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

Mitochondrial DNA polymorphisms associated with longevity in a Finnish population

Received: 1 July 2002 / Accepted: 29 August 2002 / Published online: 17 October 2002 © Springer-Verlag 2002

Abstract Sequence variation in mitochondrial DNA (mtDNA) may cause slight differences both in the func- tioning of the respiratory chain and in free radical produc- tion, and an association between certain mtDNA hap- logroups and longevity has been suggested. In order to de- termine further the role of mtDNA in longevity, we stud- ied the frequencies of mtDNA haplogroups and hap- logroup clusters among elderly subjects and controls in a Finnish population. Samples were obtained from 225 per- sons aged 90–91 years (Vitality 90+) and from 400 mid- dle-aged controls and 257 infants. MtDNA haplogroups were determined by restriction fragment length polymor- phism. The haplogroup frequencies of the Vitality 90+ group differed from both those of the middle-aged con- trols (P=0.01) and the infants (P=0.00005), haplogroup H being less frequent than among the middle-aged subjects (P=0.001) and infants (P=0.00001), whereas haplogroups

U and J were more frequent. Haplogroup clusters also dif- fered between Vitality 90+ and both the middle-aged sub- jects (P=0.002) and infants (P=0.00001), the frequency of haplogroup cluster HV being lower in the former and that of UK and WIX being higher. These data suggest an asso- ciation between certain mtDNA haplogroups or hap- logroup clusters and longevity. Furthermore, our data ap- pear to favour the presence of advantageous polymor- phisms and support a role for mitochondria and mtDNA in the degenerative processes involved in ageing.

Introduction

Longevity shows maternal inheritance, suggesting a role for mitochondrial DNA (mtDNA) in the process of ageing (Abbott et al. 1978; Brand et al. 1991; Sont and Vanden- broucke 1993; Korpelainen 1999). MtDNA is a mater- nally inherited 16,568-bp haploid genome that encodes 13 subunits of the respiratory chain complexes. Its mutation rate is 10 times faster than that of the nuclear genome and, consequently, the mean pairwise difference between pop- ulations is approximately 50 (Ingman et al. 2000). This high mutation rate is attributable partly to the lack of an effective DNA repair mechanism and partly to the con- stant exposure of mtDNA to oxygen free radicals. Mito- chondrial oxidative phosphorylation (OXPHOS) is a ma- jor contributor to oxygen free radicals, further supporting the role of mitochondria and mitochondrial DNA in age- ing (Wei et al. 1998; De Benedictis et al. 2000; Golden and Melov 2001).

A.-K. Niemi · K. Majamaa (✉ ) Department of Neurology, University of Oulu, P.O. Box

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Oulu, Finland e-mail: kari.majamaa@oulu.fi, Tel.: +

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A.-K. Niemi · K. Majamaa Department of Medical Biochemistry and Molecular Biology, University of Oulu, P.O. Box 5000, 90014 Oulu, Finland

Laboratory of Gerontology, Tampere School of Public Health, University of Tampere, Tampere, Finland

Polymorphisms in mtDNA may cause subtle differ- ences in the encoded proteins and, thus, subtle changes in OXPHOS activity and free radical production. This pre- disposes an individual or people sharing the same mtDNA genotype to an earlier onset of degenerative cellular processes, such as the accumulation of somatic mtDNA mutations and a decline in OXPHOS capacity. Alterna- tively, some of the polymorphisms could be beneficial. Common polymorphisms in mtDNA determine classes of related genotypes, haplogroups, that can be detected by

Department of Microbiology and Immunology, University of Tampere Medical School and Tampere University Hospital, Tampere, Finland

Department of Forensic Medicine, University of Tampere Medical School and Centre for Laboratory Medicine, Tampere University Hospital, Tampere, Finland

restriction fragment length polymorphism (RFLP) analy- sis. The frequencies of mtDNA haplogroups vary between ethnic groups (Torroni et al. 1996; Richards et al. 1998; Wallace et al. 1999), the European population being al- most exclusively distributed among the nine haplogroups designated as H, I, J, K, T, U, V, W and X, whereas hap- logroups A, B, C, D and E are specific to Asian popula- tions and haplogroups L1, L2 and L3 to African popula- tions (Wallace et al. 1999).

siblings among them was low. Information from hospital records of the Vitality 90+ subjects was used to evaluate the role of the mtDNA haplogroups as risk factors for diseases, such as coronary artery disease, heart failure, peripheral artery arteriosclerosis, stroke, heart infarction, pulmonary embolism, cancer, diabetes, de- mentia and Parkinson’s disease.

Methods

Total DNA was isolated from blood by using a QIAamp Blood Kit (Qiagen, Hilden, Germany) or, in the case of the infants, by using a non-enzymatic salt precipitation method (Lahiri and Nurnberger 1991). MtDNA haplogroups were determined by restriction frag- ment analysis (Finnilä et al. 2001). The 3010G→A polymorphism defining the haplogroup subclusters H1 and J1 was analysed by conformation-sensitive gel electrophoresis, in which a fragment spanning nucleotides 2866 and 3263 was amplified and subjected to analysis as described earlier (Finnilä et al. 2000).

An association has been reported between certain mtDNA haplogroups and longevity. The frequency of haplogroup J is significantly higher among male centenar- ians in northern Italy (De Benedictis et al. 1999) and se- quencing of the entire mtDNA of 11 Japanese centenari- ans has revealed polymorphisms 3010G→ A, 5178C→ A → and 8414C T to be more frequent than in controls → (Tanaka et al. 1998). Furthermore, 9055G A has been found to be more frequent among French (Ivanova et al. 1998) and Irish centenarians (Ross et al. 2001) than in controls.