Mitochondrial DNA Damage Patterns and Aging: Revising the Evidences for Humans and Mice

Nadiya Kazachkova

doi:10.14336/ad.2013.0400337

Abstract

A significant body of work, accumulated over the years, strongly suggests that damage in mitochondrial DNA (mtDNA) contributes to aging in humans. Contradictory results, however, are reported in the literature, with some studies failing to provide support to this hypothesis. With the purpose of further understanding the aging process, several models, among which mouse models, have been frequently used. Although important affinities are recognized between humans and mice, differences on what concerns physiological properties, disease pathogenesis as well as life-history exist between the two; the extent to which such differences limit the translation, from mice to humans, of insights on the association between mtDNA damage and aging remains to be established. In this paper we revise the studies that analyze the association between patterns of mtDNA damage and aging, investigating putative alterations in mtDNA copy number as well as accumulation of deletions and of point mutations. Reports from the literature do not allow the establishment of a clear association between mtDNA copy number and age, either in humans or in mice. Further analysis, using a wide spectrum of tissues and a high number of individuals would be necessary to elucidate this pattern. Likewise humans, mice demonstrated a clear pattern of age-dependent and tissue-specific accumulation of mtDNA deletions. Deletions increase with age, and the highest amount of deletions has been observed in brain tissues both in humans and mice. On the other hand, mtDNA point mutations accumulation has been clearly associated with age in humans, but not in mice. Although further studies, using the same methodologies and targeting a larger number of samples would be mandatory to draw definitive conclusions, the revision of the available data raises concerns on the ability of mouse models to mimic the mtDNA damage patterns of humans, a fact with implications not only for the study of the aging process, but also for investigations of other processes in which mtDNA dysfunction is a hallmark, such as neurodegeneration.

Highlights

Aging can be defined as a “progressive, generalized impairment of function, resulting in an increased vulnerability to environmental challenge and a growing risk of disease and death” [1]
Evidences accumulated over the years strongly suggest that damage in mitochondrial DNA (mtDNA) contribute to aging in humans
Despite the fact that mice have differences in physiological properties, disease pathogenesis as well as life history, when compared to humans, they share genomic similarities and have been extensively used as models of human aging, namely on what concerns the investigation of the association of aging with mtDNA alterations

Summary

Copy number

Studies performed to date in humans are not consensual, providing distinct insights concerning the relation between aging and mtDNA copy number. Comparing studies, which used the same methodology (RT-qPCR), opposite results are reported for mice: decrease of mtDNA copy number with age [33] and increase with age [34, 35] (Table 1B). To control for a possible effect of the tissue being analyzed, Masuyama et al [35] reported results for several tissues from mice (brain, heart, lung, kidney, liver, spleen, skeletal muscle and bone), at five different ages (2, 4, 8, 21.7 and 65.2 weeks); their results demonstrated that mtDNA content of the liver decreased with age, whereas it increased in the remaining analyzed tissues. Two studies [45, 55], demonstrated low levels of deletions in brain tissues, which can be due to the particular regions of the brain and to differences in the methodology used (as reported above for copy number). The earliest deletions were reported for blood and brain tissues (8 weeks) [33]

Point mutations

Findings

Discussion