S imilar effects were observed in wild type mice but not their peroxisome proliferatoractivated recep tor counterpar ts.These resu lts suggest that RESV is ab le to penetrate thebloodbrain barrier and that it exer ts strong neuroprotective effects, even at low doses, after strokeor neurotoxic injury.Inbred knockout mice that lack SIRT show developmen tal defects and have a low surv ival rate and a sign ificantly shorter lifespan compared with wild type mice, although out breeding seems to improve the phenotype sign ificantly. It has been postulated that the main function of sirtuin proteins is to promote survival and stress resistance in times of adversity.An evolu tionary advan tage arising from the ability to modify lifespan in response to environmen tal conditions could have allowed these enzymes to be conserved among all species, and to take on new functions in response to new stresses and demands on the organism.This cou ld explain why the same familyof enzymes has dramatic effects on lifespan in disparate organisms with seeming ly dissimilar causes of ag ing.The data from lower organisms have provoked in tense research into the function of sirtuin proteins in mammalian systems.An in vitro screen for activators of SIRT identified RESV as the most potent of inducers of deacety lase activ ity.The importance of substrate choice in vitro highlights the possibility that RESV might alter the substrate specif icityof SIRT in vivo.Previous studies suggest that Olmesartan antiox idant enzymes such as catalase and superoxide dismutase could induce lifespan ex tension.However, the efficacy of antioxidantdrugs as antiag ing molecu les is unclear because the ex tensions to lifespan could be abolished in the Olmesartan presence of ROS. Thus, it could be argued that the potential beneficial effects of RESV on aging are not exclusively mediated by its antioxidant properties.Recentstud ies have also demonstrated that the positive effects of RESV on aging tissues, specifically brain, heart and skeletal muscle, were not associated with an increase in SIRT expression.Thus, it has been proposed that the antiaging effects of RESV may be independent of SIRT activ ity.Atall even ts, the complexity of the mechanism of action of RESV is increasing, since recentdata suggest that the administration of RESV does not reduce the levelsof oxidative stress markers of DNA damage.Therefore, it is also not clear how RESV and dietary restr iction increase life span, although it has been proposed that mTOR activation might constitute an additional pathway involved in th is process that is activated by food depr ivation.Further in depth stud ies are required regarding the potential in teraction between RESV and mTOR activation. Of particular interest is the fact that SIRT not only deacetylateshistones to med iate gene silencing, but is ab le to interact with and deacety late some wellknown transcrip tional regulators, thereby specif ically modulating various biolog ical processes. Hence, modulating the expression of SIRT or its activity by using sirtu inactivating compounds such as RESV will have pleio tropic effects.SIRT is a major modulatorof metabolism and also seems to be endowed with neuroprotective activ ities, as suggested by research with models of HD or AD.

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