In conclusion, our study provides new insights into the role of mtDNA variability in human aging and longevity. By comparing the mtDNA pool of healthy centenarians with that of younger people, we have identified specific haplogroups that may be associated with successful aging. These findings have important implications for the development of new strategies for promoting healthy aging and extending lifespan.In the geographic areas of northern Italy, effects caused by genetic drift could be excluded as the existence of a true positive association between inherited mtDNA variants and long life expectancy is therefore likely in males of this geographic area. As for the second question, consider that groups are categories defined on the basis of mutations shared among different individuals. Therefore, each haplogroup encompasses many genotypes, and its composition is defined by the frequency of the population (22). The different results obtained in northern and southern Italy are not unexpected if we consider that northern and southern Italian populations have different histories as well documented by both historical and genetic studies (23). In any case, longevity could be achieved through various strategies according to various pools and environments. The latter emphasizes the importance of having rapid cheap genetic markers, such as haplogroups, to study the role of mtDNA on longevity in various populations from various geographic areas. In this regard, it should be noted that the Mt5178A mutation in Japanese centenarians (12) is included in the haplogroup extremely frequent in Asia but absent in Europe (22). This finding raised two questions: 1) Why were these phenomena not observed in females? 2) Why were these phenomena not observed in southern Italy? As for the first question, different findings in males and females have already been observed in gene/longevity association studies (20, 21). This is not unexpected if we consider that longevity is a multifactorial trait where the phenotypic effect of a certain gene can differ between genders. These data show that at least in males from a well-defined geographic area, not only the haplogroup frequency distribution is different between centenarians and younger people but also a specific haplogroup (J) is significantly more frequent in individuals selected for longevity. We could speculate that the J haplogroup includes an mtDNA type (present in northern Italy only) carrying mutations that improve the starting OXPHOS levels, thus delaying age-related mitochondrial decline or lowering the frequency of age-related diseases, such as dementia, Parkinson's, and cancer, where reactive oxygen species and mitochondrial dysfunction may play a role (6). Indeed, the centenarians tested in our study (as well as the controls) were clinically healthy, had quite an active lifestyle, and had escaped the above-mentioned age-associated diseases. The finding that J accounts for only a small proportion of the centenarian sample is not in disagreement with a possible role played by mtDNA in longevity. Since longevity is a complex trait, a number of loci other than mtDNA, with epistatic and pleiotropic effects, are likely to be responsible for this phenotype (24). In conclusion, the data reported here confirm in a European population the mtDNA/longevity association observed in the Japanese (12). The implications of these results can be far-reaching, taking into account the important role of mitochondria in the aging process and in the pathogenesis of age-related diseases. Work was financed by Regione Calabria (Italy), Progetto Operativo Plurifondo 94/99; by Italian Ministry of University and Scientific Research (M.U.R.S.T. ex 40% and 60%); and by Italian Ministry of Health (grants to the Italian National Research Center on Aging). REFERENCES: Wallace, D. C. (1994) Mitochondrial genetics: a paradigm for aging and degenerative diseases? Science 256, 628–632; Cortopassi, G. A., Shibata, D., Soong, N. W., and Arnheim, N. (1992) A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging human tissues. Proc. Natl. Acad. Sci. USA 89, 7370–7374; Melov, S., Shoffner, J. M., Kaufman, A., and Wallace, D. C. (1995) Marked increase in the number and variety of mitochondrial DNA rearrangements in aging human skeletal muscle. Nucleic Acids Res. 23, 4122–4126; Kadenbach, B., Münch-er, C., Frank, V., Müller-Höcker, J., and Napiwotzki, J. (1995) Human aging is associated with stochastic somatic mutations of mitochondrial DNA. Mutat. Res. 338, 161–172; Larsson, N. G., and Clayton, D. A. (1995) Molecular genetic aspects of human mitochondrial disorders. Annu. Rev. Genet. 29, 151–178; Wallace, D. C. (1995) Mitochondrial DNA sequence variation in human evolution and disease. Proc. Natl. Acad. Sci. USA 92, 5975–5982; Brand, F.N., Kiely, D., Kannel,W.B., andI'm sorry, but there is no text enclosed in ``` ``` to be processed. Please provide the text so I can assist you.