The effects of dietary restriction on mitochondrial dysfunction in aging

Age-associated alterations in the mitochondrial electron transport system (ETS) may lead to free radical generation and contribute to aging, The complexes of the ETS were screened spectrophotometrically in gastrocnemius of young (10 month) as well as older (20 and 26 month) B6C3F1 female mice fed an nd libitum (AL) diet or a restricted (DR) in total calories diet (40% less food than AL mice), The activities of complexes I, III, and IV decreased significantly by 62%, 54%, and 74%, respectively. in old AL mice (AL(20)) compared to young AL mice (AL(10)). Complexes I, III, and IV from DR10 mice had activities that were significantly lower than those seen in AL(10) mice (suggesting a lower total respiratory rate or improved efficiency). By contrast, complex II activity did not decrease with age (actually increased, but not significantly) in AL(20) mice. Complex II was decreased across age in DR mice. K-m for ubiquinol-2 of complex III was significantly increased in AL(10) animals (0.33 mM vs. 0.26 mM in DR10 mice) and was further increased with aging (0.44 mM in AL(20) vs. 0.17 mM in DR20 mice). This suggests obstruction of binding, inhibition of electron now in aging, which could yield premature product release as a free radical. Total complex IV by V-max was highest in AL(10) mice, but the proportion of complex as high-affinity sites was lower (69%) than in either DR10 (80%) or DR20 (80%). The percentage of high-affinity sites decreased to only 45% in AL(20) mice, and V-max was reduced by 75 percent. In AL(26) mice high-affinity sites decreased to 33 percent. At physiologic concentration of reduced cytochrome c, significant dysfunction of complex IV in AL(20) or AL(26) mice would be expected with obstruction of overall electron transport. The age-associated loss of activity and function of complexes I, III, and IV mag contribute to increased free radical production. Lack of sufficient DNA repair in mitochondria and juxtaposition to the ETS adds to susceptibility and accumulation of mtDNA and other mitochondrial macromolecular damage, DR seems to retard this deterioration of mitochondrial respiratory function by preserving enzymatic activities and function.