Mitochondria--a nexus for aging, calorie restriction, and sirtuins?

Abstract

Recent studies of calorie restriction in several organisms demonstrate an increase in mitochondrial activity that is associated with the salutary effects of this dietary restriction regimen. In this Essay, I speculate on how an increase in mitochondrial activity might provide benefit and discuss how diet, mitochondria, and sirtuins might interact in a pathway to slow aging and associated diseases.

Figure 1. Calorie Restriction Pathways in Different Species

In yeast, SIR2 has been implicated downstream of mitochondrial changes in response to calorie restriction (CR), whereas in mammals the SIR2 ortholog SIRT1 has been implicated upstream of mitochondrial changes. In C. elegans, sirtuins have not been implicated in dietary restriction to date. The pathway in mice shows that the increase in mitochondrial number and activity may work via the mitochondrial sirtuins SIRT3, 4, and 5 or by reducing reactive oxygen species (ROS). The drug Resveratrol and CR may increase SIRT1 activity, which is part of an autoregulatory feedback loop that includes the enzyme endothelial nitric oxide synthase (eNOS).

Figure 2. Mitochondrial Biogenesis and Reactive Oxygen Species

Shown is mitochondrial biogenesis during calorie restriction versus ad libitum feeding in mice and its proposed effects on reactive oxygen species (ROS). In the ad libitum case, the number of electron transport chains is low, and if the rate of entry of electrons (red e^-) exceeds the slowest step of flow through the chain, stalling of electrons at mitochondrial complexes I and III (blue e^-) and production of ROS will be favored. During calorie restriction, mitochondrial biogenesis increases the number of electron transport chains, thereby reducing the rate of electron entry per electron transport chain. Calorie restriction may also increase the fraction of electrons that bypass complex I by entering the electron transport chain via the electron transfer flavoprotein dehydrogenase (ETF). These effects may reduce the production of ROS during calorie restriction and hence mitigate cellular damage, aging, and disease.