Junkfood Science: Living longer with resveratrol — a different perspective

December 30, 2008

Living longer with resveratrol — a different perspective

Has the secret of the Fountain of Youth been discovered? Is it really possible to reset our biological clocks and protect ourselves from the aging process? Can a miracle pill cure all the major killers of aging, including diabetes, heart disease and Alzheimer’s, and add 30 healthy years to our life?

Live To Be 150 … Can You Do It? Barbara Walters breathlessly reported on her ABC anti-aging special on April 1st, that Dr. David Sinclair says he’s found the genetic key of longevity in mice, as well as a molecule that turns the gene on so that people in their 80s could live like they’re in their 50s. Resveratrol, as found in red wine...about a thousand bottles a day. “Some would say you’re raising expectations that can’t possibly happen,” she asked him in her interview.

“But it’s true,” said Dr. Sinclair. “What can I say? If we cure the major killers of Western society, people will live longer, healthier lives.”

Ms Walters’ reported that he’d teamed up with Dr. Christoph Westphal and together they’d raised $100 million for research. If all goes well with the clinical trials on type 2 diabetes, Dr. Westphal said, they’ll seek FDA approval in the next five years.

Resveratrol — making news for years

Dr. David Sinclair, Ph.D., associate professor of Pathology and Co-Director of the Paul F. Glenn Laboratories for the Biological Mechanisms of Aging at Harvard Medical School in Boston, is the name behind resveratrol research. He’s been featured in media for years — including Forbes, Fortune, Scientific American, Wall Street Journal, Newsweek, Charlie Rose and Barbara Walters — making similar anti-aging claims of the antioxidant resveratrol, as found in red wine.

Dr. Sinclair was also featured on a video made for the multi-level marketing dietary supplement company, Shaklee Corporation, as a member of its Scientific Advisory Board. Shaklee sells Vivix Cellular Anti-aging Tonic, which is advertised as a blend of polyphenols with resveratrol in an amount equivalent to 3,000 glasses of red wine. There seems to be nothing this miraculous tonic and “revolutionary breakthrough” isn’t claimed to do. Each health benefit claim, according to Shaklee, is based on more than two thousand published studies.

In the Shaklee video, Dr. Sinclair said that resveratrol molecules have worked in every organism they’ve fed them to, turning on the pathway that repairs DNA cellular damage to slow the aging process. By concentrating resveratrol, made by plants to protect themselves from stress, we can get the same natural benefits, he said, and it could potentially have a big impact on aging and the major degenerative diseases.

“We have the technology now to make molecules, consumer products and drugs that can give you the benefits of diet and exercise without actually having to do those things,” he said. He added that he is interested in the whole polyphenyl family of compounds and the health benefits they can impart, singly or preferably in combination, with resveratrol. “When you turn on the body’s natural defenses, you might expect remarkable things and that’s what we’re seeing in the clinic and in human trials against diabetes and hopefully, soon, in many others,” he said. We may find a group of people living longer. “Hopefully, I’m one of them,” he said, saying that he believes in resveratrol so much he’s taken it for years.

With Dr. Christoph Westphal, M.D., Ph.D., he founded Sirtris Pharmaceuticals to develop anti-aging drugs. Dr. Sinclair now co-chairs its Scientific Advisory Board while Dr. Westphal serves as Chief Executive Officer. Sirtris was bought by GlaxoSmithKline earlier this year for $720 million, in a deal that reportedly earned Dr. Sinclair more than $8 million and $297,000 a year in consultant fees.

Amidst all of this excited media coverage, the public heard little to nothing about what the body of scientific research actually showed or the red flags of concern and cautionary warnings.

Another news story — conflicts of interest

This past week, Dr. Sinclair made the news in a different way when the Wall Street Journal reported that he’d resigned from his paid position on the Scientific Advisory Board of Shaklee. According to the WSJ story, Dr. Sinclair “now says his name has been misused in connection with Vivix,” in ways that imply he endorsed Vivix. He has demanded that Shaklee cease using his name.

Note that Dr. Sinclair wasn’t admitting that he may have been overstating the research to imply endorsement for resveratrol supplements, only that his statements were being used to imply an endorsement for Shaklee’s resveratrol supplement.

