The potential impact of the apo A-IV polymorphism on lipid and lipoprotein plasma concentrations was analyzed.Homozygotes with the (1:1) allele have lower LDL-C and apo B concentrations than the (1:2) heterozygotes, which differs from the observation that the (1:2) allele reduces the levels of these parameters [16]. On the other hand, homozygotes with the (1:1) allele exhibit higher TG and apo B values than the (1:2) heterozygotes, consistent with other studies [18,19]. Our findings support the modulating function of apo A-IV alleles on plasma lipoproteins in adults. However, discrepancies with other reports could be due to variations in sex ratio, age range, and diet responsiveness of different populations studied. In centenarians, although these associations presumably confer an advantage, they are not statistically significant, probably due to an attenuation of the allele-modulating effect with aging. For example, the HinfI polymorphism is significantly associated with Lp(a) concentration in centenarians, where homozygotes with ((cid:27):(cid:27)) have a higher value than heterozygotes with ((cid:27):(cid:28)). This is consistent with the high incidence of ((cid:27):(cid:27)) genotype in this group. VNTR does not appear to be significantly related to lipoprotein parameters. However, some gradient concentrations (i.e. LDL-C and TG) can be observed. In particular, an association between (3:3) and ((cid:27)13) genotypes and increased Lp(a) medians can be seen in centenarians, where these genotypes are most frequent. According to the proposed role of apo A-IV [13], modulation of LPL activity could affect LDL-C levels. Modulation of reverse cholesterol transport and LCAT activity could affect HDL-C levels. Changes in either amino acid 347 or 360 of the protein sequence and deduced structure [11,12] could modify the domain where they are located. Allele variants of these loci could act on these mechanisms and influence the physiological functions of the molecule, presumably with a different impact on each lipoprotein class. For example, we found an inverse relationship between LDL-C and apo B with the two loci in adults and centenarians, leading to balanced lipoprotein levels. VNTR, located in the non-coding apo A-IV region, probably has no direct effect when considered alone. The higher Lp(a) concentrations observed in centenarians are possibly due to the great association with the ((cid:27)) variant at the HinfI locus, which is significantly associated with this parameter. It is difficult at present to explain a functional interaction between two apparently unrelated genes such as apo A-IV and apo(a). However, each of these genes could be involved in the pathophysiology of the cardiovascular system. In conclusion, our analysis of genetic and biochemical parameters has revealed new longevity-associated features. The high frequency of HinfI((cid:27):(cid:27)) polymorphism of apo A-IV, low levels of LDL-C, and especially high Lp(a) concentration found in centenarians add further elements to the biological longevity pattern. We suggest that a combination of genetic factors such as apo A-IV alleles with their possible impact on circulating lipoproteins, Lp(a) concentration and perhaps apo(a) isoforms together with non-genetic factors characterize some individuals in a population conferring a biological advantage that selects them for long and healthy survival. Centenarians represent a unique model to inspect on the basis of longevity. The availability of another homogeneous group for study has offered our group an important opportunity to gain better insight into biological processes of aging. We thank Mr Vito Cataldo for the reproductions. This work was supported by CNR-Targeted Aging Project grants No. 95.982.PF40, 95.973.PF40, 95.988.PF40 code no. 981740 and by MURST grants. We also gratefully acknowledge the financial support of Telethon-Italy (G. Pepe-grant No. 951).list of references on genetics and lipoproteins in relation to longevity and cardiovascular disease is provided below: