Saturday, June 28, 2008

Resveratrol: Fat Buster?

In a study by Martin Wabitsch, a pediatric endocrinologist at the University of Ulm in Germany, evidence was presented that furthers the belief that resveratrol may act as a catalyst to reduce the body's production of fat cells. This latest study was performed on human cells in a laboratory test and showed how resveratrol inhibits the number of nascent fat cells that grow into mature fat cells. If fats and carbohydrates from food cannot be transformed into fat cells, they are typically broken down and burned as energy instead. If these lab tests are an accurate indication of the actual process that takes place in the human body, it would limit the addition of fatty tissue. You know, that little (or big) spare tire you carry around your waist that you can't get rid of? This research advances evidence that explains the notion of the "French Paradox". Although the French diet tends to be high in fatty food, the overall population has a much lower obesity rate than other developed countries. Many have hypothesized that high French consumption of red wine is offsetting the high fat content. Only in the last few years has resveratrol been identified as the actual molecule in red wine that makes this happen.

For more detailed coverage of this study refer to these articles in Science News and CBS News.

Monday, June 23, 2008

Evolving Resveratrol/Sirtuin Research

As many followers of the SI Blog may recall, I have often questioned seemingly contradictory research with regard to resveratrol and sirtuins. Resveratrol clearly seems to have promising health benefits, but questions of how it works are still being answered. For recent examples, review the entries on June 4, 2008 and the strikingly differing views between Sirtis Pharmaceuticals and Elixir Pharmaceuticals as it relates to sirtuins and cancer, posted on April 8, 2008. Since it is clear that research on the mechanisms on how this all works in the body is still evolving, it never seemed prudent to follow those who choose to mega dose resveratrol (over 1 gram daily) even though they have reported only minor short term side effects, if any.

The current state of evolving research on sirtuins and resveratrol is well detailed and referenced in the following article written by Bill Sardi. As Mr Sardi is the president of a resveratrol manufacturer, I want to make it clear that I do not endorse or offer any opinion on his product versus other resveratrol products. However, I believe his article is worth reading:


The science surrounding the sirtuin family of genes that control the rate of aging is changing so fast that it begs for a scientific update. Many health and longevity seekers are drinking a bit more red wine or taking resveratrol pills in hopes of prolonging their number of healthy years. Are they doing the right thing? Well, yes, it certainly appears so. But now there is greater understanding how small molecules found in nature actually produce longevity.

The discovery that a molecule commonly found in red wine, resveratrol, activates the Sirtuin 1 DNA-repair “survival” gene, a gene that is also activated by calorie restricted diets [Science. 2000 Sep 22; 289(5487):2126-8] brought immediate hope that a molecular shortcut could be utilized rather than having to deprive oneself of food to achieve healthy longevity.

Various small molecules were tested and it was found that resveratrol activates Sirtuin 1 to a greater extent than other small molecules like quercetin, fisetin, etc. Yeast cells lived far longer when given resveratrol. [Nature 425: 191-96, 2003] Then follow-up studies showed that resveratrol extended the life of fruit flies and roundworms. [Nature 430: 686-69, 2004]

And the resveratrol story only kept getting better. Researchers in Italy showed resveratrol prolonged the life of a cold-water fish. [Experimental Gerontology 2007 Jan-Feb; 42(1-2):81-9] And there was even more excitement among biologists when resveratrol prolonged the life of a warm-blooded mammal (lab mouse) and overcame the effects of a high-fat diet. [Nature. 2006 Nov 16; 444(7117):337-42]

The race was on to develop synthetic resveratrol-like molecules that can activate the Sirtuin 1 gene to an even greater extent than resveratrol by itself. Synthetically made Sirtuin 1 gene activators which could stimulate the Sirtuin 1 gene 1000-fold were unveiled. [Aging Cell 6: 35-43, 2006]

But now the picture isn’t so clear about greater and greater Sirtuin 1 gene activation, and more genes than just Sirtuin 1 may be involved here, and there is even (a) question as to the mechanism that produces in greater amounts of Sirtuin 1 gene-derived proteins.

In an animal study, modest increases of Sirtuin 1 gene protein improved cardiac health, while greater than a 7.5 fold increase in Sirtuin 1 gene protein induced heart failure in laboratory mice. [Circulation Research 100: 1512-21, 2007] This is certainly a red flag. Over-stimulation of Sirtuin1 needs greater scientific scrutiny before mega-sirtuin activator drugs are employed.

