Mitochondrial genetics of exceptional longevity in multigeneration matrilineages

Some heritable mitochondrial DNA (mtDNA) sequence variants may slow the rate of aging. The European mitochondrial haplogroup K has previously been reported to be increased in frequency in centenarians and nonagenarians relative to its frequency in younger individuals, by standard case/control study designs. To select for mitochondrial genomes likely to carry beneficial genetic variants, we screened a large genealogical database (the Utah Population Database, UPDB) for mitochondrial lineages in which the frequency of survival past 90 years was significantly higher than in the general population, and also significantly higher than in close non-matrilineal relatives. We ranked 14,900 distinct matrilineages by the strength of their association with longevity. Full sequencing of the mtDNAs from a single individual from each of 53 matrilineages in the top longevity ranks and each of 374 control matrilineages from the general Utah population, followed by analyses of the mtDNA haplogroup frequencies, identified haplogroup K2 as the haplogroup most enriched in frequency by the longevity selection (Odds Ratio = 23.05). We then analyzed overall survival and cause-specific mortality in the several thousand individuals aged 40 years or older whose mtDNA genotypes could be imputed from the 374 fully sequenced control mtDNAs. In these control matrilineages Haplogroup K2 individuals (n=332) enjoyed a significantly lower all-cause mortality risk than the general population (HR=0.81), attributable in part to a significantly lower risk of dying from heart disease (HR=0.50), as well as lower (though not significantly lower) risks of dying from cancer (HR=0.72) and diabetes (HR=0.74). Furthermore, K2 was the only haplogroup in which mortality was reduced for all three of these common causes of death.