Abstract
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 (PRX-SO3) in the ad libitum-fed animals. An unexpected age-related decrease in the mitochondrial proteins peroxiredoxin III (Prx III) and superoxide dismutase 2 (SOD2), usually induced by increased ROS and involved in mitochondrial biogenesis, suggested a prevailing relevance of the age-reduced mitochondrial biogenesis above the induction by ROS in the regulation of expression of these genes with aging. The partial prevention of the decrease in Prx III and SOD2 proteins by CR also supported the preservation of mitochondrial biogenesis in the anti-aging action of CR. 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.
Highlights
Aging involves the progressive functional decline of tissues, which includes the dysfunction of the mitochondrial respiratory complexes leading to a reduced ATP synthesis
The tissue-specific effects of calorie restriction (CR) include the prevention of the agerelated loss of mitochondrial DNA (mtDNA) in rat liver [14] and the partial preservation of TFAM binding to mtDNA in rat brain with its relevant consequences for mitochondrial biogenesis [13]
A it is evident a 15% statistically significant decrease in the mtDNA content of old ad libitum-fed rats (AL-28) and a 19%reduced value in the very old group of ad libitum-fed animals (AL-32), with respects to the controls namely the middle age ad libitum-fed (AL-MA) rats. Such age-related decrease was fully prevented by the CR as the mean mtDNA content in the old calorie-restricted rats (CRO) was statistically not different from the animals included in the middle age group (AL-MA) value, but significantly higher than that of the ad libitum-fed age-matched counterparts (21% higher content with respects to the AL-28 animals value) and even higher than that of the AL-32 rats (25% increased content)
Summary
Aging involves the progressive functional decline of tissues, which includes the dysfunction of the mitochondrial respiratory complexes leading to a reduced ATP synthesis. Recent studies have proposed a wider model of aging where the mechanism of increased DNA damage, associated to nuclear telomeres shortening, intersects with that of the altered metabolic pathways at mitochondrial level According to such integrated view, the response to the increased DNA damage should induce activation of p53 leading to decreased mitochondrial biogenesis through suppression of the peroxisome proliferator-activated receptor-γ co-activator-1α (PPAR-γ co-activator-1α PGC-1α), which is a central regulator of mitochondrial biogenesis and function [16]. This transcriptional co-activator presents a very complex and multiform regulation of expression at different levels, enabling graduated responses to a variety of metabolic signals, including ROS amount and nutrients availability. To study the eventual changes of mtDNA content and of TFAM and other proteins amounts as well as of TFAM binding to mtDNA with aging and CR in liver was very intriguing for us, to get a deeper insight into the protective effects of the calorie restriction itself
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
