Article

Gan L, Mucke L. Paths of convergence: Sirtuins in aging and neurodegeneration. Neuron. 58: 10-14

Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158, USA.
Neuron (Impact Factor: 15.05). 05/2008; 58(1):10-4. DOI: 10.1016/j.neuron.2008.03.015
Source: PubMed

ABSTRACT

Members of the sirtuin family of protein deacetylases support and promote longevity in diverse organisms and can extend life span when upregulated. Sirtuin pathways also modulate fundamental mechanisms in aging-related neurodegenerative diseases, including protein aggregation, stress responses, mitochondrial homeostasis, and inflammatory processes. In this minireview, we will discuss how progress in understanding the neurobiology of sirtuins is shedding light on the pathogenesis of these devastating conditions. We will also examine the potential and challenges of targeting sirtuin pathways therapeutically.

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Available from: Li Gan, Sep 29, 2014
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    • "Sirtuins are conserved family of proteins that depend on nicotinamide adenine dinucleotide (NAD + ) for their deacetylase activity (North and Verdin, 2004; Sauve and Youn, 2012). They are involved in various biological functions (Finkel et al., 2009) such as control of aging (Tissenbaum and Guarente, 2001; Wood et al., 2004), longevity pathways (Gan and Mucke, 2008), DNA repair (Lombard et al., 2008), transcriptional silencing (Tissenbaum and Guarente, 2001), apoptosis (Cohen et al., 2004; Wang et al., 2006) and the control of metabolic enzymes (Schwer and Verdin, 2008). Apart from all these functions sirtuins mainly function as anti-aging genes and their NAD + dependence categorize them as a link between aging and metabolism (Guarente, 2007). "
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    ABSTRACT: The energy production and metabolic homeostasis are well-orchestrated networks of carbohydrate, lipid and protein metabolism. These metabolic pathways are integrated by a key cytoplasmic organelle, the mitochondria, leading to production of many metabolic intermediates and harvest cellular energy in the form of ATP. Sirtuins are a highly conserved family of proteins that mediate cellular physiology and energy demands in response to metabolic inputs. Mitochondria inhabit three main types of sirtuins classified as Sirt3, Sirt4 and Sirt5. These sirtuins regulate mitochondrial metabolic functions mainly through controlling post-translational modifications of mitochondrial protein. However, the biological mechanism involved in controlling mitochondrial metabolic functions is not well understood at this stage. In this review the current knowledge on how mitochondrial sirtuins govern mitochondrial functions including energy production, metabolism, biogenesis and their involvement in different metabolic pathways are discussed. The identifications of potential pharmacological targets of sirtuins in the mitochondria and the bioactive compounds that target mitochondrial sirtuins will increase our understanding on regulation of mitochondrial metabolism in normal and disease state.
    Full-text · Dataset · Dec 2014
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    • "The requirement of NAD + for deacetylation makes SIRT1 an ideal mediator of the cross-talk between metabolism and epigenetic regulation. Deacetylation of histones and non-histone substrates by SIRT1 regulates metabolism, genome stability, cell survival and inflammation (Feige and Auwerx, 2008; Gan and Mucke, 2008; Oberdoerffer et al., 2008; Vaziri et al., 2001). Previous studies have implicated SIRT1 in the neuron/astrocyte fate choice during differentiation of embryonic and adult NSCs (Hisahara et al., 2008; Prozorovski et al., 2008; Saharan et al., 2013). "
