The Doctor Weighs In

By Dov Michaeli MD, Ph.D

In 2005 National Geographic magazine had a fascinating article by Dan Buettner, about the “Blue Zones”, areas where people live to the ages of 90, 100 and older. These areas included Loma Linda, CA, Sardinia Italy, Okinawa Japan, and the Nicoya peninsula in Costa Rica.

He followed up his trip to Costa Rica with a more extensive visit, including a team of researchers, in 2007.

One of the pitfalls of studies of this sort is the verification of claims of age. For instance, a claim that made a big splash in the media several years ago concerned Bulgarian villagers who claimed that their secret to longevity is eating yogurt. A craze of yogurt swept the U.S. following publication of this story, which I am not sure has completely disappeared. That "study" was discredited because of the lack of age documentation and the exaggerated claims of extreme age because of the social benefits it provided. But in the case of Buettner’s expedition in Costa Rica, birth certificates, as well as records of the University of San José C.R. were used to verify the claims of age.

What they found

Actually, nothing extraordinary; their findings strengthened findings of other studies.

• Have a strong sense of purpose. Costa Rican centenarians have a clear mission in life, what they call plan de vida. They feel needed and want to contribute to a greater good. Interestingly, this was the salient finding in the Okinawan centenarians as well.
• Drink hard water. Nicoyan water has the country’s highest calcium content. We know from other studies that calcium is important not only for maintaining strong bones, but also for maintenance of cardiac health. There is also accumulating evidence that calcium is important in reducing the risk of colon cancer.
• Keep a focus on the family. Nicoyan centenarians tend to live with their families, and children or grandchildren provide support and a sense of purpose and belonging. Again, identical to the Okinawan centenarians.
• Eat a light dinner. Eating fewer calories appear to be one of the surest ways to add years to your life. Nicoyans eat a light dinner early in the evening. Many studies in animals amply documented the effect of caloric restriction on longevity. Their traditional diet of fortified maize and beans may be the best nutritional combination for longevity the world has ever known
• Maintain social networks. Nicoyan centenarians get frequent visits from neighbors. They know how to listen, laugh, and appreciate what they have.
• Work hard, physically. Centenerians seem to have enjoyed physical work all their lives. They find joy in everyday physical chores.
• Get some sensible sun. Nicoyans regularly take in the sunshine, which helps production of vitamin D. This vitamin is crucial for maintenance of strong bones, a healthy heart, and reduced risk of GI cancers. Of course, you’ve got to be sensible about it; stay too long in the sun and your risk of developing skin cancers, including melanoma, goes up significantly.
• Embrace a common history. Nicoyans are aware of their roots and their spiritual traditions. This is another factor in maintaining their low-stress life.

So there you have it. Don’t overeat, exercise, and don’t worry—be happy.

Oh yes, one more thing which the Nicoyans did not tell us: choose your parents very carefully.

By Dov Michaeli MD, Ph.D

Who is Edna Parker?

If you haven’t heard of her don’t fret, I haven’t either. But today, April 20, is her 115^th birthday, which makes her the longest living person in the world! How many of us can claim that? As a matter of fact, none of us, by definition.

How did she make it? Maybe it was a lifetime of chores on the family farm that accounts for Edna Parker's long life. Or maybe just good genes explain why the world's oldest known person will turn 115 on Sunday, defying staggering odds. In fact, I think both. But don’t take my word for it. There is a study called the New England Centenarian Study at Boston University , or NECS, that is collecting data on centenarians (people reaching age 100, and supercentenerians, reaching 110) in an effort to uncover the key to living to an old age. So if you want to live to a ripe old age, read on.

What exactly is the NECS

The New England Centenarian Study (NECS) is based on the conviction that centenarians are a select group of people who have a history of aging relatively slowly and who have either markedly delayed or entirely escaped diseases normally associated with aging such as Alzheimer's disease, cancer, stroke and heart disease.

The study began in 1994 as a population-based study of all centenarians living within 8 towns in the Boston area. The prevalence of Alzheimer's Disease and other dementias in centenarians was the focus. Given that the prevalence of centenarians in industrialized countries is approximately one centenarian per 10,000 people in the population, at any particular time we were studying approximately 46 centenarians within a total population of 460,000 people. The NECS has gone on to enroll centenarians from throughout the United States and other countries and has grown to be the largest comprehensive study of centenarians in the world. There are currently 1,500 subjects to-date, including centenarians, their siblings and children (in their 70s and 80s) and younger controls.

Consistent with the hypothesis that centenarians markedly delay or even escape age-associated diseases (e.g. heart attack, stroke, cancer, diabetes, Alzheimer's disease), Dr. Perls, director of the study, and his colleagues, noted that 90% of them were functionally independent the vast majority of their lives up until the average age of 92 years and 75% were the same at an average age of 95 years. Centenarians disprove the perception that "the older you get the sicker you get", centenarians teach us that the older you get the healthier you've been.

