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Sirtuins, resveratrol and human longevity

DNA double helixThere are some serious issues with the way resveratrol is being marketed.

1) A few years ago it was touted as a telomerase inhibitor and NOT to be taken with TA-65. Now there are claims that it is a telomerase activator and at least 1 study in vitro that suggests that this might be the case. However, the lab is a very distant realm from living human beings as I have often pointed out in support of TA-65. I personally sent four different brands of resveratrol to Bill Andrews at Sierra Sciences for testing before he affiliated with Isagenix and none of them tested positive for telomerase. Bill I think has tested other samples and found the same result. Thus, where the rubber meets the road, resveratrol has failed to activate telomerase. There are many reasons why this could be but one in particular is operator inexperience. This is why I went to Bill Andrews. No one on the planet has more experience with testing for telomerase activation.

2) In addition you may be aware of the 750 million dollar acquisition of Sirtris Pharmaceuticals by GSK. The “super resveratrol” Dr Sinclair produced for them was removed from phase 2 trials due to hepatotoxicity. Another thing that reportedly happened was an inability to reproduce prior results for resveratrol.

The scientific community believes that resveratrol has been seriously over-hyped by its marketers and I concur. It has pretty clearly been shown to work through adipokines and at best indirectly activates Sir 1, which has been proven to be a metabolic sensing gene and not a longevity gene, and that is at best.  Sir 6 shows some promise in humans but most of us in the field who are actually learned on the topic feel all the sittings are metabolic sensors and may exert some healthspan but not lifespan improvements, e.g. They are not true longevity genes in higher mammals and resveratrol is NOT a direct activator of any of them.

In my view, resveratrol is a good antioxidant that has merit, especially in the obese, diabetic and elderly. It is a mild mitochondrial poison, which decreases metabolism in the fashion calorie restriction does and doses should NOT exceed 300mg a day for this reason. At this point all my attempts to directly verify it has any direct actions as a telomerase activator or a Sirtuin stimulant has pointed in an opposite direction. The marketing machine, however, continues to present and represent it that way.

I would also add that I seriously doubt that resveratrol is the only natural compound that acts to improve metabolic sensing – it simply has had more money thrown at it because of its purported affiliation with Calorie Restriction (CR). CR has also been studied for 25 years now and in my opinion it has shown disappointing results in the longevity department unless you are a fruit fly, a round worm, or a very specific breed of mouse. The most common breed of mouse used in longevity experiments, known as “Black 6”, has not seen any life extension from CR.

The good news is the CR society is putting their money where their mouth is (no pun intended!) and at least planning on participating in studies that will verify or vilify what they are doing for markers of longevity. I hope they follow through with it because it may help answer the questions about CR and longevity where it really counts: you and me!

In the meantime, I would remind you that there is very strong evidence that increased telomerase expression is much more likely to extend life and repair many of the defects associated with aging than any other therapy, especially in mammals. I would also remind you that TA-65 was, is and has been the only telomerase activator that has been proven to work in mammalian studies. And that includes humans like you and me!

Doc

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Telomere maintenance – We who are about to die Salute You

centurionIn my most recent blog, The Monster is Not Born Immortal, I discussed in real time the results of Dr Maria Blasco’s most recent paper using both telomerase over expression and Calorie Restriction.

As usual, I got a bevy of comments, many of which were nasty grams and did not get published for that reason, on the blog.

People do not like to see their belief systems attacked.

The one that has come into question most recently, is based on the statement: “The only robust way to extend mammalian longevity is calorie restriction”!

Based on the recent monkey fiasco and Dr Blasco’s findings that her calorie restricted mice did NOT live longer, I think that phrase needs to be changed to:

“The only way to robustly extend mammalian lifespan is telomerase over expression!”

I honestly think Dr Blasco’s achievements in the past year warrant a Nobel Prize.

1)  She successfully extended mammalian (mouse) lifespan with the AAV 9 virus and did not increase cancer incidence.

2)  She showed how mice actually do age like people based on her assay (Life Length www.ADL.com), following the percentage of short telomeres.

3)  She showed how telomerase over expression is probably the main, if not the only key to true life extension in mammals.

Now, let’s talk briefly about calorie restriction (CR). There are approximately 10,000 people who follow the discipline worldwide, at least to some degree.  When these people die, we should salute them since they have carried on what must be the first true human longevity experiment. That is, assuming they do not believe any of the most recent findings that point away from CR as a valid life extension method.