Within a year of the report showing resveratrol molecularly mimics a calorie restricted diet, researchers at the National Institutes of Health were reporting that food deprivation activates the Sirtuin 1 gene via another gene called FOXO3a. Elimination of the FOXO3a gene in animals inhibits the starvation-increased expression of Sirtuin 1 gene proteins. Furthermore, when the p53 tumor suppressor gene is eliminated, the Sirtuin 1 gene proteins are not upregulated. Thus resveratrol is now forced to share the limelight with the FOXO3a gene and the p53 gene. Biologists now claim in mammals, p53, Foxo3a and Sirtuin 1 all constitute a nutrient-sensing pathway. [Science 2004 Dec 17; 306 (5704):2105-8] That is to say, during periods of food deprivation, a number of genes are activated in defense of the organism.

Longevity seekers will be hearing more about the family of FOXO family of genes. The Sirtuin1 activator resveratrol works in tandem with the FOXO1 gene, whose proteins are translocated to the nucleus of living cells where they decrease the generation of free radicals and inflammation. So resveratrol is effective in this regard through the action of FOXO1 gene derived proteins. [American Journal Physiology Endocrinology Metabolism 2007 Jul;293(1):E159-64]

Biologists now recognize that one of the adverse effects of high insulin levels and high insulin-growth factor signaling is suppression of the FOXO gene family. Aging is accelerated by the suppression of the FOXO gene family, which results in generation of damaging free radicals. Here is how biologists explain it:

Biologists say “an understanding of the processes controlled by these FOXOs
should permit development of novel classes of agents that will more directly
counteract or prevent the damage associated with diverse life-threatening
conditions, and so foster a life of good health to a ripe old age. Just like caloric restriction, lifespan can be increased in various species by plant-derived polyphenols, such as resveratrol, via activation of sirtuins in cells. Sirtuins, such as SIRT1 in mammals, utilize FOXO and other pathways to achieve their beneficial effects on health and lifespan. Current progress bodes well for an ever-increasing length of healthy life for those who adapt emerging knowledge personally (so-called 'longevitarians')”. [Journal Hypertension 2005; 23: 1285-309]

Even more perplexing, however, is a Harvard study showing that inhibition of Sirtuin 1 gene activity results in a decrease rather than an increase in senescence. Harvard researchers suggest that inhibitors for Sirtuin1 may have anticancer potential. [Oncogene 25: 176-85, 2006] How so? Most lay persons following this story were led to believe the Sirtuin 1 gene needs to be up-regulated rather than down-regulated to produce longevity.

Now researchers at MIT and Harvard show that a calorie-restricted diet does not uniformly activate the Sirtuin 1 gene in all organs of the body. In the liver, a high-calorie diet activates Sirtuin 1 and a low-calorie diet inhibits Sirtuin 1, which runs contrary to what was anticipated.

The researchers themselves explain it this way:

In summary, we show that the regulation of SIRTUIN1 by the diet is more
complicated than originally imagined. While it has been assumed that SIRTUIN1
activity increases generally during calorie restriction, we show that in the
liver the activity of this gene actually decreases. The regulation of SIRTUIN1
activity during calorie restriction is not only tissue-specific, but even
region-specific in non-homogeneous tissues, such as the brain. [Genes &
Development, published online June 11, 2008]


Do any of these revelations take the luster off of resveratrol? Hardly. But certainly the explanation of how resveratrol works is itself a work in progress. And while there may be momentary concern that resveratrol could in fact have the unwanted effect of inducing, or at least failing to prevent, the synthesis of fat and cholesterol in the liver, in fact, resveratrol-fed mice placed on a high-fat diet do not develop fatty liver and actually exhibit improved liver physiology and metabolic function. [Nature 444: 337-42, 2006; Cell 127: 1109-22, 2006]

And for all the followers of this unfolding discovery concerning molecularly-induced longevity who were initially introduced to the Sirtuin1 gene and seek to activate it via red wine or resveratrol pills, there is yet another revelation. At least two of the family of seven sirtuin genes share the role of lifespan regulation via nutrient availability, Sirtuin1 and Sirtuin6.
Furthermore, these same researchers who report on the role of Sirtuin6 also report that food deprivation doesn’t increase Sirtuin1 gene activity, but rather stabilizes this gene-derived protein which results in more of this protein being available. In other words, a calorie-restricted diet doesn’t increase the activity of Sirtuin6, but rather helps preserve it once it is produced. Here is how the researchers describe it:



These findings raise the possibility that, in mammals, several sirtuins mediate
the beneficial effects of calorie restriction on life span in a combinatorial
manner. Hence, a systematic approach is required when studying the role of
sirtuins in aging and calorie restriction. Furthermore, we propose that in order
to develop small molecules which could mimic the ability of calorie restriction
to prolong healthy life-span, one should search for master regulators with the
ability to promote the activities of multiple sirtuins. [FEBS Letters, In Press,
Corrected Proof, Available online 9 June 2008]

Well, there you have it, Sirtuin1 has a brother, Sirtuin6, and they are sharing the scientific limelight now with other genes, including FOXO and the p53 gene, with likely more to come. Furthermore, the activation of Sirtuin1 is not uniform in all tissues and organs and that in vitro studies (in test tubes) which measure activation of the Sirtuin1 gene may not provide a complete nor accurate picture of what is actually going on inside a living organism.