How can you predict if you have a chance to reach 100?

Not all centenarians are alike. They vary widely in years of education (no years to post-graduate), socioeconomic status (very poor to very rich), religion, ethnicity and patterns of diet (strictly vegetarian to extremely rich in saturated fats). However, the centenarians we have studied do have a number of characteristics in common:

• Few centenarians are obese. In the case of men, they are nearly always lean.
• Substantial smoking history is rare.
• A preliminary study suggests that centenarians are better able to handle stress than the majority of people.
• Our finding that many centenarians (30%) had no significant changes in their thinking abilities disproved the expectation by many that all centenarians would be demented. We also discovered that Alzheimer's Disease was not inevitable. Some centenarians had very healthy brains.
• Many centenarian women have a history of bearing children after the age of 35 years and even 40 years. From our studies, a woman who naturally has a child after the age of 40 has a 4 times greater chance of living to 100 compared to women who do not. It is probably not the act of bearing a child in one's forties that promotes long life, but rather, doing so may be an indicator that the woman's reproductive system is aging slowly and that the rest of her body is as well. Such slow aging and the avoidance or delay of diseases that adversely impact reproduction would bode well for the woman's subsequent ability to achieve very old age.
• At least 50% of centenarians have first-degree relatives and/or grandparents who also achieve very old age, and many have exceptionally old siblings. Male siblings of centenarians have an 11 times greater chance than other men born around the same time of reaching age 97 years and female siblings have an 8½ greater chance than other females also born around the same time of achieving age 100.
• Many of the children of centenarians (age range of 65 to 82 years) appear to be following in their parents' footsteps with marked delays in cardiovascular disease, diabetes and overall mortality.
• Exceptional longevity runs strongly in families. Brothers and sisters of centenarians maintain half the mortality rate of other people born in the same time period, from age 20 all the way into extreme old age. The cumulative effect of this year-to-year survival advantage is that the brothers have a 17 times greater chance of living to 100 and the sisters have an 8 times greater chance.

So there you have it. If you too want to make it to 100 you should

· Maintain a healthy lifestyle

· Pick your parents very carefully

· Join the New England Centenarian Study. Edna Parker did, and see what it got her.

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 Dov Michaeli MD, Ph.D

Some of the health advice we come across in the media and the internet is so outrageous it borders on quackery; no, it is quackery. If it wasn’t so dangerous it would be hilarious. So I thought we should all share in the hilarity. But before we proceed, a disclaimer: the following is based on actual Q and A, but the author took  literary license to highlight their innaneness (there, I finally got to use this word). So here goes:

HEALTH QUESTION & ANSWER SESSION
Q: I've heard that cardiovascular exercise can prolong life; is this true?
A: Your heart is only good for so many beats, and that's it... don't waste them on exercise. Everything wears out eventually. Speeding up your heart will not make you live longer; that's like saying you can extend the life of your car by driving it faster. Want to live longer? Take a nap.

Q: Should I cut down on meat and eat more fruits and vegetables?
A: You must grasp logistical efficiencies. What does a cow eat? Hay and corn. And what are these? Vegetables. So a steak is nothing more than an efficient mechanism of delivering vegetables to your system. Need grain? Eat chicken. Beef is also a good source of field grass (green leafy vegetable). And a pork chop can give you 100% of your recommended daily allowance of vegetable products.

Q: Should I reduce my alcohol intake?
A: No, not at all. Wine is made from fruit. Brandy is distilled wine, that means they take the water out of the fruity bit so you get even more of the goodness that way. Beer is also made out of grain. Bottoms up!

Q: How can I calculate my body/fat ratio?
A: Well, if you have a body and you have fat, your ratio is one to one. If you have two bodies, your ratio is two to one, etc.

Q: What are some of the advantages of participating in a regular exercise program?
A: Can't think of a single one, sorry. My philosophy is: No Pain...Good!

Q: Aren't fried foods bad for you?
A: YOU'RE NOT LISTENING!!! ... Foods are fried these days in vegetable oil. In fact, they're permeated in it. How could getting more vegetables be bad for you?

Q: Will sit-ups help prevent me from getting a little soft around the middle?
A: Definitely not! When you exercise a muscle, it gets bigger. You should only be doing sit-ups if you want a bigger stomach.

Q: Is chocolate bad for me?
A: Are you crazy? HELLO . Cocoa beans! Another vegetable!!! It's the best feel-good food around!

Q: Is swimming good for your figure?
A: If swimming is good for your figure, explain whales to me.


Q: Is getting in-shape important for my lifestyle?
A: Hey! 'Round' is a shape!


Well, I hope this has cleared up any misconceptions you may have had about food and diets.