In the meantime, what about all the darlings of science: mTor, Foxo, sirtuins?  More and more it looks like these are “healthspan pathways” that have the most effect when someone, or more specifically some animal, is sick or stressed.  Remember CR may be its own stress, but ultimately, even though animals who are CR’d do not live longer, they do seem to be healthier up to the point when they die.

Does this work in people?  Preliminary findings suggest that in heart disease, metabolic syndrome, diabetes and other types of similar age-related diseases, CR does indeed improve outcomes.  It also seems to help Alzheimer’s and we wonder… Cancer?

Here is where the problems start to come in.  By the time you have cancer, you might also be protein calorie malnourished and CR might worsen everything. There are studies that do show it increases mortality and morbidity in some animals. And by the way, if you want to look at a free living population of protein calorie malnourished people, try the elderly.

They seem to get sick and die at a higher rate than the rest of us! So we may find that CR ultimately shortens human lifespan in non-obese populations, echoing my title for this blog.

And while I am at it, I may as well talk about resveratrol, another darling that has lost its shimmer.  Recent studies show resveratrol does not even work through the primary sirtuin system and even if it did, that system is not a longevity pathway in people. It’s an energy management pathway.

As I have said before, it’s a decent antioxidant if you want to take it but do not look to it as a longevity drug!

Over the years, I have voiced all these opinions before and taken a lot of abuse because of my stance.

But, I really don’t care because I am not going to do anything that is not well researched and reasonably proven, and I am not going to stake my health and longevity on it either.

What about TA-65; is it a longevity drug?

Again, the abuse flows both from people who do not believe in longevity as a concept and from others who claim to have a telomerase activator of their own.

My stance remains the same:

If you want to age and die prematurely that is your choice, please proceed by all means!

TA-65 is the only telomerase activator currently available that has ANY human data and more is on the way. Since it’s not a drug, we can’t call it a longevity drug.

But, we could call it a longevity compound since it mimics many of the effects of telomerase over expression by virus or genetic manipulation, including immune boosting, bone mass improvements, anti-inflammatory effects, skin aging decrease or reversal and many metabolic turnarounds.

Since this is my passion and my profession, I want to do everything that makes sense to improve my chances, while we hash out what else is super important in this quest for a better life with better health!

We may yet find that CR makes sense for some group of sick people wanting those things, but we know TA-65 already does.

Doc

P.S. We do owe a debt of gratitude to the CR folks since they are actually trying to find an answer and are willing to sacrifice their lives and some considerable enjoyment of same to get that answer.  I sincerely hope the CR society approaches Life Length to do short telomere testing, since it may provide them with an answer that doesn’t require them to die first!

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Should you take resveratrol?

For the past decade and a half at least a billion dollars in research marketing and publicity money was spent trying to find a home for a class of epigenetic molecules (histone deacetylases) known as sirtuins.

If this sentence has your finger hovering over the mouse, ready to move onto something more interesting and familiar, HANG ON!  At least let me set up a little back ground for you.

A fellow by the name of Sinclair became pretty famous for his research into longevity by researching a molecule initially found in red wine grapes.  That molecule was known as Resveratrol. Subsequently, after a lot of typical internet finagling, the molecule became known as a fountain of youth, a telomerase activator, a telomerase inhibitor and all kinds of other confusing and wonderful things that led to at least a few hundred million dollars for various vitamin gurus and vitamin companies.

And for a long time, the claim was made that Resveratrol modified the all-important class of molecules, known as sirtuins. It was supposed to be a “sirtuin activator”.  More than one famous guru and a lot of famous supplement companies and vitamin foundations touted this as a fountain of youth.

Even the good Dr Oz got into the act, although no one is 100% sure if it was willing participation, or not.  Dr Sinclair did OK, too. He sold Sirtris Pharmaceuticals to Big Pharma giant GLaxo Smith Kline (GSK) for $750 million, one of the biggest dollar amounts for a small bio medical firm ever paid.  Soon after, some of the Sirtris execs raised some eyebrows when they (now working for GSK) started selling Resveratrol online.

Sadly for Resveratrol fans, GSK had to halt the trials on the “super” Resveratrol, developed by Sirtris, because of human toxicity and lack of efficacy. In addition, most of the findings associated with Resveratrol could not be replicated.  OOOPS!  There goes 750 million.

If you’ve ever wondered why Big Pharma has been so slow to jump on the anti-aging bandwagon and develop the magic pill they so desperately want, this is no small part of the reason. It parallels the multi-billion dollar failures, fraught with lawsuits and human harm that have occurred as a result of Big Pharma’s failures to develop effective weight loss drugs.

