Cytori Therapeutics - The Story is Getting Out

In my September 9th entry on Cytori Therapeutics, I focused on a company with an exciting platform for delivering multiple stem cell therapies and a compelling, easy to understand, story.

Now, even as the stock of Cytori Therapeutics has drifted lower over the last couple of weeks, the story certainly seems to be spreading. Ironically, the media interest is not necessarily related to the potential as a therapy to repair damaged hearts, cure incontinence or treat periodontal disease but as a natural alternative to breast implants.

While the Cytori's stem cell extracting Celution machine has been approved for use in Europe and Asia for therapeutic purposes, it is approved only for research purposes by the FDA in the U.S. However, that little detail hasn't stopped a handful of surgeons, who see this as the next great big thing in cosmetic surgery, to commence the use of the Celution in cosmetic therapies, without a requirement for FDA approval.

The idea of taking fat from one part of the body and replanting it into one's breasts, with a stem cell nourishment that enhances its stability, is not only an irresistible concept to women across the world but its a great lead in story to media outlets across the nation. In recent conference calls, Cytori disclosed that it earns $2,500 per procedure on the disposables used in each procedure. The Celution machine itself sells for about $100,000. So, while this is truly a great story that alone can be feed a stock price, the economics for Cytori seem to be in place as adipose stem cell therapies catch on.

Here are a couple of examples of the story starting to spread in the U.S. by a single doctor in Arizona:

How long will it be before we see the same stories in the bigger media markets of New York and California and, of course, national news networks. Women across the nation are sure to be clamoring for this procedure (if of course they can afford it).

Just to put things in perspective, let's not forget there are several more medically critical potential therapies of Cytori's platform other than natural breast enhancement. This is just the beginning of the story, in my opinion and as I stated in a previous entry, I do own Cytori stock and I recently picked up some warrants (CYTXW) so I am not unbiased. I impatiently wait along side other Cytori shareholders for irrational exuberance to turn a legitimately promising story into something even bigger. Do your own DD and decide for yourself.

NY Times Article Updates Srtris Pharama Progress

Interesting update covering a conference on aging at Harvard university. Click here:

What's Up With Resveratrol??

As many long time followers of this blog know, the Sirtuin Investor originated on December 1, 1997 to follow the progress of resveratrol as the basis of new therapies and longevity and to try and make some money by following the companies involved in this pursuit. The word "sirtuin" is the enzyme that is stimulated by the resveratrol molecule in the body and is believed to provide health benefits to the body and potentially slow down the aging process. Sirtris Pharmacueticals, the leading company that created all the excitement surrounding resveratrol, IPO'd in May 2007 at $10 per share and was closely followed on this blog. In August 2008, Sirtris was acquired by GlaxoSmithkline PLC for $22.50, representing an annualized return of over 100% since the IPO, making many readers of this blog happy yet, at the same time, somewhat ambivalent that the long term investment thesis of the Sirtuin platform never had the opportunity to develop (i.e a possible 10-bagger) . Since then, this blog has focused on a handful of exciting, yet sometimes highly speculative, investment ideas and will continue to do so to try and find ideas that can fund a long life. However, at this time the Sirtuin Investor would like to take a step back and focus on resveratrol usage once again with two new polls:

What is your daily dose of resveratrol?

How has resveratrol helped you?

If you have ever used resveratrol please vote!

Cytori Stem Cell Platform Expands

Last week I wrote about the many potentials of Cytori Therapeutic's Celution system that extracts stem and other regenerative cells from a patient's own fat cells. Today, the potential for the expansion of the platform to treat gum disease was highlighted in pre-clinical study results released in a press release from Cytori. The results suggest that the use of uncultured fat derived regenerative cells significantly improved the effects of periodontal disease, evidenced by significantly improved alveolar bone healing and decreased gingival (gum) invasion of the defect.

Of course, this data is pre-clinical in nature and must pass clinicical trials in humans. However, it illustrates my underlying investment thesis on the vast potential of Cytori's PLATFORM:

ONE MEDICAL TECHNOLOGY-----> MULTIPLE POTENTIAL APPLICATIONS

I expect more positive data over the next six months and believe the stock will react positively.

These are the personal views of The Sirtuin Investor. Do your own due diligence.

Cytori Therapeutics - Irresistible Stem Cell Story?

Although the issue is on the back burners of the news these days, remember all the controversy surrounding embryonic stem cells? Is it morally acceptable to use discarded embryos to procure stem cells for the potential treatment of life threatening diseases? Its a tough question embroiled in an emotional tug of war between religious beliefs and the needs of the desperately ill. Well, there is at least one company whose stem cell technology has shown great potential to side step this issue altogether....and its trading at levels that make it a potential 10 bagger (disclosure: I just bought a bunch of shares a few days ago).

I've been following Cytori Therapeutics for a couple of years and believe it is poised to become a big winner. I will provide a simplified summary of my thoughts on Cytori here and provide the links that will allow you do do your own due diligence.

Cytori's main product is a machine called the Celution. The Celution uses adipose tissue (also known as fat tissue) extracted from a patient's body and processes it through centrifugal and proprietary enzyme technology. The end product is a concentrated mixture of the patient's own stem and other regenerative cells that can be put to use to help treat damaged or diseased body parts. It may sound like science fiction but the Celution is already in use in Europe and Japan and is currently before the FDA for approval as a medical device in the U.S. Here are some of the bullet points that get me excited at the potential for this stock:

• THE PLATFORM: The Celution is a platform for the delivery of stem cells where the potential therapeutic applications are only limited in number by the imagination of the medical profession. (Remember the Sirtris Pharmacueticals platform previously mentioned on this blog that lead to a buyout by Glaxo at a 100% premium?) Currently Cytori is sponsoring clinical trials for the treatment of breast reconstruction and heart disease. However, others in the medical field are evaluating Celution derived cells for use in the treatment breast augmentation (bigger breasts without the silicone), periodontal disease (regrowing diseased gums), urinary incontinence (fixing leaky faucets)and other potential treatments are surely on the way. The beauty of this platform is that Cytori provides the technology and the disposables (recurring revenue stream) and the medical field works for Cytori to find the applications that have the most potential.
• HARVEST PATIENT'S OWN STEM CELL'S: Cytori's process uses a patient's own stem and regenerative cells that are extracted DURING the operation for which the stem cells will be used. No ethical issues about destroying embryos. No concerns about compatibility. No concerns about supply other than the patient's own fat level (look at your own stomach...are you a candidate?) IMHO, this is a great sell from a marketing perspective. Less worries about adverse effects or concerns about foreign stem cells.
• FDA APPROVAL PROCESS: The FDA recently determined that the Celution would be evaluated as a medical device. This was an important step in Celution's approval process in the U.S. and represents a quicker path to commercialization as opposed to being evaluated as a drug.
• SMALL MARKET CAP: At current levels (i.e. when I started writing this piece with CYTX at about $3.00), CYTX has a market cap of only $112 million compared to other stem cell stocks like OSIR (Osiris Therapeutics) at $263 million, the precieved leader GERN (Geron) at $656 million and STEM (Stem Cells) at $181 million. Yet, on a price to sales basis, CYTX is cheaper than all of them: CYTX: 7.6 OSIR: 8.7 GERN: 427 STEM: 359. I believe that the lack of publicity of Cytori's story in the U.S. is one of the major factors that have kept Cytori's value below that of its peers.
• GREAT STORY: I love a stock with a great but simple story based upon on American ingenuity. A story that can create excitement once the general public becomes aware of it. A story that is fundamentally easy to understand. The greatest gains in the market, the ones that eventually lead to irrational exuberance and skyrocketing stock prices, are often those stocks with exciting stories that are easily understandable. Cytori fits the bill, IMHO: Extract body fat...put fat into a machine to extract concentrated mixture of stem cells...reinsert cells in your damaged body part. Oprah, are you listening? Gotta love it.

