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Review
. 2013;75:669-84.
doi: 10.1146/annurev-physiol-030212-183800. Epub 2012 Oct 1.

Metabolic and Neuropsychiatric Effects of Calorie Restriction and Sirtuins

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Free PMC article
Review

Metabolic and Neuropsychiatric Effects of Calorie Restriction and Sirtuins

Sergiy Libert et al. Annu Rev Physiol. .
Free PMC article

Abstract

Most living organisms, including humans, age. Over time the ability to do physical and intellectual work deteriorates, and susceptibility to infectious, metabolic, and neurodegenerative diseases increases, which leads to general fitness decline and ultimately to death. Work in model organisms has demonstrated that genetic and environmental manipulations can prevent numerous age-associated diseases, improve health at advanced age, and increase life span. Calorie restriction (CR) (consumption of a diet with fewer calories but containing all the essential nutrients) is the most robust manipulation, genetic or environmental, to extend longevity and improve health parameters in laboratory animals. However, outside of the protected laboratory environment, the effects of CR are much less certain. Understanding the molecular mechanisms of CR may lead to the development of novel therapies to combat diseases of aging and to improve the quality of life. Sirtuins, a family of NAD(+)-dependent enzymes, mediate a number of metabolic and behavioral responses to CR and are intriguing targets for pharmaceutical interventions. We review the molecular understanding of CR; the role of sirtuins in CR; and the effects of sirtuins on physiology, mood, and behavior.

Figures

Figure 1
Figure 1
Calorie restriction impacts numerous physiological functions and parameters, which may ultimately affect health and longevity. The most heavily influenced physiological characteristics are presented in this flowchart. A few genes may mediate the impact of calorie restriction; the most fundamental ones are genes encoding nutritional sensors such as sirtuins (SIRT1–7), adenosine monophosphate–activated protein kinase (AMPK), and target of rapamycin (TOR) and genes involved in insulin signaling. Downstream effects of calorie restriction include decreases in cancer incidence, the suppression of reproduction, alterations of metabolic functions with increased fat oxidation, alterations of mood (higher degrees of anxiety and susceptibility to depression), increased aggression, and increased DNA repair. Calorie restriction robustly increases the longevity and health of laboratory animals; however, its applicability to humans is unknown.
Figure 2
Figure 2
Sirtuins are a family of proteins ranging from bacteria to humans and contain conserved sirtuin motifs. Mammals have seven homologs of sir2 enzymes (SIRT1–7). SIRT1, -6, and -7 are found primarily in the nucleus; SIRT3, -4, and -5 are mitochondrial; and SIRT2 is cytoplasmic. Sirtuins have NAD+-dependent protein deacetylase activity and ADP-ribosyltransferase activity. In addition, SIRT5 has desuccinylase and demalonylase activity.
Figure 3
Figure 3
SIRT1 mediates the liver’s response to fasting. In the early stages of fasting, CREB/CRTC2 turn on gluconeogenesis and increase SIRT1 production. Via negative feedback, SIRT1 deacetylates CRTC2, which causes SIRT1 degradation. At the same time, SIRT1 deacetylates and activates PGC-1α and FOXO transcriptional factors to turn on genes necessary for response to long-term fasting.
Figure 4
Figure 4
SIRT1 and SIRT6 may work in concert to suppress inflammation. SIRT1 directly deacetylates the p65 subunit of NF-κB and thus reduces the ability of NF-κB to activate the transcription of proinflammatory genes. Additionally, SIRT1 activates the production of SIRT6, which deacetylates histones at the promoters of NF-κB-regulated genes to suppress inflammation.
Figure 5
Figure 5
SIRT3 controls key aspects of mitochondrial function. SIRT3 deacetylates and activates glutamate dehydrogenase (GDH), ornithine transcarbamoylase (OTC), 3-hydroxy-3-methylglutaryl CoA synthase 2 (Hmgcs2), acetyl-CoA synthetase 2 (ACS2), and long-chain acyl-CoA dehydrogenase (LCAD). Such activation of mitochondrial metabolism is conducted in unison with the activation of systems that detoxify reactive oxygen species (ROS). SIRT3 activates isocitrate dehydrogenase 2 (IDH2) and superoxide dismutase (SOD2) by deacetylating lysines 53, 68, and 122 of SOD2 to stimulate ROS detoxification.
Figure 6
Figure 6
SIRT1 in the brain is involved in a number of processes that affect neuronal health, neurogenesis, and behavior. (a) SIRT1 can deacetylate retinoic acid receptor β (RARβ), which causes the heterodimerization of RARβ with retinoid X receptor (RXR) on the promoter of ADAM10, which encodes α-secretase. Increases in the abundance and activity of ADAM10 direct amyloid precursor peptide (APP) processing toward the α-secretase pathway. This in turn leads to less β-secretase cleavage of APP and thus less Aβ production, which is protective against Alzheimer’s disease. (b) SIRT1 deacetylates and activates TORC1 by promoting its dephosphorylation and its interaction with CREB. Brain-derived neurotrophic factor (BDNF) and PGC-1α are key targets of SIRT1 and TORC1 transcriptional activity. Both targets counteract the toxic effects of the Huntingtin protein and protect against Huntington’s disease. (c) SIRT1 limits miR-134 expression via a repressor complex containing the transcription factor YY1. If SIRT1 is downregulated and miR-134 expression is increased, CREB and BDNF are downregulated, thereby impairing synaptic plasticity. (d) SIRT1 deacetylates and thus activates the neuronal helix-loop-helix 2 (NHLH2) transcription factor, which in conjunction with SP1 controls the transcription of monoamine oxidase A (MAOA). MAOA activity alters the abundance of neurotransmitters, such as serotonin and noradrenaline, which in turn influence an animal’s mood and behavior. (e) SIRT1 knockout results in decreased extracellular signal–regulated kinase 1/2 (ERK1/2) phosphorylation and in altered expression of hippocampal genes involved in synaptic function. SIRT1 knockout animals have compromised cognitive functions, reinforcing the notion that SIRT1 is indispensable for normal learning, memory, and synaptic plasticity. (f) SIRT1 binds the CLOCK-BMAL1 complex in a circadian manner and promotes the deacetylation and degradation of cytochrome PER2. The PER2/CRY complex suppresses the activity of CLOCK/BMAL1, forming a negative feedback loop that results in periodic oscillation of the abundance of these molecules. SIRT1 is required for normal circadian transcription of core clock genes in the liver and connects cellular metabolism to the circadian rhythm. (g) SIRT1 protects against Parkinson’s disease by deacetylating heat shock factor 1 (HSF1) to increase activation of its targets, such as heat shock protein 70 (HSP70). Interestingly, the induction of HSF1 activity requires the overexpression of both SIRT1 and the A53T disease gene.
Figure 7
Figure 7
SIRT6 inhibits carcinogenesis by inhibiting the Warburg effect, contributes to DNA repair activation, and suppresses inflammation. Hypoxia-inducible factor 1α (HIF-1α) may be the major target of SIRT6 and the main link between this sirtuin and glucose homeostasis. DNA repair and telomere maintenance also depend on SIRT6 activity.

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