Prof. Masashi Tanaka

Director and Leader of the Core Research Team; Department of Genomics for Longevity and Health, Tokyo Metropolitan Institute of Gerontology (TMIG), Tokyo, Japan.

BIOGRAPHY

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Mitochondrial Genomics for Longevity and Health

Polymorphisms in the human mitochondrial genome have been used for elucidation of the phylogenetic relationships among various ethnic groups. Because analysis by mitochondrial genetics has detected pathogenic mutations causing mitochondrial encephalomyopathy or cardiomyopathy, most of the mitochondrial single nucleotide polymorphisms (mtSNPs) found in control subjects have been regarded as merely normal variants. We cannot exclude, however, the possibility that the mitochondrial functional differences among individuals are ascribable at least in part to the mtSNPs of each individual. Human life span in ancient history was much shorter than that at the present time. Therefore it is reasonable to speculate that certain mtSNPs that predispose one toward susceptibility to adult- or elderly-onset diseases, such as Parkinson’s disease and Alzheimer’s disease, have never been a target for natural selection in the past. Similarly, thrifty mtSNPs that had been advantageous for survival under severe famine or cold climate conditions might turn out to be related to satiation-related diseases, such as diabetes mellitus and obesity. To examine these hypotheses, we have constructed a mtSNP database by sequencing the entire mitochondrial genomes from 672 subjects: 96 in each of 7 groups, i.e., centenarians, young obese or non-obese subjects, diabetic patients with or without major vascular involvement, patients with Parkinson’s disease, and those with Alzheimer’s disease. A mtSNP, 199T>C in the major noncoding region, was detected in 8 of the 96 patients with Alzheimer's disease, whereas this substitution was detected in 20 of the 96 centenarians. This 199T>C transition associated with longevity was detected in various haplogroups. Another mtSNP, 13651A>G (ND5:Thr439Ala), was not detected in 96 patients with Alzheimer's disease, whereas this substitution was detected in 5 of the 96 centenarians. This 13651A>G transition represents haplogroup D4a. Two synonymous mtSNPs, 5147G>A and 5417G>A in the ND2 gene, were detected in 9-10 of the 96 patients with Alzheimer's disease, whereas these substitutions were detected in 2 of the 96 centenarians. The 5147G>A and 5417G>A transitions predisposing to Alzheimer's disease represent haplogroup N9a. These results suggest that these distinct mtSNPs contribute to susceptibility to Alzheimer's disease. Present data point out necessity of large-scale case control studies and functional analysis of mitochondria.