**4. Sirtuins: Antioxidant mechanisms and autophagy**

Other of the important roles of sirtuins related to metabolism and aging is based on their activity to maintain cellular antioxidant mechanisms and autophagy systems. A great body of evidence has accumulated indicating that at the same time that sirtuins are modulating metabolism, they also regulate, in a coordinated mechanism, antioxidant systems and recycling systems in cells.

Altered ROS levels are observed in several age-related illnesses including carcinogenesis, neurodegenerative, fatty liver, insulin resistance, cardiac resistance, etc. In mitochondria MnSOD is the primary ROS scavenging enzyme to converts superoxide to hydrogen peroxide that is further converted to water by catalase and other peroxidases. In this mechanism SIRT3 exert a key role since changes in lysine acetylation modifies MnSOD activity in mitochondria (Ozden et al., 2011). Further, CR effect depends, at least in part, on sirtuin regulation but at the same time oxidative stress is reduced in CR by activation of antioxidant systems such as SOD2 in mitochondria by SIRT3 (Qiu et al., 2010).

In heart, the aging-related decrease in MnSOD and catalase expression accompanied by increase in the levels of oxidative damage indicated by TBARS and 4-HNE has been related to the decrease in the expression of SIRT1 (Ferrara et al., 2008).

Sirtuin-Dependent Metabolic Control and Its Role in the Aging Process 109

dietary restrictions (Bamps et al., 2009; Imai, 2009). Overexpression of SIRT1 in mice protects animals against metabolic damage caused by a fat-rich diet (Herranz et al., 2010). On the other hand, mice lacking SIRT1 show deficiencies in metabolism and are unable to increase lifespan in calorie restriction conditions (Herranz & Serrano, 2010). Further, resveratrol, a polyphenol considered as activator of sirtuins protects against metabolic and age-related diseases (Lagouge et al., 2006) and also increase lifespan in animals fed with fat-rich diets (Baur et al., 2006). However, accordingly with the above indicated recent studies that indicate that sirtuins do not affect longevity, in normal diet conditions, resveratrol is unable to increase lifespan in mice although delays age-related deterioration (Pearson et al., 2008). Many researchers have also demonstrated the role of sirtuins in protection of cell and tissues against different forms of injury through activation of FoxO and intracellular antioxidant

It has been recently proposed that energy metabolism can be importantly involved in the accumulation of high levels of advanced-glycosylation end (AGES)-products into cells and, then, in the impairment of cell and tissue activity (Hipkiss, 2008). In this process, NAD+/NADH ratio is importantly involved. Decrease of NAD+ availability in ad libitum conditions decreases metabolism of triose phosphate glycolytic intermediates such as glyceraldehydes-3-phosphate and dihydroxyacetone-phosphate. These compounds can spontaneously decompose into methylglyoxal (MG), a highly toxic glycating aging that produces AGES. AGES and MG can be involved in mitochondrial dysfunction, the increase in ROS production and also affect gene expression and intracellular signaling. However, under CR or exercise NADH is oxidized to NAD+ and also NAD+ synthesis is activated. NAD+ not only activate sirtuins but also reduces the levels of MG and then, reduces the deleterious effects of this compound (Hipkiss, 2008). This hypothesis directly links metabolism and its regulation to cell damage and then to aging indicating that sirtuins are directly involved in a more balanced metabolism and then, are important factors to be considered in aging, longevity and healthspan. Taken together, it seems clear that sirtuins are key factors in metabolic homeostasis and can increase healthspan and also show prolongevity effects in conditions of metabolic stress such as western food rich in

In the present chapter we have resumed the complex system regulated by sirtuins and involved in metabolic aspects that affect aging. Aging is a process that courses with the accumulation of damage into cells and organs. Most of the energy spent by cells is used to maintain the biological structures and the order into cells and tissues. When energy is deficient or the injury increases, damage in cells accumulates in structures that cannot be eliminated and that disturb their correct physiologic mechanisms. Accumulation of aberrant structures ends in the incapacity of cells to function properly and then, produce the decline in functionality found in aging. Sirtuins are key factors in this process. These deacetylases link energetic status of the cell with regulation of aerobic metabolism, reparation activities and antioxidant systems preventing the accumulation of damaged structures. Although the right role of these sirtuins in longevity is currently questioned, their activity as core of several regulatory processes make them important regulators in, at least, the correct

systems (Hsu et al., 2010).

unsaturated fat.

**6. Conclusion** 

physiology of the organism until death.

Regarding recycling mechanism a correct balance between biogenesis and recycling of damaged structures is essential to maintain a correct homeostasis in the cell. Caloric restriction induces autophagy through induction of SIRT1. Transgenic expression of SIRT1 in human cells and in *C. elegans* induces autophagy whereas knockout of SIRT1 in the same cells and organisms prevents autophagy induced by resveratrol or nutrient deprivation (Morselli et al., 2010). Autophagy induction has been also related to the extension of lifespan by some agents such as spermidine and resveratrol in organism such as yeast, nematodes and flies (Morselli et al., 2009). In this process, deacetylation of FOXO3 by SIRT1 seems to be essential to the induction of the expression of genes involved in autophagy in caloric restriction (Kume et al., 2010). FOXO is an essential factor in the induction of autophagy and, as it has been above commented, in the antitumoral role of sirtuins (Zhao et al., 2010). All these works and some other more indicate that sirtuins not only control metabolism regulating essentially mitochondrial respiration and fatty acid oxidation but also regulate in a coordinated way the expression and activity of endogenous antioxidant systems and autophagy processes to eliminate damaged structures including mitochondria.
