Evidence for the Importance of Mitochondrial Function in Rat Longevity

There is a lot of evidence to indicate the great importance of mitochondria, the power plants of the cell, in aging and longevity. Mitochondrial composition and resistance to oxidative damage correlates well with the varied life spans of different mammalian species, for example. Many measures of mitochondrial activity and function correlate with natural variations in longevity within a species, such as the balance between ongoing mitochondrial fission and fusion examined in the paper here. Taken together, these are signposts that should lead us to prioritize work on the SENS approach to making mitochondria resistant to damage and dysfunction. Mitochondria have their own DNA, separate from that in the cell nucleus, and it can become damaged in ways that produce spreading cellular malfunctions and consequent oxidative damage to proteins and tissues throughout the body. Using gene therapies to make backup copies of the vital parts of this DNA in the cell nucleus will prevent this type of age-related damage from causing harm: even if these copied genes are deleted from mitochondria, the relevant protein will still be generated in the nucleus and put to work.

Extremely interesting for aging research are those individuals able to reach older ages still with functions similar to those of younger counterparts. We examined liver samples from ad libitum-fed old (28-month-old, AL-28) and ad libitum-fed very old (32-month-old, AL-32) rats for a number of markers, relevant for mitochondrial functionality and mitochondrial DNA (mtDNA) content. As for the mtDNA content and the protein amounts of the citrate synthase and the antioxidant peroxiredoxin III there were no significant changes in the AL-32 animals. No significant longevity-related change was found for TFAM amount, but a 50% reduction in the amount of the Lon protease, responsible for turnover of TFAM inside mitochondria, characterized the AL-32 rats. No longevity-related change was observed also for the amounts of the mtDNA repair enzymes OGG1 and APE1, whereas the intra-mitochondrial amount of the cytochrome c protein showed a 50% increase in the AL-32 rats, indicating a likely reduced initiation of the intrinsic apoptotic pathway.

Totally unexpected was the doubling of two proteins, very relevant for mitochondrial dynamics, namely MFN2 and DRP1, in the AL-32 rats. This prompted us to the calculation of all individual mitochondrial fusion indexes that grouped together in the AL-32 rats, while in the AL-28 animals were very different. We found a strong positive correlation between the fusion indexes and the respective mtDNA contents in two AL-28 and four AL-32 rats. This supports the idea that the limited prevalence of fusion above a still active mitochondrion fission should have ensured a functional mitochondrial network and should have led to a quite narrow range of high mtDNA contents, likely the best-suitable for extended longevity. Our findings strongly suggest that, among the multiple causes leading to the longevity of the AL-32 rats, the maintenance of an adult-like balance of mitochondrial dynamics seems to be very relevant for the regulation of mtDNA content and functionality.

Link: http://dx.doi.org/10.1016/j.exger.2016.09.010


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