Finally, an exercise regimen I found in a Man's Health magazine. I have been following it religiously:

You have to give this a try, it really works.

This exercise is suggested for mature adults, to build muscle strength in the arms and shoulders. It seems so easy, so I thought I'd pass it on. I suggest doing it three days a week.
Begin by standing on a comfortable surface, where you have plenty of room at each side. With a 5-lb potato sack in each hand, extend your arms straight out from your sides and hold them there as long as you can.

Try to reach a full minute, and then relax.

Each day, you'll find that you can hold this position for just a bit longer. After a couple of weeks, move up to 10-lb potato sacks. Then try 50-lb potato sacks and then eventually try to get to where you can lift a 100-lb potato sack in each hand and hold your arms straight for more than a full minute. (I'm at this level)

After you feel confident at that level, put a potato in each of the sacks.

And remember:

"Life should NOT be a journey to the grave with the intention of arriving safely in an attractive and well preserved body, but rather to skid in sideways - beer in one hand - chocolate in the other - body thoroughly used up, totally worn out and screaming "WOO HOO, What a Ride"

Dov Michaeli MD, Ph.D is in the biotech industry and is a nut when it comes to diet and exercise.

The recent posting by Dr. Salber describing the ostensible superiority of wine drinking over beer or spirits reminded me that I actually saw with my own eyes one of the confounding factors of the study, namely, lifestyle differences.

In the mid-80's, I was a visiting scholar at the University of Turku (also called Oulu ) where the study was done.
OuluOn weekend nights the streets were littered with drunks asleep (comatose is a more apt description of their state) on the sidewalks, the gutters, and the roads. It was a sobering sight to behold: well-dressed, seemingly upright citizens, mostly men, wallowing in the mud. I asked my colleague, a surgeon at the University hospital, what was the drink of choice. It was vodka, he said. What about beer? That’s for kids. And wine? Only women and intellectuals drink wine; and they rarely get drunk.

I remember thinking at the time: these people are not going to live very long. In fact, the three most common causes of their demise were heart disease, liver disease, and accidents (like being run over by a car while sleeping on the road). So, anybody who has been to Oulu would tell you—this is not a good study, and scientists who live in Oulu should have known better.

Wine is good for you

True, but up to a point. Studies have shown that men who drink up to 2 glasses of wine a day, and women 1 glass a day (sorry, life is not fair) are less prone to coronary disease and cardiac events.

The mechanism of such a blessed effect of wine is not really understood. Several studies have shown that wine (especially red, some claim) causes elevation of HDL, the “good” cholesterol.

But don’t forget a big caveat: Our eagerness to believe in something can color our judgment. The facts however, cannot be changed by beliefs, however ardent.

Is all “good” cholesterol the same?

In March of last year Pfizer withdrew the experimental drug torcetrapib from clinical trials because it caused excess mortality due to cardiovascular events over the placebo. That was quite a shock, because the drug was designed to elevate HDL (good cholesterol) levels. Why the drug caused higher mortality we do not know yet, but one theory is gaining prominence: not all HDL is born equal.

There are most likely variants of HDL that are actually “bad” cholesterol. Ansell and his coworkers (Circulation, vol.108, pp. 2751-2756, 2003) studied people who had very high HDL levels, but still developed heart disease. In lab assays they found that these people’s form of HDL promoted deposition rather than removal of cholesterol from the artery walls. Could it be that Pfizer’s ill-fated drug promoted the wrong kind of HDL? Quite likely.

HDL is actually a family of particles, varying in their protein components, size, and other parameters. In the heart of Tuscany (the wine country of Italy ) there is a village where people were found to have very low levels of HDL, but were not prone to heart disease. Aha! The protective effect of wine, you might eagerly conclude. But what about other villages in the area? They too drink, but have “normal” levels of cardiovascular disease (and normal levels of HDL). So what gives?

A toast to Milano

It turns out that the people in this village have a variant of a protein that is part of the HDL particle, called Apo A-1. The variant, Apo A-1 Milano is apparently responsible for the protective effect, despite the low levels of HDL in the blood. In fact, Nissen and his colleagues from the Cleveland Clinic showed that five infusions of this protein shrank plaques in the arteries (Nissen et al. J. Am. Med. Assoc. vol. 290, pp. 2292-2300, 2003).

What this study shows us is that our classification of HDL as “good cholesterol” should be reconsidered. There is probably “good” and “bad” HDL cholesterol. As scientists almost invariably say at the end of a paper: more work needs to be done.

Nothing is simple…

Dov Michaeli MD, Ph.D

Would you believe it? I found this report on a three-decade study of wine drinkers on Wine Spectator Online. The study itself was published in a respected peer-reviewed medical journal, the Journal of Gerontology. The results are the stuff wine-marketers (and wine lovers) dream about: Wine drinkers had a lower mortality rate compared to drinkers of other alcoholic beverages.

