NY Times Article - More on Sirtirs, Sirtuins and Resveratrol

You'd think that Sinclair, Westphal and Sirtris Pharmacueticals would be less inclined to push the media/press envelope now that Sirtris is part of GlaxoSmithKline. Not true. See the latest feature article in the NY Times. One interesting excerpt: Glaxo is considering the marketing of SRT501 as ad over the counter resveratrol supplement. If you are looking to try resveratrol today be sure to vist SI Blog sponsors on this page.

New Study: Resveratrol Helps Prevent Breast Cancer

New research into the health benefits of resveratrol continue. The latest comes out of the Eppley Institute for Research in Cancer and Allied Diseases at the University of Nebraska Medical Center. This new research published in the July 2008 edition of Cancer Prevention Research shows that resveratrol inhibits can cancer formation in Breast tissue. An excerpt from the study follows:

Resveratrol decreased estrogen metabolism and blocked formation of DNA adducts in cells treated with TCDD and/or estradiol. Resveratrol also suppressed TCDD and/or estradiol-induced cell transformation. Thus, resveratrol can prevent
breast cancer initiation by blocking multiple sites in the estrogen genotoxicity
pathway

The entire study can be read here.

The body of evidence continues and expands as to the positive effects of resveratrol on the human body. As with other recent research, this latest study shows that megadoses of resveratrol were not required to gain the anti-cancer benefits.

New Resveratrol Research Thows a Curveball

Just as many have become confident that the fountain of youth can be found in a daily dose of resveratrol, new research is clouding the issue. The latest research on mice comes from the National Institute of Aging and was the result of a collaborative effort between the laboratories of Rafael de Cabo, Ph.D., of the Laboratory of Experimental Gerontology at the NIA; David A. Sinclair, Ph.D., of the Glenn Laboratories for Molecular Biology of Aging at Harvard Medical School; and an international group of researchers. This research showed:

The Good:

• Improved heart health.
• Improved bone density.
• Improved motor skills and coordination.
• Significantly reduced incidence of cataracts.
• Improved quality of life.
• Increased lifespan for mice fed a high calorie diet.

However, resveratrol DID NOT extend the lifespans of mice fed a normal diet. For now at least, this research debunks the belief that high doses of resveratrol mimic the life extending benefits of a calorie restriction diet.

Meanwhile another study performed by a group lead by Valter Longo, a molecular geneticist at USC, found in laboratory tests that reducing the level of SirT1 activation in neurons decreased the cells sensitivity to oxidation when compared to normal SirT1 activation (for those unfamiliar with SirT1 and other sirtuins, they are the genes believed to be activated by both a calorie restriction diet and resveratrol). However eliminating the SirT1 gene completely, caused the mice to die young.

What this all means is certainly still open to debate, interpretation and motivation. Sirtuin Investor has pointed out previously seemingly conflicting results on whether activation or deactivation of sirtuins is preventative to various types of cancer (see blog entry dated April 30, 2008.) It is advisable to read through all the research and and to look behind the catch phrases put out by the often superficial media. As the sirtuin research picture becomes less focused, shareholders of Sirtris Pharamcueticals who were dismayed by the cash tender offer by Glaxo may now be feeling a little more placated with the $22.50 per share in their pockets! Stay tuned.

Elixir Licenses Boston University SIRT1 Modulators

Trying to stay in the game of Sirtuin based drug development, Elixir Pharmaceuticals has signed an exclusive licensing agreement with Boston University to key intellectual property covering discoveries regarding the use of modulators of SIRT1.

Expert from Elixir press release:

"Modulation of SIRT enzymes has attracted considerable attention because of
their potential to address a broad range of diseases," stated Dr. Peter
DiStefano, Elixir's Chief Scientific Officer. "Based on nearly a decade’s-worth
of research, Elixir has amassed a broad intellectual property estate, which
includes compounds that activate SIRT1 and compounds that inhibit SIRT1. It is
an exciting time to be working in SIRT development and we are pleased to have
added this intellectual property from Dr. Stephen Farmer’s lab at Boston
University to our portfolio."

In January 2008, Elixir was forced to postpone its IPO due to unfavorable market conditions.

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.

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.

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.

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.

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?

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.