Well there you have it. I only wish I had finished this entry on the day I started it with CYTX still at around $3.00 per share. Like most story stocks it jumped on a news release issued yesterday. There could be more to come. Do your own due diligence.

Quadramed (QDHC) - Microcap with Potential

I came across Quadramed Corporation (QDHC ,$6.52) by doing a database screen that focused on small cap companies with good valuation metrics little or no debt and significant insider buying. When I run this type of screen I will often come across a couple of dozen companies. Further fundamental research is required to filter thorough the list to come up with investment ideas that are worthy of my commitment. What piqued my interest about Quadramed, other than the screened criteria, was the sector it is in...software and systems for Electronic Health Records. The reason I find this industry very interesting is the great emphasis the Obama administration is putting into this area in the hope to reduce health care costs. In fact, the stimulus package passed earlier this year had approximately $19 billions set aside for health care technology. These are huge numbers that Quadramed is well positioned to take advantage of.

I will not provide a full blown research report on Quadramed but I will provide some of the numbers and reasons why I believe this company could be a double or triple within a year. No one should blindly listen to an anonymous blog (even a great one like Sirtuin Investor!) but should do there own homework (and I provide the links below to do so).

1. Market Cap: $56 million...Enterprise Value: $30 Million...yes this certainly is a micro cap. I like to keep a large portion of my assets in fixed income and make speculative but well thought out investments in under followed stocks. With a market cap so tiny, QDHC has no sell side Wall Street ANALyst coverage. I love this about a stock because if I Am correct and the company's earnings begin to accelerate, the ANALysts should take notice and provide a catalyst for stock appreciation
2. Tiny Float: 4.84 million shares outstanding. This can work both ways, making it hard to liquidate in a weak market and difficult to buy if the company starts to gain momentum on the upside. Since I believe QDHC is well positioned for growing EPS and, as a result, appreciating stock price...I love a small float. Small floats have been personally lucrative for me in the past.
3. Forward P/E = 6. According to Yahoo which I believe is coming from a single Reuters estimate.
4. New CEO: QDHC just snagged an executive from mega health care technology company McKesson to be its new CEO. His contacts should certainly help QDHC capture some of the stimulus money and his desire to move to QDHC gives me an independent opinion on QDHC prospects.
5. Insider Buying: 405,000 shares in just the last 6 months. I love insider buying in small cap stocks and, in this case, I suspect it is related to insiders' belief of how the recently passed stimulus package will stimulate new sales.
6. No Long Term Debt and Lots of Cash: $24,000,000 in cash or $2.89 per share. QDHC does have 4,000,000 share of convertible preferred stock outstanding with a conversion rate of $15 or so per share that was issued when the common stock was substantially higher in 2005. I look at this as a cheap source of financing that never has to be repaid and can possibly be bought back at a discount.
7. 1:5 Reverse Stock Split in June 2008: No one wants to own a stock that does a reverse split. A reverse split tends to drive down a stock further. However, if you are purchasing QDHC post the reverse split, you get the advantage of a lower valuation due to the the stigma of such. Remember, a reverse split, just like a regular stock split, has absolutely no effect on the finances or fundamentals of a company.
8. Recurring Revenues: I forgot the percentage but a significant portion of QDHC's revenues come from recurring maintenance and servicing contracts. Do your own DD here.

Well there you have it, an under-followed or should I say COMPLETELY IGNORED small cap stock (just look at the average daily volume) with, in my humble opinion, a compelling story. An investment in QDHC may help some of those resveratrol users that plan to live to 100 build up their nest egg (remember, Immortality is Expensive). You must, however, do your own due diligence.

Municipal Auction Investment Plan

Sorry, I haven't posted in a while as I've been focusing on making money in this volatile market. I've set up another blog with an investment idea that sophisticated Sirtuin Investor followers may want to examine. A Triple A rated debt security of a large utility with the potential to pay 18% if enough investors follow through on the plan. Click here to read about the idea.

OBAMA Budget Continues Push For Biofuels

President Obama revealed his proposed 2010 Budget that followed through on the American Recovery and Reinvestment Act of 2009 and set down a guantlet to attempt to propel the United States towards a future of cleaner energy and energy independence. The section of the budget related to the Department of Energy clearly indicates that the favoritism showed towards the oil industry at the expense of alternative energies is being reversed. Once again I point to Verenium Corpration, a pure play cutting edge cellulosic ethanol company with the backing of BP and old connections to Stephen Chu, Energy Secretary, as a company positioned to lead Mr. Obama's energy revolution. According to the Wall Street Journal, the oil industry is reeling from the new reality:

That has oil companies hopping mad. The American Petroleum Institute said
higher taxes would stifle oil-patch investment and job creation. “I don’t see
how this bolsters energy security,” API spokeswoman Cathy Landry said. BP
executive Lamar McKay told Congress Wednesday that taxing “core energy” while
subsidizing new energy would do nothing to help the nation’s energy
security.

It will be very interesting to see how this radical new direction in energy policy progresses over the next decade. Fortunes could be made by playing this policy shift correctly.

Excellent Article on State of Cellulosic Ethanol

If you are following the progress in cellulosic ethanol then you will want to read this excellent article in USA Today about cellulosic ethanol and Verenium.

WSJ: David Sinclair Screws Up

Hard to believe, even when you see it with your own eyes, that David Sinclair would become associated with a organization that sells wellness products through an Amway type sales structure. He has since ended his relationship with this organization but there he is...the star of the show, in front of the Shaklee sales force conference looking more like the combination of old style tonic salesman and a motivational speaker/preacher than a respected Harvard researcher. What could he be thinking? Hasn't he made enough money with the takeover of Sirtris Pharmacueticals by Glaxo? It makes me wonder to what extent the sale of Sirtris to Glaxo for $700,000,000 was a result of good marketing versus good science! Is this a sign of honest, unbridled enthusiasm from Sinclair or an indication of shameless greed? Take the poll at the right and express your views.

New Energy Secretary Steven Chu - a Dream Choice for Verenium

Who could be a better choice for energy secretary for Verenioum shareholders' than Steven Chu, a noble prize winner in physics? The answer is a resouding "nobody". Mr. Chu is now at the forefront of cellulosic ethanol technology, as much as Verenium is, and was the catalyst behind a $500,000,000 grant from BP to the University of California Berkely last year. With recent investment of $90,000,000 by BP into a joint venture with Verenium, the circle seems to have closed and the path is now wide open for VRNM. The only hurdle left is execution. Alternative Energy and specifically non food based bio fuels now have the political backing that the oil industry has enjoyed and abused over the last 8 years. Verenium's time will soon come.

