Terra Sigillata

Revisiting resveratrol for aging

Earlier this week during Chris Mooney’s NC visit, I noted two articles in the Wall Street Journal and New York Times on reports of caloric restriction (CR) and the possibility that some drugs might replicate the health benefits of CR. The coincidence seemed quite odd, so I suspected that some major scientific publication was in the hopper.

Indeed, as revealed by Shelley Batts at Retrospectacle, the red wine antioxidant resveratrol has now been shown to increase lifespan in mice in a paper reported in this week’s issue of Nature (btw, vote for Shelley here to receive a $5000 student blogger scholarship). The bottom line is that a highly concentrated dose of this compound increases lifespan by 20%, but a human would have to drink 100 bottles of wine per day to acheive a similar effect without supplementation (and obviously die of alcohol intoxication well before any benefits are seen.). CNN, of course, blows the story completely out of proportion, as it were, with the headline: “Fat, boozing mice stay healthy.” (Note: the mice drank no alcohol but facts shouldn’t stand in the way of a sensational headline, eh?)

But let us revel in yet another example of the power and promise of natural products as human therapeutics:

WSJ’s David Stipp has a nice article this morning where the hype (first paragraph) is followed by the appropriate sober cautions:

The resveratrol study was conducted by researchers at Harvard Medical School and the National Institute on Aging, one of the National Institutes of Health. “The significance of the study on a scale of 10 is 11 in the aging and longevity field,” said Nir Barzilai, director of the Institute for Aging Research at Albert Einstein College of Medicine in the Bronx, N.Y., who didn’t take part in it.

But he cautioned that the study didn’t prove that resveratrol slows aging. (emphasis mine) That’s because blocking the diseases associated with rich diets isn’t the same as retarding general aging, which isn’t considered a disease. In the study, the mice lived longer, but it isn’t certain whether that’s because resveratrol slowed aging or only blocked diseases associated with rich diets.

I’ll quote further from Stipp because the WSJ article is subscription-only:

Calorie restriction, or CR, entails cutting normal calorie intake by a third or so to slow aging. Discovered in the 1930s, it has been shown to extend longevity by 30% to 40% in animals. Monkey and human studies suggest it can probably also extend human longevity. But its hunger-inducing regimen is too demanding for most people. (Thus, the standard joke about it: Even if it doesn’t extend your life, it will make it seem longer.)

Several other substances have shown hints of mimicking CR. A widely used diabetes drug called metformin, for example, activates many of the same genes that CR does. But resveratrol stands out for two reasons: It is the first compound shown to boost lifespan in widely diverse species — there are four so far — and it is a naturally occurring molecule that people have long ingested, suggesting that it is safer to take than other potential CR-imitating compounds.

Of course, as I have noted before with natural products like curcumin, the doses used in these kinds of rodent studies will be difficult to replicate in humans and may not even be safe. Again, David Stipp:

Resveratrol is considered safe at the modest doses available in the dietary supplements. But massive doses given to rats induced signs of kidney damage, anemia, diarrhea and other side effects, according to a 2002 toxicity report on resveratrol by the National Institute of Environmental Health Sciences.

The toxic doses were roughly equivalent to a person taking many thousands of resveratrol pills a day. The study noted that there were no observable adverse effects in rats at doses comparable to a human taking hundreds of the pills daily, a dose far higher than that used in the study described in Nature.

In passing on Monday morning, Chris Mooney mentioned to me that he had interviewed some of the principals in this research at least two years ago. One, Dr David Sinclair, has established a company, Sirtris Pharmaceuticals, to take advantage of the data they have generated with resveratrol in yeast and rodents. In fact, Sinclair is senior author of the Nature paper. His company, which has raised over $82 million of venture capital funding, is working with semi-synthetic analogs of resveratrol that exhibit far greater potency and may be useful as drugs at reasonable human doses. His primary competitor is from another company, Elixir Pharmaceuticals, started by MIT’s Leonard Guarente, Sinclair’s former mentor.

Others will hold forth on the mechanism of resveratrol’s action in mimicking caloric restriction (it activates mammalian homologues of the yeast SIR [silent information regulator] gene family, especially the SIRT1/Sir2 deacetylases that seems crucial for the multiple actions on pathways central to insulin sensitivity and mitochondrial bioenergetics.)

What interested me was what our colleague Mooney said almost three years ago. So, I dug up the article, from 05 Jan 2004, that Chris believes was published originally in some magazine and is archived at a site run by the Alliance for Aging Research. Mooney discussed then the work of Sinclair and others:

Combined with the Holzenberger study, this work strongly implies that the same endocrine systems control aging in worms, fruit flies, and mice, wrote gerontologist David Gems of the University College London, U.K. If so, they could also regulate aging in humans. The mouse studies, says Johnson, thus suggest bona fide pharmaceutical targets for drug discovery efforts. The fact that drug companies have already done a great deal of research on the insulin pathway in search of diabetes drugs could provide researchers with a head start in developing novel antiaging compounds.

The section of the article under the header, “Raise Your Glass,” makes for some impressive, prescient writing by Mooney that holds up today:

Resveratrol, Sinclair finds, also activates the human analog of Sir2p, known as SIRT1, when tested on cultured human cells in the laboratory. The central question now, wrote Sinclair, is, “Do sirtuin activators extend life span in higher organisms?”

