Damage to DNA is especially important for aging. High DNA repair could contribute, in principle, to lower such damage in long-lived species. However, previous studies showed that repair of endogenous damage to nuclear DNA (base excision repair, BER) is negatively or not correlated with mammalian longevity. However, we hypothesize here that mitochondrial, instead of nuclear, BER is higher in long-lived than in short-lived mammals. We have thus measured activities and/or protein levels of various BER enzymes including DNA glycosylases, NTHL1 and NEIL2, and the APE endonuclease both in total and mitochondrial liver and heart fractions from up to eight mammalian species differing by 13-fold in longevity. Our results show, for the first time, a positive correlation between (mitochondrial) BER and mammalian longevity. This suggests that the low steady-state oxidative damage in mitochondrial DNA of long-lived species would be due to both their lower mitochondrial ROS generation and their higher mitochondrial BER. Long-lived mammals do not need to continuously maintain high nuclear BER levels because they release less mitROS to the cytosol. This can be the reason why they tend to show lower nuclear BER values. The higher mitochondrial BER of long-lived mammals contributes to their superior longevity, agrees with the updated version of the mitochondrial free radical theory of aging, and indicates the special relevance of mitochondria and mitROS for aging.
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Base excision repair
Endonuclease III homolog 1
Reactive oxygen species
Voltage-dependent anion-selective channel 1
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The authors acknowledge the veterinary staffs of the Madrid Norte and Segovia abattoirs for facilitating the access to the tissue samples from mammals of large body size. GB and RG conceived and designed the experiments; ML-T, IS-R, and AG collected the samples from the abattoirs; RG performed the experiments; GB and RG wrote the manuscript; GB, RG, ML-T, IS-R, and AG revised the manuscript.
This investigation was supported in part by a grant from the Spanish Ministry of Economy and Competitiveness (BFU2011-23888) and PR BIO MET 0155.
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Gredilla, R., Sánchez-Román, I., Gómez, A. et al. Mitochondrial base excision repair positively correlates with longevity in the liver and heart of mammals. GeroScience 42, 653–665 (2020). https://doi.org/10.1007/s11357-020-00158-4
- DNA repair
- AP endonuclease
- DNA glycosylases