New Sirtuin Hypothesis by David Sinclair Group

Seeking to unblock the mysteries of whether sirtuins (more specifically SIRT1) actually hold the secrets to aging, a group of scientist lead by David Sinclair of Sirtris Pharmacueticals (now part of GlaxoSmithKline ) has put forward the latest hypothesis on the mechanisms of SIRT1's role within a cell. For those not well versed in molecular biology, the hypothesis is rather complicated. Sirtuin Investor will attempt to simplify it into layman's terms:

1. Each cell has a double strand of DNA that, if stretched out, would extend over six feet long.
2. Each of these DNA strands has about 20,000 genes or so.
3. Under normal operations, each cell must provide instantaneous access to a very limited number of genes depending on the cell type (i.e. blood, pancreatic, renal, bone marrow, etc.)
4. The primary role of the SIRT1 is to help a cell SUPPRESS all the genes it shouldn't be accessing.
5. SIRT1 also has an important secondary role...to act as the cell's handyman, moving into action to repair any breaks in DNA strands within the cell.
6. Unfortunately, when the SIRT1 puts on its handyman hat and moves into action to make DNA repairs within the cell, it temporarily vacates its chief role as gene suppressor. Remember, only a handful of specialized genes are supposed to be active within any given cell type.
7. With SIRT1 distracted from it's primary role, normally dormant genes can wake up start partying, in the process, playing havoc and causing damage to the cell (think of a bunch of teenagers at house party when naive parents go on vacation). In the best case scenario, this cumulative damage is what we see in ourselves as normal aging.
8. Find a way to over express SIRT1 (analogous to finding surrogate parents while the real ones are on vacation) and there are less opportunities for cell damage....and the aging process is slowed down.

Whether this hypothesis gains wide support is open to debate. However, the hypothesis is tantalizingly seductive. Only time will tell whether the idea of a fountain of youth is a reachable goal or still a distant fantasy.

One final thought: you think the social security system (and our entire financial system) is in trouble now, just think about what will happen if we achieve the ability to extend our lifetimes by 20%? Oy Vey! Keep taking that resveratrol!

New Sirtris Study Results Reported

Sirtris Pharmacueticals recently released the results of a new study on mice that, it claims, further validates Sirt1 as a target for the treatment of metabolic disorders and endurance enhancement, an excerpt of which follows:

"The NAD+-dependent deacetylase SIRT1 controls metabolic processes in response to low nutrient availability. We report the metabolic phenotype of mice treated with SRT1720, a specific and potent synthetic activator of SIRT1 that is devoid of direct action on AMPK. SRT1720 administration robustly enhances endurance running performance and strongly protects from diet-induced obesity and insulin resistance by enhancing oxidative metabolism in skeletal muscle, liver, and brown adipose tissue. These metabolic effects of SRT1720 are mediated by the induction of a genetic network controlling fatty acid oxidation through a multifaceted mechanism that involves the direct deacetylation of PGC-1α, FOXO1, and p53 and the indirect stimulation of AMPK signaling through a global metabolic adaptation mimicking low energy levels. Combined with our previous work on resveratrol, the current study further validates SIRT1 as a target for the treatment of metabolic disorders and characterizes the mechanisms underlying the therapeutic potential of SIRT1 activation."

With evidence that SRT1720 "robustly enhances endurance running performance and protects from diet induced obesity" it would not be a leap of faith to hypothesize that the professional sports world is already ahead of the pack in trying resveratrol supplements to improve athletic performance. After all, resveratrol does not have the issues of being a banned substance.

The entire study is available for purchase here.

Obama Victory Bodes Well for Verenium

One of the stark policy differences between John McCain and Barak Obama was their respective differences on ethanol. Obama favors ethanol subsidies, McCain opposes them. McCain essentially gave up on Iowa, the largest corn producing state in the nation with this position. If the consideration is solely corn based ethanol, there is justification for McCain's position. Corn based ethanol provides very little net energy gain, if any, over the underlying fossil fuels that go into the process of making it and has had the unintended effect of raising food prices. However, the fallacy of McCain's policy is that it fails to consider the next generation of ethanol technology called cellulosic ethanol. President Obama understands that cellulosic ethanol is the end game due to clear advantages over corn based ethanol:

1. Use of non-food crops
2. Use of relatively low-cost feedstock
3. Use of marginal lands for feedstock growth
4. A very beneficial net energy balance
5. Use of less fertilizer and water.

With the victory of Barak Obama, Verenium is now firmly seated in driver's seat of this emerging revolution in biofuels. Verenium's landmark agreement with British Petroleum has positioned VRNM to be one of the top performers over the next 12-24 months in the opinion of the SI Blog.

To learn more about Verenium and its potential, visit these SI blog entries:

Focus on Verenium and Cellulosic Ethanol
Forbes Article Highlights Accelerating Race for Cellulosic Ethanol Production
Interview With Verenium's John Howe

Do your own due diligence.

Resveratrol and Weight Loss - Personal Experience

As many readers of this blog have learned, the benefits of resveratrol seem to be numerous. Just read down the entries of the SI blog and you will find many blog entries highlighting the numerous potential health benefits of resveratrol.

My own personal experience seems to confirm one benefit: weight loss. I've been using resveratrol for over a year and a half. During that time frame, my weight has slowly declined from 193lbs t0 183lbs. I'm 6 feet tall and my goal is 180lbs. I don't believe my calorie intake has lessened and I my activity levelhasn't changed. Research has shown resveratrol's effect on fat cells. My personal experience seems to confirm this. Additional comments from other personal experiences are encouraged.

With that, I have started a new poll. Has resveratrol helped you lose weight?

OFF TOPIC: Two New Polls

Given the historic events over the last few weeks the Sirtuin Investor is conducting 2 new polls:

1) Should some form of the plan to approve the purchase of up to $700,000,000,000 (that's a lot of zeros) in mortgage backed securities be approved in order to help save the economy?

2)How will you vote for president?

Vote now.

Resceratrol: Now its Radiation Protection?

In a seemingly endless string of research into the potential health benefits of resveratrol, new research from researchers at the University of Pittsburgh shows that resveratrol, when altered with acetyl, protected cells from radiation in mouse models. The study was led by Joel Greenberger, M.D., professor and chairman of the Department of Radiation Oncology at the University of Pittsburgh School of Medicine.

This new research adds to resveratrol's reputation as a compond with an expanding universe of health benefits. In other unrelated research resveratrol has already been shown to have potential in many diseases of the aging.

Interview With Verenium's John Howe

Click here to watch a very relevant interview with John Howe of Verenium Corp.

Obama Versus McCain on Cellulosic Ethanol

Verenium investors should be aware of the materially different positions on cellulosic ethanol held by the two presidential candidates:



OBAMA's website..straight forward policy on ethanol:

• Develop the Next Generation of Biofuels: Barack Obama will work to ensure that advanced biofuels, including cellulosic ethanol, are developed and incorporated into our national supply as soon as possible. Obama will invest federal resources, including tax incentives, cash prizes and government contracts into developing the most promising technologies with the goal of getting the first two billion gallons of cellulosic ethanol into the system by 2013.

McCain's own word....against subsidies for ethanol

Verenium enters Landmark Agreement with BP

Like most small caps, the stock price of Verenium Corporation (profiled here on May 21, 2008) has languished with the stock market since the SI Blog expanded coverage to cover promising companies outside the sirtuin space with the elimination of Sirtris Pharmacueticals as a public company. Today however, Verenium Corporation, followed in the steps of Sirtris by announcing a landmark agreement with an industry leader. In this case it was British Petroleum. Unlike Sirtris, however, Verenium management, which owns an astounding 54.67% of the company, decided that the upside was too promising to sell the entire company to BP. The deal calls for the establishment of a joint venture to commercialize celluslosic ethanol and it includes $90,000,000 of financing from BP over the next 18 months

One major catalyst for this agreement is certainly recently passed legislation that mandates 21 billion gallons of advanced biofuel production by 2022, of which 16 billion gallons must come from cellulosic ethanol. That's one hell of a mandate considering that the cellulosic ethanol industry doesn't really exist right now. Any company that can take advantage of this legislation will have a very lucrative business. More importantly, that company will help us move forward towards true energy independence. Cellulosic ethanol has five principal advantages over much criticized, and rightfully so, corn based ethanol:

1. it uses non-food crops
2. it uses relatively low-cost feedstock
3. it uses marginal lands for feedstock growth
4. it has a beneficial net energy balance
5. it uses less fertilizer and water.


