7 replies to this topic

[niner]

A while ago I read about autopsies done on extremely old (110+) people. There's one doctor who has done a bunch of them, and he noted that they all had extensive systemic amyloid deposits. Not just in the brain, a la Alzheimer's, but everywhere. Hmm. sounds bad, I thought. Tonight my wife and I were sitting at the dinner table, and between bursts of noise from our 2 small boys, I was describing to her the structure of resveratrol. Then she said "that sounds like diethylstilbestrol. have they done repro tox on it?" (It's really cool to be able to have this kind of conversation at home...) So I was just doing some research on that question, and I ran across a nice paper about Transthyretin, the protein responsible for much of this amyloidosis. Turns out that resveratrol is one of a number of compounds (including DES) that inhibit the formation of transthyretin fibrils. The full text paper is here: http://www.jbc.org/c...ll/279/51/53483 Another paper is abstracted below. Resveratrol is probably not the last word in amyloidosis prevention, any more than it's the last word in sirtuin activation, due to its rapid conjugation and attendant poor bioavailability. Nevertheless it's a nice effect!

Nat Struct Biol. 2000 Apr;7(4):312-21.
Erratum in: Nat Struct Biol 2000 May;7(5):431.
Comment in: Nat Struct Biol. 2000 Apr;7(4):259-60.

Rational design of potent human transthyretin amyloid disease inhibitors.

Klabunde T, Petrassi HM, Oza VB, Raman P, Kelly JW, Sacchettini JC.

Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843, USA.

The human amyloid disorders, familial amyloid polyneuropathy, familial amyloid cardiomyopathy and senile systemic amyloidosis, are caused by insoluble transthyretin (TTR) fibrils, which deposit in the peripheral nerves and heart tissue. Several nonsteroidal anti-inflammatory drugs and structurally similar compounds have been found to strongly inhibit the formation of TTR amyloid fibrils in vitro. These include flufenamic acid, diclofenac, flurbiprofen, and resveratrol. Crystal structures of the protein-drug complexes have been determined to allow detailed analyses of the protein-drug interactions that stabilize the native tetrameric conformation of TTR and inhibit the formation of amyloidogenic TTR. Using a structure-based drug design approach ortho-trifluormethylphenyl anthranilic acid and N-(meta-trifluoromethylphenyl) phenoxazine 4, 6-dicarboxylic acid have been discovered to be very potent and specific TTR fibril formation inhibitors. This research provides a rationale for a chemotherapeutic approach for the treatment of TTR-associated amyloid diseases.

PMID: 10742177

[bgwowk]

Holy cow.

[Ghostrider]

Sounds like the buy one, get one free affect :-). I really look forward to hearing about followup research on this supp.

[maxwatt]

Resveratrol is probably not the last word in amyloidosis prevention, any more than it's the last word in sirtuin activation, due to its rapid conjugation and attendant poor bioavailability.

Yet resveratrol has strong in vivo effects in mice. The conjugation is conversion to a glycocide in the liver, no? This makes it water-soluble, and if I remember and understand what I gleaned in reading, this is the molecule that is transported into the cell where it docks with the SIRT genes, activating them. The genes stay activated for how long? Hours, days, weeks? It would appear that there is a saturation level, where most, or all of an organism's cells have their SIRT genes activated, and resveratrol intake will match the rate of deactivation.

This omits the fact that there are seven known SIRTs, some in the nucleus, three in the mitochondria, one in the nucleolus..... and that the known sirtuins activate them in different ratios!!!

[niner]

Yet resveratrol has strong in vivo effects in mice. The conjugation is conversion to a glycocide in the liver, no? This makes it water-soluble, and if I remember and understand what I gleaned in reading, this is the molecule that is transported into the cell where it docks with the SIRT genes, activating them. The genes stay activated for how long? Hours, days, weeks? It would appear that there is a saturation level, where most, or all of an organism's cells have their SIRT genes activated, and resveratrol intake will match the rate of deactivation.

This omits the fact that there are seven known SIRTs, some in the nucleus, three in the mitochondria, one in the nucleolus..... and that the known sirtuins activate them in different ratios!!!

It is both glycosylated and sulfated, with sulfation dominating, I think. Levels of free (unconjugated) resveratrol have been measured in serum at something less than 2% of the total dose. It may be that the entire effect is due only to this tiny amount of free resveratrol, or possibly one or more of the metabolites are active. I'm pretty sure that the question of active metabolites is being/has been looked at, but I haven't seen anything on it yet. The conjugates are probably not getting into cells in appreciable quantities. I'm pretty sure that the sirtuin activation is due to simple binding, and not to a covalent modification, so I doubt that the activation lasts longer than the resveratrol is around. If resveratrol were actively transported into cells, and not pumped out, then it might be possible to saturate them, in effect, with more resveratrol than was in the extracellular fluid. I don't know that's the case, though. The fact that the Sirtris compound that's acetylated in the 4' position is both inactive in vitro and more active in vivo than plain resveratrol suggests that at least the 4' conjugates are not sirtuin activators. It is hypothesized that the 4'-O-Acetyl RSV is getting into cells, then the acetyl group is being cleaved by intracellular esterases resulting in free RSV in the cell. As you increase the dose of RSV, the small free fraction would presumably increase as well, perhaps even more if you had enough RSV to saturate the conjugation mechanisms. I don't know that they are easy to saturate though.

[niner]

The genes stay activated for how long? Hours, days, weeks?

Maxwatt, in my previous post I think I misunderstood what you were getting at. The sirtuin proteins may only be transiently activated, but while activated they deacetylate something that changes the expression of various genes. Those genes would have their expression levels changed for a longer time. Exactly how long is a really interesting question, because it would determine how often we need to activate the sirtuins. We might be able to take RSV only one day a week, for example. We might be able to fast or go on CR one day a week, which a lot of people would not have so much trouble doing.

Any of you molecular biologists know anything about the timeframe of gene expression alterations? How soon are things re-acetylated?

[malbecman]

Not a molecular biologist here but more of a biochemist-pharmacologist....

Don't forget that Sinclair, in his Nature paper, mentioned a dose dependency in the positive effects he was describing at 5 and 22 mg/kg/day. He only reported the higher dose results as they saw a greater effect.

So while the timeframe of gene expressions alterations is a good question, it definitely appears to be important to have enough circulating ResV (whether metabolized or free, I don't know exactly which) to get more into the cells and activate those genes we are all so interested in. So they don't appear to be saturating at the lower dose levels, at least....

Edited by malbecman, 20 February 2007 - 07:07 PM.

[opus12ga]

Slightly off topic, if anyone is interested they should check out a small Austalian company called Prana (it is traded on the NYSE under Pran). They may very well have come up with a viable treatment for alzheimer's. Washes away the plaques. It is in a Phase IIa trial now, which should be done by the fourth quarter of this year. It is possible that it will be available to the public next year. If so, it could be a true wonder.