

The Lp(a) concentration is unexpectedly high in cen- tenarians. This reveals to be essentially sex-independent and can be considered mostly unaffected by other fac- tors such as drugs, smoking, alcohol, etc. in consider- ation of the clinical and behavioural features of these subjects, and according to the others’ report [27]. The Lp(a) level increasing influence of genetic factors such o as the apo E 4 allele [40] can be also excluded in our centenarian group where this allele has been found to be rare (0.3 vs. 0.8 in our adults), and totally absent as the homozygous genotype (unpublished). In many cen- tenarians the Lp(a) concentration exceeds the threshold of risk of CAD and CVD. This increased value, in the absence of chronic or acute-phase diseases, can derive from a general remoulding of the plasma parameters with aging or is genetically determined by apo(a). Thus, the data on Lp(a) in centenarians draws an unusual pattern, since a so-called atherogenic marker does not preclude longevity. As already proposed for other genes [5], the hypothesis can be put forward that the risk conferred by the high concentration of Lp(a) in young people is offset by some unknown long-term protective effect. Although Lp(a) is supposed to be associated to atherothrombotic effects, it may be no longer related to

Then, the potential impact of the apo A-IV polymor- phism on the lipid and lipoprotein plasma concentra- tions was analyzed. In adults, the ((cid:27):(cid:27)) homozygotes have LDL-C and apo B concentrations lower than the ((cid:27):(cid:28)) heterozygotes, in apparent contrast with the

  Lp(a) 0-25@Lp(a) 26-50EI Lp(a) 51-75BLp(a) 76-100 YSaWNN 31STIVISOFORMS

Fig. 3. Lp(a) isoforms in centenarians divided into groups with respect to the Lp(a) plasma concentrations expressed as mg:dl.