SIRT3 Knockout Increases Life Extension Resulting from Calorie Restriction
Unexpectedly, researchers find that knockout of SIRT3, involved in mitochondrial function, increases the gain in life span exhibited by calorie restricted mice. Yet it does so while reducing physical fitness. Work on SIRT3 and aging typically focuses on upregulation of SIRT3, as this is beneficial to mitochondrial function, particularly in the damaged tissue environment of later life. Loss of SIRT3 modestly accelerates aging; add calorie restriction, however, and it becomes beneficial to life span, while still having a negative impact on physical performance. The data here for the combination of SIRT3 knockout and calorie restriction is an illustration of the point that everything in cellular biology and aging is a great deal more complex than we would like it to be.
One of the hallmarks of calorie restriction (CR) is the preservation of mitochondrial function through reducing oxidative stress, enhancing fuel utilization, and maintaining mitochondrial dynamics and integrity. Previous studies have proposed that Sirtuin3 (SIRT3)-dependent deacetylation may play a major role in modulating mitochondria under CR. Nonetheless, direct evaluation of the contribution by SIRT3 to CR-dependent lifespan extension and mitochondrial performance during aging is lacking.
Here, using male Sirt3+/+ (wild type) and Sirt3-/- mice, we report that SIRT3 is required for whole-body aerobic capacity but is dispensable for CR-dependent lifespan extension. Under CR, loss of SIRT3 (Sirt3-/-) yielded a longer overall and maximum lifespan as compared to Sirt3+/+ mice. This unexpected lifespan extension was associated with altered mitochondrial protein acetylation in oxidative metabolic pathways, reduced mitochondrial respiration, and reduced aerobic exercise capacity. Also, Sirt3-/-CR mice exhibit lower spontaneous activity and a trend favoring fatty acid oxidation during the postprandial period.
This study shows the uncoupling of lifespan and healthspan parameters (aerobic fitness and spontaneous activity) and provides new insights into SIRT3 function in CR adaptation, fuel utilization, and aging.