Sirtuin activators

被引:149
作者
Alcain, Francisco J. [1 ]
Villalba, Jose M. [1 ]
机构
[1] Univ Cordoba, Fac Ciencias, Dept Biol Celular Fisiol & Immunol, Cordoba 14014, Spain
关键词
aging; metabolic diseases; resveratrol; sirtuin activators; sirtuins; CALORIC RESTRICTION; LIFE-SPAN; OXIDATIVE STRESS; HUMAN SIR2; SACCHAROMYCES-CEREVISIAE; LOW BIOAVAILABILITY; ALZHEIMERS-DISEASE; METABOLIC DISEASE; THERAPEUTIC ROLE; INCREASED DOSAGE;
D O I
10.1517/13543770902762893
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Background: Sirtuin 1 - 7 (SIRT1 - 7) are deacetylases that are dependent on NAD+ for their activity. SIRT1 down-regulates p53 activity, increasing lifespan, cell survival, and neuroprotection; it also deacetylates peroxisome proliferator-activated receptor-gamma and its coactivator 1 alpha, promoting fat mobilization, increasing mitochondrial size and number, and positively regulating insulin secretion. Sirtuins link nutrient availability and energy metabolism. Calorie restriction, which increases lifespan and is beneficial in age-related disorders, activates sirtuin. Major efforts are thus focused to developing sirtuin activators. Objective: After discussing the potential involvement of sirtuins in pathophysiological processes, this review looks at new, synthetic sirtuin activators. Conclusions: To date, resveratrol is the most potent natural compound able to activate SIRT1, mimicking the positive effect of calorie restriction. Resveratrol might help in the treatment or prevention of obesity and in preventing the aging-related decline in heart function and neuronal loss. As resveratrol has low bioavailability and interacts with multiple molecular targets, the development of new molecules with better bioavailability and targeting sirtuin at lower concentrations is a promising field of the medicinal chemistry. New SIRT1 activators that are up to 1000 times more effective than resveratrol have recently been identified. These improve the response to insulin and increase the number and activity of mitochondria in obese mice. Human trials with a formulation of resveratrol with improved bioavailability and with a synthetic SIRT1 activator are in progress.
引用
收藏
页码:403 / 414
页数:12
相关论文
共 86 条
[11]   SirT1 Regulates Energy Metabolism and Response to Caloric Restriction in Mice [J].
Boily, Gino ;
Seifert, Erin L. ;
Bevilacqua, Lisa ;
He, Xiao Hong ;
Sabourin, Guillaume ;
Estey, Carmen ;
Moffat, Cynthia ;
Crawford, Sean ;
Saliba, Sarah ;
Jardine, Karen ;
Xuan, Jian ;
Evans, Meredith ;
Harper, Mary-Ellen ;
McBurney, Michael W. .
PLOS ONE, 2008, 3 (03)
[12]   Phase I dose escalation pharmacokinetic study in healthy volunteers of resveratrol, a potential cancer chemopreventive agent [J].
Boocock, David J. ;
Faust, Guy E. S. ;
Patel, Ketan R. ;
Schinas, Anna M. ;
Brown, Victoria A. ;
Ducharme, Murray P. ;
Booth, Tristan D. ;
Crowell, James A. ;
Perloff, Marjorie ;
Gescher, Andreas J. ;
Steward, William P. ;
Brenner, Dean E. .
CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION, 2007, 16 (06) :1246-1252
[13]   Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic β cells [J].
Bordone, L ;
Motta, MC ;
Picard, F ;
Robinson, A ;
Jhala, US ;
Apfeld, J ;
McDonagh, T ;
Lemieux, M ;
McBurney, M ;
Szilvasi, A ;
Easlon, EJ ;
Lin, SJ ;
Guarente, L .
PLOS BIOLOGY, 2006, 4 (02) :210-220
[14]   Mechanism of human SIRT1 activation by resveratrol [J].
Borra, MT ;
Smith, BC ;
Denu, JM .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (17) :17187-17195
[15]   Stimulation of muscle cell glucose uptake by resveratrol through sirtuins and AMPK [J].
Breen, Danna M. ;
Sanli, Toran ;
Giacca, Adria ;
Tsiani, Evangelia .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2008, 374 (01) :117-122
[16]   Resveratrol content of some wines obtained from dried Valpolicella grapes: Recioto and Amarone [J].
Celotti, E ;
Ferrarini, R ;
Zironi, R ;
Conte, LS .
JOURNAL OF CHROMATOGRAPHY A, 1996, 730 (1-2) :47-52
[17]   Tissue-specific regulation of SIRT1 by calorie restriction [J].
Chen, Danica ;
Bruno, Joanne ;
Easlon, Erin ;
Lin, Su-Ju ;
Cheng, Hwei-Ling ;
Alt, Frederick W. ;
Guarente, Leonard .
GENES & DEVELOPMENT, 2008, 22 (13) :1753-1757
[18]   Calorie restriction increases muscle mitochondrial biogenesis in healthy humans [J].
Civitarese, Anthony E. ;
Carling, Stacy ;
Heilbronn, Leonie K. ;
Hulver, Mathew H. ;
Ukropcova, Barbara ;
Deutsch, Walter A. ;
Smith, Steven R. ;
Ravussin, Eric .
PLOS MEDICINE, 2007, 4 (03) :485-494
[19]   Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase [J].
Cohen, HY ;
Miller, C ;
Bitterman, KJ ;
Wall, NR ;
Hekking, B ;
Kessler, B ;
Howitz, KT ;
Gorospe, M ;
de Cabo, R ;
Sinclair, DA .
SCIENCE, 2004, 305 (5682) :390-392
[20]   Sirtuin gene expression in human mononuclear cells is modulated by caloric restriction [J].
Crujeiras, A. B. ;
Parra, D. ;
Goyenechea, E. ;
Martinez, J. A. .
EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, 2008, 38 (09) :672-678