WSJ also reported that Harvard has been reviewing Dr. Sinclair’s connection with Shaklee and that Sirtris Pharmaceuticals-GSK was working on its own resveratrol drug for diabetes. In a statement, according to WSJ: “Shaklee said that ‘every implied product endorsement was in Dr. Sinclair's own words and every Shaklee use of his name — whether in print or video — was pre-approved by him in keeping with our agreement.’”

Dr. Sinclair’s assertion took the biggest beating in the video WSJ posted on its website. It showed Dr. Sinclair speaking at the Shaklee sales meeting this past August, saying to the sales people:

Over a year ago, we set out together to do this, to make a product that you could actually activate these genetic pathways that can slow down aging. Together, as part of the Shaklee family…we can take this technology right now, to our friends, to our family, and really have the benefits of this new technology right now, within our lifetimes.

This news story has fueled debates over financial disclosures among researchers. The concerns over potential conflicts of interest haven’t focused so much on the funding for research. We can’t automatically assume that research funding means an investigator is guilty of misconduct. That would be falling for the ad hominum fallacy of logic and neglecting the fact that money for research has to come from somewhere. It’s also easy to forget that all sources can potentially impart bias and that government and nonprofit grants can come with as many strings to conform to agendas, as those from industry.

What makes this situation different is that it calls to question whether the integrity of science is compromised when researchers accept money to endorse products, and allow their names and universities to be used in product marketing, especially when the products are the very ones they are researching. Are many researchers able to remain objective when they have significant interests in the outcomes of the research — more specifically, maintain objectivity when interpreting and reporting the findings? Or, is the urge to overstate the favorable evidence and downplay the limitations too great?

Only the science itself can help us answer those questions.*

The landmark resveratrol research

There’s a reason resveratrol studies haven’t been reviewed at JFS to date. Only clinical trials on people offer information we can use, but there have been no randomized controlled clinical trials of resveratrol on humans published. [Regular readers will remember only two exceptions to reporting only human research: a study on a worm and one on zebra finch.]

Nor has the research to date provided anything of direct benefit to the public. While people aren’t lab rats, even the mice studies have yet to find credible support for claims surrounding resveratrol. And you are certainly not a yeast cell, worm, fly or fish! Studies done in a test tube on yeast cells, worms, flies, fish, mice and other species are preliminary investigations and have a long way to go before they’re ready for prime time. But even those done on resveratrol to date have been controversial.

Reporting on laboratory research, as scientists explore various theories and hit endless dead ends before finding one that might have potential, is of interest to chemists and biologists, but not much help to the general public. Lab research is years from becoming clinically-proven treatments for us. Once out of the lab, there’s still years of clinical trials on humans — phase I, phase II and phase III clinical trials — each to answer different and important questions. [Covered here.]

A search of Clinicaltrial.gov, where clinical trials are registered, found no registered trial on resveratrol for diabetes or aging led by Drs. Sinclair or Westphal, conducted at Harvard, or funded by Sirtris. In other words, seeking FDA approval to market a resveratrol drug to prevent diabetes, Alzheimer’s, heart disease or cancers, let alone extend lifespans, isn’t going to be happening anytime soon, despite what we’ve been hearing.

But the media didn’t wait for clinical trials. In November 2006, a mouse study by Dr. Sinclair and colleagues was published in Nature. It reportedly demonstrated resveratrol was the anti-aging secret and can extend life. This is the landmark resveratrol study that has made the news for more than two years ever since.

Resveratrol, like antioxidants, has been chic, all the rage, popular and newsworthy. No one has stopped to read the study and notice that it didn’t actually find what it was being claimed to have found. Nor, has anyone reported that, to this day, it has yet to be independently replicated.

Briefly, at one year of age, an unknown number of male mice were fed their standard diet or a high-calorie diet along with resveratrol at two concentrations. After six months, there was a “clear trend towards increased survival and insulin sensitivity at the high dose,” the Harvard authors wrote in the introduction, so the study was continued only at the higher dose. At the end of the 114-week study period, they reported that 42% of the high calorie diet with resveratrol group had died and 42% of the standard diet control group had died. As the authors wrote in their conclusion: “We cannot yet confidently predict the ultimate mean lifespan extension.”

In other words, this study didn’t test two groups of mice similarly eating ad lib, with the only difference being the resveratrol given one group. It did not actually show resveratrol itself extended lifespan.

