Authors: 
R.T. Hepple, D.J. Baker, M. McConkey, T. Murynka, and R. Norris
Category: 
Oral
Conference: 
Abstract: 

Aging is associated with impairment in mitochondrial function that has been implicated in tissue dysfunction particularly in post-mitotic tissues. We examine here the impact of long term caloric restriction (CR), begun in juvenile male Fischer 344 X Brown Norway F1-hybrid rats, on the age-associated decline in oxidative capacity and mitochondrial function across a range of metabolic and contractile phenotypes in skeletal muscles, and in the most highly aerobic muscle, heart. Interestingly, in both skeletal muscle and heart, in vitro cytochrome oxidase activity is lower in young adult CR animals despite normal aerobic function in situ and in vivo, indicative of a higher oxygen affinity of mitochondria in CR. On the other hand, in contrast to the 25-46% decline in markers of oxidative capacity in cardiac and various distal hindlimb skeletal muscles of ad libitum fed (AL) animals between 8-10 mo (young adulthood) and 35 mo (senescence), there is no decline in CR across the same absolute age (35 mo old) or relative age (35% survival rate: 35 mo of age in AL, 40 mo of age in CR) range. In seeking to explain the means by which CR maintains oxidative capacity with aging, we show that CR acts principally to maintain mitochondrial function rather than content (citrate synthase protein not affected by age or dietary treatment, despite cytochrome oxidase decline with aging in AL), and that this is unrelated to the frequency of mtDNA deletions (although CR protects oxidative capacity in plantaris muscle and mixed gastrocnemius muscle with aging, the frequency of mtDNA deletion fragments is lower only in the plantaris muscle of aged CR animals) but rather is consistent with a maintained drive on mitochondrial biogenesis (more gradual decline in PGC-1 gene expression with aging in CR). Thus, our results show that CR completely prevents the age-associated decline in oxidative capacity in heart and skeletal muscles at least out to 35% survival rate in male F344BN rats, and that this effect is consistent with a protection of mitochondrial function secondary to a better maintained drive on mitochondrial biogenesis.

Keywords (Optional): 
mitochondria
caloric restriction
mitochondrial DNA
mitochondrial biogenesis