The earliest molecular theory of aging proposed that reactive oxygen species (ROS) damage macromolecules progressively over time, leading to a gradual decline in cellular function (Harman, 1956). ROS are produced as by-products of electron transport by the cells’ power plants for energy, mitochondria, during the generation of ATP by respiration (Wallace, 2005). Thus, it has also been supposed that mitochondria play a uniquely important role in aging. Indeed, many constituents of mitochondria, such as the mitochondrial genome and components of the electron transport chain, are damaged with aging, consistent with their proximity to the site of ROS production. Furthermore, individuals with mitochondrial genetic diseases (Wallace, 2005) or mice that generate frequent mutations in mitochondrial DNA (Kujoth et al., 2005; Trifunovic et al., 2004, 2005) display phenotypes that resemble premature aging.
By this reckoning, it was first suggested that calorie restriction (CR), a dietary regimen that is known to extend life span in rodents and other organisms, exerts its salutary effects by slowing carbohydrate use, respiration, and the rate of damage produced by ROS. However, several recent findings have prompted a re-evaluation of this perhaps naive idea. First, a more careful examination of the physiology of CR has demonstrated that this regimen does not slow respiration but in several examples actually upregulates mitochondrial function (see below). Second, CR appears to be a regulated rather than a passive process and requires regulatory proteins, such as the sirtuins, to exert its effects (Guarente, 2006). This family of antiaging proteins, related to the yeast SIR2 and its mammalian ortholog SIRT1, comprises NAD-dependent protein deacetylases (Imai et al., 2000; Landry et al., 2000) that increase life span in yeast, the worm Caenorhabditis elegans, and the fruit fly Drosophila. Three of the seven mammalian sirtuins (SIRT3, 4, and 5) are targeted to mitochondria, and SIRT1 itself is a regulator of mitochondrial biogenesis (Guarente, 2006). Other regulatory proteins involved in metabolism, such as the TOR and FOXO proteins (Kaeberlein et al., 2005a; Kenyon, 2005), may also play important roles in CR, but their connection to mitochondria is less clear.
These findings lead to a picture in which CR can exert a positive effect on mitochondria, boosting mitochondrial activity and hence providing at least some of the salutary effects of CR. In this Essay, I will review examples in which CR and sirtuins upregulate the activity of mitochondria in different organisms. Moreover, I will present several speculative models to explain how upregulation of mitochondrial biogenesis may confer antiaging effects on cells and organisms.
Mitochondria and CR-Induced Longevity
A regimen of moderate CR in yeast extends replicative life span of mother cells and increases respiration by funneling more pyruvate to the mitochondria for metabolism to CO2 at the expense of fermentation (Lin et al., 2002) (see Figure 1). Importantly, blocking respiration by deleting the gene for cytochrome c1 prevents this CR-driven extension in life span. Moreover, increasing respiration in yeast constitutively through the enforced expression of the HAP4 transcriptional driver of mitochondrial biogenesis results in a long life span under normal caloric conditions that is not extended further by CR. The additional respiration during CR increases the activity of yeast SIR2 and thereby extends life span.