The mitochondrial contribution to longevity: a balance of mitochondrial dynamics and mtDNA content

Aging is a complex process involving structural and functional deterioration of biomolecules leading to the progressive decline of organism physiological fitness, increasing the vulnerability to death. Individuals able to reach older ages with functions still similar to those of younger counterparts are extremely interesting in aging research. 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 relevant markers of mitochondrial functionality and mitochondrial DNA (mtDNA) content. No changes in both mtDNA and TFAM amount were found with increasing age. No age-related change was observed also for the amounts of the mtDNA repair enzymes OGG1 and APE1. A doubling in the content of mitofusin 2 (Mfn2) and dynamin related protein 1 (Drp1), involved in mitochondrial dynamics, was unexpectedly found in the AL-32 rats. This prompted us to the calculation of individual fusion indexes (Mfn2/Drp1 ratio) and a correlation analysis with mtDNA content. 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 marked, but defined prevalence of fusion above fission may ensure a functional mitochondrial network and may lead 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.