**5. Sirtuins, prolongevity or healthspan effect?**

The prolongevity effect of sirtuins was initially determined in yeast (Kaeberlein et al., 1999) and lower metazoan such as *C. elegans* (Tissenbaum & Guarente, 2001) and in *D. melanogaster* (Rogina & Helfand, 2004). However, very recently, these results have been revised and the prolongevity effect of sir2 in these animals has been related to transgenelinked genetic effects other than overexpression or sir2.1 in *C. elegans* or dSir2 in *D. melanogaster* (Burnett et al., 2011; Viswanathan & Guarente, 2011). Further, along last year, a considerable body of evidences indicates the controversial aspect of sirtuins in longevity studies. Calorie restriction clearly exerts a prolongevity effect on many organisms. In this effect, sirtuins were described as important factors in yeasts (Lin et al., 2000), *C. elegans* (Y. Wang & Tissenbaum, 2006) and *D. melanogaster* (Rogina & Helfand, 2004). However, other studies in yeast and *C. elegans* have argued about the role of sirtuins in caloric restrictiondependent longevity (Kaeberlein, 2010; Kenyon, 2010). Further, in mammals, overexpression of SIRT1 in mice does not increase lifespan (Herranz & Serrano, 2010).

These new concerns about the promising role of sirtuins in longevity do not affect other important functions of sirtuins in cell physiology. There is also an overwhelming body of evidences indicating that sirtuins play a crucial role in metabolic homeostasis. As, the activity of sirtuins depends strictly on the levels of NAD+ which acts as co-substrate in the deacetylation activity catalyzed by sirtuins, changes in NAD+ levels, reflecting modifications in the metabolic status of the cells, would modulate sirtuin activity. NAD+-dependence for sirtuin activity in cells confers to sirtuins the integrative role of metabolic sensors that modulates cell changes depending on the metabolic status of the cells. Furthermore, the broad group of targets of sirtuins activity in cells confers to these proteins the capacity to modulate executive proteins and also to influence transcription factors and histone proteins to change not only protein activity but also gene expression profile in cells accordingly to changes in metabolism (Canto & Auwerx, 2009).

In mammals, SIRT1 mediates the metabolic and transcriptional adaptations after nutrient deprivation or energy stress changes. These adaptations are centered in a higher respiratory activity of mitochondria. Calorie restriction induces the expression of sirtuins in many tissues and likely this regulation is related to the changes in metabolism found under 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 systems (Hsu et al., 2010).

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 unsaturated fat.

#### **6. Conclusion**

108 Bioenergetics

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.

of SIRT1 in mice does not increase lifespan (Herranz & Serrano, 2010).

changes in metabolism (Canto & Auwerx, 2009).

The prolongevity effect of sirtuins was initially determined in yeast (Kaeberlein et al., 1999) and lower metazoan such as *C. elegans* (Tissenbaum & Guarente, 2001) and in *D. melanogaster* (Rogina & Helfand, 2004). However, very recently, these results have been revised and the prolongevity effect of sir2 in these animals has been related to transgenelinked genetic effects other than overexpression or sir2.1 in *C. elegans* or dSir2 in *D. melanogaster* (Burnett et al., 2011; Viswanathan & Guarente, 2011). Further, along last year, a considerable body of evidences indicates the controversial aspect of sirtuins in longevity studies. Calorie restriction clearly exerts a prolongevity effect on many organisms. In this effect, sirtuins were described as important factors in yeasts (Lin et al., 2000), *C. elegans* (Y. Wang & Tissenbaum, 2006) and *D. melanogaster* (Rogina & Helfand, 2004). However, other studies in yeast and *C. elegans* have argued about the role of sirtuins in caloric restrictiondependent longevity (Kaeberlein, 2010; Kenyon, 2010). Further, in mammals, overexpression

These new concerns about the promising role of sirtuins in longevity do not affect other important functions of sirtuins in cell physiology. There is also an overwhelming body of evidences indicating that sirtuins play a crucial role in metabolic homeostasis. As, the activity of sirtuins depends strictly on the levels of NAD+ which acts as co-substrate in the deacetylation activity catalyzed by sirtuins, changes in NAD+ levels, reflecting modifications in the metabolic status of the cells, would modulate sirtuin activity. NAD+-dependence for sirtuin activity in cells confers to sirtuins the integrative role of metabolic sensors that modulates cell changes depending on the metabolic status of the cells. Furthermore, the broad group of targets of sirtuins activity in cells confers to these proteins the capacity to modulate executive proteins and also to influence transcription factors and histone proteins to change not only protein activity but also gene expression profile in cells accordingly to

In mammals, SIRT1 mediates the metabolic and transcriptional adaptations after nutrient deprivation or energy stress changes. These adaptations are centered in a higher respiratory activity of mitochondria. Calorie restriction induces the expression of sirtuins in many tissues and likely this regulation is related to the changes in metabolism found under

**5. Sirtuins, prolongevity or healthspan effect?** 

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 physiology of the organism until death.

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#### **7. Acknowledgment**

The research group is financed by the Andalusian Government as the BIO177 group and P08-CTS-03988 project financed by FEDER funds (European Commission). Research has been also financed by the Spanish Government grants DEP2009-12019 (Spanish Ministry of Science and Innovation), and PI080500 (FIS, Carlos III institute). Authors also thank to the National Institutes of Health grant 1R01AG028125-01A1. Authors are also members of the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto Carlos III.

## **8. References**


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**Energy Metabolism in Children and Adolescents** 

Energy metabolism is the most integral body function, and, as any functional activity, it has an effect on energy expenditure. Body energy expenditures are composed of three unequal parts: basal metabolism, energy supply of functional activity and energy expenditure on growth, development and the adaptive processes. The proportion of these expenditures is

Basal metabolism (the minimum level of energy production in conditions of complete rest), in its turn, is composed of three primary energy expenditure types: minimum level of vital physiological functions; intracellular futile cycles of biochemical processes; and reparative

With age, basal metabolism expenditure and growth and development expenditure is considerably reduced, while functional expenditure can increase (for instance, muscle energy expenditure of an adult can be sometimes more than that of a child), but in any case

Methodological requirements for basal metabolism measuring are hard to be implemented outside a clinic, therefore metabolism in a state of rest is most commonly measured (lying down, comfortable temperature, 2-4 hours after food intake, without any stress factors), which is approximately 10-20% more than the level of basal metabolism. Present-day children have resting metabolism values even lower than standard norms of basal metabolism (Kornienko, 1979), proposed by Harris and Benedict (1919), which might be the result of acceleration of growth and development, observed up to the 1980s (Godina, 2009). With age the rate of resting metabolism (per body mass unit) is reduced – from infancy to the adulthood– by 1.5 – 2 times.

Since Max Rubner's time (1883) it has been known that as mammals gain body mass, heat production per mass unit is reduced, while the metabolism rate, relative to the surface space, is practically constant ("the rule of surface"). These metabolism changes were primarily explained by thermoregulation expenditure, but it turned out that in a thermoneutral conditions, without any extra heat production, this alignment persists. Moreover, this relation between metabolism rate and body size is observed in invertebrates

determined by the stage of individual development and specific life conditions.

processes, including growth and development expenditure.

The reasons for this reduction have been discussed for the last 150 years.

they undergo important qualitative changes.

**2. Age changes of basal metabolism** 

(Schmidt – Nielsen, 1987; Ivanov, 1990).

**1. Introduction** 

Valentin Son'kin and Ritta Tambovtseva

*Institute for Developmental Physiology Russian Academy of Education, Moscow* 

*Russian Federation* 

