benefits splash of red wine 710 x 475

There is a lot of buzz in the press about red wine, resveratrol, and longevity. Here is the real inside story of how resveratrol, the chemical in red wine that impacts longevity, works its wonders.

Yep, I am going to talk to you about cell biochemistry. But, I promise, I will make it as simple as I can. It is a tale about genes. In particular, it is the story of a gene called SIR2 (or “Silent Information Regulator”—sounds kind of creepy, huh?)

 

First, a bit of history

In 2000, Lenny Guarente and three of his postdoctoral students discovered a key chemical in yeast cells—one that plays a key role in the energy metabolism. This chemical, named NAD (or Nicotine Adenine Dinucleotide) activates a gene in the yeast cells, called SIR2.

When the cell is flush with nutrients, NAD levels are low and the SIR2 gene is inactive. On the other hand, a whole raft of genes, ones that have to do with “normal functioning” of the organism, like insulin and insulin receptors, as well as reproduction, are active.

When nutrients are scarce, NAD levels go up and SIR2 is activated. It, in turn, inactivates the “normal functioning” genes. One of the many things that happens as a result of SIR2 activation is insulin level decline. This makes sense because, in conditions of nutrient scarcity, you don’t need as much insulin…as too much insulin in the face of low nutrient levels could lead to a dangerously low level of blood glucose. In this state of nutrient scarcity, we also find that the gears of the aging process are slowed. This explains, at least in part, the link between caloric restriction and longevity.

Shortly after the discovery of SIR2 in yeast, the equivalent gene in mice was discovered. It was named SIRT1 (which stands for “SIR Two One”). Next, scientists discovered the enzyme sirtuin, a protein that carries out the instructions coded in SIR2/SIRT1 genes. So, now we have a feedback loop. High nutrient levels lead to low NAD levels and suppression of SIR activity. Low nutrient levels lead to high NAD levels, expression of SIR activity, and production of the enzyme, sirtuin. NAD serves another function in this biochemical pathway; it binds to the sirtuin molecule and causes its activation.

 

Enter Sinclair and resveratrol

In 1995, David Sinclair, an Aussie, joined Guarente’s lab as a postdoctoral student. In 2003, he discovered that a substance that is present in the skin of red grapes and in red wine, resveratrol, seemed to activate SIR2 in yeast mimicking the low nutrient, low NAD status of the cell. Yeast cell longevity just about doubled after resveratrol was added to their culture mix.

Moving on to the current report, Sinclair’s research group at MIT and another research group, headed by Rafael Cabo at the National Institute of Aging, reported the results everyone is talking about in the November 1st online publication of Nature.

The researchers fed mice a high-calorie diet (60% fat), causing them to become obese. Half of the mice on the high-calorie diet also received resveratrol. A third group that received a normal diet, served as a control.

Here are the results:

  • The fat mice on the high-fat diet that received resveratrol ended up living significantly longer than mice on the same bad diet that did not get to eat resveratrol.
  • The obese mice that got resveratrol lived as long as the control mice that were fed a normal diet and maintained a normal weight. This is an important finding because it appears that resveratrol prevented the shortening of lifespan that is ordinarily associated with obesity.
  • The obese mice that did not receive resveratrol showed all the signs of metabolic syndrome like high blood sugar, high insulin levels, and enlarged livers. The obese group that received resveratrol did not develop this syndrome. Their blood sugars, insulin levels, and liver size of obese resveratrol-eating mice were indistinguishable from the normal weight, normal diet mice. Again, it looks like resveratrol prevents these obesity-related pathologies.
  • Finally, it is of interest that the obese mice who did not receive resveratrol were sluggish, lost motor control, and had reduced endurance as measured by running on a treadmill. The ones receiving resveratrol were almost twice as fit by the treadmill test and were more vibrant.

 

Not yet ready for prime time

So, will resveratrol be a simple antidote to our current obesity and diabetes crisis? It is probably too early to tell. Some important questions remain. Here are some:

  • Will resveratrol show any benefits in animals on a normal diet? Will it have an equally significant life-extending effect? Evidently, this experiment is already underway.
  • Exactly what does resveratrol do inside of the cell? Does it act on the SIR gene directly or does it act on the enzyme sirtuin or does it affect both? And once sirtuin is activated, what exactly does it do? Does it act directly to “silence” some or all of the genes controlling aging, fertility, and other normal functions? The answers to these questions may one day allow scientists to tease out or even separate the control of these functions.
  • Will resveratrol have the same effects in humans? Drug developers know through long experience that mice are not men. Many a drug that cured cancer in mice were either too toxic in humans or were just plain ineffective.
  • If it does work in humans, what dose level is needed? The mice in the experiment received the equivalent of humans consuming about a thousand bottles of wine per day!
  • So this leads to the next concern. Will effective doses of resveratrol be safe in humans? Obviously, if we try to use red wine as the vehicle for consuming resveratrol, our metabolism may be healthier but our brains will be fried!

 

So what is a mere mortal to do while we wait for the scientists to sort all of this out?

Here are my suggestions (the doctor is now weighing in):

  • Enjoy up to a glass or two of red wine per day. But no more! Several studies have demonstrated that the maximum benefits are obtained at this level. More than that, and the negative effects of alcohol consumption, such as cirrhosis of the liver, kick in.
  • You can also ingest resveratrol from non-alcoholic sources, like red grapes and grape juice. This seemed to have gotten lost in the midst of all the media hoopla about the benefits of red wine.
  • There are several companies that market food supplements of resveratrol. But, caveat emptor: Supplements may vary from 100% of the stated content to 0%. The food supplement market is an unregulated “Wild West”. Buying a resveratrol supplement that has hardly any resveratrol will be dangerous for your pocketbook. But, more importantly, very high amounts of resveratrol (unlikely), or, more likely, some toxic contaminants of the supplement could turn out to be hazardous to your health.

I will be writing more about the intricacies of cell life and death in future posts. I hope you will join me as I explore this vast and fascinating topic.

Dov Michaeli, MD, PhD
Dov Michaeli, MD, PhD loves to write about the brain and human behavior as well as translate complicated basic science concepts into entertainment for the rest of us. He was a professor at the University of California San Francisco before leaving to enter the world of biotech. He served as the Chief Medical Officer of biotech companies, including Aphton Corporation. He also founded and served as the CEO of Madah Medica, an early stage biotech company developing products to improve post-surgical pain control. He is now retired and enjoys working out, following the stock market, travelling the world, and, of course, writing for TDWI.

3 COMMENTS

  1. thanks for this wonderful story really true points you mentioned here i appreciate your thoughts.

  2. How long do you think it will take them to complete the scientific study on longterm use of resveratrol to prove whether or not it has anti aging benefits? I am asking since it was recently found and some studies could take up to 10 years or so?

  3. Aside from the fascinating fountain of youth possibilities related to sertuins there are also potential financial opportunities. Dr. David Sinclair, the researcher mentioned in your article has teamed up with other leading experts in this field to form a biopharmecuetical company seeking to produce treatments for several diseases of aging. The company, called Sirtis (SIRT:NASDAQ), is already in clinical trials for diabetes treatments that work by activating sirtuin enzymes to control gloucose levels. SIRT scientists are already moving beyond resveratrol and have created a new chemical entity that is 1,000 times more potent than resveratrol in activating sirtuin enzymes. Aside from the potential drug blockbuster potential, the universal fantasy of slowing the aging process could make SIRT the stock to own for the next decade. If the SIRT story continues on its currrent sucess track it could easily become the Google of big pharma.

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