No, the study was not performed in California's Napa Valley nor in the Loire Valley in France. Rather it was done in Finland (there's wine in Finland?) by Timo Strandberg and colleagues, researchers at the University of Oulu. At the start of the study in 1974, 2,468 businessmen and male executives, ages 40-55, were assessed at the Institute of Occupational Health in Helsinki for cardiovascular risk factors and alcoholic beverage preferences.  Only 131 of these men did not use alcohol, 455 did not report a single beverage preference, and 694, 251, and 937 preferred beer, wine, and spirits, respectively.

 The researchers tracked these men down for a re-assessment in 1985 and again in the year 2000. As you can imagine, some of these guys were a bit “long in the tooth” by the end of the study. Others had died or just dropped out (of the study).  Study subjects were included in the final calculations only if they were constant in their preference for one type of alcohol (e.g., wine, beer, or spirits) over the others.  By the time of the second stage of the study, in 1985, only 1,369 men were available to be reassessed. Some dropped out of the study, some changed alcohol habits and 93 of the men had died. By the time of the final calculations, in 2002, there were 1,127 men left in the study who drank three or less drinks per day and had not changed their drinking preferences over the course of the study.

Here are the results:

The men remained pretty constant in their choice of alcoholic beverage and there was not a significant difference in the amount they drank between the different beverage groups.

 Men with wine preference had the lowest total mortality of the three groups due to lower cardiovascular mortality. Compared to the spirits drinkers, wine drinkers had a 34% lower total mortality.  Beer drinkers had a 9% lower mortality than spirits imbibers.  Should we break out a bottle of pinot to celebrate the good health of wine drinkers? 

Best keep the cork in the bottle for now. There are some confounding variables. It turns out wine drinkers had healthier habits than beer and spirits guzzlers. They exercised more and smoked less, both factors associated with better health and lower mortality.   In other words, it may not have been the wine that led to a good long life, rather wine drinkers might be more health conscious.

Here's how the Strandberg, the lead researcher, sums it up:

"Is it the drinker rather than drink characteristics, as healthier men preferred wine?" It could also be that "spirit preferrers may lead a more dangerous life, with more risk factors, and all hidden aspects may not be culled in an epidemiologic study." What he is pointing out, rightfully so, is that care has to be taken in interpreting the results of this type of study.

Oh well. It did sound too good to be completely true -- kind of like reading that dark chocolate lowers blood pressure, but only if you don't eat so much that you get weight-related hypertension. 

Back to the fruits and veggies.

Pat Salber, MD

A few weeks ago, a fascinating story about the effect of the mind on physical well-being was widely published in the newspapers. A group of hotel room maids received a physical exam and were told that their work, making beds, cleaning baths, and vacuuming rooms is equivalent to daily moderate exercise and is good for their health and fitness. Another group of maids, in another hotel, received the physical exam only. Three weeks later, the maids who had been told that they were in good physical shape reported feeling in good health, had a low rate of absenteeism, and reduced their blood pressure from the initial exam. None of these were evident in the control group. Impressive, but hardly compelling. The usual criticisms of small groups, non-random selection, the short observation time—all these are real experimental issues, and “more studies are necessary” is the usual caveat following such experiments.

Enter the immune response.

During the last two decades sporadic reports were published in the scientific literature, claiming that both in animals and humans, state of mind had a significant effect on immunity. Stress in animals suppressed their immune response and increased their susceptibility to infection and cancer. Similar results were shown in humans, albeit under less controlled conditions.

Now comes a report in the April issue of the Journal of the American Geriatric Society, by Drs. Irwin and Holmsted of UCLA and Dr. Oxman of UCSD. They examined the effect of tai-chi on elderly people’s immunity to shingles, caused by a virus called varicella zoster.

The randomized, controlled clinical trial included 112 healthy adults ages 59 to 86 (average age of 70). Each person took part in a 16-week program of either Tai Chi or a health education program that provided 120 minutes of instruction weekly. Tai Chi combines aerobic activity, relaxation and meditation, which the researchers note have been reported to boost immune responses. The health education intervention involved classes about a variety of health-related topics.

After the 16-week Tai Chi and health education programs, with periodic blood tests to determine levels of VZV immunity, people in both groups received a single injection of VARIVAX, the chickenpox vaccine that was approved for use in the United States in 1995. Nine weeks later, the investigators did blood tests to assess each participant's level of VZV immunity, comparing it to immunity at the start of the study. All of the participants had had chickenpox earlier in life and so were already immune to that disease.

Tai Chi alone was found to increase participants' immunity to varicella as much as the vaccine typically produces in 30- to 40-year-old adults, and Tai Chi combined with the vaccine produced a significantly higher level of immunity, about a 40 percent increase, over that produced by the vaccine alone. The study further showed that the Tai Chi group's rate of increase in immunity over the course of the 25-week study was double that of the health education (control) group. The Tai Chi and health education groups' VZV immunity had been similar when the study began.