Verenium Investor Day Presentation

On May 28, 2008, Verenium Corporation held an Investor's Day conference at its pilot cellulosic ethanol plant in Jennings, Louisiana. The very informative presentation, held in front for analysts and investors, discussed its specialty enzyme business that may hold one of the keys to the promise of cellulosic ethanol. Do your own due diligence by watching the very informative presentation here. Those who invest the time will find the presentation very intriguing and potentially rewarding.

Focus on Verenium and Cellulosic Ethanol

The last few years have brought the United States to a realization that many have feared for some time: Both our national security and economy is vulnerable to the vagaries of the oil markets. This is a stggering realization if you have the courage to really ponder it. Imagine, the most powerful country on the planet (at least until recently) is not in control of its own destiny. With this in mind, our leaders in Washington made a big push to ethanol in an energy bill passed a couple of years ago that included mandates and generous subsidies to quickly get production ramped up. Unfortunately, currently the only economical method in the U.S. to produce ethanol is with corn as its input. Unfortunately, corn based ethanaol has proven to be more of a problem than a solution. First of all, many believe the amount of fossil fuel needed to produce corn-based ethanol approaches or exceeds the energy output of the ethanol produced. Secondly, corn is a food staple and the increase in corn based ethanol production has had a direct effect on both food supplies and food inflation, as anyone who visits a grocery store can attest. That's were Verenium Corporation comes in.

Corn based ethanol has always been seen as a stepping stone to the ultimate goal of producing it from cellulosic ethanol. Cellulolsic ethanol includes corn stover, switch grass, and other forms of biomass. The problem has been that the technology to produce ethanol from these readily available, environmentally friendly sources, has yet to be proven on a commercial scale. That's were Verenium comes in.

Verenium is a company that came about as a result of a merger of two entities in June 2007:

1. Diversa Corporation - a global leader in enzyme technology and
2. Celunol Corporation - a leading developer of cellulosic ethanol process technologies and projects.

The pending energy bill, which passed with enough votes to make it veto proof, has new important incentives to transition our nation from unattractive corn based ethanol to cellulosic ethanol. Do your own DD about VRNM. Here is my short synopsis:

THE GOOD: VRNM has decades of enzyme research and hundreds of millions in accumulated R&D. The justified bad press on corn based ethanol has unjustly negatively effected the stock of VRNM which is developing the attractive cellolosic alternative. The pending 2008 energy bill recognizes the need to move from corn to cellulous and is very favorable in this regard with up to a huge $1.01 tax credit per gallon.

THE BAD: Cost overruns at the company's demonstration plant have put pressure on the company's finances and it will need to raise capital or find a corporate backer.

THE UGLY: The February 2007 convertible offering in conjunction with a call spread on its own stock was an expensive piece of financing sold mostly to hedge funds that short the VRNM stock as a hedge to its long position. As a result the stock price has and will be volatile.

Short Term CATALYST: The passage of the energy bill.

Simply put, the risk/reward profile of VRNM is very high. If VRNM can show in its current demonstration projects that it has viable technology to produce commercial scale cellulosic ethanol, it could become an easy 1o-bagger. If it fails or runs into major roadblocks the risk is your entire investment.

Do your own DD and pass this link on to those who may be interested.

Sirtuin Investor to Expand Coverage

With the acquisition of Sirtis Pharmacueticals by Glaxo, the universe of publicly traded companies strictly focused on sirtuin research has declined by 100% to zero. When I began this blog back in December 2007 , I did so with the intent of following the long term story of sirtuins, primarily from an investment standpoint. I believed that as the sirtuin story played out, the ride would be an exciting and rewarding one for those who hopped on. Well, the ride was certainly rewarding....it just happened to come to an unexpected detour, well before anticipated, with the acquisition of Sirtris by Glaxo.

With all endings come new beginnings. While the sirtuin story is still extremely fascinating, the only pure play investment opportunity in this area has disappeared and the initial focus of the Sirtuin Investor blog no longer makes much sense. However, immortality IS STILL EXPENSIVE and it seems to be getting more expensive each day. Since reveratrol believers still expect to extend their lives, they need to find ways to finance it. I will attempt to find investments that will replace SIRT in my portfolio and share them on this blog. I will not attempt to flood this page with dozens of ideas but focus on a few stocks that have various risk/reward profiles. I keep most of my assets in municipals giving me the luxury of placing a few large high risk/high reward bets. In every case these are just my own personal ideas and readers need to do their own due diligence.

