Abstract
Tissue specific somatic mutations occurring in the mtDNA control region have been proposed to provide a survival advantage. Data on twins and on relatives of long-lived subjects suggested that the occurrence/accumulation of these mutations may be genetically influenced. To further investigate control region somatic heteroplasmy in the elderly, we analyzed the segment surrounding the nt 150 position (previously reported as specific of Leukocytes) in various types of leukocytes obtained from 195 ultra-nonagenarians sib-pairs of Italian or Finnish origin collected in the frame of the GEHA Project. We found a significant correlation of the mtDNA control region heteroplasmy between sibs, confirming a genetic influence on this phenomenon. Furthermore, many subjects showed heteroplasmy due to mutations different from the C150T transition. In these cases heteroplasmy was correlated within sibpairs in Finnish and northern Italian samples, but not in southern Italians. This suggested that the genetic contribution to control region mutations may be population specific. Finally, we observed a possible correlation between heteroplasmy and Hand Grip strength, one of the best markers of physical performance and of mortality risk in the elderly. Our study provides new evidence on the relevance of mtDNA somatic mutations in aging and longevity and confirms that the occurrence of specific point mutations in the mtDNA control region may represent a strategy for the age-related remodelling of organismal functions.
Highlights
It has been recognized for a long time that age-related random damages to mtDNA and the consequent decrease in the respiratory chain capacity are among the major contributors to the aging process [1,2,3,4]
MtDNA Control Region (CR) heteroplasmy Fig.1 shows the distribution of heteroplasmy levels in Granulocytes (GR) and Lymphomonocytes (LY) from subjects collected in Bologna and Calabria
The strong correlation of the total CR heteroplasmy and the C150T heteroplasmy between sibs seems to confirm that CR heteroplasmy is genetically influenced
Summary
It has been recognized for a long time that age-related random damages to mtDNA and the consequent decrease in the respiratory chain capacity are among the major contributors to the aging process [1,2,3,4]. In the last decade different studies highlighted specific somatic mutations in the mtDNA Control Region (CR) which can reach high levels in aged individuals [7,8]. These mutations are tissue-specific and occur at mtDNA sites which are critical for replication or transcription, suggesting new important clues on the relevance of mtDNA heteroplasmic mutations in the aging process. Iwata et al [11], who analyzed the C150T mutation in leukocytes from centenarians and their offspring of an Ashkenazi Jew population, found a low incidence of the C150T mutation, but a rather high frequency of the T152C mutation They found that the heteroplasmic form of the T152C transition (presumably originated from somatic events) increases with age. On the other hand no correlation was observed between inherited mtDNA variability and mtDNA CR heteroplasmy [10]
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