Verenium is a leader in this field and is currently optimizing the nation’s first true demonstration-scale plant capable of producing ethanol from non-food cellulosic biomass sources.

Do your own due diligence and remember, if you visit this blog primarily as a resveratrol user....immortality is expensive.

New Poll on Resveratrol Usage

Back in February 2008, the SI blog ran a poll on resveratrol usage. The results were as follows:

• I don't take any --- 19%
• Up to 100 mg ----- 11%
• Up to 200 mg ----- 20%
• Up to 1,000 mg --- 26%
• Over 1,000 mg ---- 22%

Given the volume of research that has become available in the last 6 months, a new poll is now being taken to examine how usage has evolved. To participate see box at the right.

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.

Barbara Walters Special - Ground Zero for Onset of Irrational Exuberance?

Long time readers of this blog are well aware of my belief that Sirtris Pharmacueticals has the potential to be the story stock of ALL story stocks. The main ingredients are there for the onset of irrational exuberance and here is my attempt to list them in order of importance:

• The fountain of youth angle - live long and stay vigorous.
• The potential (dream?) to cure many diseases of the aging with a single pill.
• The Harvard Medical School connection combined with the incredible team of brain power put together by Sirtris.
• The idea that the body's own defense mechanism is being activated, a seemingly natural process.
• The evidence that sirtuin activation results in improved athletic performance without the nasty side effects of HGH and anabolic steroids.

It is the investor's dream to own a company BEFORE irrational exuberance manifests itself in a stock's share price with the hope that the investor can either:

1. Recognize when investor psychology has turned negative and recognize some very healthy gains OR
2. Continue to own shares and reap the ultimate of financial rewards when suspected "irrational" exuberance proves to be "rational" after all.

We've seen many examples in history of number 1 - great story stocks that never lived up to expectations. I illustrated a couple of examples in my December 17, 2007 blog entry. Smart investors capitalized and made huge sums of money on the way up...others fell victim to the hype and got burned as the story turned out to be a fantasy.

Tuesday night at 10:00 PM could mark Sirtris Pharmacueticals move into America's conscience and into Wall Street's spotlight as Barbara Walters highlights the amazing body of work at Sirtris Pharmacueticals on a special program called Live to 150...Can You Do It?. Its likely to be very compelling television and those who have been following the area of sirtuins KNOW that the actual evidence is equally compelling.

IMHO, the main hurdle to irrational exuberance in any stock at this time may be overall market pessimism. However, if there is a story that can swim up tide, IMO, we may be looking at it right here and right now.

Do your own due diligence (and remember to visit resveratrol sponsors on this page).

Multiple Potentials of the Sirtuin Platform

With each passing month, Sirtris Pharmacueticals, the leading biotechnology company in sirtuin based drug research, presents new data showing that the approach of targeting sirtuins shows promise in multiple diseases. Although we are still in the early innings of the game, the potential value being created at Sirtris is tremendous. A partial listing linked to the associated press releases that discuss progress treating various diseases is shown here:

• Optic Neuritis in a Preclinical Model of Multiple Sclerosis
• Cancer
• Type 2 Diabetes
• Alzheimer's Disease
• Huntington Disease
• Stess reistance in plants

The potential of this sirtuin platform to create a very valuable company is promising as there are multiple roads to success. Most importantly, the process of activating a natural defense process within the body seems to make the likelihood of safety high. While it is still early, so far no side serious effects have been reported in any clinical data.

Its still a long road to commercial success. However, increased valuation is usually reflected in the stock price of of a biotechnology company well in advance of the crowning event of a drug achieving FDA approval. More importantly, from an shareholder's perspective, irrational exuberance can take hold quickly once a certain level of confidence is achieved in a company's prospects. Add in some excitement in the press and some Wall Street analysts that pound the table and you've got yourself a story stock

Do your own due dilligence.

Biotech CEO Joins Sirtris Board

Sirtris Pharmacuticals announced today that Paul Friedman, president and CEO of biotech concern, Incyte Coproration, was joined its board of directors. This addition complements other industry leaders on the board including Jeffrey Capello, SVP and CFO, PerkinElmer, Inc.,
Stephen Hoffman, Ph.D., M.D., Chairman (and former CEO) of Allos Therapeutics, Inc., Richard Pops, Chairman (and former CEO) of Alkermes, Inc. Incyte Corporation is a drug discovery and development company, which focuses on developing proprietary small molecule drugs to treat human immunodeficiency virus (HIV), diabetes, oncology, and inflammation diseases. Incyte has a market capitalization of $863 million and a enterprise value close to $1 Billion.

It is interesting to observe the stream of executives from competitors and potential partners populating the Sirtris board. The industry contacts available to this board are certainly widespread. It wouldn't be a surprise if a joint venture with a major player happens sooner than the timeframe that Sirtris management has been guiding to. The recently approved patent approval granted to the company on resveratrol like NCE compounds, certainly puts Sirtris in a stronger negotiating position for a deal to happen.

Sirtris Issued Important Patent on SIRT1 Activators

Sirtris Pharmacueticals reported today a significant milestone in its strategy to become the gatekeeper to the technology involved in the activation of the SRT1 enzyme in stating that "the United States Patent Office issued to Sirtris the first patent covering a broad class of compounds that activate the enzyme SIRT1." The significance of this patent, in my opinion, is related to the phrase "broad class". It has been a goal of Sirtris to effectively control the platform of compounds that activate sirtuins. This achievement can be viewed a significant step in that goal.

If the Sirtuin platform proves to be as promising for drug development in diseases of the aging as early indications seem to indicate, this patent could be remembered as the inflection pointed that started it all for Sirtris. The obvious upside of the patent is that big pharma is much more likely to partner with Sirtris than to pursue sirtuin research on its own and risk patent infringement issues.

For those interesting in learning more about sirtuins and their promise, read through the earlier blogs on this post.

Sirtris Expands Revenue Potential into Agriculture

Capitalizing on its vast platform of life extending technologies, Sirtris announced today that it has expanded its scope into the agriculture industry by granting an exclusive license agreement to the crop science subsidiary of multi-national German conglomerate, Bayer AG. The agreement covers "worldwide rights in the field of plants to a certain Sirtris technology that contributes to cellular life span extension and stress resistance." Sirtris will receive an initial up-front payment and potential future success bound milestone payments. However, specific payment terms were not disclosed.

Without knowing the specific details of the agreement it is difficult to assess the revenue potential of this agreement. However, the agriculture industry is a huge global business and any technology that can economically and safely improve yields should prove to be lucrative.

SRT501 Shows Oral Effectiveness in Mice for MS Eye Disease

In a new study on mice, Sirtris Pharmacueticals will present today that its SRT501 drug candidate is equally effective when administered orally versus previous studies by injection in the treatment of an eye disease common in patients with multiple sclerosis (the report of the study was originally released on March 4th, 2008). The company continues to accumulate data with the goal of validating the belief that the targeting of the sirtuin genes has the potential to become a platform for drug development in the treatment of multiple diseases of the aging.

