1 Department of Biomedicine - Forskning og uddannelse, Øst, Department of Biomedicine, Health, Aarhus University2 Department of Engineering - Molecular Engineering, Department of Engineering, Science and Technology, Aarhus University3 BioPhysics and Biocomplexity and Department of Experimental Pathology, C.I. G. Interdepartmental Centre L. Galvani for Integrated Studies on Bioinformatics, University of Bologna, Bologna, 40126, Italy.4 unknown5 Max-Planck Odense Center6 Department of Biomedicine - Forskning og uddannelse, Øst, Department of Biomedicine, Health, Aarhus University7 Department of Engineering - Molecular Engineering, Department of Engineering, Science and Technology, Aarhus University
To re-examine the correlation between mtDNA variability and longevity, we examined mtDNAs from samples obtained from over 2200 ultranonagenarians (and an equal number of controls) collected within the framework of the GEHA EU project. The samples were categorized by high-resolution classification, while about 1300 mtDNA molecules (650 ultranonagenarians and an equal number of controls) were completely sequenced. Sequences, unlike standard haplogroup analysis, made possible to evaluate for the first time the cumulative effects of specific, concomitant mtDNA mutations, including those that per se have a low, or very low, impact. In particular, the analysis of the mutations occurring in different OXPHOS complex showed a complex scenario with a different mutation burden in 90+ subjects with respect to controls. These findings suggested that mutations in subunits of the OXPHOS complex I had a beneficial effect on longevity, while the simultaneous presence of mutations in complex I and III (which also occurs in J subhaplogroups involved in LHON) and in complex I and V seemed to be detrimental, likely explaining previous contradictory results. On the whole, our study, which goes beyond haplogroup analysis, suggests that mitochondrial DNA variation does affect human longevity, but its effect is heavily influenced by the interaction between mutations concomitantly occurring on different mtDNA genes.
Aging Cell, 2014, Vol 13, Issue 3, p. 401-7
genetics of longevity; longevity; mitochondrial DNA; mtDNA sequencing; oxidative phosphorylation; Genetics of longevity; Longevity; Mitochondrial DNA; Oxidative Phosphorylation