Paths of convergence: sirtuins in aging and neurodegeneration.

Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158, USA.
Neuron (Impact Factor: 15.77). 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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    ABSTRACT: Lowering caloric intake, a dietary process known as caloric restriction (CR) is the only reproducible non-genetic method that extends lifespan for most of the organisms tested, yet our understanding of how this diet works remains poor. One group of enzymes, the sirtuins, has recently emerged as leading candidates for mediators of the benefits of CR across species. In Chapter 1, the sirtuin family of deacetylase enzymes is reviewed within the context of CR-mediated biological effects in organisms. The mammalian sirtuins have emerging roles in a variety of important basic and age-associated processes like cancer, diabetes, obesity, inflammation, muscle differentiation, heart failure, and neurodegeneration, thereby attracting wide interest for promising therapeutic intervention. However, many of the mammalian sirtuins remain poorly characterized, such as the case of the mitochondrial sirtuin SIRT3. In human cell-culture studies, as discussed in Chapter 2, a new biological role is elucidated for SIRT3 as an anti-apoptotic sirtuin that protects against stress/nutrient deprivation. Prior to this work, virtually no connection existed between this sirtuin, the unique biochemical microenvironment inside of mitochondria, and cellular survival. Furthermore, in skeletal muscle studies explained in Chapter 3, a new biological role for SIRT3 is also described. As detailed in this Chapter, exercise training and CR raise SIRT3 expression in vivo, which leads to downstream activation of key pathways affecting muscle energy homeostasis. In Chapter 4, the role of sirtuins and PNC-1/nicotinamidase is considered in the model organism C. elegans. In this Chapter, it is demonstrated that the nematode PNC-1 has robust nicotinamidase enzymatic activity in vitro and that over-expression in vivo protects against stress and extends lifespan by mimicking the effects of CR. Lastly, evidence is presented that some of the sirtuins in this organism mediate the effects of CR-induced longevity, contrary to some past literature. Collectively, all of these biochemical and genetic studies, as summarized and discussed in Chapter 5, will help to further explain sirtuin-mediated mechanisms of homeostasis and aging in animals, thereby opening new routes for potential therapeutic intervention and for studying the biology of aging in vivo.
    02/2010, Degree: Ph.D., Supervisor: David A. Sinclair
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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.
    Development 12/2014; 141(24):4697-4709. · 6.27 Impact Factor
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    ABSTRACT: Impaired iron homeostasis may cause damage to dopaminergic neurons and is critically involved in the pathogenesis of Parkinson's disease. At present, very little is understood about the effect of neonatal iron intake on behavior in aging animals. Therefore, we hypothesized that increased neonatal iron intake would result in significant behavior abnormalities and striatal dopamine depletion during aging, and Sirtuin 2 contributes to the age-related neurotoxicity. In the present study, we observed that neonatal iron intake (120 μg/g per day) during postnatal days 10-17 resulted in significant behavior abnormalities and striatal dopamine depletion in aging rats. Furthermore, after AK-7 (a selective Sirtuin 2 inhibitor) was injected into the substantia nigra at postnatal 540 days and 570 days (5 μg/side per day), striatal dopamine depletion was significantly diminished and behavior abnormality was improved in aging rats with neonatal iron intake. Experimental findings suggest that increased neonatal iron intake may result in Parkinson's disease-like neurochemical and behavioral deficits with aging, and inhibition of Sirtuin 2 expression may be a neuroprotective measure in Parkinson's disease.
    Neural Regeneration Research 11/2014; 9(21):1917-22. · 0.23 Impact Factor

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