History of Resveratrol
 trans-Resveratrol - First identified as the active component in C. quinquangulata (cinnamon) extract responsible for anti-inflammatory properties.
- Normally used as a defense mechanism in plants in response to fungal pathogens and UV irradiation.
- Main source in human diet is red wine, but significant amounts are also found in grape juice, peanuts, cranberry juice, and other sources.
- There is a tremendous interest in the potential of resveratrol for various health benefits. A PubMed search for 'resveratrol' returns 2,470 scientific articles.
Resveratrol and Yeast
 Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. - Resveratrol has been extensively investigated in the Saccharomyces cerevesiae model system. In August 2003, Sinclair and Scherer reported 70% increase in yeast lifespan after induction with 10uM resveratrol.
- "In the budding yeast Saccharomyces cerevisiae, calorie restriction extends lifespan by increasing the activity of Sir2, a member of the conserved sirtuin family of NAD+-dependent protein deacetylases2, 3, 4, 5, 6. Included in this family are SIR-2.1, a Caenorhabditis elegans enzyme that regulates lifespan7, and SIRT1, a human deacetylase that promotes cell survival by negatively regulating the p53 tumour suppressor. the potent activator resveratrol, a polyphenol found in red wine, lowers the Michaelis constant of SIRT1 for both the acetylated substrate and NAD+, and increases cell survival by stimulating SIRT1-dependent deacetylation of p53."
 Resveratrol has been shown to provide a wealth of health benefits. Health Benefits of Resveratrol
- Improved cardiovascular function: resveratrol has been shown to have cardioprotective effects such as the suppression of atherosclerosis, inhibition of platelet aggregation, vasorelaxation promotion, and modulation of triglyceride blood levels, in a wide variety of in vitro and in vivo models [1-4].
- Inhibition of carcinogenesis: one well-documented effect of resveratrol is the ability to induce cell death specifically in cancerous cells. This property of resveratrol has been shown for a wide variety of cancers, including colon cancer [5-7], pancreatic cancer [8], prostate cancer [9,10], breast cancer [11,12], and skin cancer [13,14]. In fact, several phase I human clinical trials are investigating the administration of resveratrol as a cancer therapy [15,16]
- Upregulates the antioxidant systems of cells, such as SuperOxide Dismutase and glutathione, and these cells are protected against oxidative damage [16,17].
- Resveratrol decreases several modes of inflammation [18-21].
- Maintenance of neural pathways: mouse models of Alzheimers and Parkinsons demonstrate the potential of resveratrol as a neuroprotective agent in degenerative neural diseases [22,23]. Experiments with rats, mice, and gerbils show that resveratrol administration protects against brain damage following ischemic stroke [24-26].
- Improves insulin sensitivity: resveratrol has been shown as a potent therapeutic for type 2 diabetes [27]. Pharmaceuticals based on resveratrol-like compounds for the treatment of diabetes are currently in Phase I clinical trials [28].
- Mimics caloric restriction in mammals and is proven to extend lifespans in invertebrates [29,30], a fish model [31] and is shown to reduce the genetic changes associated with aging in a mammalian mouse model [4,32].
 Why resveratrol in beer?
-Beer made up 85.8% of all alcoholic beverage consumption (in total volume) in 2005.
-->Annual per capita consumption of Beer (2005) = ~20 gallons
-->Annual per capita consumption of Wine (2005) = ~2.5 gallons
-If resveratrol can be produced during fermentation, it provides an additional health benefit at no additional cost.
-->The resveratrol is produced in a ready-to-consume format!
-->Dark and anaerobic conditions required for fermentation improve resveratrol stability.
References
1: Samuel SM, et al. Akt/FOXO3a/SIRT1-mediated cardioprotection by n-tyrosol against ischemic stress in rat in vivo model of myocardial infarction: switching gears toward survival and longevity. J Agric Food Chem. 2008 Oct 22;56(20):9692-8. Epub 2008 Oct 1. PMID: 18826227 [PubMed - in process].
2: Hwang JT, et al. Resveratrol protects ROS-induced cell death by activating AMPK in H9c2 cardiac
muscle cells.
Genes Nutr. 2008 Feb;2(4):323-6.
PMID: 18850225 [PubMed - in process]
3: Gresele P, et al. Resveratrol, at concentrations attainable with moderate wine consumption,
stimulates human platelet nitric oxide production.
J Nutr. 2008 Sep;138(9):1602-8.
PMID: 18716157 [PubMed - indexed for MEDLINE]
4: Barger JL, et al. A low dose of dietary resveratrol partially mimics caloric restriction and
retards aging parameters in mice.
PLoS ONE. 2008 Jun 4;3(6):e2264.
PMID: 18523577 [PubMed - indexed for MEDLINE]
5: Juan ME, et al. Resveratrol induces apoptosis through ROS-dependent mitochondria pathway in HT-29 human colorectal carcinoma cells.
J Agric Food Chem. 2008 Jun 25;56(12):4813-8. Epub 2008 Jun 4.
PMID: 18522405 [PubMed - indexed for MEDLINE]
6: Saiko P, et al. Novel resveratrol analogs induce apoptosis and cause cell cycle arrest in HT29
human colon cancer cells: inhibition of ribonucleotide reductase activity.
Oncol Rep. 2008 Jun;19(6):1621-6.
PMID: 18497974 [PubMed - indexed for MEDLINE]
7: Marel AK, et al. Inhibitory effects of trans-resveratrol analogs molecules on the proliferation and the cell cycle progression of human colon tumoral cells.
Mol Nutr Food Res. 2008 May;52(5):538-48.
