Resveratrol and the Pharmacology of Aging: A New Vertebrate Model to Validate an Old Molecule

Abstract

The natural phytoalexin resveratrol, found in grapes and red wine, recently rose to public fame for its positive effects on longevity in yeasts, worms and flies. Resveratrol anti-cancer and anti-inflammatory in vitro action on mammalian cell cultures also suggest a possible positive effect on human health and life-expectancy. To study the effects of resveratrol on vertebrate aging is obviously a particularly relevant question. We have studied resveratrol effects in a very short-lived vertebrate: the annual fish Nothobranchius furzeri. Resveratrol treatment prolonged lifespan and delayed the onset of age-related dysfunctions in this fish. This result identifies resveratrol as the first molecule which consistently retards aging in organisms as diverse as yeast, worm, fly and fish, but it also reveals the potential of this short-lived fish as an animal model for pharmacological research. Moreover, being related to stickleback (Gasterosteus aculeatus) the "pufferfishes" Takifugu and Tetraodon, and even more closely related to medaka (Oryzias latipes), it can greatly beneficiate from the recent development of genomic resources for these fish models and in the future become a complete model system for the aging research community. PHARMACOLOGY OF AGINGThe identification of molecules which can prevent the occurrence of age-related pathologies is a remarkably important issue for contemporary medical research. However, any pharmacological research on aging needs to face the hurdle imposed by the lifespan of the available model organisms which prevents the possibility of large-scale drug discovery.All these difficulties notwithstanding, several small molecules were identified which increase lifespan of model organisms when administered with food. Some of these compounds, like ethoxyquin, 1 have toxic effects, and are able only to increase lifespan of short-lived mouse strains. Others, like deprenyl, 2,3 are psychoactive drugs and are classifies as control substance.One popular theory often invoked to explain the mechanisms of aging is the free radical theory of aging, 4 which identifies in the production of reactive oxygen species from the mitochondria the pivotal mechanism for aging initiation and progression. The importance of free radical produced by the mitochondria for vertebrate aging, is strongly suggested by the extension of lifespan and retardation of aging achieved by reducing oxidative stress through overexpression of human catalase in mice mitochondria, 5 and by the recent report that the p66shc adaptor protein gene, whose deletion causes significant life extension in mice, 6,7 can generate reactive oxygen species by a direct interaction with cytochrome c.This theory predicts that exogenously-supplied antioxidants will produce life extension. Several antioxidants such as Lipoic Acid, 8 butylated hydroxytoluene, 9 N-acetylcysteine, 10 sodium solenite, 11 sodium hypophosphite, 12 were all found, indeed, to increase lifespan in Drosophila, whereas life-extension was induced in nematodes by Ginko biloba ex...

Resveratrol: From Basic Science to the Clinic

“…Experimental observations confirmed this hypothesis, demonstrating that the polyphenol is able to slow senescence in all the organisms investigated, including yeast, 162 Caenorhabdytis elegans, 171 Drosophila melanogaster 171,172 and the fish Nothobranchius furzeri. 173 Moreover, the effect was abrogated when nutrients are limited, thus confirming that resveratrol modulates the ageing process by mechanisms related to caloric restriction, possibly by the sirtuin activation.…”

“…As discussed before, the strategies employed in these reports 173,174 are different, but the protection against high-fat diet is evident in both the studies. These results seem to be due to Sirt2 activation, but conclusive results are not obtained.…”

“…Very recently, studies by Lagouge et al 174 and Baur et al 175 have demonstrated that the phytoalexin not only increases longevity 162,[171][172][173] but also improves glucose homeostasis in mice. Moreover, both the studies suggest that these effects are due to the increased activity of PGC-1a due to the resveratrol-dependent activation of SIRT1.…”

Resveratrol prevents streptozotocin-induced diabetes by inhibiting the apoptosis of pancreatic β-cell and the cleavage of poly (ADP-ribose) polymerase

“…Many studies have shown that RSV has a wide variety of benefits in preventing illnesses such as cardiovascular disease and ischemic injuries, cancer, and in prolonging the lifespan of various organisms [7][8][9][10]. One report revealed that RSV has antihyperglycemic and antihypertriglyceridemic effects in diabetic rats [11].…”

El resveratrol protege contra la respuesta inflamatoria en páncreas secundaria al envejecimiento

“…En modelos animales se ha demostrado que la administración de resveratrol puede prolongar la esperanza de vida (Valenzano et al, 2006) debido a sus efectos de protección cardiovascular en modelos de lesión miocardio (Hattori et al, 2002;Juric et al, 2007;Gurusamy et al, 2010) hipertensión (Juric et al, 2007;) y diabetes tipo 2 (Zhang et al, 2009;Zhang et al,2010).…”