Dietary activators of Sirt1
Introduction
The search for mechanisms behind the lifespan extension effect of reduced caloric intake has been ongoing since McCay's first demonstration that calorie restriction (CR) by limiting caloric intake to 60–70% of an ad libitum diet extends the life of rodents (McCay et al., 1989). Since then, CR has been shown to have a lengthening effect on the lifespan of a number of species ranging from yeast (Lin et al., 2000) to dogs (Lawler et al., 2007) and possibly even primates (Ingram et al., 2006). Theories on the possible mechanisms involved in these lifespan extending effects have been intensively investigated, many of which have been shown to play at least some role in the CR effect. Some of these theories include decreased oxidative damage, altered glucose utilization, increased insulin sensitivity, neuroendocrine changes, enhanced stress responsiveness, hormesis, and changes in gene expression. One of the compelling findings has been the association between increased levels of sirtuins and the lifespan extension effect of CR. Sirtuins are members of the silent information regulator 2 (Sir2) family, a family of Class III histone/protein deacetylases (HDACs). The enzymatic activity of most sirtuins has been shown to be dependent on nicotinamide dinucleotide (NAD), suggesting that the activity of these enzymes is dependent on the nutritive state of the organism. Members of this family of deacetylases include five homologues in yeast (Sir2 and Hst1–4), Sir2.1 in Caenorhabditis elegans, dSir2 in Drosophila melanogaster and seven mammalian sirtuins (Sirt1–7) (Dali-Youcef et al., 2007, Frye, 1999).
Section snippets
CR and sirtuins in Saccharomyces cerevisiae
The activity of Sir2 was first shown to regulate lifespan in S. cerevisiae. In 2000, Guarente's lab discovered that Sir2 was a requirement for the increase in replicative lifespan by CR which was achieved by limiting the concentration of glucose (2–0.5%) in yeast cultures (Lin et al., 2000, Lin et al., 2002). CR in yeast by amino acid depletion also affects replicative lifespan, although the effect differed among three different histone deacetylase mutants (Jiang et al., 2002). Other Sir2
CR and sirtuins in C. elegans and D. melanogaster
In C. elegans, CR can be achieved by either diluting its food source, bacteria, or by a mutation in the EAT2 gene which affects pharyngeal function and leads to reduction of food intake (Lakowski and Hekimi, 1998). Each of these methods of CR extends lifespan in worms (Klass, 1977, Vanfleteren and Braeckman, 1999). The lifespan extension in C. elegans induced by CR has been shown to be dependent on Sir2.1 (Wang and Tissenbaum, 2006). In addition, a duplication of the Sir2.1 gene in C. elegans
CR and sirtuins in vertebrates
For more than 70 years CR has been shown to increase lifespan in mammals, yet its effect on human lifespan is still not known. One complicating factor is the unlikely probability of maintaining such a lifestyle on a long-term basis. The belief that many of the benefits of CR are due to the induction and activation of sirtuins has led to the search for sirtuin activators that may be used as dietary supplements to promote health and longevity. Sirt1 is the most extensively studied of the seven
Dietary supplements and Sirt1
There have been studies assessing the ability of different nutritive supplements to induce Sirt1 activity. Sirt1 mRNA levels were shown to increase in adipose tissue with a 16-week treatment of a combination of ephedrine, caffeine and the anti-diabetic drug Pioglitazone in nondiabetic human subjects (Bogacka et al., 2007).
It has been assumed for many years that consumption of fish on a regular basis protects from cardiovascular disease (Bang, 1990). Several studies have shown that omega-3 fatty
Plant polyphenols
Polyphenols are the most abundant antioxidants found in food. They are known to have a protective effect against cardiovascular diseases (Basu and Lucas, 2007) and cancers (Bracke et al., 2008, Kampa et al., 2007) and there is some evidence of neuroprotective effects (Singh et al., 2008, West et al., 2007). Sinclair and colleagues examined a set of plant polyphenols for their effect on Sirt1 catalytic rate. These sirtuin-activating compounds (STACs) included butein, piceatannol, fisetin,
Other Sirt1 activators
A recent study has described the identification and characterization of small molecule activators of Sirt1 that are structurally unrelated to, and 1000-fold more potent than resveratrol. These compounds bind to the Sirt1 enzyme–peptide substrate complex and enhance the catalytic activity. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose and increase mitochondrial capacity (Milne et al., 2007).
Summary
Like CR, resveratrol has been reported to extend lifespan in organisms ranging from yeast to mice fed high-fat diets. Sir2 and its mammalian homolog Sirt1 have been shown to mediate many of the health benefits including the life-extending effects of CR. Whether the beneficial effects of resveratrol and other polyphenols in mammals are mainly mediated through Sirt1 remains unclear. Resveratrol does have other cellular targets including cyclooxygenases, lipooxygenases, kinases, ribonucleotide
Acknowledgement
This research was supported by the National Institute on Aging Intramural Research Program.
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