In addition, the Tai Chi group reported significant improvements in physical functioning, bodily pain, vitality and mental health. Both groups showed significant declines in the severity of depressive symptoms.

Is this study convincing?

The study was well-designed, well-controlled and carefully executed. It is the first study in humans that lends credibility to the notion that our immune response is controlled by the brain. This study is a harbinger of more serious studies, not only demonstrating the mind/body connection, but also the physiological mechanism by which this is accomplished.

Is the day when we could will ourselves to better health far off? How exciting!

Dov Michaeli MD, Ph.D

We all know the devastating statistics:

· 13.5 million people in the US suffer from coronary artery disease

· 8 million people have diabetes type 2.

· 95,000 people are diagnosed every year with colon cancer, and a sedentary lifestyle increases the likelihood of getting this disease by 40%.

· People who don’t exercise have about a 60% increase in osteoporosis; 250,000 suffer from hip fracture every year.

· 50 million suffer from hypertension.

· More than 60 million people in the US are overweight.

You might conclude from the last bullet that obesity is the culprit. You’d be only partly right. Lack of physical fitness is the other culprit, regardless of percentage of body fat. Even if we take people with a high % of body fat (more than 25%), the relative risk of death from all causes in the fit person is half that of the unfit.

Exercise and the body.

The effects of exercise on the body are well known:

· Exercise increases HDL, the good cholesterol, by an average of 4.6%. This, in turn, results in a decreased risk of coronary artery disease.

· Exercise increases insulin sensitivity, reducing the risk of metabolic syndrome and diabetes type 2.

· Exercise strengthens the heart muscle, improving its function.

· Exercise increases bone size and density, reducing bone loss due to aging and osteoporosis.

· Exercise increases muscle strength, coordination and reaction time. Result: improved balance and stability; reduction in falls and bone fractures.

What about mind?

This is a truly fascinating story, and you can read about it in more detail in an article in Newsweek, March 26, 2007 , by Michael Craig Miller, MD, from Harvard Medical School . Here are the salient points:

· Exercise has been known for many years to give, during and after exercise an “endorphin high”. This is the feeling of satisfaction, well being, and increased self-esteem that many people experience. This effect is short term, on the order 1-2 days in duration.

· Aerobic exercise increases blood supply to the brain, thus increasing oxygen and nutrient supply to the neurons, and removing metabolic waste materials from the brain.

· Aerobic exercise increases the production of neurotrophic factors in the hippocampus.

What are neurotrophic factors?

When the nerve cells are getting organized to form the organ that we call ‘brain’ (a process that doesn’t end at birth, it actually continues until about age 20), they do it under the direction and control of peptides and proteins that are secreted by the nerve cells themselves. But the job of these factors doesn’t end there: they continue to shape, modify, and re-shape several areas of the brain. They are essential for the formation of new neurons from stem cells—a process called neurogenesis. They also are important in the formation of new connections between existing neurons—a process called neuroplasticity. These two processes are important because they are the basis for learning and memory; everything we know and remember is stored in neuronal circuits. Furthermore, the thicker the connections between the neurons the faster the flow of information in the circuits—very much like the broadband required for fast transmission of electronic signals. The brain factors cause this thickening as well.

There are several known neurotrophic factors that have been shown to increase in concentration due to a sustained, long term exercise regimen:

· BDNF (Brain-Derived Neurotrophic Factor).

· NPY (Neurpeptide Y).

· VEGF (Vascular Endothelial Growth Factor).

The fact that we can identify specific brain peptides that increase neurogenesis and neuroplasticity is interesting enough. But what makes it even more fascinating is where in the brain this increase happens.

Enter the Sea Horse.

In the temporal lobe of the brain there is an area, called the hippocampus, because it is shaped like a sea horse. This area regulates emotions and stores memories. In fact, it has been known that in aging brains and in depression, two situations in which neurogenesis and neuroplasticity are reduced, the hippocampus gets smaller. Furthermore, electroshock therapy and antidepressants caused an increase in the size of the hippocampus, apparently due to increase in neurogenesis and neuroplasticity.

It was especially gratifying to read in the latest Proceedings of the National Academy of Sciences (PNAS, vol. 104, p. 4647, 2007) the report by Warner-Schmidt and Duman. The unequivocally demonstrated that the antidepressant drug fluoxetine (Prozac) and the pain-control drug desipramine (Norpramine, Pertofran), cause a large increase in VEGF in a specific area of the hippocampus (The subgranular zone). Interestingly, desipramine’s action is inhibition of pain signals ascending through the spinal cord to the brain; in other words, it inhibits the perception of pain.

