Longevity, calorie restriction, and red wine. From Scientific American.

[drm604]

There's a link to the article at the bottom of this post. I found it difficult to find four paragraphs that gave a good understandable synopsis, so I'll try to summarize it in my own words.

It has for some time been accepted knowledge in the scientific community that "calorie restriction" can extend the lifespan of organisms 30% to 50%. This is done by reducing caloric intake 30% to 40% while supplementing to make sure that other nutritional needs (vitamins, etc.) are met. The youthful part of the lifespan is also increased and diseases such as diabetes and cancer are forestalled.

This has been repeatedly shown experimentally to work in yeast, roundworms, mice, rats, and dogs. It therefore appears to be based on some fundamental mechanism that is likely shared by all multicellular organisms. A drawback is that it interferes with the reproductive process. And, in humans, that kind of drastic calorie restriction would most likely be intolerable.

It has been discovered that calorie restriction activates molecules known as sirtuins. Experiments have shown that these molecules are almost certainly what cause the extension of life and youthfulness.

Sirtuins can be activated by means other than calorie restriction. A substance found in red wine, resveratrol, activates sirtuins. Animals fed sufficient resveratrol (but not calorie restricted) experience the same life extension effects as calorie restricted animals but without the reproductive problems.

So, is this life extension in a pill?

http://sciam.com/article.cfm?chanID=sa006&articleID=000B73EB-3380-13F6-B38083414B7F0000&pageNumber=1&catID=2

[WindRavenX]

1. It certainly can't hurt

Many Mediterranean cultures that drink red wine have demonstrated healthier cardiovascular systems, which today is the leading cause of death in western worlds.
I try to watch what I eat, exercise, and enjoy wine :)

[drm604]

3. That's true.

But the impression I get from the article is that you would have to drink a lot of red wine to get the maximum effect. The problem with that is that the healthful effects may then be offset by the deleterious effects of the alcohol.

It's my understanding that, while the French do have lower rates of heart disease, they have higher rates of alcohol related problems such as liver disease.

The real answer would appear to be supplements containing concentrated resveratrol without the alcohol.

[eShirl]

2. thanks for posting this

:)

[drm604]

4. You're welcome.

Maybe you should recommend it. I think this article deserves some attention.

[SnowGoose]

5. Resveratrol has more than one effect.

It's worth noting that it also acts as an inhibitor of the aryl hydrocarbon receptor (AhR) which mediates our metabolism of a variety of organic compounds (like dioxins and benzo(a)pyrene) by acting as a transcription factor (turning on various genes) when it detects certain toxins.

Not trying to take the wind out of your sails, but just reminding you that with something as mind-bogglingly complex as a living organism, there are few things you can change without multiple effects downstream.

Dang, I thought I'd use my 1000th post for something profound. Ah well, I guess if I had something profound to share, I'd have already said it.\

Edited for spelling.

[drm604]

6. In what way does it mediate them?

Is that inhibition necessarily a bad thing? Some toxins are metabolized into even worse things by the body. Could that possibly be the case here?

I'm not trying to argue with you. But it appears that, whatever myriad effects it has (quite possibly some bad ones), on balance it increases life and health. Of course, lab animals may not be exposed to as many toxins as people so, if this is a problem, it may not show up in the lab.

It might be an interesting experiment to compare four groups of mice. One group on a normal diet. One on a normal diet with toxin exposure. One being fed resveratrol, and one fed resveratrol and exposed to the same toxin as group two.

[SnowGoose]

7. Sure, some metabolites are worse than their parent compounds.

Clearly in some cases, you'd benefit from a less robust response. I have actually been considering an experiment using a genetically-engineered "knockout" mouse that lacks the AhR to see if some of the immune effects of cigarette smoke operate through this pathway. Interestingly, since these animals are so danged expensive, I had earlier proposed using resveratrol to block the receptor - we decided not to do it because there are too many other effects for my experiment.

In answer to your question of how it works, (this is from memory, so keep that grain of salt handy), AhR floats around in the cytoplasm, until it binds a xenobiotic like TCDD (the really bad dioxin). Then it changes conformation slightly and binds with another cytoplasmic protein ARNT. Together, the activated complex crosses from the cytoplasm into the nucleus (or nuculus if you're GWB) where it binds to certain regulatory regions on the DNA and initiates the expression of genes regulated by those regulatory elements. I believe cytochrome 1A1 is the one people talk about (there are lots of cytochromes, and they're usually described as CYP and then some numbers and letters to tell you which family of CYP). These cytochromes typically put a polar group (like an alcohol) on a non-polar compound (like toxicants or even drugs) so that it will become more water soluble and be eliminated from the body in the urine or some other pathway. In some cases, this is a good thing, in other cases not so much.

Blocking the metabolizing enzymes can also significantly effect the metabolism and elimination of other drugs you might be taking. The amount of resveratrol you'd get in a glass of wine isn't likely to be a big deal in that regard. The amount you'd get in a concentrated form like a pill could be a different story.

It may also be of interest that resveratrol is somewhat estrogenic - acts as a female hormone. Maybe this is significant to you, maybe not.

I don't actually think resveratrol is bad for you - certainly not in the levels you'd get it from natural foods. At those levels, it sure looks like it has lots of good effects (anticancer, antioxidant, antiplatelet, etc). At higher levels, though, it has been shown to induce DNA strand breakage.

I expect that you already know about this, but in case not, I'd encourage you to have a look at www.pubmed.gov. It's your pathway to peer-reviewed scientific publications in the life sciences. Put your search terms in and click go. If you're not a biologist, I'd suggest starting with the "reviews" tab on your results - those are the ones that contain more background to get you started. Most of the articles aren't free yet (the abstracts are), but some of the papers themselves are freely available to the public - they'll say if they are.