It is this author’s opinion that there is too much reductionist thinking here. Genes do nothing in themselves, they react to biological stressors, such as excess food, food deprivation, radiation, heat, cold, etc. Genes can also be targeted by molecules in the diet, but apparently in not such a narrow way, but rather more broadly. Albeit, the very advantage these small natural molecules like resveratrol have is that they affect a broad array of genes. [Journal Nutritional Biochemistry 2005 Aug; 16(8):449-66]

The human genome consists of 30,000 genes. Upcoming global gene array studies will provide a broader picture of how dietary-derived molecules affect the genome. Cherry-picking a single gene to describe it as “the holy grail” of aging may have been a bit premature. How many genes does a calorie restricted diet significantly upregulate? Around 200.

The next round of scientific discoveries will soon compare the effect of a calorie restricted diet, a resveratrol-supplemented diet, and a diet where multiple small molecules have been employed.
These are challenging studies because calorie restriction induces hundreds (if not hundreds of thousands) of biological changes, making it difficult to identify those that are causal, say researchers. [Journal of Nutrition 2001; 131:918S-923S]


However, aging results in different gene expression patterns specific to each tissue in the body, and the good news is that most alterations produced by aging can be completely or partially prevented by caloric restriction in both heart and skeletal muscle. [Cardiovascular Research 66: 205-12, 2005] Therefore, calorie restriction mimics with small molecules are very promising.

The small molecules that exert the greatest effect over the genome in regard to aging will all be found to be mineral chelators or controllers. [Neurobiology Aging. 2008 Jul; 29(7):1052-9; FEBS Letters 2003 Sep 11; 551(1-3):58-62; Ageing Research Reviews 2003 Jan;2(1):25-37] The gradual accumulation of minerals in the body, once full childhood growth has been achieved, explains the progressive aging experienced by humans. Removal of these minerals (chelation) holds the promise of restoring a youthful state to aging cells, tissues and organs, with the prospect of a biologically unlimited lifespan. –Copyright Bill Sardi, June 21, 2008.

Friday, June 13, 2008

Forbes Article Highlights Accelerating Race for Cellulosic Ethanol Production

A June 12th article in Forbes Auto highlights what is becoming a desperate race to produce low cost cellulosic ethanol. As I've prevoiusly reported on this blog, it is clear how disastrous an effect corn based ethanol has had on food inflation without doing much, if anything, to wean us off fossil fuels. With the USDA now reporting falling 2008 corn production, a crisis is in corn based ethanol production is taking hold. The mad rush towards corn based ethanol production of a couple of years ago is likely to be followed by a new rush for cellulosic ethanol production. This race is already in full swing as at least a half a dozen start ups are plowing money into cellulosic ethanol research.

Mark my words:


"Wall Street ANALysts are missing the
boat on the cellulosic ethanol story!"


At some point in the near future this will change and the ANALysts are likely to hop on the bandwagon. Refer to my blog entry on Verenium Corp. for the Sirtuin Investor pure play pick in this arena. Wall Street hasn't caught on yet and thus the current $2.27 VRNM stock price may represent a very favorable entry point with a market cap of only $145 million. According to Yahoo, only two ANALysts currently have ratings on VRNM.
These are the personal views of the Sirtuin Investor and should not be relied upon for your investment decisions. Do not make any investing decisions without first doing your due diligence.

Friday, June 6, 2008

SI Editorial: The U.S. Energy Dilemma

ITS HERE. The ugly Day of Reckoning in U.S. Energy Policy has arrived and there is plenty of blame to go around. Decades of inaction by our government, endless roadblocks by environmental groups, little national interest in conservation and an auto industry with a short term agenda that focused solely on the big profits of BIG SUVs. All these factors have finally caught up with us. It was inevitable......just a matter of time. Pay day has arrived and it's both painful and ugly.


NOW WHAT??????

