In recent years, researchers have shown that introducing additional mitochondrial transcription factor A (TFAM) can reverse some age-related loss of mitochondrial function. Research on mitochondrial protofection seems to have been sidetracked by this finding also - the researchers were using TFAM as a part of a means to replace damaged mitochondrial DNA, but are now more focused on TFAM itself, arguably a less useful path forward.
In this research, scientists show that TFAM levels differ in old and young rats, and life-long calorie restriction eliminates that difference. Calorie restriction slows aging and improves near every measure of metabolism examined to date, so we should expect to see it reduce any given difference between old and young tissues. As for many lines of research, this points to the importance of mitochondria in aging:
Aging affects mitochondria in a tissue-specific manner. Calorie restriction (CR) is, so far, the only intervention able to delay or prevent the onset of several age-related changes also in mitochondria. Using livers from middle age (18-month-old), 28-month-old and 32-month-old ad libitum-fed and 28-month-old calorie-restricted rats we found an age-related decrease in mitochondrial DNA (mtDNA) content and mitochondrial transcription factor A (TFAM) amount, fully prevented by CR. We revealed also an age-related decrease, completely prevented by CR, for the proteins PGC-1α, NRF-1 and cytochrome c oxidase subunit IV, supporting the efficiency of CR to forestall the age-related decrease in mitochondrial biogenesis. Furthermore, CR counteracted the age-related increase in oxidative damage to proteins, represented by the increased amount of oxidized peroxiredoxins in the ad libitum-fed animals.
To investigate further the age- and CR-related effects on mitochondrial biogenesis we analyzed the in vivo binding of TFAM to specific mtDNA regions and demonstrated a marked increase in the TFAM-bound amounts of mtDNA at both origins of replication with aging, fully prevented by CR. A novel, positive correlation between the paired amounts of TFAM-bound mtDNA at these sub-regions was found in the joined middle age ad libitum-fed and 28-month-old calorie-restricted groups, but not in the 28-month-old ad libitum-fed counterpart suggesting a quite different modulation of TFAM binding at both origins of replication in aging and CR.
Considering all together the present results, we demonstrate in rat liver a very articulated age-related decrease in mitochondrial biogenesis leading to the loss of mtDNA probably also through the increase of TFAM binding to both origins of replication. [This] gives an interesting and novel clue to evaluate the preservation of mitochondrial biogenesis as very relevant in the anti-aging action of CR. Of course, future work will be necessary to further verify such hypothesis also in consideration of the therapeutic applications that might lead, through up-regulation of PGC-1α expression and maintenance of mtDNA, to a longer-lasting mitochondrial functionality.