Take care.

[drm604]

9. Estrogen

The Sciam article did mention the similarity to estrogen but said that it was very mild.

I'll do some more reading in my spare time. I posted a link to an interesting Pubmed article which shows a positive effect from the inhibition, at least in one specific circumstance.

[drm604]

12. Pubmed

I did a pubmed search on resveratrol as you suggested. It's definitely fascinating stuff. I've only read the first 20 or so of the abstracts that it returned. There were one or two that were completely over my head but the rest all seemed positive - induction of apoptosis in cancer cells, protection against osteoporosis, preventing ischemic death in cardiac cells, protection of transplanted organs, cataract prevention, cancer prevention, protection from hypertension induced cardiac damage, and inhibition of ethanol-induced lipid peroxidation. Of course there's no way of knowing if any of these findings were borne out by later studies. It all seems way to good to be true and it's entirely possible that in some cases they found what they wanted to find, but where there's smoke there's usually at least a small fire and there does seem to be plenty of smoke here.

[drm604]

8. Resveratrol...protects sperm from DNA damage...caused by benzo(a)pyrene.

Resveratrol, a natural aryl hydrocarbon receptor antagonist, protects sperm from DNA damage and apoptosis caused by benzo(a)pyrene: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11780955&dopt=Abstract

[marcapolo]

10. thanks for the post

Depending on what study you read, the average American consumes about 2100 to 2200 calories a day (and many of them are consuming a lot more), whereas the average human consumes 1500 calories a day. So a caloric reduction of 30% wouldn't actually be that out of line. As for wine, it does seem like the studies show that you have to drink a lot of red wine to benefit from the sirtuins, antioxidants, etc., and by that time you probably ARE going to be experiencing deleterious effects from the alcohol. It's my personal theory that the reason why Mediterranean cultures have less heart disease is not so much b/c of what they're eating and drinking but what they're doing (i.e. they walk everywhere; are less stressed; and get together with their friends, families, and communities more). I'm not advocating eliminating wine--even if it doesn't increase the quantity of life, it sure adds to the quality.

[drm604]

11. Calorie reduction.

The reduction they're talking about is way more than that. They're not talking about a reduction of 30% off of what the average American consumes. They are talking about a reduction of 30% to 40% below what would normally be considered a healthy amount. They're talking about a reduction so stringent it would cause constant hunger, a need for vitamin and mineral supplementation to make up for nutritional shortages, and a greatly reduced sex drive. It would be very difficult psychologically to maintain the reduction they're talking about.

It's fine to have personal theories but studies do show that resveratrol DOES increase lifespan in laboratory animals. I doubt that those animals get more exercise, or have a better social life, than the control group. That said, the benefits seen in Mediterranean cultures are not as dramatic as what's been seen in lab animals. As you say, if they drank enough to get those levels of benefits the alcohol would probably cancel out those benefits.

As SnowGoose has pointed out, there may be drawbacks to taking too much resveratrol, but I suspect that supplements equivalent to what you'd get in a few glasses of wine each day may do some good with little risk. But I'm certainly not a doctor or a biologist so that's just my uninformed opinion.

[Lydia Leftcoast]

13. A further disadvantage of extreme calorie restriction would be that if the

person ever went off it for even a little while, they would really pack on the weight, because their metabolism would have slowed down.

[drm604]

14. That's a very good point.

This is purely anecdotal (and second hand anecdotal at that) but my brother tells me that he saw some people who are actually attempting to practice this type of calorie restriction on a TV show. He tells me that they were extremely emaciated and when asked if they ever got hungry one man responded with something like "hell yes! I'm constantly hungry." One man actually ended up cutting back on the restrictions somewhat because his wife threatened to leave him if he didn't put some weight back on.

This, as well as common sense, tells me that these restrictions would be nearly impossible to maintain for the rest of your life, and you might not want to live all that long in that state anyway!

[Lydia Leftcoast]

15. Yes, my father participated in medical experiments during WWII

He was a conscientious objector, and his alternative service was to be a guinea pig for Ancel Keyes' experiments on nutrition.

One of the experiments was on extreme calorie reduction, and he said that not only was he hungry all the time but all he ever dreamed about was food. The whole group became obsessed with food.

[drm604]

16. That's exactly the problem.

With lab animals in cages, you can control the amount of food available to them and there's nothing they can do about it. But it's different with people. Very few could maintain this regimen and I don't think that I'd want to even if I could. But it appears that there may be an alternative.

Out of curiosity, would you mind my asking what his health was like since then? Is it possible it was improved by the experiment?

[Lydia Leftcoast]

17. No, he lived to be 77, which is not terribly old these days

I never noticed anything unusual about his health as I was growing up--he was not at all health conscious, since few people were in those days-- but he began developing Parkinson's disease and dementia at the age of 69.

It's impossible to tell whether the experiments ultimately affected his health one way or another.

[Nikia]

18. I don't really know if it is healthy for people

Maybe, supplements do help people remain healthy despite the restriction. Generally people who restrict, anorexics, become unhealthy. Since many anorexics are women, many of them experience at least temporary loss of their periods and can end up with osteporosis, in their twenties, and permanent reproductive problems even if they regain weight. There can be damage to other organs as well. Twenty percent of anorexics will die from their disorder. Problems can be exaserbated by the fact that unlike lab animals, humans will usuaully try to have normal lives. Some anorexics are also athletes or compulsive exercisers. Even those who do not, may have active jobs and lives.
I also recall reading that thin elderly people who lose weight, which is not uncommon in the elderly, increase their risk of death, especially from infectious diseases.

[drm604]

19. Those are all good reasons

why calorie restriction is not workable for humans.

That's why they are trying to understand the mechanism and find alternative ways to exploit it.