These mice live an average of 2.5 years (130 months), yet the authors didn’t report what happened as the mice reached old age. Did they even live out their life expectancy, let alone longer? Instead, the claim of a statistical 30% benefit came only when the mice were compared to mice that were force-fed unnaturally high calorie diets of 60% fat — a diet that bears no resemblance to what humans eat and is nearly twice the fat that even Americans eating a fatty Western diet consume. Nor could any comparisons be made to credibly suggest anything about fat people because as a group they eat no differently than naturally thin people.

This year, the Harvard group published a study that better isolated resveratrol’s effect, from extreme dietary manipulations. In a press release on July 3, 2008, Sirtris Pharmaceutical reported that it had found that resveratrol [a polyphenolic SIRT1 activator] mimics calorie restriction in mice and may extend life by inducing similar pathways in mitochondrial gene expression in vivo. The study behind that press release, led by Dr. Sinclair, was published in the August 6th print edition of Cell Metabolism. It turned out, however, to have actually reported that resveratrol induced gene expression patterns in some tissues similar to caloric-restricted mice without extending lifespan. Mice “fed a standard diet did not live longer when treated with resveratrol. Our findings indicate that resveratrol treatment does not increase the longevity of ad-libitrum-fed animals when started midlife,” the researchers concluded. Resveratrol failed to actually help the mice live longer.

Also in that July issue of Cell Metabolism, Dr. Matt Kaeberlein, with the Department of Pathology at the University of Washington, Seattle, Washington, wrote about the “ongoing saga of sirtuins and aging,” saying that “sirtuins are known to slow aging in simple eukaryotes,” however in mammals, viewing sirtuins as antiaging proteins may be overly simplistic. As he explained, evidence in the same issue of Cell Metabolism showed “that SIRT1 has properties consistent with both pro- and antiaging functions in mice.” In other words, it appears resveratrol may also increase aging.

This is reminiscent of the popular misunderstandings surrounding antioxidants and the free radical theory, and why antioxidants continue to not prove to have special benefits in human studies, and in some cases suggest harmful effects. Many antioxidants are really redox agents (antioxidants in some instances and working as pro-oxidants in others, actually producing more free radicals) and could increase risks for things like cancer. Especially at larger doses, researchers have also cautioned that antioxidants can alter a number of body functions, hormones, metabolism and absorption of minerals. [Covered here.]

Cause to pause — cautionary notes

Before going on, it might be helpful to get some background information on resveratrol and sirtuins and the body of evidence. A family of genes that makes proteins called sirtuins have been theorized as playing a role in mitochondria (the energy centers of cells) and to correlate to genes activated during caloric restriction in animal studies. Among the molecules that can activate the sirtuin genes is a resveratrol-like compound that acts on the SIRT1 gene. Actually, they don’t know exactly what the pathway involved may be, as they’ve used a proxy measure of SIRT1 activity to show a correlation between the more active enzyme and mice treated with resveratrol.

Resveratrol is produced when plants are stressed, as a survival response. The resveratrol used in these studies, however, isn’t at the amounts found in nature. That’s because, as Dr. Westphal has said, native resveratrol isn’t effectively absorbed in our gut and can’t reach the bloodstream. We’d also have to take hundreds a day of the “resveratrol dietary supplements” being sold to reach the levels being researched in these studies.

More precisely, as research led by Dr. Thomas Walle, Ph.D., at the department of cell and molecular pharmacology and experimental therapeutics at MUSC in Charleston, South Carolina, has reported, the benefits attributed to dietary resveratrol are based on laboratory modeling. However, it’s not clear whether the drug even reaches the areas where it’s said to act, especially in humans. They found in a brave group of human volunteers that only trace amounts of resveratrol could be detected in the blood stream after it was ingested. Most of it was just excreted in the urine. While resveratrol had low bioavailability, it isn’t known if it might potentially accumulate anywhere in the body and produce long term effects or what those effects might be.