Unfortunately, there will be much pain before we can get out of this mess. It will take a national effort to make it happen. The stark reality is scary. Not only is our lack of an energy policy hurting our standard of living, even worse, we no longer control our own destiny!! How scary is it that other countries control whether or not we can heat our homes in the winter or drive our cars in the summer? The Sirtuin Investor proposes the following common sense solutions:


  • Remove the Roadblocks to Nuclear Power. - it's not perfect but it is efficient, abundant and produces NO CO2. France generates 80% of its electrical power from nuclear energy!!

  • Sell Oil and Gas Exploration Leases off the coast of the continental shelf - we have two coastlines that may hold billions of barrels of oil. However, they have been off limits to drilling due to environmental concerns. It is understandable and reasonable to be concerned for our environment. However, desperate times call for desperate measures. Look at what Brazil has accomplished. At this point ANWAR is a no brainer. Are working class people less important than caribou?

  • Embrace Cellulosic Ethanol - don't be swayed by the fiasco of corn based ethanol as it was always intended to be a stepping stone. Once again another country had the vision that we, up until this point, failed to see. Brazil is energy independent. We can get there too with the big legislative push currently in place for cellulosic ethanol. To learn more click here. You may even make some money.

  • Continue to Push For Renewable Energy - we are on the road to progress in this area. Wind, Solar, Municipal Waste, Geothermal, Hydro, Tidal Energy. These are the long term answers that will eventually make a difference. How could anybody argue with off shore wind turbines, for God's sake? But they do!!

  • Conservation - with energy prices at current levels conversation is finally happening on its own inertia. Big SUV's are finally being shunned by consumers. However, legislation should be enacted to officially require significant improvements in auto gas mileage requirements, something that should have been accomplished decades ago.

Nothing stated above is earth shattering. But we are where we are due primarily to a failure of our government act. It is important to get congress to take action now. Those inclined to do so should click on the little e-mail link below to forward this editorial to their representative in congress. Also forward to friends, enemies and acquaintances.

Wednesday, June 4, 2008

New Study: Low Dose of Resveratrol Mimics Calorie Restriction Diet

In an interesting new study of resveratrol, researchers from the University of Wisconsin concluded that low doses of resveratrol mimicked the effects of a calorie restriction diet in mice. That is good news for those who have been reluctant to take mega doses of resveratrol but have chosen to take lower doses.

An abstract of the study follows:

Resveratrol in high doses has been shown to extend lifespan in some studies in invertebrates and to prevent early mortality in mice fed a high-fat diet. We fed mice from middle age (14-months) to old age (30-months) either a control diet, a low dose of resveratrol (4.9 mg kg−1 day−1), or a calorie restricted (CR) diet and examined genome-wide transcriptional profiles. We report a striking transcriptional overlap of CR and resveratrol in heart, skeletal muscle and brain. Both dietary interventions inhibit gene expression profiles associated with cardiac and skeletal muscle aging, and prevent age-related cardiac dysfunction. Dietary resveratrol also mimics the effects of CR in insulin mediated glucose uptake in muscle. Gene expression profiling suggests that both CR and resveratrol may retard some aspects of aging through alterations in chromatin structure and transcription. Resveratrol, at doses that can be readily achieved in humans, fulfills the definition of a dietary compound that mimics some aspects of CR.

A dose of 4.9 mg per kilogram of body weight was given to mice in a study reminiscent to the celebrated Harvard study in November 2006 by David Sinclair. The media attention that followed helped set the stage to orchestrate the IPO of Sirtris Pharmacueticals. From a resveratrol users perspective a 200lb. and 150lb. individual would take a daily dose of 445mg and a 334mg, respectively to mimic the doses in the study. Another interesting aspect was that the beneficial results were observed in "middle aged" mice as well as "old aged" mice. Surprisingly, the study concluded that Sirt1 levels were not over expressed as in previous studies although the health benefits were evident. To read the study in its entirety, click here.

To the Sirtuin Investor, a couple of questions: Will an even lower dose produce the same results? What are the implications of this study to the drug candidate NCE's of Sirtris Pharmacueticals that are 1,000 more times as potent as resveratrol?

Monday, June 2, 2008

Glaxo Sirtris Merger is now Final

The completion of the merger between GlaxoSmithKline PLC and Sirtris Pharmaceuticals was announced today with 97% of shareholder's tendering shares. This transaction puts an end to the only pure play sirtuin investment available to retail investors. Another Cambridge, Mass. based sirtuin focused company, Elixir Pharmacueticals, previously postponed its IPO due to poor equity markets in January 2008 and withdrew its IPO filing with the SEC last month. Don't be surprised if the IPO is revisited this year.

The Sirtuin Investor wishes Glaxo and Sirtris great success in pursuing the promise of sirtuins to treat diseases of the aging.