Effects of aging and caloric restriction on mitochondrial energy production in gastrocnemius muscle and heart

Abstract

Mitochondria are chronically exposed to reactive oxygen intermediates. As a result, various tissues, including skeletal muscle and heart, are characterized by an age-associated increase in reactive oxidant-induced mitochondrial DNA (mtDNA) damage. It has been postulated that these alterations may result in a decline in the content and rate of production of ATP, which may affect tissue function, contribute to the aging process, and lead to several disease states. We show that with age, ATP content and production decreased by approximately 50% in isolated rat mitochondria from the gastrocnemius muscle; however, no decline was observed in heart mitochondria. The decline observed in skeletal muscle may be a factor in the process of sarcopenia, which increases in incidence with advancing age. Lifelong caloric restriction, which prolongs maximum life span in animals, did not attenuate the age-related decline in ATP content or rate of production in skeletal muscle and had no effect on the heart. 8-Oxo-7,8-dihydro-2'-deoxyguanosine in skeletal muscle mtDNA was unaffected by aging but decreased 30% with caloric restriction, suggesting that the mechanisms that decrease oxidative stress in these tissues with caloric restriction are independent from ATP availability. The generation of reactive oxygen species, as indicated by H2O2 production in isolated mitochondria, did not change significantly with age in skeletal muscle or in the heart. Caloric restriction tended to reduce the levels of H2O2 production in the muscle but not in the heart. These data are the first to show that an age-associated decline in ATP content and rate of ATP production is tissue specific, in that it occurs in skeletal muscle but not heart, and that mitochondrial ATP production was unaltered by caloric restriction in both tissues.

Metabolic Reprogramming in Dietary Restriction

“…DR attenuates the age-associated increase in rates of mitochondrial ROS generation in multiple tissues and reduces the accrual of oxidative damage [58-61, 87, 88], Mitochondrial function is preserved with age in DR animals, and the loss of mitochondrial membrane fluidity is delayed [89] compared to control animals. Reduction of mitochondrial H 2 0 2 production and oxidative damage to mtDNA in rat gastrocnemius muscle with DR has been described [90] and we have reported that DR in monkeys lowers oxidative damage in skeletal muscle [91]. More recently, the role of ROS has broadened to encompass the control of normal cellular functions (e.g.…”

Two subpopulations of mitochondria in the aging rat heart display heterogenous levels of oxidative stress

“…Some studies report an increased oxidant generation with age [23], whereas others, including Drew and coworkers, using a SSM-enriched preparation, observed no change in mitochondrial oxidant production [24][25][26]. Apparent discrepancies in the extent of age-related changes in mitochondrial oxidant appearance and oxidative stress may reflect the differences in mitochondrial isolation procedures and resultant heterogeneity in the amount of IFM and SSM obtained in sample preparations.…”

Age associated low mitochondrial biogenesis may be explained by lack of response of PGC-1α to exercise training

“…This was independently confirmed by the group of Bruce Ames (Hagen et al 1997). In 2003, it was shown in skeletal muscle that age causes a decrease in ATP content and production by approximately 50% in isolated rat mitochondria (Drew et al 2003). Since the promotion of mitochondriogenesis is critical to prevent aging, an obvious approach was to try and enhance it by physical exercise (Holloszy and Booth 1976;Davies et al 1982).…”