9E Health-Promoting Effects of Wine Phenolics 581
silencing at telomeres, DNA repair, and ribosomal DNA recombination (Guar-
ente 1999; Imai et al. 2000). Caloric restriction has been shown to extend life
span through activation of the silencing information regulator 2 (Sir2) gene inSac-
charomyces cerevisiae(Lin et al. 2000) andCaenorhabditis elegans(Tissenbaum
and Guarente 2001). The human homologof Sir2, SIRT1, is a p53 deacetylase
that promotes cell survival by negatively regulating the p53 tumor suppressor (Luo
et al. 2001; Vaziri et al. 2001). Inducing SIRT1 expression by caloric restriction
promotes long-term survival of mammalian cells (Cohen et al. 2004). Recently it
has been shown that SIRT1 controls the gluconeogenesis/glycolytic pathway in the
liver in response to fasting signals through the transcriptional coactivator of PGC-1
(Rodgers et al. 2005), suggesting a role for SIRT1 in energy metabolism, diabetes,
and life span. Thus, the use of molecules that trigger SIRT1 activity, mimicking the
effect of caloric restriction, would allow individuals to eat normally while the body
responds as though food were in short supply. Different plant polyphenols have been
found to stimulate SIRT1 activity; these include quercetin, piceatannol, and resver-
atrol (de Boer et al. 2006; Howitz et al. 2003). These and other compounds were
found to have a chemical structure similar to that of thetransstilbene ring. Thus, the
transstilbene resveratrol showed the highest stimulation of SIRT1 activity (Howitz
et al. 2003). Resveratrol has since been demonstrated to effectively extend life span
in different species, includingS. cerevisiae(Howitz et al. 2003),C. elegans,andthe
fruit flyDrosophila melanogaster(Wood et al. 2004), an effect that is dependent on
the Sir2 gene. In mammals, resveratrol has been shown to exert a protective effect
in several disease models, including cancer and diabetes (Garvin et al. 2006; Su
et al. 2006). The SIRT1 pathway also improves health and survival in mice on high-
calorie diets (Baur et al. 2006) and protects against neurodegeneration in mouse
models of Alzheimer’s disease and amyotrophic lateral sclerosis (Kim et al. 2007).
The amount of resveratrol in grapes and red wine, however, is relatively low and
depends on several strain-related and environmental factors, which together with
the low bioavailability of resveratrol in mammals, its low solubility, and sensitivity
to light and oxidation (Yang et al. 2007), may limit the achievement of target plasma
concentrations from normal food ingestion. Also, although it has been shown that
polyphenols protect against several pathological processes associated with aging
and have remarkable effects mimicking caloric restriction in vitro and in animal
models, it is not known whether resveratrol or other SIRT1 activators can extend life
span in humans. Further proof that a drug extends life span would require difficult,
extended clinical trials. Nevertheless, this promising effect of resveratrol along with
the other cardioprotective effects of wine polyphenols support the contention that
moderate wine consumption is health promoting.
The beneficial effects of wine may not be attributable to a single polyphenol
but rather to the complex mixture of polyphenols it contains. There is evidence
that antioxidant properties underlie most of the effects of wine, but at the same
time, certain effects cannot be mimicked by common dietary antioxidants. Although
polyphenols are not apanacea, those present in red grape and its derivatives appear
to exert beneficial effects on health.