Damn! The basics of human behavior and human existence are so friggin’ complicated!

Hint: now that we are beginning to piece together the epigenome and the role of epigenetics in all cellular functions, the day is coming when both magic pills will become available.  Heck, we already have TA-65!

Historically, the link between research and eventual true human longevity will go straight through TA-65. Not so, with Resveratrol.

Now, all is not lost for Resveratrol.  It turns out it’s a good antioxidant and a modifier of some important molecules, known as “adipokines”, which help the body manage energy, glucose, fat and stress – all important stuff.  This cannot help but influence telomere health, at least indirectly. But as I proved to myself and at least a few people who would listen (along with some help from super scientist Bill Andrews of Sierra Sciences), Resveratrol is neither telomerase activator nor inhibitor.

OK, now let’s back up to the molecules that started all this – sirtuins.  I predicted a bunch of things, when I wrote my portion of The Immortality Edge and the many newsletters that have followed since then. One of them was that calorie restriction would be a totally impractical way to extend life, and the other was that telomeres and sirtuins would be linked.  I said that I thought telomeres would eventually be shown to influence the activity and expression of sirtuins.

While that last thing has not yet come true, its corollary has.  Sirtuins have begun to be shown to influence telomere length.

There are seven or eight specific sirtuins for humans that we know of.  So it’s time for another prediction!

I predict the sirtuins will turn out to be like the Chakras – an energy centered concept that features in tantric and yogic traditions of Hinduism and Buddhism.

We started out hearing about seven or eight and now there are at least 21!  I am willing to predict we’ll wind up with at least 21 sirtuins, when it’s all said and done, and no, I am not implying the two concepts are linked.  Or am I!?

Anyway, the most studied sirtuin is SIR 1.  Most studies have shown that this protein only confers stress resistance and improved health in the face of stress itself. Then again, who among you eats perfectly, sleeps perfectly and lives a stress-free life!  We don’t even know what those things mean for most people.  Again, as epigenetics evolves and allows the study of individual metabolomics (how each of us processes everything!), we will have an answer and it is not likely to be the same for all of us by a long shot!!! But the sirtuins will be a big part of it and of course, so will your telomeres!

The problem with the sirtuins as longevity molecules is that up until now, SIR 1 the most studied of them, did not confer longevity. SIR6 however, may in humans. Notice I said “up until now”. A recent study (see below) suggests that there are genetic variants, that do indeed make a population of people stand out for their longevity.  Now the study has some shaky/shady assumptions and statistical play.  But it is still intriguing and needs further study, of course.

I would like to suggest, to the authors, that they reverse the direction of their study and see what role telomere length has on the expression of the sirtuins, specifically SIR1 and 6.  Then I think we will really get somewhere.

It won’t get GSK their $750 million back, nor will it restore Resveratrol to its (funnily continued!) much vaunted status as a longevity drug.  But it will get us closer, in a meaningful way, to solving what I think is the disease called aging.

In my next life, I want to come back as a basic science researcher.  Then again, if I live long enough, I could go back and swap my MD for a PhD and have a ball.

Anything is possible, so don’t give up – and take your fish oil, TA-65 and if you must, your Resveratrol.

Biogerontology. 2012 Apr;13(2):119-31. Epub 2011 Oct 5.

Telomere maintenance genes SIRT1 and XRCC6 impact age-related decline in telomere length but only SIRT1 is associated with human longevity.

Kim S, Bi X, Czarny-Ratajczak M, Dai J, Welsh DA, Myers L, Welsch MA, Cherry KE, Arnold J, Poon LW, Jazwinski SM.

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Why not resveratrol?

red wine photoI got an interesting question from a reader who wanted to know why “resveratrol” was not mentioned in our book, The Immortality Edge.  Given all the hype that resveratrol continues to get, it’s a fair question. But in that last sentence is the answer, “hype”.  I can remember someone writing in and saying her doctor told her to pick either TA-65 or resveratrol, because one was a telomerase activator and the other (resveratrol) an inhibitor and they should not be taken together, because they counteract each other.  She stopped the TA-65 (no, not because of cost), because she could not imagine life without resveratrol. This is not the first time I have seen or heard of absolute devotion to resveratrol.  Frankly, this kind of almost religious ardor, over a supplement, should be reserved for something that has actually panned out and been proven – like fish oil!

Resveratrol made its reputation based on the “fact” that it activated a class of histone deacetylases (that there, is one of them epigenetic type terms) known as “sirtuins”. Sirtuins were thought to be longevity molecules, for a long time, before cracks in that argument began to appear. Hundreds of millions of dollars were spent on resveratrol research and sirtuin research, in the hopes of finding the “secret molecule of longevity”. As always happens in today’s world, rumors started and the internet bred more and viola; you now have the wonder drug resveratrol, key to the sirtuins, gateway to the same benefits of calorie restriction for longevity…

Now for a little reality check.

Let’s start with the biggest bomb first. Glaxo Smith Kline, a pharmaceutical giant, paid $720 million to aquire Sirtris Pharmaceuticals, a company headed by Harvard resveratrol guru, David Sinclair. While it is not 100% clear what happened afterward, rumor has it, that much of the data provided prior to the sale, including that on resveratrol and its more potent synthetic analogs, could not be reproduced by GSK’s scientists. Then the actual resveratrol-derived compound, that was in clinical trials, caused several cases of kidney failure and that was the end of “resveratrol as a drug”. That, we do know for sure – no rumors.

Next, it was found that resveratrol probably does not directly interact with sirtuins at all, but works via a different class of energy sensors called “adipokines”, making it a metabolic shepherd, not a longevity one; although fixing a sick metabolism might indeed boost longevity, at least to a more normal level than dying prematurely!  This association with an entirely different class of molecules broke the knee jerk association of resveratrol with sirtuins. Or at least it should have! There are still a ton of folks out there, who didn’t get the message and continue to publish outdated and incorrect information about resveratrol and sirtuins.

Next, the whole sirtuin deal came into question. The longevity gains shown with sirtuins were shown to occur only in metabolically stressed animals, not normal healthy ones. Finally, it was recognized, that people who express dramatically higher amounts of sirtuins, because of a genetic aberration, do not live longer than “normal” people. Fortunately, they don’t die younger either. But sirtuins seem to work only when the organism is under stress.  Guess what. Aging is stress. Diabetes is stress. Obesity is stress, so sirtuins remain attractive candidates for intervention into the diseases of aging and improving health span, if not life span. Sooner or later, Big Pharma will have its sirtuin activator.

Now our book, The Immortality Edge, is the first and only book of its kind about telomeres. Resveratrol has been touted as both a telomerase activator and telomerase inhibitor. How can it be both? Well, technically speaking, there is similar information concerning fish oil (Undarti Das et al.). It is possible for compounds to act one way on cancer cells and another on aging or regular “healthy cells”, that are non-cancerous. So far so good, right – I should have put resveratrol in the book. Well, I did a little research on my own, with my friend Dr Bill Andrews, who tests for telomerase activity like no one else! I sent in several samples of resveratrol, from different well-known reputable manufacturers and not one of them had any effect on telomerase, at all.  I believe Bill has tested other samples as well and has NEVER found one iota of telomerase activation from anyone’s resveratrol. In addition, there is a guy out there who purports himself as a “student of longevity”. He had a web site and was selling potential “telomerase activators” and his own brand of resveratrol. This guy was and is very popular and has a forum that many people visit and pontificate in all manners about longevity. His particular brand of resveratrol was toxic to human cells at relatively low concentrations and his telomerase activators didn’t activate squat. Now he sells TA-65, which does work on telomerase, so he finally got it right!

So, is resveratrol toxic? Is it worthless? Generally the answers would be no and no, if you get a reputable brand. But, in spite of the occasional article that comes out claiming it’s a telomerase activator, we could never demonstrate that with commercial brands, nor has there ever been any human testing outside of cultures in a dish. Because of its interaction with adipokines, resveratrol does indeed seem to have some important metabolic benefits, especially if you are fat or diabetic. It may help you be healthier, which is a huge thing. But, it probably won’t help you live longer. I should also mention that, as a plant-based polyphenol, it is a potent antioxidant and I used it long before it was popular, in a sadly now defunct supplement a few of you will remember as Super Wrinkle Guard. So, I am not “anti-resveratrol”. I am simply interested in facts.

The compound we chose in The Immortality Edge is far less known, but at least as interesting to me as resveratrol and its cousin pterostilbene. Instead of coming from red wine, like resveratrol, we chose the polyphenolic extract of the aronia melanocarpa berry, which has the highest polyphenol content, anthocyanins, flavonols and cinnamic acids of all of the berry families, including the much vaunted blueberry! Aronia is not a telomerase activator or a longevity inducer either, but when it is finally studied, it will be found to be more potent in most aspects than resveratrol.

That said, if you like resveratrol and want to keep taking it, do so by all means. Just don’t expect it to function like TA-65.

Doc