Not surprisingly, aerobic exercise does the same thing. We even know how this happens on the molecular level—through the action of the very same brain factors: BDNF, NPY, and VEGF.

The take home lessons

· We now know beyond the shadow of a doubt that aerobic exercise increases the feeling of well being, increases learning capacity and improves memory.

· Aerobic exercise ameliorates depression and is becoming an additional tool in the treatment of this disease.

· Aerobic exercise reverses the effects of aging on the brain.

· Aerobic exercise may reduce the perception of pain—an important implication for people suffering from chronic pain, such as arthritis.

One final note: to all you Yoga practitioners, iron pumpers, and assorted other exercise enthusiasts—these effects on the brain were demonstrated only with aerobic exercise. Sorry.

Dov Michaeli, MD, Ph.D

I have been thinking about aging recently. I am not getting any younger, my loved ones are not young either; for heaven's sake--my little kids are in their forties (well, very very early forties). So where do you turn for sage advice? my favorites are the ten commandments. No, not THE Ten Commandments. I am talking about George Carlin's infinite empathy and wisdom-cum- smile. So here they are:

HOW TO STAY YOUNG

by George Carlin

1. Throw out nonessential numbers. This includes age, weight and height. Let the doctor worry about them. That is why you pay him/her.

2. Keep only cheerful friends. The grouches pull you down.

3. Keep learning. Learn more about the computer, crafts, gardening, whatever. Never let the brain idle. " An idle mind is the devil's workshop." And the devil's name is Alzheimer's.

4. Enjoy the simple things.

5. Laugh often, long and loud. Laugh until you gasp for breath.

6. The tears happen. Endure, grieve, and move on. The only person who is with us our entire life, is ourselves. Be ALIVE while you are alive.

7. Surround yourself with what you love, whether it's family, pets, keepsakes, music, plants, hobbies, whatever. Your home is your refuge.

8. Cherish your health: If it is good, preserve it. If it is unstable, improve it. If it is beyond what you can improve, get help.

9. Don't take guilt trips. Take a trip to the mall, to the next county, to a foreign country, but NOT to where the guilt is.

10. Tell the people you love that you love them, at every opportunity.

AND ALWAYS REMEMBER:

Life is not measured by the number of breaths we take, but by the moments that take our breath away.


Woopdeedo, who cares ..

nobody couldn't have said it better.

Thanks, George; I already feel younger.

Dov Michaeli

On January 3, 2006, the New York Times  published an very interesting article by Gina Kolata, an award winning Science reporter, on the intriguing relationship between education (years spent in school) and longevity. This is an extremely complex subject that we will need to come back to it in future postings to try to unravel some of the knotty issues involved.  

But for now, I want to focus on one topic in the article that had little to do with education, rather it dealt with the role of social networks.  Dr. Lisa Berkman , cited in the article, is a professor of public policy at the Harvard School of Public Health. In the 1970’s she worked at a San Francisco health care center that served Chinatown, North Beach (an Italian neighborhood), and the Tenderloin (a district populated with homeless people who lived on the street, mentally ill people, drug addicts and just plain poor people).  She observed that in Chinatown and North Beach people enjoyed tight and extensive social networks, made up of closely-knit families, friends and neighbors who cared for each others. In the Tenderloin people “were sort of dumped”, suffering from almost total isolation.

Thirty years later, after studying another group, Seventh-Day Adventists, well-known for their social cohesiveness as well as prolonged life span, she came to the conclusion that social isolation is associated with twofold to fivefold (i.e. 200% to 500%!) increases in mortality rates. This correlation has been corroborated in many other studies and in many other countries. Such a ‘hazard ratio’ (a term used in epidemiological studies, meaning the hazard of dying in the experimental group over the hazard in the general population) is so compelling that even one who insists on biochemical/molecular evidence of causality must sit up and take notice.

And indeed, it reminded me of the Okinawan people who are one of the longest-living society on earth. Their active lifestyle and healthy diet still don’t completely account for their outsized longevity. The distinguishing feature in their culture is the extremely close-knit family, the active role that grandparents and great grandparents take in the daily chores of the family, and the unusual respect and reverence they are being treated with.

And then there is the well-known observation that married men live significantly longer than single men. Or the statistic that societies that regard the care of older people as a societal obligation, such as Holland and the Scandinavian countries, also have some of the lowest mortality rates of the industrialized countries.

Is there a biological explanation?

In insect societies, a bee or a wasp separated from her nest will simply curl up and die within a day or two. Solitary wasps, on the other hand, live happily their full life span without ‘feeling’ the need for social contact. If you had a chance to observe bees’ behavior in their hive you’d be struck by the constant touching and stroking of each other with their antennae. Part of it is a form of transmission of information through pheromones, including and ‘I.D. scent’ that says “you belong”.

