Mitochondrial DNA Haplogroup D4a Is a Marker for Extreme Longevity in Japan

Abstract

We report results from the analysis of complete mitochondrial DNA (mtDNA) sequences from 112 Japanese semi-supercentenarians (aged above 105 years) combined with previously published data from 96 patients in each of three non-disease phenotypes: centenarians (99–105 years of age), healthy non-obese males, obese young males and four disease phenotypes, diabetics with and without angiopathy, and Alzheimer's and Parkinson's disease patients. We analyze the correlation between mitochondrial polymorphisms and the longevity phenotype using two different methods. We first use an exhaustive algorithm to identify all maximal patterns of polymorphisms shared by at least five individuals and define a significance score for enrichment of the patterns in each phenotype relative to healthy normals. Our study confirms the correlations observed in a previous study showing enrichment of a hierarchy of haplogroups in the D clade for longevity. For the extreme longevity phenotype we see a single statistically significant signal: a progressive enrichment of certain “beneficial” patterns in centenarians and semi-supercentenarians in the D4a haplogroup. We then use Principal Component Spectral Analysis of the SNP-SNP Covariance Matrix to compare the measured eigenvalues to a Null distribution of eigenvalues on Gaussian datasets to determine whether the correlations in the data (due to longevity) arises from some property of the mutations themselves or whether they are due to population structure. The conclusion is that the correlations are entirely due to population structure (phylogenetic tree). We find no signal for a functional mtDNA SNP correlated with longevity. The fact that the correlations are from the population structure suggests that hitch-hiking on autosomal events is a possible explanation for the observed correlations.

The mitochondrial‐derived peptide MOTS‐c: a player in exceptional longevity?

“…reporting no association between mtDNA haplogroups and EL (Pinos et al ., 2012) but Dominguez‐Garrido and co‐workers finding that the Caucasian haplogroup J (which would be associated with lower mtDNA damage) might confer a higher chance to attain high longevity (85+years) compared with other haplogroups in Northern Spaniards (Domínguez‐Garrido et al ., 2009). On the other hand, although mtDNA haplogroups D4b2b, D4a, and D5 are not associated with type 2 diabetes (Fuku et al ., 2007), they are linked with EL in Japanese population (Alexe et al ., 2007; Bilal et al ., 2008). We also showed that the mtDNA m.1382A>C polymorphism, which is specific for the ancestor haplogroup D4b2, is associated with EL in the Japanese population (Alexe et al ., 2007).…”

Mitochondrial Haplogroups A and M7a Confer a Genetic Risk for Coronary Atherosclerosis in the Japanese Elderly: An Autopsy Study of 1,536 Patients

“…We previously showed that haplogroup D4a is a marker of extreme longevity in Japan 9,10) . The present study, however, produced an apparently opposite result, with haplogroup D4a appearing to be a risk factor for myocardial infarction in men.…”

“…We previously reported significant associations between specific mitochondrial haplogroups and cardiovascular and metabolic diseases as well as longevity among the Japanese 9,10) : haplogroup A was a risk factor for atherothrombotic cerebral infarction 7)…”

“…We previously reported significant associations between specific mitochondrial haplogroups and myocardial infarction 6) , atherosclerotic cerebral infarction 7) , metabolic syndrome 8) and longevity among the Japanese 9,10) , and type 2 diabetes among both Japanese and the Koreans 11) . A recent study also indicated significant associations between haplogroup T and coronary artery disease and diabetic retinopathy in Middle European Caucasians 12) .…”

Relationship between mitochondrial haplogroup and psychophysiological responses during cold exposure in a Japanese population

“…There have been many earlier reports of a relation between haplogroup and physiological function. Examples include haplogroup J in Europe, which is associated with small maximum oxygen consumption (Marcuello et al, 2009), and haplogroup D in Japan, which tends to be associated with longevity (Tanaka et al, 1998;Bilal et al, 2008). Another example is that there are differences between groups in terms of the risk of acquiring diabetes mellitus or lifestyle-related diseases Tanaka et al, 2007).…”