My first stock of focus will be Verenium Corporation, a company focused on cellulosic ethanol. At this time I provide only a link to their home page for those who wish to do their own research. I will follow-up shortly with a blog entry that will share my own views on the merits of this investment.

Poll Closed - 63% Oppose Merger

The unscientific SI poll on whether or not Sirtris should sell the company to GlaxoSmithKline has closed. Of the 44 who voted, 63% where against the merger. It is interesting to note that in such a difficult equity market, a solid majority of those polled would rather forego the sure thing of an 84% premium, in order to take a gamble on the long term prospects of the sirtuin platform.

From the Sirtuin Investor perspective, after reading the entire offer document, it became very clear that Sirtris management did a very thorough job in shopping the company around after Glaxo expressed interest in an acquisition. Up until this point, Sirtris had been seeking a smaller equity investment from several big Pharma companies at a price of $25 per share. After the overture by Glaxo to acquire the entire company, Sirtris hired JP Morgan to entertain other potential offers and provide a fairness opinion. No other suitors emerged and Sirtris did a fine job in procuring a $22.50 cash tender offer price at a time when the shares in the company were selling in the $12 range. An amazing thing about the offer was how well kept a secret it was. There was absolutely no indication in the stock price or volume that any indication of the negotiations had leaked out. Although I've criticized senior management for insider sales at such an early stage of development of the technology, the insider sales continued throughout the period of negotiations at prices well below the final tender offer price.

As a shareholder, as we count down to the ending of Sirtris as an independent public company, I want to congratulate and thank Sirtis senior management for their efforts and wish them success in capitalizing on the amazing potential of the sirtuin platform. As the Sirtuin Investor, I've partially lost my reason for existence with the elimination of the only pure play sirtuin investment available to the public. Now what do I DO?? I'll either need to expand the scope of this blog or put it to rest. Stay tuned.

Cancer and SRT1: Elixir Versus Sirtris??

Based on seemingly conflicting statements from competing biotechnology companies, it appears that Sirtris Pharmaceuticals and Elixir Pharmaceuticals have conflicting views on the mechanism of how the modulation of SIRT1 expression may one day be used as a cancer treatment. Judge for yourself:

Excpert from Sirtris press release dated April 16, 2008 :

Sirtris Pharmaceuticals, Inc. (NASDAQ: SIRT), a biopharmaceutical company
focused on discovering and developing small molecule drugs to treat diseases of
aging, announced that a research team led by the company's two Scientific
Advisory Board co-chairs has demonstrated that overexpression of the
SIRT1 enzyme can suppress tumor formation and growth in a preclinical
mouse model of colon cancer, providing the first in-vivo data that SIRT1 can
suppress tumor cell development. The paper, titled SIRT1 Deacetylase Suppresses
Intestinal Tumorigenesis and Colon Cancer Growth, appears in today's issue of
the scientific journal PLoS One.

Excerpt from Elixir website:

Conversely, blocking the amount or activity of SIRT1 has recently been
shown to reverse "epigenetic silencing," a phenomenon that decreases the
expression of important tumor suppressor genes. The implication of these
findings is that blocking SIRT1 could be important in combating several types of cancer. These observations highlight the large potential, and explain the recent interest, in the discovery and development of compounds which could either
increase or decrease the enzymes of this important class of SIRT targets.

If anyone with technical knowledge of this topic has a logical explanation for this seemingly conflicting information, please post a comment to explain.

Will Another Sirtuin Suitor Emerge?

It has now been confirmed by the market, that the intellectual property of the sirtuin platform Sirtris has put together over the last several years has a definitive minimum value of $720,000,000. However, based upon the total lack of buying in advance of the $22.50 buyout offer it is unlikely that Chris Westphal actively shopped the company around to other big pharmaceutical companies. This was an extremely well kept secret. In fact, on the trading day preceding the announcement of the offer, SIRT shares actually declined by over 4%. These observations lead me to believe (and hope) that another large drug company bid is NOT out of the question. If you follow the industry, the drug pipelines at many companies in big pharma have been seen as weak by analysts. It is the pipeline that drives value at these companies.