The mouse study by Dr. Sinclair’s group, published in the 2006 issue of Nature, that set the media ablaze, came with a press release. The public has heard little to nothing about the caveats noted in a review article on resveratrol research that was published in the same issue. This paper was written by biology of aging researchers Dr. Matt Kaeberlein, Ph.D., the primary investigator at Kaeberlein Lab at the University of Washington Medical Center in Seattle; and Dr. Peter S. Rabinovitch, M.D., Ph.D., professor of pathology, Joint Full Member of the Fred Hutchinson Cancer Research Center, and Director of the Nathan Shock Center of Excellence in the Basic Biology of Aging at the University of Washington.

Resveratrol’s role in aging first became of particular interest to gerontologists, they said, with a letter published in the 2003 issue Nature that reported discovering three molecules that can activate sirtuins. It was written by Dr. Sinclair and colleagues and claimed that resveratrol could increase lifespan in yeast 70% by activating particular enzymes (protein deacetylases) of the SIR2 family of proteins (sirtuins).

However, said Drs. Kaeberlein and Rabinovitch, the results from that first yeast study have remained controversial and other researchers have been unable to replicate its findings. Their own research, published in the Journal of Biological Chemistry in 2005, found “resveratrol has no detectable effect on SIR2 activity in vivo, as measured by rDNA recombination, transcriptional silencing near telomeres, and life span.” They concluded: “In light of these findings, the mechanism accounting for putative longevity effects of resveratrol should be reexamined.”

“Subsequent work has suggested that resveratrol has modest effects on lifespan in both worms and flies, and a more substantial effect on lifespan in a short-lived fish,” they wrote in their 2006 Nature review. The source of the suggestion of possible effects on lifespan in worms and flies was a letter published in a 2004 issue Nature by Dr. Sinclair and colleagues, based on tests on Caenorhabditis elegans and Drosophila melanogaster.

The source for suggestions of an effect on the lifespan of fish, according to Drs. Kaeberlein and Rabinovitch, was a small study done on a rare species (Nothobranchius furzeri) found in southeastern Africa. This species is an evolutionary oddity and has the shortest known lifespan (12-13 weeks in captivity) of any vertebrates on the planet. In this study, researchers at Scuola Normale Superiore in Pisa, Italy, fed 110 fish resveratrol in three different concentrations and reported a correlation to genetic expressions of aging biomarkers at a cellular level found in these vertebrates and prolonged lifespan at the highest doses (and shortened life at the lowest dose). Resveratrol was associated with delayed decay of locomotor activity and cognitive performances and reduced expression of neurofibrillary degeneration in the brain, they said. But, the Italian researchers urged caution. The mortality trajectories in these fish were like those seen when the water temperature is reduced, they said, not like those seen in caloric restriction. They also “observed that resveratrol induced an early increase in death rate after administration.”

Based on these findings,” said Drs. Kaeberlein and Rabinovitch, “it has been proposed that resveratrol increases lifespan in several different organisms by a mechanism similar to dietary restriction.”

The source of this proposal was a 2006 Nature review article written by Dr. Sinclair and colleague Joseph Baur at Harvard. At that time, their November 2006 mice study hadn’t yet been published. “Despite scepticism concerning its bioavailability, a growing body of in vivo evidence indicates that resveratrol has protective effects in rodent models of stress and disease,” wrote Drs. Sinclair and Baur. This data was the basis for their conclusions of resveratrol’s “potential as a therapeutic for humans.”

Drs. Kaeberlein and Rabinovitch said that while Dr. Sinclair’s group “favor the view that many (perhaps all) of the beneficial properties of resveratrol are the result of increased sirtuin activity, and various studies have supported the idea that sirtuins underlie the effects attributed to resveratrol in vivo… there is a surprising lack of biochemical evidence that resveratrol directly increases sirtuin-mediated deacetylation of biologically relevant substrates, and some evidence that it may not. Resveratrol is also known to interact with numerous proteins and pathways…” Resveratrol is not the last hope of gerontologist or even the best, they wrote.

Did you pick up the red flags? It’s not like this is an obscure field of medical research and that virtually every pharmaceutical company in the world isn’t looking for an anti-aging drug and cure for diabetes and other diseases of old age! When extraordinary claims that overstate the quality of the evidence come from one source, let alone from Harvard, and haven’t been independently replicated, that’s a red flag of caution before buying it.

Should you start popping resveratrol?

Not only have two dubious studies done in 2006 — one on mice and one on vertebrae — been all the evidence the media’s needed to produce years of sensational stories, they’ve also been all that a massive and thriving business of online companies have needed to market resveratrol dietary supplements, with promises of life extension benefits for humans.