But is it possible that such pheromones evolved to occupy such a central role in the bee’s physiology as to make life without it impossible? If so, this would be an extreme case of ‘enforced socialization’, essentially saying “socialize or die”! Another intriguing possibility: the touching and stroking with the antennae could be the equivalent of grooming in primates. Monkeys that don’t get their daily dose of touching, stroking and grooming become depressed. So do human infants. Could it be that bees require the same tactile sensation?

What could be the biological mechanism that would curtail the lifespan of a bee separated from her hive? I don’t think we know. But there must be one.

What about us, humans?

It is known that social isolation is a stressful state, and conversely, social support reduces stress. Put in a biological context -- stress is expressed biologically by chronically elevated levels of the stress hormones cortisol and epinephrine (aka adrenaline). We know that these hormones are pro-inflammatory. The inflammatory response has been associated with coronary heart disease, autoimmune diseases, and cancer. In fact, we now know in precise molecular detail how this happens.

The stress hormones cause the release of peptides from white blood cells that are called interleukins. These peptides allow cells to ‘talk’ to each other and thus coordinate the inflammatory response and the immune response. A certain amount of the stress hormones is actually normal, and it results in the production of normal physiological levels of interleukins. This allows us to have an appropriate levels of inflammation and immune function necessary to protect us from foreign invaders and, in some cases, cancer. But when stress hormones are chronically elevated, over months and years, the protective function of the inflammatory and immune responses is turned into a pathological process that causes a variety of diseases, and death.

Mind you, this is speculation. All I did here is connect the dots of isolated biological and medical studies, most of them in the test tube or in animals. But what I wanted to demonstrate is that a biological basis for something as ‘social’ as social isolation and longevity most probably does exist.

Should we wait for the ultimate proof?

Absolutely not! Social policy should be based on solid evidence, and the hazard ratios of social isolation are so compelling as to make them an appropriate basis for policy. The cost of social isolation in human and economic terms is very high. We should take it very seriously now, as a huge wave of aging boomers is upon us.

by Dov Michaeli, MD, PhD

Our immune response is usually characterized as the recognition of “self” from “non-self,” or as the response to “danger signals.”  Although there are some subtle distinctions between the two, we will not concern ourselves with them here. Rather, we’ll examine how the immune response works, why it is important to our survival and how we can boost its function.

How does immunity work?

There are two ways our immune response can protect us from foreign invaders like viruses and bacteria. One is through white blood cells known as T lymphocytes or T-cells.  T-cells have the uncanny ability to tell a normal cell from a cell which had been invaded by pathogens.  When T-cells find cells that are not normal, for example, cells that are infected, they eliminate the offending cells. This is called cell-mediated immunity or CMI.

The other way T lymphocytes protect us is by reacting with another type of white blood cell called B lymphocytes. These cells are veritable factories of antibodies, which are proteins that circulate in the blood looking for the infectious organisms, binding with them and ‘neutralizing’ them.

The most amazing attribute of T lymphocytes or antibodies produced by the B lymphocytes is their exquisite specificity. That is to say, if a T lymphocyte or an antibody is designed to attack a flu virus of a certain strain-it will attack this strain, and only this strain. This is, by the way, why we have to get a different flu vaccine every year- the virus mutates and therefore requires an antibody with a different specificity to neutralize it.

The T cells are formed in the thymus an organ that is prominent in the neck area of young people, but shrinks to unnoticible proportions in as we age.  T lymphocytes get their name from the thymus. 

In an early stage of their development, they are ‘naïve.’  That means they have not yet acquired their specificity .  As these lymphocytes mature, however, they acquire a specificity, for example, against a specific flu virus strain.  This occurs because of an actual encounter with the virus or some part of it. The result of this interaction is an "educated" T lymphocyte --a lymphocyte that can perform its function in protecting us against the flu virus.

In the human body, as in the rest of life, no resource is infinite.  This is true for the pool of naïve (or non-specific)lymphocytes as well. Starting at about age 30, the thymus, where the T lymphocytes are being formed, begins to shrink (this is called involution of the thymus).  As a result, the supply of naïve T lymphocytes progressively diminishes.

What that means is that older people slowly lose their capacity to mount an immune defense against new pathogens if they have not already "educated" T Lymphocytes at a younger age. To give you a real world example: 70-80% of people between the ages of 16 and 65 will be protected from the flu if they get vaccinated; but only 30-40% of elderly people will be protected.

So what does it have to do with longevity?

In a word: everything. The main reason for the improved longevity since the 18^th century (the age of Enlightenment) is the "discovery" of the scientific method.  It started with the discovery of the microscope by the Dutch scientist von Loevenhook.  Then there was the discovery, by a French scientist, of the connection between bacteria and disease and ways to kill them by pasteurization (yes, you probably guessed his name -- Pasteur).  Another milestone was the discovery of antibiotics in the 1940’s by Fleming.  He received the Nobel prize for the discovery of penicillin.  These were the miracles of the 19th century.   In those days, old people didn’t die of cancer, they died of infections.   They simply did not live long enough to develop cancers  that occur related to aging.