Most Sirtuin Investor Readers Using Resveratrol

The SI Blog Resvertrol Usage Poll is has closed. Not suprisingly 80% of those polled are taking resveratrol. Almost 1/2 of those polled are taking in excess of 200mg per day. Here are the final results:

I don't take any --- 19%
Up to 100 mg ----- 11%
Up to 200 mg ---- 20%
Up to 1,000 mg -- 26%
Over 1,000 mg --- 22%

Given that Sirtris dosed at 5,000 mg and 2,500 mg in its recent Type 2 Diabetes clinical trial without any significant adverse effects it does not seem surprising that those somewhat knowledgable about sirtuins are taking rather high doses.

Cancer and Sirtuins: Activate or Supress??

There seems to be some conflicting ideas with regard to targeting sirtuins to fight cancer. Sirtris is researching how activation of sirtuins can stop cancer growth while others are looking to de-activate sirtuins to achieve the same result:

From Sirtris 2/20/08:

CAMBRIDGE, Mass., Feb 20, 2008 (BUSINESS WIRE) -- Sirtris Pharmaceuticals, Inc.
(NASDAQ: SIRT), a biopharmaceutical company focused on discovering and developing small molecule drugs to treat diseases of aging, announced that Sirtris co-founder David Sinclair, PhD, Harvard Medical School Associate Professor of Pathology, will present data showing that SIRT1 activation can suppress tumor formation and growth in the intestine and colon in a preclinical model of colon cancer. These are the first in-vivo data showing that SIRT1 overexpression can suppress tumor formation and growth. These data are the work of Sirtris Scientific Advisory board co-chairs Sinclair and Leonard Guarente, PhD, the Novartis Professor of Biology at the Massachusetts Institute of Technology

From Sirtris 2/21/08:

The National Cancer Institute will test the compounds in well-established cancer cell lines which were previously used in the development of novel and existing chemo-therapeutics. The cell lines to be tested include some of the most common cancer types. The program will also test Sirtris' compounds using in-vivo mouse tumor models to determine if the compounds reduce or limit the growth of the tumor cells. Previous studies have shown that calorie restriction--a method which has been shown to increase SIRT1 activation--can exert strong tumor suppressor effects in mammals and increase lifespan in organisms. Through direct activation of the SIRT1 enzyme with Sirtris' compounds, researchers in this study will be able explore the enzyme's role in tumor suppression along multiple pathways.

Exerpt from From University of Bath press announcement (undated, but recent):

"...Studies have shown that increased levels of these enzymes, known as sirtuins,
are found in tumours from a range of different cancer types.

This suggests that, by finding a way of preventing these enzymes from working, it may be possible to halt the progression of cancer by stopping tumour cells from
dividing and growing. "

Sirtuins In Men's Skin Beauty Product??

Sirtuin activation has now found its way into men's high end skin care products as a company called Alford & Hoff has jumped on to the band wagon. As sirtuin research expands exponentially and continues to show expanding potential health benefits, the roster of companies looking to capitalize also continues to expand. Are we in the early stages of a mania? Time will tell. An interesting aspect of this sirtuin based product expansion is whether any of these companies are researching patent infringement issues before coming to the market. The other angle is whether these products really do anything!

Chris Westphal Comments on Stock Price

At the BIO CEO & Investor conference today, Chris Westphal commented on the stock price action of SIRT since the IPO. He mentioned how the stock rallied strongly after the IPO and corrected down significantly after the 6 month lock-up expired and venture capitalists sold off 20% of the market capitalization over the last six weeks. Of most interest to the Sirtuin Investor was his comment regarding SIRT's stock price... "...has corrected down significantly. We view this as a buying opportunity for the company."

I'm glad to hear Dr. Westphal say this and I expect that he and other top SIRT employees will refrain from any further insider sells, 105b-1 plan or not, for the forseeable future as discussed in previous blog entry dated January 31st.

SRT501 Not Likely a Stand Alone Type 2 Diabetes Drug

In the Q&A at the BIO CEO & Investor Conference, Christoph Westphal mentioned that SRT501's future as a drugable treatment of Type 2 Diabetes may lie in the pairing of it with other drugs such as metamorfin. The NCE, which is 1,000 times more potent than SRT501, is viewed within the company as the better candidate for stand alone type 2 diabetes treatment. Data in the next few months should provide the information necessary to make this determination on SRT501.

Do your own DD.

SRT501 To test Against Cancer in 2008

At the BIO Investor & CEO Conference today, Dr. Chris Westphal disclosed that Sirtris Pharmacueticals would commence SRT501 clinical trials in humans for the treatment of cancer. He mentioned that many resveratrol studies have shown effects on cancer.

From Wikipedia:

Cancer Prevention
In some lineages of cancer cell culture, resveratrol has been shown to induce apoptosis, which means it kills cells and may kill cancer cells.[35][36][37][38][39][40] Resveratrol has been shown to induce Fas/Fas ligand mediated apoptosis, p53 and cyclins A, B1 and cyclin-dependent kinases cdk 1 and 2. Resveratrol also possesses antioxidant and anti-angiogenic properties.[41][42]

Resveratrol is under extensive investigation as a cancer chemopreventive agent.[43][44] Indeed, there are studies showing that small doses of dietary resveratrol can reduce colon carcinogenesis in rats and mice.[45] One German study has already been shown to that under special conditions, resveratrol induces apoptosis in human fat cells. In addition, it inhibits production of cytokines which are involved in the development of obesity-related disorders.[46]

Do your own DD.

Hopping onto the Sirtuin Bandwagon

We are now seeing other groups hopping onto the sirtuin bandwagon. Here are a couple of non profit research centers, one in India and one in PA that are combining forces in the area of sirtuins.

Press Release
Wistar on Sirtuins

SI projects that before this year is done we will begin to see one or more OTC Bulletin Board stocks pop up (probably through reverse mergers) with no real hope of commercial success but with fantastic claims of grandeur. Their press releases will focus on the huge size of the market of drugs related to diseases of the aging. It happens all the time once a great idea catches fire.

Basic Foundation of Type 2 Diabetes Treatment Crumbles

In a startling development in Type 2 diabetes treatment, a wide held pillar of belief that aggressively keeping one measure of blood sugar (called HbA1c) below 6 instead of the standard 7.5 would reduce heart attacks and other cardiovascular events has crumbled. Businessweek has a very thorough article on this startling development.

How this will effect Sirtris Pharmaceutical’s SRT501 and NCE diabetes drug candidates cannot be known at this time. However, I find this excerpt from the Businessweek article particularly interesting:

"However, the evidence that aggressive blood sugar control using drugs brings benefits has always been weak. Proponents of more intensive drug treatment cite a landmark study started back in the 1970s called the U.K. Prospective Diabetes Study (UKPDS). In that trial, researchers followed thousands of patients with type 2 diabetes for more than a decade, comparing those who merely got advice on diet and lifestyle to those who took drugs to lower their blood sugar and keep it under tighter control. The researchers claimed the more aggressive treatment worked to reduce the complications of diabetes, which include kidney failure, blindness, amputation of infected limbs, and cardiovascular disease.

But in fact, the benefits seen in the trial were tiny or nonexistent. The study's authors had to torture the data to reach their conclusions, charges Dr. Robert Ewart, associate professor of family and community medicine at Southern Illinois University School of Medicine. "The UKPDS was a particularly egregious example of data manipulation," he says. "There just isn't any evidence that tight control of type 2 diabetes improves outcomes."

Ewart has plenty of company in doubting the trial. No oral diabetes drug "has ever been shown to do anything really good for any patient," adds Dr. Nortin Hadler, professor of medicine at the University of North Carolina at Chapel Hill. "No leg, eye, kidney, heart, or brain have ever been spared." And in a recent New England Journal of Medicine commentary, Dr. Clifford Rosen, chair of the Food & Drug Administration advisory committee that evaluated one such drug (GlaxoSmithKline's (GSK) Avandia), wrote that "the two largest randomized, placebo-controlled trials in patients with type 2 diabetes, the United Kingdom Prospective Diabetes Study and the University Group Diabetes Program, failed to find a significant reduction on cardiovascular events even with excellent glucose control.""

It is nearly impossible to come to any firm conclusions, with any level of certainty, that can interpret this new data. However, no one can argue that the best treatment for type 2 diabetes is what most humans seemingly don't want to hear: EAT LESS AND EXCERCISE MORE! In other words, live a healthy lifestyle. That is where it seems that targeting sirtuins may have advantages over other drug treatments. The basic premise behind sirtuin research is that the activation of certain sirtuins can mimic a calorie restriction diet (CRD). Long time readers on this blog understand that there are many studies that indicate that a CRD has been proven to increase longevity and fight off disease in many mammals (new readers should review early entries on the SI blog to learn about CRD). Could it be that mimicking a healthy diet may be the best way to treat Type 2 Diabetes for those who cannot live a healthy lifestyle on their own? Only time will tell. Interesting stuff.

Sirtris Signs Leonard P. Guarente to Exclusive

Sirtris Pharamcueticals today announced today Leonard P. Guarente, PhD, Novartis Professor of Biology at the Massachusetts Institute of Technology, has signed a new, exclusive consulting agreement with Sirtris Pharmaceuticals. Dr. Guarente first joined Sirtris’ Scientific Advisory Board as Co-Chair in November 2007. Prior to joining Sirtris, Dr. Guarente was formerly a co-founder of Cambridge, Mass. based Elixir Pharmacueticals, another sirtuin focused startup. Elixir recently postponed its planned IPO. Sirtris has establish a leading edge roster of sirtuin research expertise and this new agreement further solidifies its position.

SIRT High Price Poll Closed - 2008 Thoughts

The results of the poll conducted on this blog regarding expectations for the 2008 high stock price of SIRT are now final. No consensus was formed. If you ignore the $10 choice, which is already incorrect, the other choices: $20 -> 23%, $30-> 29% & $40 or above-> 27% or above were pretty much the same.

One year is an eternity in stock market time and the ultimate correct prognostication will be determined by three main factors:

1) Progress in clinical trials and any other related news (i.e., big pharma deals).
2) Level of insider selling.
3) General market conditions.

Sirtuin Investor has a personal 2008 price target of $33 per share with the caveat that insider selling remains somewhat muted throughout the year. Now a little commentary. IMHO, at this early timeframe in SIRT's business business plan, employee and executive insiders have not yet earned the right to sell their shares, from a moral standpoint, despite limited legal restrictions from doing so under SEC regulations. Employee insiders will only legitimately earn the windfall that comes from sales of cheap SIRT stock when at least one of the following occurs:

1) 4 years have passed from the IPO date.
2) Average monthly volume exceeds 500,000 shares for a three month period.
3) The company is on a clear path to profitability.

My logic for these parameters is as follows:

1)4 years have passed from the IPO date.
Once 4 years have passed from the IPO date, the investing public will likely have all
the data it needs to make an informed decision on whether SIRT will ultimately achieve its goals. By this time, any hype created by SIRT management will either have been validated or disproved and a true legimate measurement SIRT's efforts will be reflected in its stock price. In other words, the playing field will have been reasonably leveled between insiders and outside shareholders with regard to where this company is ultimately headed as substansive results of clinical trials will be available.

2)Average monthly volume exceeds 500,000shs for a three month period.
This will be an indication that the company has generated sustainable widespread market interest and will allow insiders to sell without significantly effecting the stock price.

3)The company is on a clear path to profitability.
In the final analysis, this is the only true measurement of management and
employee effectiveness. Until SIRT reaches this, albeit subjective, moment in its history, employee insiders will not have legitimately earned the proceeds of windfall personal stock sales to the public, IMHO.

If 2007 is any indication, 2008 will be a volatile year. As always, do your own due dilligence.
Comments are welcome!

Smoking Linked to Sirtuin Destruction

As reported in Science Daily, the importance of sirtuins to health continues to expand. Now, A University of Rochester scientist has discovered that the toxins in cigarette smoke wipe out the SIRT1 gene. The research shows that without this gene we not only lose a bit of youthfulness -- but the lungs are left open to destructive inflammation and diseases such as chronic obstructive pulmonary disease (COPD) and lung cancer.

With each new resveratrol study, it becomes more clear that sirtuins play a vital role in the many aspects of health and vitality. Harnessing the power of these genes will likely play a critical role in future treatments for many diseases of the aging, a basic premise in the business plan of Sirtris Pharmacueticals.

It is interesting to see that, based on the resveratrol usage poll being conducted on this blog, that many are not waiting for long term studies to get the benefits of resveratrol. Do your own due dilligence.

Sirtris Releases New NCE Mice Study

Sirtris Pharmacueticals reported today that one of its new chemical entities, which is 1,000 times more potent than resveratrol, reduces fat, boosts exercise endurance and improves insulin sensitivity in mice on a high-fat diet. Aside from the diabetes potential of the NCE, Sirtuin Investor wonders: Could SIRT's NCE, at some point, could become the next performance enhancing drug to hit the sports world? Only unlike, steroids it may have a safe profile without steroid side effects. Time will tell.

Nonetheless, while preliminary with regard to human trials, this is certainly good news for SIRT and they will present the data this Saturday at the Keystone Symposia on Diabetes Mellitus, Insulin Action and Resistance Conference.

Elixir Pharmacueticals Postpones IPO

As speculated on the SI blog on January 8th, Elixir Pharmaceuticals has been forced to postpone its IPO, scheduled for this week, as plunging equity markets made a successful offering unrealistic. It is not clear when, or if, the IPO will move forward. Interestingly, it appears that underwriters pulled the plug at the last minute as a NASDAQ ticker symbol, ELXR, was set up today. It is unclear how ELXR will respond to its failed capital raising efforts. Timing is everything.

New Poll on Resveratrol Usage

Many of those who are interested in sirtuins and the possibility of investment opportunities in the same are also likely to be interested in the potential health benefits of taking resveratrol, an activator of sirtuins. The Sirtuin Investor Blog has set up a new poll to find whether readers are taking resveratrol and, if so, how much. The results should be interesting.

Encouraging Price Action on SIRT

After rallying sharply and immediately on the positive SRT501 clinical data on January 8th, SIRT shares subsequently relinquished most of its gains. However, as the market has had time to digest the SRT501 data and the implications of potential future value, the subsequent price action has been very encouraging, given the weak overall markets:



Sirtuin Investor believes that SIRT could easily move towards the upper teens ($17-$19)within the next two weeks as institutional interest increases. Importantly, based on the low volume observed during this rise, the advent of irrational exuberance is still a way off (see SI BLOG 12/17/07).

Do your own due diligence and remember the SI proverb: immortality is expensive.

ELIXIR Pharmacueticals Prices IPO

In an amendment to its S-1 filing with the SEC, Elixir Pharmaceuticals revealed that it hopes to sell 5,750,000 shares at $16 or $92,000,000, an increase of $1 per share over an earlier filing. Apparently, ELXR and its underwriters hope to ride the wave of excitement generated by both Sirtris and other companies that presented at the JP Morgan Health Care conference.
ELXR S-1A Filing
The Sirtuin Investor speculates that the current equity market anxiety will make a successful IPO difficult. If the IPO is successful, Elixir will become the third public company that has announced a formal research program that focuses on sirtuins in the development of new drugs, Pharmion and Sirtris are the others.

Due your own due dilligence and remember....immortality is expensive

SI Blog Covers the JPMorgan Presentation

A few of the Sirtuin Investor observations from the JP Morgan presentation (readers can review the actual press release on the Sirtris news feed shown in right column):

-Christoph Westphal, M.D., Ph.D., CEO and Vice Chair of Sirtris made an eloquent and highly well thought out step by step presentation that took the audience from the first studies on calorie restriction in the 1930s to the just released clinical data on SRT501.

-SRT501 provides a 5 fold exposure to resveratrol than the natural substance.

-Mr. Westhpal's most significant quote: "...to summarise the data, we are certainly positively surprised."

-Finally, here is the prospective news flow calendar:



As the chart shows, the news flow will remain healthy throughout the year.

Carefully do your own due dilligence because immortality is expensive.

As Predicted on SI Blog : SRT501 Clinical Results Released

As speculated on this blog, Sirtris Pharmacueticals released the results of its Phase 1b clinical study of SRT501 at the 26th Annual JPMorgan Healthcare Conference. The news was terrific:

"This 28-day Phase 1b study was designed to assess the safety, tolerability and pharmacokinetics of once-daily, orally administered doses of either 2.5 g or 5 g of SRT501 in patients with Type 2 Diabetes who were naïve to other diabetes drug treatments. Both doses of SRT501 were found to be safe and well-tolerated, and pharmacokinetics, a measure of drug levels in the blood, were identical at days one and 28, suggesting no drug accumulation. There were no serious adverse events and no dose-related adverse events. Importantly, SRT501 showed a statistically significant improvement in an oral glucose tolerance test on day 28 at two hours and a trend towards lower fasting plasma glucose levels."

For SIRT investors the good news translated into a 14% gain in after hours trading as SIRT rose sharply from $13.19 at the close to $15 at 5:00PM. Tomorrow should be a very interesting day.

SIRT SEC Filing - Emphasis on Change in Control

In an 8-k filing filed yesterday changes were made to the employment agreements of senior management. The most interesting aspect was related to a change in control:

"On January 2, 2008, upon a recommendation of the Compensation Committee of the Board of Directors, the Company entered into amended and restated employment agreements with Christoph Westphal, Garen Bohlin, Peter Elliott and Michael Jirousek, to make the payments and benefits payable to these executive officers in certain circumstances more consistent with each other and reflective of current market terms for similarly situated executives. The agreements provide that a certain percentage of the options and restricted stock held by each of these executive officers, other than Mr. Westphal, will vest upon a change in control (as defined in the agreements), and the remainder of the options and restricted stock will vest upon termination by the Company without cause (as defined in the agreements) or by the employee for good reason (as defined in the agreements) within a certain time period following the change in control. Mr. Westphal's employment agreement was amended to provide that all of Mr. Westphal's unvested options, in addition to his restricted stock, will fully vest upon a change in control. Additionally, if any of Messrs. Westphal, Bohlin, Elliott or Jirousek is terminated during a specified period following a change in control without cause or for good reason, each officer, other than Mr. Westphal, will each receive a lump sum payment equal to 12 months base salary. Mr. Westphal will receive a lump sum payment equal to 18 months of base salary. Each executive officer will also receive a pro-rata portion of the target bonus he would have received for the year in which the termination occurs."

Those who have closely followed SIRT and this blog are aware that big Pharma has been keenly interested in the progress Sirtris has made on Sirtuin research. These amendments to management compensation agreements appear to be a tacit acknowledgement that at as SIRT progresses as the leader in sirtuin research, it will further position itself as an attractive acquisition target.

Do your own DD.

Small Float: The Good, the Bad and the Ugly

For investors in SIRT, the last month and a half has seen both titillating exhilaration and stomach churning pain. This stock chart clearly illustrates this:



We all love to feel the exhilaration and loathe to feel the pain. However, a story stock such as SIRT with low float and limited liquidity, where the future is unlimited but the risks are high, tends to act in this schizophrenic manner. Throw in some venture capital sales of cheap stock and a lull in the news flow and the SIRT stock chart speaks for itself. The interesting thing about story stocks like SIRT is that when substantive good news comes along, sharp declines are often followed by steep climbs. One way to deal with this volatility is to own a long term core position and an equal trading position. Own no more in total than you can afford to lose and take the trading position off the table after a sharp rise. How sharp a rise? Who the hell KNOWS!!! That is the $501,000,000 question.

With SRT501 clinical trials from India due out any day now and with a little luck, we could see the chart turn upside down!!



On January 7th, SIRT is presenting at the 26th Annual JPMorgan Healthcare Conference. Clould this be the day they announce the SIRT501 clinical trial results?

Good luck and do your own due diligence.....and please visit our sponsors on this blog. Remember, immortality is expensive!

More Evidence that Sirtuins and SIRT are Below Radar

This is an excerpt from an article written by the president of one of the many resveratrol manufacturers:

"Will humans commonly live 120 years and beyond, beginning anytime soon? "If red wine pills do slow the aging process, the public hasn't responded to the news headlines. Resveratrol pills aren't in the top 100 selling herbal supplements," say Bill Sardi, of Resveratrol Partners LLC (dba Longevinex®)."

The fact that resveratrol is still not in the top 100 selling herbal supplements is further evidence, IMHO, that the story for Sirtris is still well under the radar screen of wall street investors. Think about it for a minute. With all the hoopla about resveratrol, the mouse study and Sirtris, can it be that there are still over 100 other supplements still outselling resveratrol?? If the vitamin set hasn't recognized a supplement with such startling potential than it is clear that the story on Sirtris has yet to be told and sold. This tells me that Sirtris Pharmacueticals is still somewhat of an enigma to investors and that irrational exuberance is still a long way off.

If SIRT lives up to its promise it may very well become the greatest story stock ever told.

Pharmion Just Getting Started with Sirtuins

From a recent Pharmion SEC Filing:

"The Company made significant progress in the third quarter advancing its product pipeline. Pharmion initiated several clinical studies across its portfolio, including a Phase 3 study in small cell lung cancer for Amrubicin, Phase 1 and Phase 2 studies in solid tumors and CLL for MGCD0103, opened centers and began enrolling patients in the dose escalation study for oral Azacitidine, and commenced our research program targeting sirtuin inhibitors. Research and development (R&D) expenses totaled $29.1 million for the third quarter of 2007, compared to $16.7 million for the third quarter of 2006. For the nine months ended September 30, 2007, research and development costs totaled $72.0 million, compared to $50.2 million for the nine-month period ended September 30, 2006."

It is very interesting to see that a large cap pharma is just now initiating its research into Sirtuins. Sirtris has over 140 patents in this area and with this intellectual property is attempting to position itself as the gatekeeper of Sirtuin technology. These patents could prove to be especially valuable as this field of science progresses.

Waiting for Irrational Exuberance

We have seen it many times in the stock market. An idea, a concept, a dream that takes a company's stock price to valuations that can never be justified.

It happened to Ballard Power Systems, when the promise of a fuel cell car that emits only water put its stock into the stratosphere. Early investors made windfalls until the stark realities of putting a hydrogen fuel cell car on the road brought BLDP's stock price back down to stark reality:



It also happened to Human Genome Sciences when it began work on mapping the human genome. The excitement generated pushed HGSI from the single digits to over $100 a share. Only problem? Nobody was thinking about where the profits would come from:



Ideas, concepts or dreams that can capture the imagination of investors and cause them, en masse, to behave irrationally and drive a stock price up to unsustainable heights don't come along every day. More practically, recognizing these gems before the masses isn't so obvious. If one is lucky enough to come across a BLDP or an HGSI before the exuberance kicks in then one is sitting on a potential gold mine. The biggest challenge will be determining when the exuberance is peaking and/or the underlying story is failing to keep up with the dream and gold mine threatens to transoform into into a deadly land mine.

In my view Sirtris Pharamcuticals fits the bill of a company with a story that can capture the imagination of the masses. The underlying concept is exciting and relatively simple to understand:

1) Those who partake in a calorie restriction diet live longer and stay healthier.
2) Recent research has shown this "cause and effect" is due to the activation of certain enzymes within the body's cells, called sirtuins, that seem to put the body into some kind of heightened defensive state.
3)When taken in high doses, resveratrol, a naturally occurring compound found in grape skin and other plants, seems to activate sirtuins without the need for calorie restriction.
4) SIRT is the leading company trying to take this concept to the next level by developing treatments for diseases of the aging such as type 2 diabetes and cancer.

Whether SIRT succeeds in its ultimate mission is still open to conjecture and may not even matter as long as it sees success in early clinical trials, SIRT is in the bottom of the first inning of this story and, in my view, a little more progress will allow SIRT to capture investors' imagination like HGSI and BLDP did in the recent past. HOW CAN ONE NOT GET EXCITED ABOUT THE FOUNTAIN OF YOUTH???

Hopefully, SIRT will differentiate itself from BLDP and HGSI by making its dream a reality. However, even if SIRT fails in its ultimate goals, this dream is one that can capture investors' imagination.

Type 2 Diabetes Progress Continues

The progress continues....

http://www.businesswire.com/portal/site/google/index.jsp?ndmViewId=news_view&newsId=20071213005158&newsLang=en

... and SIRT management is sharing its findings in the most appropriate forums.

Elixir: Another Sirtuin IPO on Calendar

Another sirtuin company is looking to raise funding in an IPO. Also based in Cambridge Massachusetts, Elixir Pharmaceuticals has a couple of other drug targets other than Sirtuins that it has licensed from other companies. One of the most interesting aspects of the pending Elixir IPO is that one of its co-founders recently defected from Elixir to join SIRT:

http://www.xconomy.com/2007/11/19/sir2-roads-diverged-elixir-co-founder-joins-rival-sirtris/

It seems to speak very highly of the potential of Sirtris that Leonard Guarente, who some feel may be a future Nobelist, left his own company to join its main rival in the area of Sirtuins. Mr. Guarante is credited with discovering that the activation level of the Sir2 enzyme increases the lifespan of mice, yeast, worms, and other organisms.

Explanation For Recent SIRT Decline

On November 30th, SIRT stock price began a steep decent after an equally sharp rise. I had suspected that a venture capital investor had decided to take some money off the table but the insider trading reports had yet to confirm this. Now it is clear. Polaris Venture Management Company, a venture capital firm and owner of over 3,000,000 shares, disposed of 1,000,000 shares on November 30th. Since the sale is listed as a non-open market transaction, I suspect that Polaris purchased a derivative from a dealer, probably a collar, and that the dealer dumped the underlying stock as part of its hedge. A zero cost collar would cap an investor's upside and place a floor on his downside at no cost to the investor. The dealer would need to sell stock to hedge, often without much regard for price.

SIRT is a stock that has a potentially fantastic future, however, until the visibility of its potential is confirmed investors can expect volatility, exciting up days and stomach turning downturns. Keep an even keel!!

Meanwhile, SIRT announced today that the National Institute of Aging (NIA) has selected one of its SIRT1 activators for an Interventions Testing Program to study the effects of SIRT1 activation on aging. More evidence of SIRT's clear leadership in this exciting field.

Do your own DD.

A Good Entry Point for SIRT

SIRT has been very volatile over the last few weeks:

A sharp rise from $16 to $21 in late November was followed by a sharper decline to $14.50 in the next few days. It is easy to see that the sharp rise was related to the following press release that illustrated the huge potential in SIRT's game plan: http://biz.yahoo.com/bw/071128/20071128005806.html?.v=1 .

However, the subsequent decline is more puzzling. One theory on the sharp decline would be insider selling. Since it has now been longer than 6 months since SIRT's IPO, the underwriter's lock-up for insider selling has now expired. However, no insider sells of either officers or venture capital firms that provided the seed money have shown up in SEC filings. At this time I can only conclude that the sharp selloff is a result of speculative short term trading activity that we see all the time in today's markets.

I've listened to many presentations by firm management. The often giddy excitement shown by management in interviews, conference calls and investor presentations seems to be genuine although even they cannot know for sure if their efforts will eventually lead to blockbuster drugs. However, investing is never a sure thing and you must always do your own risk/reward analysis. I firmly believe that SIRT is a stock with tremendous upside, a potential ten bagger within a few years. However, one must put up with and accept stomach turning volatility.

The time to buy a story stock like SIRT, IMHO, is when the story hasn't changed yet the stock price has taken a hit. I believe NOW is that time, with SIRT trading under $15 and over 30% off its recent highs. Results of the firm's Phase 1B study on Type2 diabetes are due out within the next month and should provide a legitimate new catalyst to move SIRT to a new trading range.

Do your own DD.

The Genesis of the Age of Life Extention

In November 2006, to much worldwide press excitement, researchers released a report that showed how a component in grape skin, called resveratrol, significantly extended the lives of mice raised on a high fat diet. The biological mechanism that achieved these results in mice is both fascinating and exciting. It could hold the key to the body's ability to control, or at least, significantly slow down the aging process. Without getting into the hard core science of this new discovery I provide here a brief outline of the current understanding of this mechanism that may have brought us to the Genesis of the Age of Life Extention:

1) It has long been known that a diet that dramatically restricts calorie input by 30% to 40% has tremendous health benefits (but who wants to be hungry and scrawny??). This is referred to as the Calorie Restriction Diet ("CRD"). http://nymag.com/news/features/23169/ Lab animals and even some humans who have tried the CRD do not suffer from age related diseases such as diabetes and cancer for example.

2) Recent research has found that normally inactive enzymes in most living cells called sirtuins are activated when a cell is subject to a CRD. When a cell is getting normal nutrition sirtuins remain inactive. This defense mechanism is believed to be a surviving trait of the evolutionary process that would help protect an organism from long periods where nutrition is scarce.http://www.hopkinsmedicine.org/press/2003/January/030104.htm

3) When activated, a certain sirtuin has been shown to reduce glucose production levels and slow the aging process in mice. http://www.sciencedaily.com/releases/2007/08/070815154329.htm

4) High levels of resveratrol, a compound found in many fruits especially in red grape skin, have been shown to activate sirtuin enzymes in the body. http://www.drpressman.com/Library/Resveratrol.htm

5) A little company called Sirtris Pharmacueticals is the leader in sirtuin research and has numerous patents to show for it. SIRTRIS already has a proprietary stable formula of resveratrol in clinical trials to treat Type 2 diabetes. It has also developed a non-resveratrol based small molecule that is 1000 times more potent than its resveratrol based product. http://www.sirtrispharma.com/Science/Technology/tabid/3732/Default.aspx

I will be following this company through this blog as The Sirtuin Investor as I am fascinated by long term implications of sirtuins and the potential to earn substantial returns investing in them. Live longer requires having extra money, so pairing the two goals on this blog are the perfect complements.