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Sirtuin activators and inhibitors

Authors

  • José M. Villalba,

    1. Departamento de Biología Celular, Fisiología e Inmunología, Facultad de Ciencias, Campus Universitario de Rabanales, Edificio Severo Ochoa, Universidad de Córdoba, Campus de Excelencia Internacional Agroalimentario, ceiA3, 14014-Córdoba, Spain
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  • Francisco J. Alcaín

    Corresponding author
    1. Departamento de Ciencias Médicas, Facultad de Medicina, Campus de Ciudad Real, Universidad de Castilla la Mancha, 13071-Ciudad Real, Spain
    • Departamento de Ciencias Médicas, Facultad de Medicina, Campus de Ciudad Real, Universidad de Castilla la Mancha, 13071-Ciudad Real, Spain
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    • Tel: +34 926 295300 ext 6638; Fax: +34 957 218634


Abstract

Sirtuins 1-7 (SIRT1-7) belong to the third class of deacetylase enzymes, which are dependent on NAD+ for activity. Sirtuins activity is linked to gene repression, metabolic control, apoptosis and cell survival, DNA repair, development, inflammation, neuroprotection, and healthy aging. Because sirtuins modulation could have beneficial effects on human diseases there is a growing interest in the discovery of small molecules modifying their activities. We review here those compounds known to activate or inhibit sirtuins, discussing the data that support the use of sirtuin-based therapies. Almost all sirtuin activators have been described only for SIRT1. Resveratrol is a natural compound which activates SIRT1, and may help in the treatment or prevention of obesity, and in preventing tumorigenesis and the aging-related decline in heart function and neuronal loss. Due to its poor bioavailability, reformulated versions of resveratrol with improved bioavailability have been developed (resVida, Longevinex®, SRT501). Molecules that are structurally unrelated to resveratrol (SRT1720, SRT2104, SRT2379, among others) have been also developed to stimulate sirtuin activities more potently than resveratrol. Sirtuin inhibitors with a wide range of core structures have been identified for SIRT1, SIRT2, SIRT3 and SIRT5 (splitomicin, sirtinol, AGK2, cambinol, suramin, tenovin, salermide, among others). SIRT1 inhibition has been proposed in the treatment of cancer, immunodeficiency virus infections, Fragile X mental retardation syndrome and for preventing or treating parasitic diseases, whereas SIRT2 inhibitors might be useful for the treatment of cancer and neurodegenerative diseases.

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