Journal of Aging Research The impact of mtDNA deletions on nuclear DNA has also been suggested as a potential determinant of aging in diﬀer- ent organisms. Various studies have investigated whether the migration of mtDNA sequences from mitochondria to the nucleus could be relevant in the aging process. Gene transfer from organelles to the nucleus has occurred repeatedly during eukaryote evolution [82], but inappropriate de novo insertion of mtDNA fragments into human chromosomal DNA has been reported to result in rare severe genetic diseases [83]. In the ﬁlamentous ascomycete fungus Podospora anse- rina, mtDNA instability is thought to play an important role in the aging process [84] and rearrangements of the mtDNA are considered as a hallmark of senescence in wild- type strains. These rearrangements include the systematic ampliﬁcation of the ﬁrst intron of the cytochrome c oxidase subunit-I gene as circular DNA molecules [85]. Twenty years ago, integration of these mtDNA plasmids within the nuclear genome was reported to take place during senescence in P. anserina [86]. In the last few years the hypothesis of insertion of mitochondrial DNA fragments into nuclear DNA as aging factor [87] has been tested by diﬀerent research groups. It has been reported that migration of mitochondrial DNA fragments into the nucleus aﬀects the survival rates in Saccharomyces cerevisiae [88]. In S. cerevisiae mtDNA fragments are initially present as circular molecules in the nucleus, and the frequency of integration events into chromosomal DNA increases during lifespan [88]. Cheng and Ivessa have reported that in S. cerevisiae mutants with a higher translocation rate of mtDNA fragments into the nucleus than in wild-type strains, chronological lifespan is reduced, while in mutants showing a reduced translocation rate of mtDNA fragments in the nucleus, the chronological lifespan is extended. Moreover, Caro et al. [89] have reported that mitochondrial DNA sequences into nuclear DNA accu- mulate with aging in rat liver and brain. Furthermore, the integration of the mitochondrial sequences seems to occur at speciﬁc sites of the chromosomes instead of randomly. Taken together, it appears likely that mtBER has an important role in the aging process due to its role avoiding mtDNA mutations. Caloric restriction (CR) is a well-known experimental manipulation that reduces the accumulation rate of mtDNA mutations [90, 91] and increases maximum life span in several species [92]. Various investigations have studied the role of DNA repair mechanisms on the beneﬁcial eﬀects of CR. Caloric restriction has been reported to promote genomic stability, at least in part, by a general enhancement of nuclear DNA repair mechanisms [93]. However, although total [94] and nuclear [95, 96] BER capacity in diﬀerent rat brain regions and tissues have been shown to be increased in CR animals when compared to ad libitum fed animals [94], investigation of the BER activities in the mitochondrial compartments has shown that mtBER capacity did not change in liver and even decreased in the brain and kidney of caloric restricted rats. [96]. The lower mtBER capacity observed in restricted rats would be in agreement with the fact that mitochondria from caloric restricted rodents have been shown to generate ROS and accumulate oxidative damage to mtDNA at lower rates than 5 ad libitum fed animals [92]. Hence, when the generation of mitochondrial ROS and the levels of mtDNA damage are signiﬁcantly reduced, it may be possible for the organism to invest less energy in mtDNA repair capacity without negative consequences. On the other hand, diﬀerent studies have reported that deﬁciencies and changes in mitochondrial BER ﬁdelity occur during aging, particularly in postmitotic tissues. In verte- brates, the most important postmitotic tissue is probably the brain, due to its main role in homeostasis of the organism. Mitochondrial BER capacity has been described to be organ- speciﬁc, with the brain being one of the tissues with the lowest capacity [97]. Various studies have reported an age- related decline in DNA glycosylase activities brain cortical mitochondria in rats [98] and mice [45, 99], suggesting that mtBER may play a critical role in the maintenance of the central nervous system during aging [100]. In addition, important diﬀerences in mtBER have been observed among various brain regions during aging [45]. The cortical region and the cerebellum have been described to accumulate less mtDNA lesions with aging and to be more resistant to oxidative stress conditions [101]. Interestingly, those regions showed higher BER capacity than hippocampus, which has been described to be a much more vulnerable region in the brain [101, 102]. A recent investigations has reported that the age-related decline in brain mtBER occurs speciﬁcally at the synapses [103], stressing the relevance of the central nervous system heterogeneity in these processes. Moreover, deﬁciencies in mtBER in skeletal muscles during aging have been suggested to contribute to age-related sarcopenia [104]. Finally, poten- tial age-related changes in mtBER have been investigated in other aging models such as P. anserina as well; again, aging was associated with a decrease in mitochondrial BER [7], probably contributing to the observed mtDNA instability in the aged fungi [105]. In conclusion, several investigation support that age- related mtBER impairment and increased mtDNA instability contribute to aging. Further investigations are required to clarify the precise mechanisms and whether other DNA repair mechanisms mitochondrial and/or nuclear are also involved in the aging process. Moreover, better knowledge of how mitochondrial DNA repair mechanisms function will help to ﬁnd strategies to potentially retard mtDNA mutation generation and hence cellular dysfunction observed during aging. References [1] V. A. Bohr, “DNA damage and its processing. Relation to human disease,” Journal of Inherited Metabolic Disease, vol. 25, no. 3, pp. 215–222, 2002. [2] D. M. Wilson III, V. A. Bohr, and P. J. McKinnon, “DNA dam- age, DNA repair, ageing and age-related disease,” Mechanisms of Ageing and Development, vol. 129, no. 7-8, pp. 349–352, 2008. [3] V. A. Bohr, “Rising from the RecQ-age: the role of human RecQ helicases in genome maintenance,” Trends in Biochem- ical Sciences, vol. 33, no. 12, pp. 609–620, 2008.