Some complement components are encoded by genes related to human leukocyte antigen (HLA). The HLA complex represents the system of immunity which is better defined at the genetic level, and there are data showing different distributions of certain HLA alleles in aged cohorts, as compared to young healthy controls (7-10). However, it is not yet known whether a clear-cut relation exists between HLA haplotypes and longevity and this raises the need for further studies on different HLA genes included in extended haplotypes with classical class I and IT antigens (11). Class III genes encode non-HLA-related products and also some of the complement components (C4, C2, and BF) inIn young subjects (n=224, age 13, frequency .03%), the widespread longevity in developed countries has rendered it possible to study healthy centenarians (27,28). Despite the identification of genetic units for certain human diseases (35), the great majority of individuals carrying such alleles are healthy. Even in diseased cohorts, the linkage of these alleles with certain HLA class I and II phenotypes makes it impossible to identify with certainty the genetic elements responsible for the disease. The partial defect of C4, a complement component of the classical pathway, which is potentially capable of damaging self-tissues when locally activated by immune complexes, is known to be fully compatible with good health. Finally, the distribution of class III alleles varies widely according to ethnic background; hence, inferences on their relationship to pathology have to be considered within this framework. Moreover, major histocompatibility complex (MHC) allele and haplotype frequencies differ markedly even within different regions of the same country (36). Any demographic change in recent times, like migration into or within a country or differential reproduction rates within ethnic subsets, rather than differences in fitness, could be responsible for observed different distributions. To partially overcome such confounding effects, our studied cohorts were recruited with contributions from Northern, Central, and Southern Italy; hence they represent the Italian population as a whole. To our knowledge, this is the first study of the complement system in centenarians and aged people. Our main findings are that the CH50 and AP50 complement hemolytic activity as well as the C3 and C4 serum concentrations are well preserved in both centenarians and elderly persons. Similar findings have already been reported when other aspects of nonspecific immunity have been examined in healthy elderly persons (6,29). The increase in CH50 and AP50 activities, previously reported in elderly persons (30), can be attributed to different criteria in the selection of the tested individuals. In our study, the centenarians and the elderly subjects were carefully selected for their healthy status, although the Senieur protocol should be revisited to be adapted to centenarians (6), and the controls were healthy blood donors.

The environment, including lifestyle, diet, and climate, influences longevity and the quality of life, but genetic factors also seem to play a role because lifespan is species-specific (31). Mice of different inbred strains show different longevity when reared in identical laboratory conditions (32). In humans, longevity has been shown to have often familial distribution, and the occurrence of concordance in premature death between adoptees and their biological parents also points towards genetic influences (7,33). The immune system is an important survival factor because it protects against foreign intruders, and it is one of the factors that contribute to efficiently controlling the selective pressures that are bringing human longevity to a higher limit. The immune system also exerts an influence on longevity per se and on the quality of life of elderly persons. This is less obvious, but it can be easily inferred because components of the immune system are finely regulated by genetic factors. Some of the pathological abnormalities more frequently observed in older age groups suggest that the immune system may be involved in their pathogenesis.

In conclusion, extreme longevity may not be a privilege of a few individuals endowed with exceptional genetic prerogatives but rather a potential attribute of the normal human genome with a certain tolerance for some variations not directly responsible for overt pathology. This study was supported by grants from the Ministero Universita Ricerca Scientifica e Tecnologica (40% nationally divided and 60% local) and by the Consiglio Nazionale Ricerca (grant 95.4383.04). We thank Prof. F.Tedesco for reviewing the manuscript and Prof. Maria Brai for statistical analysis.