more frequent among Japanese centenarians than among controls (Tanaka et al. 1998). Furthermore, the 5178C al- lele is more frequent among elderly hospital patients than among young ones suggesting that this allele predisposes subjects to late-onset diseases or that subjects having the 5178A allele remain healthier and live longer (Tanaka et → al. 1998). The 5178C A polymorphism defines hap- logroup D, which is one of the four major Asian hap- logroups (Torroni et al. 1993). Recent data on complete → mtDNA sequences indicate that the 3010G A polymor- phism is the only sequence variant that is common to hap- logroups D and J (Herrnstadt et al. 2002). However, this does not explain the associations detected among Japan- → ese and European centenarians, as 3010G A appears to have the opposite effects in these two populations. It is therefore obvious that sequence variation in the entire genome must be considered in order to account for the ef- fects of mtDNA haplogroups on longevity.

and mtDNA haplogroups D and J suggest either advanta- geous polymorphisms within these haplogroups or mildly deleterious polymorphisms within the remaining hap- logroups. In order to test the hypothesis that new poly- morphisms are part of an adaptive evolution, we calcu- lated the average substitution frequencies for the mtDNA haplogroups by using data on 192 complete mtDNA se- quences from Finns (Finnilä et al. 2001). A haplotype ly- ing between the African, Asian and European haplo- groups was taken to be the most recent common ancestor. Surprisingly, the average frequency of substitutions was higher in those haplogroups that were found more fre- quently among the Vitality 90+ subjects (Fig.1). The data therefore suggest that some substitutions can be advanta- geous, supporting the hypothesis of adaptive evolution.

We have found an association between certain mtDNA haplogroups or haplogroup clusters and longevity. Each of the mtDNA haplogroups is determined by a single an- cient polymorphism, even though they harbour a great number of other nucleotide variants. Polymorphisms in mtDNA may be mildly deleterious, causing a subtle de- crease in OXPHOS activity and an increase in the fre- quency of somatic mtDNA mutations. The differences in mtDNA haplogroup frequencies between the present Vi- tality 90+ group and the controls suggest either a contri- bution from mildly deleterious polymorphisms that shorten the life span in the younger age groups or from advantageous polymorphisms that lengthen the life span in the elderly. Our data appear to favour the presence of advantageous polymorphisms and support a role for mi-

Nucleotide changes in mtDNA, either non-synony- mous substitutions in structural genes or substitutions in the biogenesis genes, form a continuum from deleterious mutations that cause early onset diseases to mildly delete- rious polymorphisms that may predispose subjects to age- related degenerative diseases, to neutral variants, or even to polymorphisms that may be advantageous. The non- neutral evolution of mtDNA has been suggested by many authors (Watt and Dean 2000; Gerber et al. 2001) and an increased non-synonymous versus synonymous substitu- tion rate has been taken to suggest the presence of mildly deleterious variants (Rand and Kann 1998; Watt and Dean 2000), although originally it was thought to result from adaptive fixation of advantageous mutations (McDonald and Kreitman 1991). The association between longevity

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