Tissue-specific regulation of SIRT1 by calorie restriction

Abstract

Calorie restriction (CR) has been reported to increase SIRT1 protein levels in mice, rats, and humans, and elevated activity of SIRT1 orthologs extends life span in yeast, worms, and flies. In this study, we challenge the paradigm that CR induces SIRT1 activity in all tissues by showing that activity of this sirtuin in the liver is, in fact, reduced by CR and activated by a high-caloric diet. We demonstrate this change both by assaying levels of SIRT1 and its small molecule regulators, NAD and NADH, as well as assessing phenotypes of a liver-specific SIRT1 knockout mouse on various diets. Our findings suggest that designing CR mimetics that target SIRT1 to provide uniform systemic benefits may be more complex than currently imagined.Supplemental material is available at http://www.genesdev.org.Received January 11, 2008; revised version accepted April 29, 2008. Caloric intake influences life span, and the incidence of diseases in animals (Koubova and Guarente 2003). Food excess accounts for the recent historic increase in metabolic disorders in humans. Conversely, calorie restriction (CR) promotes metabolic fitness, long life, and disease protection in rodent models (Weindruch 1988). Several genetic pathways have been identified that govern diet, metabolism, and life span (Van Remmen et al. 2001;Koubova and Guarente 2003;Kenyon 2005;Sinclair 2005).Genes related to yeast SIR2, called sirtuins, encode NAD-dependent deacetylases, and promote longevity in yeast, worms, and flies (Chen and Guarente 2007). In model systems ranging from yeast to mice, sirtuins have also been associated with the salutary effects of CR. The mammalian Sir2 ortholog SIRT1 targets numerous regulatory factors affecting stress management and metabolism (Sinclair 2005;Chen and Guarente 2007). The levels of SIRT1 have been reported to increase in rodent and human tissues in response to CR (Cohen et al. 2004;Nisoli et al. 2005;Civitarese et al. 2007), and this increase is proposed to cause favorable changes in metabolism and stress tolerance triggered by this diet. The polyphenol resveratrol has also been proposed to partially mimic CR by activating SIRT1 to induce beneficial effects on health (Baur et al. 2006;Lagouge et al. 2006). Results and DiscussionTo address the relationship between SIRT1 activity and the diet, we first analyzed SIRT1 protein levels in the liver, white adipose tissue (WAT), and skeletal muscle in mice fed ad libitum (AL) or CR. While SIRT1 was induced in the WAT and muscle, as previously reported (Cohen et al. 2004;Nisoli et al. 2005;Civitarese et al. 2007), levels surprisingly were lower in CR liver (Fig. 1A). It is not clear whether the increased SIRT1 expression in CR liver reported by Cohen et al. (2004) is specific to rat or to the time point when the tissue samples are removed from animals after daily feeding. Because SIRT1 activity is also regulated by the NAD/NADH ratio (Lin et al. 2004), we determined NAD and NADH levels in these tissues. Whereas the NAD/NADH ratio increased significantly in the muscle during...

Caloric restriction and heart function: is there a sensible link?

“…Table 1 summaries some of the most important signaling molecules involved in CR-induced biological and physiological responses. FOXO ↓ [89,97] GSK-3β ↓ [93,98] HIF-1 ↓ [95,99] HSF-1 ↑ [94] HSP-70 ↑ [94,100] mTOR ↓ [90,101] NF-κB ↓ [81,82,95,97] PGC-1α ↑ [91,92] PPAR α ↑ [91,102] SIRT1 ↑↓ [92,93,103] ↑=increase in signal transduction; ↓=decrease in signal transduction.…”

Do Sirtuins Promote Mammalian Longevity?: A Critical Review on Its Relevance to the Longevity Effect Induced by Calorie Restriction

“…The results also raise the possibility that SIRT1 may not be the only factor, but rather one of several components that regulate CR-mediated lifespan extension, as neither overexpression of SIRT1 nor resveratrol extended lifespan in mammals. Notably, Chen et al (2008) showed that CR does not increase SIRT1 in whole tissue. It is likely that the use of tissue-specific SIRT1 transgenic mice could be more effective in clarifying the role of SIRT1 in CR-mediated lifespan extension.…”

“…SIRT1 in the hypothalamic arcuate nucleus SIRT1, the most extensively studied member of the sirtuin family, regulates energy metabolism in the hypothalamus and is induced by a negative energy balance (Chen et al, 2008;Cohen et al, 2004). SIRT1 is expressed in the orexigenic neuropeptide Y (NPY)/Agouti-related peptide (AGRP) and anorexigenic proopiomelanocortin (POMC) neurons, which are major components in regulating feeding and energy expenditure in the arcuate nucleus of the hypothalamus (Sasaki and Kitamura, 2010).…”

“…Moreover, SIRT1 overexpressing mice exhibit several phenotypes resembling CR mice: they are leaner, metabolically more active, and show low insulin and fasted blood glucose levels (Bordone et al, 2007). However, the requirement for SIRT1 in CRmediated lifespan extension is under debate, as the mechanism of SIRT1 activation in response to CR remains unclear and because CR increases SIRT1 levels in some tissues (Chen et al, 2008).…”

Sirtuins and inflammation: Friends or foes?

“…Steatosis is accompanied by liver inflammation, with an increase in TNF and IL-1 synthesis and in total macrophage markers such as F4.80. However, it must be noted that Guarente's team has observed an opposite outcome in a similar model of liver-specific SIRT1 deletion, with SIRT1 absence proving to have a beneficial effect on several metabolic parameters following HFD, even if no effect on NFkB acetylation or liver inflammation was reported [30]. The increase in F4.80 expression in Purushotham's study suggests an important macrophage infiltration and this prompted the authors to disrupt SIRT1 in macrophages and assess the consequences of HFD feeding [29].…”