biological activities of resveratrol
DESCRIPTION
Biological Activities of ResveratrolTRANSCRIPT
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Biological activities of resveratrol
1 The research program: cell and molecular biology of longevity1. The research program: cell and molecular biology of longevity
2. Biological activities of resveratrol in mammals (including humans)
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Animal lifespans
S l d s CenturiesSeveral days Centuries
lifespan Harriet, who died on Friday, June 23, 2006 at the age of 176 years is said to be the
The mayflyLifespan: ~ 1day!
oldest animal in captivity, according to the Guinness Book of Records.(AP/Australia Zoo)
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y = 6.4471x0.138
R2 0 3395
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Log Adult Mass (g)Log Adult Mass (g)
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Why?
How?
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Cells of longer-lived animals are
hard to kill
- increased cellular t i t i stress resistance in
longer-lived animals
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Stress resistance of skin fibroblasts correlates with species MLSP
Kapahi et al., 1999, Free Radic. Biol. Med.
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Long-lived Snell dwarf mice have t i t t fib bl tstress resistant fibroblasts
Snell & normal mouse lifespan plot Snell cells resistant to stressors
Murakami et al., Am. J. Physiol. 2003
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Species-omics
Identifying cellular characteristics that co-evolve with longevity and might explain stress resistanceg p
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Molecular mechanisms underlying longevity in animals
Two experimental models:Two experimental models:
(1) The long-lived Snell dwarf mouse
(2) A comparative model using mammalian and avian species(2) A comparative model using mammalian and avian species
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What have we learned?
C ll l h t isti s C ll l h t isti s Cellular characteristics that do not correlate,
or correlate negatively, with longevity
Cellular characteristics that correlate
positively with longevitywith longevity
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MnSOD correlates with longevity
Dermal fibroblasts
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MnSOD correlates with longevity
mammalian brain tissue
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MnSOD prevents cytochrome c release during cell stress
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Cytochrome c is a key cell death signal
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Ellen Robb, PhD candidate
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Resveratrol does everything!
Anti-cancer activity
Anti-oxidant
Anti aging Anti-aging
Neuroprotective
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What is the effect on human cells of long-term exposure to resveratrol?
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No effect of resveratrol on most antioxidant enzymes
t li id di te.g. cytosolic superoxide dismutase
0, 50 or 100 M trans-resveratrol
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But, a huge effect on MnSOD!
0, 50 or 100 M trans-resveratrol
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MnSOD effect observed in a wide variety of cell typese
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myoblasts Neuroblastoma cells
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Proof that this matters?
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Greater MnSOD levels paralleled by greater cellular stress resistance
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ResveratrolControl
Figure 1: Chronicexposureofmusclecells,lungcellsandneuralcellsto50Mresveratrolaffordsprotectionagainstcelldeathinducedbytheoxidativestressorsp g yhydrogenperoxideandparaquat.DatapointrepresentsLD50foragiventoxin,Cellsurvivalwasevaluatedbytrypanblueexclusion.Datarepresentsthemeanof5independentmeasurements SEM.*=P
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Greater MnSOD levels paralleled by greater cellular stress resistance
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Figure 1: Chronicexposureofmusclecells,lungcellsandneuralcellsto50Mresveratrolaffordsprotectionagainstcelldeathinducedbytheoxidativestressorshydrogenperoxideandparaquat.DatapointrepresentsLD50foragiventoxin,Cellsurvivalwasevaluatedbytrypanblueexclusion.Datarepresentsthemeanof5independentmeasurements SEM.*=P
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Greater MnSOD levels paralleled by reduced replicative growth rate
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Human lung fibroblast cells
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How is resveratrol regulating MnSOD levels?
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Resveratrol is a phytoestrogen
R t lResveratrol
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Estrogen (estradiol) elicits a similar MnSOD effect
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50uM RES
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Lung fibroblasts; 72 hours incubation
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An estrogen receptor inhibitor abolishes (nearly) effects of resveratrol or estradiol on MnSOD
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resveratrol + ICI
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Lung fibroblasts; 72 hours incubation
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An ER beta agonist, but not an ER alpha agonist reproduces resveratrol effect on MnSOD
2,3-bis(4-hydroxyphenyl) proprionitrile (DPN)
propylpyrazole triol (PPT)
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Our working model
ER Cytosol
MAPKERK1/2
NFBNFB
MnSOD alteredROSmetabolism
Nucleus
MnSOD antiapoptoticMnSOD
Othergenes Mitochondria
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Delivering results
Problems with resveratrol bioavailability
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Dietary resveratrol delivery in mice
Increasing brain MnSOD
Jonathon Brotchie
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Dietary resveratrol delivery in mice
Increasing brain MnSOD
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Silicon nanocapsule delivery of resveratrol with Paul Zelisko
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Conclusions
In human cells resveratrol interacts with ERbeta Transcriptional upregulation of MnSOD (progressive and big!) Increased MnSOD makes mitochondria resistant to cyt c releaseIncreased MnSOD makes mitochondria resistant to cyt c release Increased MnSOD alters mitochondrial reactive oxygen metabolism Altered ROS metabolism influences cell replication (signal) Red wine consumption provides low amount of bioavailable resveratrolp p Resveratrol-mediated MnSOD induction assisted by delivering in lipid Maybe promote also using silicon nanocapsules (more work)
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Future goals
Refine strategy to increase RES bioavailability (RES supplemented wines?)
Explore related polyphenols & phytoestrogens (-quercetin does not work similarly)
E l f RE b l Explore activities of RES metabolites
Human trials?
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This work was done by:
Kurtis Salway, M.Sc. candidate
Melissa Page, PhD candidate
Ellen Robb, PhD candidate
Melanie Brown, M.Sc.
Our research is supported by: