The Doctor Weighs In

By Dov Michaeli MD, Ph.D

“Go to the ant, my son

Observe her ways

And wisen”

King Solomon, Proverbs (free translation).

Undoubtedly you have seen pictures of those emaciated characters who practice calorie restriction in the name of living a long, long life. The normal daily diet of an adult male contains about 2000-2400 calories. The ‘calorie restriction’ people limit their diet to about half of that. They may live longer, but are they happier? Hard to tell; they are going to die hungry but maybe also happy, for the ordeal is finally over.

One of the organisms that provided the ‘intellectual’ basis for this cruel and unusual experiment in long living is called C. elegans.

Where in the world is C. elegans?

Caenorhabditis elegans (Caeno, recent; rhabditis, rod; elegans, nice), is a free-living, non-parasitic soil nematode that can be safely used in the laboratory and is common around the world. It is small (about 1 mm in length) and has a short life cycle. From egg to egg takes about 3 days, and its life span is around 2 to 3 weeks under suitable living condition. What is unique to this organism is that wild-type (normal, non-mutated) individuals contain a constant 959 cells. The position of cells is constant as is the cell number. Moreover, it is transparent. It is easy to track cells and follow cell lineages. This provides a great tool for research on how genes influence cell fate. These traits enable the study of the biology of a single cell in an intact, living organism.

The genome size of C. elegans is about a hundred million base pairs. This is approximately 20X bigger than that of E. coli and about 1/30 of that of human. But, as its genome is surprisingly similar to that of humans (40% homologous), C. elegans became an attractive organism in the study of human biology and diseases.

The insulin-like pathway of C. elegans

Among those remarkably human-like genes are the ones that control energy metabolism, and specifically those coding for an insulin-like pathway. Genetic analysis now conclusively demonstrated that several of those genes, when mutated, extended life through reducing the activity of this insulin signaling pathway; in other words, life was extended by reducing the metabolic rate. Conversely, there is now considerable evidence showing that senescence (aging) is associated with increased metabolic rate.

Therefore, a logical conclusion would be that an insulin-like pathway drives senescence in C. elegans by enhancing metabolic activity. Right? Not quite…Genetic manipulation has now demonstrated that it is the insulin-like pathway specifically in neurons, not muscle or other highly metabolically active tissues, that regulate life span in C. elegans. And consider this: in humans the neurons most sensitive to insulin are probably the hypothalamic neurons that regulate metabolism and body weight, destruction of which leads to profound metabolic impairment.

Biology never ceases to confound our most ‘obvious’ theories. Although many hypotheses were offered to explain this unexpected discovery, in truth scientists were stymied.

 A tantalizing clue

In a paper published this week in Nature, scientists from the University of Washington in Seattle reported on an intriguing discovery. They screened 88,000 chemicals for the ability to extend the lifespan of adult C. elegans. They found that a drug that was once used as an antidepressant in humans, increased lifespan by 30%. The drug, a tricyclic, is called mianserin and was marketed as Tolvol, before being largely phased out of the market.

Its mode of action is interesting; it blocks two serotonin receptors, SER4 which signals the presence of food, and SER3, which signals starvation, in C. elegans. But the blocking action of the drug is not equal—it blocks SER 4 (food available) ten fold more than SER3 (starvation). The authors state: “In this way, mianserin might potentially create a ‘perceived’ state of starvation that, despite adequate food intake, would activate mechanisms of lifespan extension downstream of dietary restriction”.

Or in other words: it is not the actual caloric restriction and starvation that is responsible for lifespan extension. It is rather the perception of starvation that causes the brain to activate the mechanisms that lead to life extension. Which may explain the original observation that disruption of the insulin pathway in neurons, and not in muscles or other ‘obvious’ tissues, that leads to prolongation of lifespan.

Another example of mind over body. Or is it perception trumps reality?

Whatever the philosophical musings this experiment evokes, the practical implication is awesome: we won't have to spend a lifetime in starvation in order to live an extra few years. Drugs will be available that would allow us to literally have the cake, eat it and live long enough to tell the tale to our great-great-great grandchildren.

Dov Michaeli MD, Ph.D is in the biotech industry

by Pat Salber, MD

There is a short article by Nicholas Bakalar from NY Times News Service in local papers today.  The jist of the article is that the amount of caffeine in three cups of coffee or tea each day may help older women maintain mental sharpness - unfortunately, there doesn't appear to be an effect in older men.

"Le Study" is from French researchers and is published in the journal Neurology in August 2007.  Karen Ritchie, a researcg durectir with the French National Institute for Health and Medical Research is the lead author.  The study included more than 7,000 men and women, average age 74 years old, who were followed for over four years.  They were asked about their coffee and tea intake and their mental acuity was measured by standard tests of visual skills and verbal recall.  The researchers also collected information from the study participants about their education, income, depression, alcohol, and tobacco use, among other factors.

After controlling for other variables, the researchers found that women at age 65 who drank three or more cups of coffee or tea a day were about 30% less likely to have a significant decline in verbal skills than those folks who consumed a cup or less.

By age 85, caffeine drinking women were 70% less likely to suffer deficits in mental acuity compared with women who drank less than a cup of coffee or tea. 

Lead author Ritchie said in the NY Times article "please don't rush out and start drinking coffee.  To suddenly start drinking large quantities of coffee is still really premature as a preventive measure."

In the course of my medical career, coffee has gone from good to bad and now back to good again.  It's hard to say what to make of this latest study.  I would say it is probably a safe course, if you enjoy drinking coffee, to continue to consume it in moderate quantities.  I would wait for confirmatory studies before rushing to Starbucks or Peets to load up on coffee beans as a prophylactic measure against Alzheimers or other age-related declines in mental sharpness.

By Dov Michaeli MD, Ph.D

Clinical researchers at the University of Glasgow published in the September issue of the Annals of the Rhumatic Diseases an unassuming, almost self-effacing study on the effect of diet on rheumatoid arthritis. Here is the stated objective of the study: “To overcome obstacles to healthy eating by a community-based intervention promoting a Mediterranean-type diet in patients with rheumatoid arthritis or RA living in socially deprived areas of Glasgow.” What was this modest paper doing amongst all the high-powered papers on the molecular mechanisms of rheumatic diseases and the latest potent therapies based on insights into those mechanisms?

The study

Methods: 130 female patients with RA aged 30–70 years (median 55), disease duration 8 years were recruited from three hospital sites. The intervention group (75 patients) was taught how to switch to the Mediterranean diet, which is rich in fruits, vegetables, fish and olive oil. They attended weekly 2-hour sessions for 6 weeks in the local community, including hands-on cooking classes backed up with written information. The control group (55 patients) were given dietary written information only. Both groups completed food frequency questionnaires (FFQs), and clinical and laboratory measures were assessed at baseline, 3 and 6 months.

Results: By way of introduction: Statistical significance requires that a “p value” will be < 0.05. That means that the result has less than 5% probability of being due to chance rather than due to the treatment. If the p value is < 0.01, the result has less than 1% probability of being due to chance, and is considered “highly significant”.

Significant benefit was shown in the intervention group compared with controls. For patient global assessment at 6 months (p = 0.002), pain score at 3 and 6 months (p = 0.011 and 0.049), early morning stiffness at 6 months (p = 0.041) and Health Assessment Questionnaire score at 3 months (p = 0.03). Analysis of the FFQs showed significant increases in weekly total fruit, vegetable and legume consumption and improvement in the ratio of monounsaturated:saturated fat intake and systolic BP in the intervention group only. The cooking classes were positively received by patients and tutors; cost/patient for the 6 week course was £84 ( EUR124 or $168).

So what’s the big deal?

I think that the study is important for three main reasons:

1. Once again simple measures, in this instance a good diet, proved to be the most effective means of warding off disease. Diet rich in fruits and vegetables, fish and olive oil has been shown to improve cardiac health (note the reduced systolic blood pressure in the intervention group), weight control and diabetes, and certain cancers (notably colon cancer).
2. The Mediterranean diet can also be dubbed “the anti-inflammatory diet”. Among many factors that mediate inflammation there is a class of small molecules called prostaglandins. Not all prostaglandins are born equal; some are pro-inflammatory (they cause inflammation) and others are anti-inflammatory. RA is caused, in part, by the pro-inflammatory prostaglandins. Steroids, by the way, inhibit the synthesis of prostaglandins, hence their anti-inflammatory action. There are other drugs that inhibit the synthesis of prostaglandins that are not steroids. These are called non-steroidal anti inflammatory drugs or NSAID, like aspirin and ibuprofen (Advil). Indeed, these drugs are the first line of defense in newly diagnosed RA. But the drugs are not risk-free. Steroids taken on a chronic basis have many serious adverse effects: suppression of the immune response, bone loss, fluid retention, mood disturbances. NSAID  cause stomach irritation, ulcer and bleeding. On the other hand, olive oil and fish (part of the Mediterranean diet), are rich in monounsaturated fatty acids. Rather than the sledge hammer effect of the drugs, these fatty acids very subtly divert the synthesis of prostaglandins from the pro- inflammatory to the anti-inflammatory ones. No immunosuppression, no bone loss, no ulcer. Once again, nature provided a clean and simple solution that has eluded the best minds in drug development.
3. The inflammatory response is gradually assuming a central role in many diseases that have not been on the usual suspects list: diabetes, atherosclerosis, coronary heart disease, all the autoimmune diseases (such as rheumatoid arthritis, lupus, systemic sclerosis or scleroderma), and even certain cancers. The effect on our health and our national health budget of an anti-inflammatory diet, such as the Mediterranean diet, could therefore be enormous. I can foresee a time when insurance companies would reduce the premiums of people who stick to a regimen of regular exercise and an anti-inflammatory diet, just as they do now for non-smokers.

So, hooray to the modest clinicians who published this unassuming work. Their conclusion: “Results demonstrate that a 6 week intervention can improve consumption of healthier foods. If implemented more widely it may prove a popular, inexpensive and useful adjunct to other RA treatment.” To this I would add: "this study provided a scientific basis for a wider adoption of a diet that could revolutionize our eating habits, our health and our health care." I guess those Scots are not given to such overt enthusiasm; is it the climate?

By Dov Michaeli MD, Ph.D

The theory that selenium is ‘good for you’ has just suffered a body blow—supplementation actually causes an increase in the prevalence of type 2 diabetes.

Why is selenium a food supplement?

The theories range from the sublime to the ridiculous. I still remember that runners swore by selenium as a performance enhancer. It didn’t do it for me, so I asked for the evidence. In a word: there was none.

Another ‘theory’ is that selenium is important in the prevention of HIV/AIDS. Evidence? Sub Saharan Africa has a low selenium content in the soil, and a high incidence of HIV. The exception is Senegal , where the soil content is high and, wouldn’t you guess, HIV incidence is lower. Enough said.

A more serious theory is that it acts as an antioxidant. True enough, in vitro (in the test tube) it works as advertised. Oxygen free radicals are injurious to cells, to organs, and probably to the whole body. In fact, one of the leading theories on the causes of aging and its attendant diseases is the damage wrought by those pesky radicals. One of the enzymes that is tasked with ‘sopping up’ oxygen free radicals is called glutathione oxidase and selenium is a cofactor or necessary part of its structure—without it the enzyme cannot function. Wouldn’t you then assume that selenium supplementation should be ‘good for you’? Indeed, severe deficiency of selenium can result in myocardial necrosis (Keshan disease); it is so rare, you’d be hard pressed to find it in many medical textbooks.

The reason selenium deficiency is so rare is that we need it only in trace amounts. The daily requirement is about 70 mcg, and we can get all of it and a lot more, from nuts, legumes, meats and fish.

If a little is good, isn’t more even better?

Absolutely not! Selenium has a narrow “therapeutic window”, meaning that above this narrow range it becomes toxic. Symptoms of selenium toxicity range from garlic odour on the breath, gastrointestinal disorders, hair loss, sloughing of nails, fatigue, irritability and neurological damage. In fact, in the midwest plains and the rocky mountains there is a weed aptly called locoweed, which concentrates selenium from the soil. Horses and cows grazing on it develop severe neurological symptoms mimicking BSE, otherwise known as Mad Cow Disease. So far no human cases of locoweed intoxication have been reported. But with new vegan dishes being invented every day in trendy restaurants, and more and more people grazing in them, who knows?

Add diabetes to the catalog of selenium diseases.

A recent article in the Annals of Medicine (21 August, 2007, vol. 147, pp.217-223) reports findings from a study called the nutritional prevention of Cancer. Patients were randomly assigned to receive 200 mcg of selenium daily for 7.7 years, or placebo. The study design was excellent: it was randomized, double blind, and the initial levels of selenium in the blood were measured before the onset of the trial, so that a reliable baseline was established for each individual. Follow up blood levels of selenium were measured throughout the trial period.

The trial was not designed to measure diabetes, and the investigators relied on medical records and oral reports. Nevertheless, the results were compelling. And surprising.

They found that among the subjects who took selenium supplementation, those with the top third selenium concentration in the blood had a 270% increase in probability of becoming diabetic over the placebo group.

About 35% of the U.S. population take daily multivitamins. The common concentration is only 20 mcg, which is 29% of daily requirement. No danger there. But 1% ( about 2.5 million people) take selenium supplements of 200 mcg a day. These are big numbers, and can go part way in explaining where non-obese type 2 diabetics come from .

What’s the take home lesson?

Do not take selenium supplements; there is no scientific basis to any of the claims of benefits to mega doses (200mcg and higher). There is compelling evidence that they are harmful. The low concentrations found in multivitamins (20 mcg) are most likely harmless. Whether they do any good is another question; there is no evidence that they do.

The bigger lesson from this study is that the whole food supplements field is rife with unsubstantiated claims, and outright falsehoods. Caveat emptor.

Dov Michaeli MD, Ph.D. is a biochemist and a drug researcher in the biotech industry.

by Dov Michaeli

Sometimes revolutionary developments come out of the most unexpected corners. There is new branch is medical research called regenerative medicine.

The “old” way of treating disease (which we are still practicing today) is through drugs that treat the consequences of the disease. For instance, anti-inflammatory drugs to treat arthritis, or statins to lower cholesterol through inhibition of its synthesis, or chemotherapeutic drugs to kill tumor cells.

The bold vision of investigators in the regenerative medicine field is to simply replace the ailing organ with a healthy one. I am not talking about transplantation; I am talking about stem cells that can be programmed to replace an injured muscle, a severed spinal cord, or damaged pancreatic beta cells that can no longer synthesize insulin. This is a breathtaking paradigm shift that promises to revolutionize the way medicine will be practiced in the not so distant future.

Out of left field

As our attention was riveted on “the big stuff” of stem cells, a barely noticed report, published in the February issue of The Archives of Dermatology (vol. 143, pp. 155-163, 2007), looked at the mode of action of a dermal filler used in cosmetic medicine to treat facial wrinkles. The report, by a group from the department of Dermatology at the University of Michigan, showed that contrary to the belief that the material (Restylane is made up of a substance called cross-linked hyaluronic acid) acted simply by physical expansion of the skin volume, it actually had a biological effect.

What is a wrinkle?

The skin is made up of a thin outer layer of cells called epidermis, and a much thicker layer called dermis. The bulk of the dermis is composed of a protein called collagen, as well as smaller amount jelly-like materials, hyaluronic acid being one of them. Collagen is synthesized by special skin cells called fibroblasts.

In a young person the fibroblasts have a stretched appearance and secrete copious amounts of the collagen, enough to make up for the continuous degradation of skin collagen by an enzyme called collagenase. In older people the fibroblasts become more relaxed and rounded, and secrete less collagen, not enough to counteract the losses due to the degradation by collagenase. Slowly but surely, enough collagen is removed, the dermal structure collapses, and we get the dreaded wrinkles.

What the investigators found is that the hyaluronic acid in Restylane caused the re-stretching of the fibroblasts, causing them to increase their synthesis of collagen. As a bonus, the material also reduced the activity of the enzyme collagenase. The key to achieving this effect was the repeated injection of the material, 6-12 months apart, until enough stretching of the fibroblasts took place. How long would this effect last? This is still unknown, but the thought is that as long as the injected material is present the fibroblasts would remain stretched and synthesize more collagen.

Why is it exciting?

First, if confirmed, it promises to make us look young forever, or at least as long as we live. Isn’t that what all aging boomers look for?  But more importantly, here is the first realization of the regenerative medicine dream: use of the body’s own cells to regenerate damaged organs.

I love this study, because out of the limelight of the titanic stem cell struggles a relatively unknown group of dermatologists found a simple, and vastly more practical solution then stem cells to rejuvenation the sagging skin—simply stretch the old fibroblasts.   The study used Restylane only because it was started before a similar product, Juvéderm, was available. In my estimation, both products should work equally well; but the proof will require another study.

Here is another interesting aspect of progress in medicine. The material was originally intended as a physical filler; nobody had any grandiose thoughts about profound biological effects. After all, collagen itself was used as a filler to treat wrinkles, and indeed that is all it was—a filler, which degraded with time.

Hyaluronic acid, quite unexpectedly, opened new avenues for research in tissue regeneration. Would we be able soon to grow pre-existing brain neurons in Parkinson’s or Alzheimer’s patients by simply injecting ‘brain filling material’? If you asked this question a few months ago you’d be laughed out of the room. It is now totally plausible. Isn’t that exciting?

Dov Michaeli MD Ph.D. is in the biotech industry, engaged in drug development.

Today I saw Constance Congdon's adaptation of Moliere's 17th century play, "The Imaginary Invalid" and was rolling in the aisle with laughter.  But, as in all things humorous, there is an underlying, stinging veracity that makes you ponder, seriously, the very topics that have made you laugh.

First, some pictures, and then, the prologue to this wonderful play:

And now, back to the prologue of the play:

"We are doctors come to warn you of the phonies out to harm you, could your guru be a schmuck?  If it quacks, then it's a duck!

Your guru scoffs at your queries, and all his precious theories won't stand up to some flack?  If it ducks, then it's a quack! (Quack!)

If you are plagued by tintinitis, aggravated by bursitis, fatigue and headaches, with a rash...keep both hands upon your cash.  If someone sells you magic mud that will purify your blood, they are a lying sack.  If it ducks, then it's a quack.

Do not order things by mail that have just now gone on sale, straight to you from Tripoli, made from a secret recipe devised by monks (It's never nuns)....it might give you the runs.  There is something quite demonic in a high colonic.  Watch your purse and watch your back.  If it ducks, then it's a quack!

We're not doctors, we are actors, we refuse to be retractors.  Oh yes, verily, forsooth, we are here to tell the truth.

We PLAY doctors come to warn you of the phonies out to harm you.  Could your guru be a hack?  If it ducks, then it's a quack."

If you would like to learn more about "Growth Hormone Schemes and Scams,"  and other quackery, check out QuackWatch.org.  It is an eye opener.  Quack!

Pat Salber, MD