A review of all the diseases of the aging that are potential targets of the sirtuin platform will make it clear why Glaxo made its bid and why another drug company might feel compelled to take a close look at the bid and carefully evaluate whether a higher bid is in order. A higher bid is still a long shot but it is not out of the question.

GlaxoSmithKline offers $22.50 Cash for Sirtris - HOLD OUT FOR MORE!!

In a surprise move, Sirtris Pharamacueticals agreed to a sell out its future for $22.50 per share in an all cash deal worth $720,000,000. This offer certainly substantiates the sirtuin technology platform that Sirtris has been developing over the past several years. However, this is a bittersweet deal for the Sirtris faithful. As posited many times on this blog, the potential of this stock is immeasurable.

The Sirtuin Investor is taking a position on this deal: DON'T SELL @ $22.50!! While this may be a futile attempt as 21.84% of the shares are held by insiders with institutional investors owning another 30.40%, I believe Sirtris shareholders would be better off riding this thing for a few years. Chris Westphal had been guiding for some time now that a joint venture deal with big pharma was possible within a year or so. Readers of this blog KNOW that a future SI hope for SIRT, aside from its potential of becoming a successful drug company, was the potential for irrational exuberance to take hold at some point. Those dreams end with a cash buyout!

When those proxies come in the mail....VOTE NO! And let your views be known by voting in the SI new poll regarding the buyout. Comments about the deal are encouraged.

Second Clinical Trial Results of SRT501 Released

Sirtris Pharmacueticals reported the results of its second Phase 1b clinical study yesterday on SRT501, which involved twice daily dosages of 1.25 grams and 2.50 grams. This study follows up on the safety results of the first study, released this past January, of a single daily doses of 2.50 grams and 5.0 grams. The only difference between the two clinical trials were a single daily dose versus a twice daily dose of the same aggregate daily dosage. Both clinical results demonstrated no significant safety issues. Both studies also showed a lowering of glucose in Type 2 Diabetic patients and signs of efficacy and dose response although the primary focus of the studies were safety.

While this is good news it is hardly unexpected given the safety results of the first study. The more important test of SRT501's viability, will be later on this year when phase 2a data on the effectiveness of SRT501 in combination with the standard of care, metformin will be released. Even if SRT501 does well in this 2a trial, SIRT's 1,000 times more potent NCE may be the more likely candidate to become a stand alone diabetes drug candidate.

In any case, it is the potential of the vastness of the sirtuin platform and the role that Sirtris seemingly plays as gatekeeper with its numerous patents, that makes this a very promising play in biotechnology.

Do your own due diligence.

Home Garden Resveratrol Experiment

The recent announcement by Sirtris regarding its licensing agreement with Bayer Life Sciences got me thinking about my tomato garden. Every spring, I plant six tomato plants and by July the plants bear fruit. There is nothing like the taste of home grown tomatoes. If you've ever grown tomatoes you've probably observed that, in some years, the leaves on the plant may discolor, from the bottom up, and eventually fall off. If it gets really bad the entire plant can die off. The fruit is typically not effected in mild cases but tomato yields may suffer. This is usually caused by a plant fungus that often hits tomato plants called septoria.

I plan on performing my own personal experiment in this year's crop. When I plant my tomato plants this year, I plan on sprinkling 100mg of resveratrol onto the soil surrounding the eventual root spread of 3 out of the 6 tomato plants. Since, resveratrol is a phytoalexin produced naturally by several plants when under attack by bacteria or fungi, it will be interesting to see whether providing resveratrol directly to the roots will have any effect. I'll be reporting on the results as the plants grow. If any SI readers wish to perform the same experiment we can compare notes.

Highlight of the Barbara Walters Sirtris Interview

When Barbara asked David Sinclair.. "I think a lot of people will say you're raising expectations, this can't possibly happen." Sinclair answered "My answer to that is, I agree but its TRUE. What else can I say. Aging is really a set of diseases and if we slow them down and cure them, people will live longer, healthier lives." CEO Westhphal added " The major diseases of western society are EXACTLY the diseases that should be able to be treated with the drugs we're developing."

With that the three of them raised their wine glasses and toasted "To the future".........Martin Scorsese couldn't directed a better script, IMHO.

Are you convinced? Skeptical? Are Sirtuins the answer? Is Sirtris the real deal? Vote your your opinion on the new poll to the right and share the actual program excerpt below with friends.

As always, do your own due diligence.