Sinclair says he thinks the answer might be yes. What’s more, he says that soon-to-be-published research will describe a previously unknown connection between the IGF-1/insulin and Sir2 pathways. At several meetings in 2003, researchers in the United States and the Netherlands reported that SIRT1 controls the activity of a set of specialized proteins in the insulin/IGF-1 signaling pathways that control gene activity. These proteins, in turn, appear to turn on genes that defend cells against so-called oxidative damage, which occurs when the chemically unstable byproducts of metabolism relentlessly assault our DNA and cellular machinery. This finding is particularly exciting because many scientists believe that oxidative damage fuels cell deterioration and thus aging.

Given the hint of such linkages, and looking ahead to 2004, Sinclair says we might be reaching a point of convergence between a body of research concerning genes that control longevity and an even more vast body of research on calorie restriction. “Things are pointing towards a day, maybe not too far in the future, where we would have final proof that these two fields have merged,” he says.

I had a good laugh, as I’m sure Chris will as well, from an anonymous commenter who wrote then:

Chris Mooney is just one gullible guy. But then he listens to the experts who, so far, haven’t come up with a single thing to advance longevity or slow aging. Instead we see Olshansky and Binstock quibbling about anti-aging medicines. The idea prevails that somehow advances in pharmacology and stem cell research is going to make a big or even just a minor difference when, so far, there is no evidence that either will make one iota of difference.

It’s always been impressive to me to see scientific hypotheses ideas hold up and bear out over years or decades. But having spent a few days with Mooney and learn of his drive and intellect made me realize also how impressive it is to see the hunches of a good science journalist hold up and bear fruit nearly three years later.

Well done, Mr. Mooney.

Note added in proof: Coturnix/Bora notes that the eastern NC sweet, aromatic wines made from Scuppernong and Muscadine grapes rank much higher in resveratrol content that all Vitus vinifera grapes used to make “fine wines” and provides some scientific references. Hopefully ncwine.org will pick up on these reports today.

Comments

  1. #1 sweetpea
    November 2, 2006

    Erleichda and I will continue our red wine research!!! Although our resulting dosages of this compound are quite low, our studies to date suggest, that while consumption might not have the exaggerated health benefits suggested by some recent news stories, consumption can significantly enhance a good meal and increase life’s enjoyment. We will continue to follow the grape!!

  2. #2 coturnix
    November 2, 2006

    I just had 2003 Old Patch Red from Trentadue Winery (in Sonoma Valley) last night and it was surprisingly excellent. It may not have as much resveratrol as scuppernong, but it tasted MUCH better! Have you ever tried it?

  3. #3 Shelley Batts
    November 2, 2006

    Very informative, and thanks for the shout-out! :D

  4. #4 George Smiley
    November 4, 2006

    “Others will hold forth on the mechanism of resveratrol’s action in mimicking caloric restriction (it activates mammalian homologues of the yeast SIR [silent information regulator] gene family, especially the SIRT1/Sir2 deacetylases that seems crucial for the multiple actions on pathways central to insulin sensitivity and mitochondrial bioenergetics.)”

    Too bad about the enzymology, the mechanism, and Mooney’s precience:

    J Biol Chem. 2005 Apr 29;280(17):17038-45
    Substrate-specific activation of sirtuins by resveratrol.
    Kaeberlein M et al.

    Resveratrol, a small molecule found in red wine, is reported to slow aging in simple eukaryotes and has been suggested as a potential calorie restriction mimetic. Resveratrol has also been reported to act as a sirtuin activator, and this property has been proposed to account for its anti-aging effects. We show here that resveratrol is a substrate-specific activator of yeast Sir2 and human SirT1. In particular, we observed that, in vitro, resveratrol enhances binding and deacetylation of peptide substrates that contain Fluor de Lys, a non-physiological fluorescent moiety, but has no effect on binding and deacetylation of acetylated peptides lacking the fluorophore. Consistent with these biochemical data we found that in three different yeast strain backgrounds, resveratrol has no detectable effect on Sir2 activity in vivo, as measured by rDNA recombination, transcriptional silencing near telomeres, and life span. In light of these findings, the mechanism accounting for putative longevity effects of resveratrol should be reexamined.

  5. #5 drcharles
    November 4, 2006

    great review, thanks for taking the effort. yours is better journalism than what i’ve read in the online news.

  6. #6 Abel Pharmboy
    November 8, 2006

    Thanks, all, for your comments – Dr Charles, you are my med writing hero so I am blushing.

    However, scientifically, “George Smiley” has an excellent point regarding the mechanism of prolongation of life in yeast, at least. The JBC paper he notes is free-access and details that the fluorophore used on the peptide for deacetylation assays increases the affinity of the substrate for SirT1 roughly 35-fold (compare Fig. 7A with 7B). Using native peptides (and a standard tritiated acetate release assay), resveratrol was shown to have absolutely no effect.

    So, the sirtuin activation may be an artifact of the fluor used in the high-throughput assay – a general cautionary note for anyone using similar, non-native kits for assessing enzyme activity.

    However, the bottom line of life-prolongation in yeast and signaling pathway effects in high-caloric diet mice still stands. It just seems to me that the pleiotropic effector underlying these diverse effects of resveratrol may not be the sirtuins. Thanks for the tip, George.