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    ABSTRACT: The balance between self-renewal and differentiation of adult neural stem cells (aNSCs) is essential for the maintenance of the aNSC reservoir and the continuous supply of new neurons, but how this balance is fine-tuned in the adult brain is not fully understood. Here, we investigate the role of SIRT1, an important metabolic sensor and epigenetic repressor, in regulating adult hippocampal neurogenesis in mice. We found that there was an increase in SIRT1 expression during aNSC differentiation. In Sirt1 knockout (KO) mice, as well as in brain-specific and inducible stem cell-specific conditional KO mice, the proliferation and self-renewal rates of aNSCs in vivo were elevated. Proliferation and self-renewal rates of aNSCs and adult neural progenitor cells (aNPCs) were also elevated in neurospheres derived from Sirt1 KO mice and were suppressed by the SIRT1 agonist resveratrol in neurospheres from wild-type mice. In cultured neurospheres, 2-deoxy-D-glucose-induced metabolic stress suppressed aNSC/aNPC proliferation, and this effect was mediated in part by elevating SIRT1 activity. Microarray and biochemical analysis of neurospheres suggested an inhibitory effect of SIRT1 on Notch signaling in aNSCs/aNPCs. Inhibition of Notch signaling by a γ-secretase inhibitor also largely abolished the increased aNSC/aNPC proliferation caused by Sirt1 deletion. Together, these findings indicate that SIRT1 is an important regulator of aNSC/aNPC self-renewal and a potential mediator of the effect of metabolic changes.
    Full-text · Article · Dec 2014 · Development
    • "Mounting evidence indicates sirtuins (SIRTs) exert neuroprotective effects in several models of neurodegeneration (Outeiro et al., 2008; Tang and Chua, 2008; de Oliveira et al., 2010). SIRTs, a family of NAD + -dependent enzymes with seven isoforms identified (SIRT1-7), are implicated in the control of a variety of biological processes including transcriptional silencing, chromosomal stability, cell cycle progression, apoptosis, autophagy, metabolism, growth suppression, inflammation , and stress response (Gan and Mucke, 2008; Haigis and Sinclair, 2010). "
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    ABSTRACT: Alzheimer’s disease is a chronic neurodegenerative disorder that progressively destroys all the neurocognitive abilities of the patient. Despite research efforts, so far no disease modifying therapy is available. Neuropathological hallmarks are beta-amyloid peptide (Abeta) accumulation and the occurrence of neurofibrillary tangles (NFT), however it is inaccurate to consider these as the only key changes present in AD brain. Commonly Abeta accumulation is thought a triggering mechanism in AD that induces a cascade of events all pathognomonic, leading to activation of apoptotic program and neuronal loss. Among these, a protracted reactive astrogliosis, at present, is attracting much attention so that any tool able to blunt such a pathological event is regarded as a potential strategy for future treatment. Sirtuin enzymes (SIRT) are a family of highly conserved protein deacetylases that depend on nicotinamide adenine dinucleotide (NAD+) for their activity. There are seven sirtuins in mammals and these proteins have been linked with caloric restriction and aging by modulating energy metabolism, genomic stability and stress resistance. Sirtuin enzymes are potential therapeutic targets in a variety of human disease. In particular, modulation of sirtuin activity has been speculated to impact the course of several aggregate-forming neurodegenerative disorders, including Alzheimer's disease. In this context, and on the basis of our preliminary observations, it arose the hypothesis that activation of SIRT1 or inhibition of SIRT2 would prevent reactive gliosis. Primary rat astrocytes, obtained from newborn Sprague-Dawely rats and activated following beta amyloid 1-42 (Aβ 1-42) exposure, were treated with resveratrol (RSV) or AGK-2, a SIRT1 activator and a SIRT2-selective inhibitor, respectively. Results confirmed that Aβ 1-42 peptide affects cell vilability after 24 h treatment and induces astrocyte proliferation after 72 h of treatment. Both RSV and AGK-2 were able to antagonize these events. Moreover, RSV and AGK-2 reduced astrocyte activation, as demonstrated by the decrease in GFAP and S100B expression, as well as both compounds showed the property to blunt the production of pro-inflammatory mediators, such as iNOS and COX-2. These data provides novel findings about the therapeutic potential of SIRT modulators, and suggest promising strategies for AD treatment.
    No preview · Conference Paper · Sep 2014
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