PMID: 18384089 [PubMed - indexed for MEDLINE]
8: Bernhaus A, et al. Antitumor effects of KITC, a new resveratrol derivative, in AsPC-1 and BxPC-3 human pancreatic carcinoma cells. Invest New Drugs. 2008 Oct 8. [Epub ahead of print]
PMID: 18841326 [PubMed - as supplied by publisher]
9: Seeni A, et al. Suppression of Prostate Cancer Growth by Resveratrol in The Transgenic Rat for Adenocarcinoma of Prostate (TRAP) Model.
Asian Pac J Cancer Prev. 2008 Jan-Mar;9(1):7-14.
PMID: 18439064 [PubMed - in process]
10: Horvath Z, et al. Novel resveratrol derivatives induce apoptosis and cause cell cycle arrest in prostate cancer cell lines.
Anticancer Res. 2007 Sep-Oct;27(5A):3459-64.
PMID: 17970095 [PubMed - indexed for MEDLINE]
11: Filomeni G, et al. trans-Resveratrol induces apoptosis in human breast cancer cells MCF-7 by the activation of MAP kinases pathways.
Genes Nutr. 2007 Dec;2(3):295-305. Epub 2007 Oct 18.
PMID: 18850184 [PubMed - in process]
12: Schlachterman A, et al. Combined resveratrol, quercetin, and catechin treatment reduces breast tumor growth in a nude mouse model.
Transl Oncol. 2008 Mar;1(1):19-27.
PMID: 18607509 [PubMed - in process]
13: Jang M, Cai L, et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes.
Science. 1997 Jan 10;275(5297):218-20.
PMID: 8985016 [PubMed - indexed for MEDLINE]
14: van Ginkel PR, et al. Resveratrol inhibits uveal melanoma tumor growth via early mitochondrial dysfunction.
Invest Ophthalmol Vis Sci. 2008 Apr;49(4):1299-306.
PMID: 18385041 [PubMed - indexed for MEDLINE]
15: http://www.clinicaltrials.gov/ct/show/NCT00256334
16: http://www.cancer.gov/clinicaltrials/CCUM-2004-0535
17: Ellen L. Robb, et al. Molecular mechanisms of oxidative stress resistance induced by resveratrol: Specific and progressive induction of MnSOD, Biocehm and Biophys Res Comm, 2008
18: Kode A, et al. (2007). "Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells". Am J Physiol Lung Cell Mol Physiol.. doi:10.1152 (inactive 2008-06-20). PMID 18162601.
19: Venkatachalam K, et al. Resveratrol inhibits high glucose-induced PI3K/Akt/ERK-dependent interleukin-17 expression in primary mouse cardiac fibroblasts.
Am J Physiol Heart Circ Physiol. 2008 May;294(5):H2078-87. Epub 2008 Feb 29.
PMID: 18310510 [PubMed - indexed for MEDLINE]
20: Zhu J, et al. Anti-inflammatory effect of resveratrol on TNF-alpha-induced MCP-1 expression in adipocytes.
Biochem Biophys Res Commun. 2008 May 2;369(2):471-7. Epub 2008 Feb 20.
PMID: 18291098 [PubMed - indexed for MEDLINE]
21: Kennedy A, et al. Conjugated linoleic acid-mediated inflammation and insulin resistance in human adipocytes are attenuated by resveratrol.
J Lipid Res. 2008 Sep 5. [Epub ahead of print]
PMID: 18776171 [PubMed - as supplied by publisher]
22: Kim D, et al. SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis.
EMBO J. 2007 Jul 11;26(13):3169-79. Epub 2007 Jun 21.
PMID: 17581637 [PubMed - indexed for MEDLINE]
23: Jin F, et al. Neuroprotective effect of resveratrol on 6-OHDA-induced Parkinson's disease in rats.
Eur J Pharmacol. 2008 Oct 10. [Epub ahead of print]
PMID: 18940189 [PubMed - as supplied by publisher]
24: Sinha K, et al. Protective effect of resveratrol against oxidative stress in middle cerebral
artery occlusion model of stroke in rats.
Life Sci. 2002 Jun 28;71(6):655-65.
PMID: 12072154 [PubMed - indexed for MEDLINE]
25: Inoue H, et al. Brain protection by resveratrol and fenofibrate against stroke requires
peroxisome proliferator-activated receptor alpha in mice.
Neurosci Lett. 2003 Dec 11;352(3):203-6.
PMID: 14625020 [PubMed - indexed for MEDLINE]
26: Wang Q, et al. Resveratrol protects against global cerebral ischemic injury in gerbils.
Brain Res. 2002 Dec 27;958(2):439-47.
PMID: 12470882 [PubMed - indexed for MEDLINE]
27: Milne JC, et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes.
Nature. 2007 Nov 29;450(7170):712-6.
PMID: 18046409 [PubMed - indexed for MEDLINE]
28: http://www.sirtrispharma.com/pipeline-SRT501.html
29: Howitz KT, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan.
Nature. 2003 Sep 11;425(6954):191-6. Epub 2003 Aug 24.
PMID: 12939617 [PubMed - indexed for MEDLINE]
30: Wood JG, et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans.
Nature. 2004 Aug 5;430(7000):686-9.
PMID: 15254550 [PubMed - indexed for MEDLINE]
31: Valenzano DR, et al. Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate.
Curr Biol. 2006 Feb 7;16(3):296-300.
PMID: 16461283 [PubMed - indexed for MEDLINE]
32: Baur JA, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006 Nov 16;444(7117):337-42. Epub 2006 Nov 1.
PMID: 17086191 [PubMed - indexed for MEDLINE]
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