authors: Anna-Kaisa Niemi, Antti Hervonen, Mikko Hurme, Pekka J. Karhunen, Marja Jylhä, Kari Majamaa

Title: Mitochondrial DNA polymorphisms associated with longevity in a Finnish population

Abstract:

The study aimed to determine the role of mitochondrial DNA (mtDNA) in longevity by analyzing mtDNA haplogroups and haplogroup clusters among elderly subjects and controls in a Finnish population. The results showed significant differences in haplogroup frequencies between Vitality 90+ cases and both middle-aged controls and infants. The frequency of haplogroup H was lower in the Vitality 90+ group than in the controls and infants, while haplogroups U and J were more frequent. Haplogroup clusters also differed between Vitality 90+ and both middle-aged subjects and infants, with the frequency of haplogroup cluster HV being lower in the former and that of UK and WIX being higher. These data suggest an association between certain mtDNA haplogroups or haplogroup clusters and longevity.

Introduction:

The study aimed to investigate the role of mtDNA in longevity, as it has been suggested that sequence variation in mtDNA may cause slight differences in the functioning of the respiratory chain and free radical production. As mtDNA is maternally inherited, it has been proposed that mtDNA plays a role in the process of aging. Polymorphisms in mtDNA may cause subtle differences in OXPHOS activity and free radical production, predisposing individuals or groups to an earlier onset of degenerative cellular processes involved in aging.

Methods:

Samples were obtained from 225 persons aged 90 or 91 years (Vitality 90+), 400 middle-aged controls, and 257 infants from a defined geographical region in Finland. MtDNA haplogroups were determined by restriction fragment length polymorphism. The frequency of mtDNA haplogroups was evaluated by the exact test of population differentiation or the 2 test or Fisher's exact test.

Results:

The haplogroup frequencies of the Vitality 90+ group differed significantly from those of both the middle-aged controls and infants. Haplogroup H was less frequent in the Vitality 90+ group than in the controls and infants, while haplogroups U and J were more frequent. Haplogroup clusters also differed between Vitality 90+ and both middle-aged subjects and infants, with the frequency of haplogroup cluster HV being lower in the former and that of UK and WIX being higher. These data suggest an association between certain mtDNA haplogroups or haplogroup clusters and longevity.

Conclusion:

The study suggests an association between certain mtDNA haplogroups or haplogroup clusters and longevity, supporting previous findings on the role of mtDNA in aging. The study also supports the presence of advantageous polymorphisms and a role for mitochondria and mtDNA in the degenerative processes involved in aging.Controls, whereas that of sub-cluster J2 was 4.4% in Vitality 90+ and 1.8% in the controls, suggesting that the higher frequency of haplogroup J in Vitality 90+ is attributable to an increase in subcluster J2.

Discussion:

We found significant differences in mtDNA haplogroup frequencies between the Vitality 90+ subjects and the controls. Haplogroup H was less frequent among the Vitality 90+ cases than among the middle-aged controls or the infants, whereas haplogroups J, U, and K were more frequent. The differences in haplogroup frequencies between the three age groups were similar to the age-related trend in haplogroup frequencies detected in a series of approximately 800 Italians (De Benedictis et al. 2000). Furthermore, we found that the frequencies of related haplogroups had similar tendencies to increase or decrease in most cases and, consequently, the haplogroup cluster HV was significantly lower among the Vitality 90+ subjects than among the controls, whereas those of clusters UK and TJ were higher. These data suggest an association between certain mtDNA haplogroups or haplogroup clusters and longevity.

Frequencies of mtDNA haplogroup clusters among Vitality 90+ cases and controls:

We then analyzed the frequencies of the clusters of phylogenetically related haplogroups HV, UK, TJ, and WIX. Again, the Vitality 90+ group and the controls differed (P=0.002; Table 2), the frequency of cluster HV being lower among the Vitality 90+ cases (P=0.001), whereas that of cluster UK was higher (P=0.014). The number of samples belonging to cluster WIX was almost twice as high in the Vitality 90+ group as in the controls (P=0.078).

The Vitality 90+ cases also differed from the infants in this respect (P=0.00001), their frequency of cluster HV being significantly lower (P=0.001), whereas those of clusters WIX (P=0.048) and UK (P=0.05) were higher, and that of cluster TJ significantly higher (P=0.004). The controls and the infants did not differ significantly from each other (Table 2).

The maternal lineage of the Vitality 90+ group and the two anonymous control groups was not known, introducing a possible confounding effect. However, the Finnish population is ethnically homogeneous, and immigration from other countries has been negligible (Korkiasaari and Söderling 1994). Migration within Finland remained at approximately 4% in the 20th century, increasing only to 5.5% between 1946-1950 (Koskinen et al. 1994). The settlement of Finns from southeastern Karelia after World War II has probably not affected the mtDNA gene pool, as there is no difference in haplogroup frequencies between the present Karelians and Finns (Simoni et al. 2000). Homogeneity among the three groups is further suggested by the observations that an mtDNA lineage introduced by earlier founders will make a larger contribution to the contemporary population than lineages introduced later (Heyer 1995). Therefore, we believe that the differences detected between Vitality 90+ and the two control groups represent true differences.

Association between mtDNA haplogroups and clinical phenotypes: