systems. While diet and obesity are certainly the primary contributors to this problem, the relationship of wine consumption and type 2 diabetes follows the now-familiar J-shaped curve. To some extent this is likely a statistical marker for other healthy behaviors, in that wine drinkers tend to be better educated, exercise more, and eat healthier diets, but recently there has been a convergence of diabetes research and anti-aging. Resveratrol and its derivatives are central to understanding the biochemistry of diabetes on a molecular level.
Type 2 diabetes is characterized by reduced insulin sensitivity and relative insulin deficiency, marked by inflammation in islet cells with deposition of amyloid oligopolymers. Therapies may be based on either enhancing insulin production by targeted reduction of islet cell inflammation or improving insulin sensitivity and glucose metabolism. As with amyloid in neural tissues, resveratrol has an inhibitory effect in islet cells.
An experimental model for diabetes can be produced by administration of streptozotocin, which has specific toxicity for mammalian pancreatic islet cells. Oral administration of resveratrol to streptozotocin-induced diabetic rats for 30 days reduces blood glucose, glycosylated hemoglobin, and downstream markers of diabetes to a degree comparable to standard diabetes medications. Additionally, insulin levels are increased and key enzymes of carbohydrate metabolism are returned to near-normal levels, along with improved hepatic glycogen levels.20 In an obese rat model of metabolic syndrome, long-term administration of resveratrol near-normalizes serum lipids, reverses hypertension, reduces hepatic lipid content, and reduces inflammatory status as measured by increased adiponectin and decreased tumor necrosis factor-alpha. Resveratrol has been shown to improve insulin sensitivity and up-regulate adipokine expression in adipose tissue, which plays an important role in metabolic homeostasis.
Glucose metabolism is mediated by adenosine monophosphate protein (AMP) kinase, an evolutionarily conserved enzyme which regulates cellular glucose uptake. AMP kinase also inhibits cholesterol and triglyceride synthesis and adipocytes lipolysis, and modulates insulin secretion. Mice on a high-fat diet but deficient in AMP kinase do not respond to resveratrol as do wild-type mice, who experience an increase in metabolic rate, insulin sensitivity, and physical endurance along with decreased fat accumulation. This indicates that resveratrol functions as an AMP kinase activator. The adipose-derived cytokine adiponectin, also an AMP kinase activator, is independently up-regulated by resveratrol. Leptin, which regulates appetite and energy expenditure, is elevated in obesity and down-regulated by resveratrol in a dose-dependent manner in isolated adipocytes.
The role of resveratrol in modulating the complex endocrine functions of adipose tissue are still being deciphered, but on balance appear to be beneficial based mostly on in vitro studies. It should be noted that another wine phenolic, quercetin, has also been reported to have anti-diabetic activity via many of the same pathways as resveratrol.
Sirtuins and Lifespan Extension: Is Resveratrol a Sirtuin Activator?
Beyond reduction in the incidence of degenerative and life-threatening diseases, the best-known means of extending lifespan is caloric restriction. This phenomenon has been known for many years, at least on an experimental basis. In order to achieve the effect, a reduction in caloric intake of at least 30-40% from ad libitum consumption is required to produce the change in metabolism that characterizes the effect. Prolongation of natural lifespan in the range of 30% or more, along with reduced incidence of diseases and markers of aging can be achieved in rhesus monkeys. It is believed to be an evolutionary adaptation to periods of famine or environmental stress, and is conserved from primitive organisms to mammals. However, dietary restriction of this magnitude is severe and impractical, so deciphering the underlying mechanisms and means of harnessing these processes has been one of the primary goals of anti-aging research.
Leonard Guarente is credited with the discovery of the epigenetic functions of sirtuins, now known to be the mediators of the caloric restriction phenomenon.21 Sirtuin enzymes are highly conserved evolutionarily, with homologs in all eukaryotic organisms. Sirtuins are histone deacetylases (HDAC’s), whose function is gene activation or silencing, the term deriving from genes known as “silent information regulators.” The sirtuins involved in the caloric restriction effect, known as type III HDAC’s, are nicotinamide adenine dinucleotide (NAD)-dependent, which is how the nutritional environment is sensed. This results in fundamental alterations in mitochondrial biogenesis, primarily in adipose tissue. (“Sirtuin” refers to the enzyme, the abbreviation “Sir” or Sirt” refers to the corresponding gene.)
Figure 4. Sirtuin “family tree”
In addition to promoting longevity, sirtuins mediate a range of healthspan-related effects through actions as diverse as improving insulin sensitivity, neuroendocrine modulation, reducing inflammation, and up-regulation of favorable adipokines. Sirtuins are involved in Alzheimer’s disease, telomere function, and expression of genes related to aging. Targeted activation of sirtuins has become an active frontier of biomedical research.
The tantalizing prospect of sirtuin activation for lifespan extension without caloric restriction appeared in 2003 with a publication claiming an increase in replicative lifespan in Saccharomyces cerevisiae (brewer’s yeast) via activation of sirtuins by resveratrol.22 Using chemical libraries to search for a sirtuin activator, the research group hit upon wine phenolics as a class and resveratrol in particular as the only category with significant activity. A fluorescence assay was used to link sirtuin activation to the resveratrol trigger. Given that sirtuins are evolutionarily conserved and the effect appeared specific, the same process should be repeatable in more complex organisms, and considerable media attention was devoted to the story.
The original findings were quickly followed up with reports of resveratrol activating sirtuins and extending lifespan up the phylogenetic ladder. The effect was seen in the roundworm Caenorhabditis elegans and the fruitfly Drosophila, and the homologous SIR genes identified (Sir1 and dSir2, respectively.) An important next step up the ladder is vertebrates, with a convenient model being a short-lived type of fish called Nothobranchius, with a similar response.
In mice however the lifespan extension phenomenon could not be duplicated, though several other favorable results were observed. Specifically, resveratrol countered the effect of a toxic high fat diet, leading to normalization of liver function and metabolic parameters, and prevented the premature death normally associated with murine obesity. Exercise tolerance was increased with a resveratrol-enhanced diet, and in primates early signs are that degenerative diseases are lessened. However, the hope for lifespan extension with resveratrol supplementation began to be questioned.
An early challenge came from failure to replicate the original results from yeast cells in other labs. The effect was noted to be substrate-specific and culture strain-specific. The fluorescence assay was questioned as producing possibly artifactual results, in that sirtuins could be made to fluoresce by resveratrol without being active. The improvements in the mice on the high fat diet were explained as a simple, if potent antioxidant effect to counter the hepatotoxicity of the specific fatty diet. Furthermore, roundworms have been shown to live longer in a bath of the antioxidant enzyme superoxide dismutase (SOD), indicating that for some primitive organisms life can be extended without sirtuin activation. Despite these contradictory findings, research labs around the world began to work on resveratrol and resveratrol derivatives, with the hope of finding variants with greater efficacy and specific clinical applications.
Additionally, clinical trials were instituted on several fronts, including Alzheimer’s disease (NCT00678431, recruiting as of January 2010, and NCT00743743, not yet recruiting); diabetes (NCT01158417, recruiting); melanoma (NCT00721877, closed); colon cancer (NCT00920803, closed, and NCT00256334, recruiting), and others. In November 2010, however, GlaxoSmithKline announced the abrupt suspension of a clinical trial with the promising resveratrol