Unthinkably, the same consumers who would probably be horrified by a harmless chemical found in parts per billion in their food are rushing to ingest a chemical produced in a laboratory at 3,000 times greater concentrations than found in foods and believe it will improve their health. And spend $100/month to boot.

Similarly, few people would be in favor of the FDA approving drugs, especially for healthy people to take for life, that haven’t been clinically shown to be safe and effective. Yet, dietary supplements are able to bypass the requirement for clinical evidence.

Before popping those resveratrol supplements on the market, it’s important to know that there are no standards for the methods various manufacturers use to isolate resveratrol. It’s no safer than experimenting with any other new manmade chemical developed in a laboratory. Since dietary supplements aren’t regulated by the FDA, there are no quality standards, nor have any of the supplement makers published data on the variability between their different lots in the amounts of resveratrol they contain.

No one knows what dose in humans is safe, effective or what the risks of taking them for years might be, such as developing cancer. None of the resveratrol supplements have published toxicology tests and there is no information on how they might interact with other drugs. Given the unknowns and lack of clinical research on humans, benefits that are speculative at best, and reasons to indicate potential risks for harm (especially given what has been learned about other antioxidants at high doses), no credible medical professional would recommend anyone begin a life-long resveratrol supplement regimen.

Drs. Kaeberlein and Rabinovitch had similar concerns. To anyone wondering if they should start supplementing their diets with resveratrol, they wrote: “Our advice is to exercise caution.” The safety of resveratrol at the high doses being tested is unknown, especially taken over years or even decades. “Even modest side effects could have dramatic consequences,” they wrote. “For now, we counsel patience. Just sit back and relax with a glass of red wine…”

© 2008 Sandy Szwarc

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* Even without getting into the scientific research itself, all of the clues are there to help us figure out if these claims of benefits for humans are credible. Falling back on those basic tenets for protecting ourselves against health fraud and fake remedies make a surprisingly good place to start.

As covered here, to evaluate any new modality, there are some simple things that can also help us know if something is sound. To start:

● if it’s been tested in phase III, human clinical trials that are well-designed to be fair tests, and clearly shown to be safe and effective, based on objectively-measured hard clinical outcomes, rather than false surrogate endpoints;

● if its potential benefits outweigh the risks;

● if the research has been independently replicated and holds up to the body of evidence and biological plausibility;

● and if the research has been published in peer-reviewed scientific literature.

What doesn’t matter is many people agree, how prestigious or famous the person is who’s selling the remedy, how many amazing testimonials or before-and-after pictures we’re shown, how much news coverage it gets, how polished the product literature or website looks, or how impressive the accompanying bibliography.

Interventions that claim to slow aging or prevent diseases associated with old age — such as cancers, heart disease, diabetes or dementia — have long been a source for spurious modalities. One of the most popularly believed adages is that lots of antioxidants can avert free radical damage and prevent chronic diseases and enable us to live longer. Decades of randomized, placebo-controlled clinical trials, however, have failed to support such abilities of antioxidants — or any dietary factor. People around the world have enjoyed a wide range of diets with no common relationship to lifespans or health. Even the recent Cochrane Systematic Review of every clinical antioxidant trial conducted since 1945 found not a single one had been able to find a tenable effect. [Covered here.]

Humans have been trying to find the secret to longer life throughout recorded history, and countless people have claimed to have found it. But haven’t. Fifty-one of the world’s most recognized scientists in the field of human aging, concerned about the continued quackery surrounding aging, recently examined the scientific research and published their findings in Scientific American and the Journal of Gerontology: Biological Sciences and is available online here. Their concluding remarks said:

Since recorded history individuals have been, and are continuing to be, victimized by promises of extended youth or increased longevity by using unproven methods that allegedly slow, stop or reverse aging. Our language on this matter must be unambiguous: there are no lifestyle changes, surgical procedures, vitamins, antioxidants, hormones or techniques of genetic engineering available today that have been demonstrated to influence the processes of aging.

The next anti-aging remedy that comes along will, no doubt, claim to be different and be the miracle breakthrough. It will probably be endorsed by highly degreed professionals from prestigious institutions who say they know they’ve finally found the secret. Look for the clues.

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