But, you might ask, didn’t our ancestors have an immune response to protect them? Yes, they did. And indeed younger people could survive their infectious disease surprisingly well. But as their immune response started to decline after age 30, they started to succumb.

Does this have any relevance to longevity in the 21^st century? Yes, because when we fail to mount an immune response due to age or disease (a condition called ‘immunodeficiency’), drugs alone are of limited utility.

How can we boost the immune response in the elderly?

The answer to that is still being investigated. But there is research, conducted by Richard Miller and his colleagues at the University of Michigan, showing that mice on caloric restriction suffer less infections and live significantly longer.

But this is mice.  What about men (and women)? To do an experiment on humans will be tough, long and expensive. But researchers at the Oregon National Research Primate Center reported in the Dec.4 issue of the Proceedings of the National Academy of Sciences (http://pnas.org) that in calorie-restricted old monkeys (30% reduction of normal diet) 30-35% of the total T cell pool were naïve T lymphocytes.  Monkeys of the same age on a regular diet had only 20-25% of these lymphocytes. This is a 50% increase in naive lymphocyte in the calorie-restricted group which is very impressive. This experiment unequivocally demonstrates that caloric restriction slows down immunological aging.

Did the boost in immunity result in increased longevity?

We don’t know yet because the monkeys are still alive and kicking -- so the experiment will have to continue for a longer period of time.  However, mouse data from the University of Michigan, that show an increased immune capacity coupled with increased longevity, are very intriguing.

Bottom line-what shall I do?

As far as I am concerned, calorie restriction (CR) to the degree used in these experiments may not be worth the pain for ordinary humans.  CR may boost my immune response,.  I may even live longer- but you call that living? Starving for life??

I’d much rather exercise aerobically on a regular basis for the following reasons:

• It makes me feel better
• It makes my brain work better
• It also might help me live healthier and longer

In addition to a good diet and exercise, I also have a couple of glasses of red wine with dinner.  It tastes great and it makes me  feel great.  It may also  make my life on earth a bit longer, but certainly, it makes my life a lot more pleasant.

Le’chaim (to life)!

Posted by Dov Michaeli, MD, PhD

Our grandmas taught us that there are “good” foods and “bad” foods. Right? “Eat your carrots, they are good for your vision” “Drink your milk, it will make your bones strong” Eat your spinach and you can have muscles like Popeye, the Sailor Man (toot toot) Well, our receptivity to that kind of advice is not lost on the food industry. Check out this article on “functional foodmakers” (did you know there was such a thing?) that I found on the London Times Online. It is titled “Coming soon, ice creams to boost your immunity level.” What are functional foods anyway? Functional foods are foods that have a function, usually as the result of adding some type of additive. For example, iron is added to bread flour to prevent iron deficiency anemia and calcium is added to orange juice to help prevent osteoporosis. These foods are now no longer just plain foods, they are functional foods. The implication is that they are really, really good for you.

Click to read more ...

Dov Michaeli, MD, PhD explores the impact of aerobic exercise on brain function.

Aerobic exercise and the brain

Now, I want to turn our attention to the brain. Don't worry, I will come back and tell you how this all relates to the titillating findings I wrote about in my last post on the relationship between resveratrol and endurance. But first let's examine the results of a study of the impact of aerobic exercise on brain function.

We know from prior studies that aerobic exercise has beneficial effects on brain function in older adults. For example, compared to elderly people who are sedentary, seniors who engage in regular aerobic exercise demonstrate the following:

• They are more nimble at being able to switch between mental tasks
• Their working memory improves significantly, and
• They can better screen out distractions

In a recent study, reported in the November 2006 issue of the Journal of Gerontology, Dr. Arthur Kramer and his research colleagues delve deeper into the relationship between aerobic exercise and improved brain activity. They used sophisticated brain imaging techniques to demonstrate that these improvements in brain function have an anatomical basis.

They showed that new neurons were formed as a result of aerobic physical activity. This phenomenon is called neurogenesis. Until quite recently, the idea that new neurons could be formed in adults was considered heretical. The researchers noted that exercise-related neurogenesis was especially prone to occur in the frontal lobes of the brain. These are the areas of the brain that are responsible for cognitive functions, such as thinking, working memory, attention.

Furthermore, they showed they showed a large increase in the “white matter” in the brains of exercising seniors. The white matter contains the connections between the neurons (which constitute the “gray matter” of the brain). A particularly important area of white matter is an area called the corpus callosum. The corpus callosum connects the two hemispheres of the brain, right and left. Increased volume of this area explains the observation that exercise increases the integration and coordination of the right and left brains and, thus, increases cognitive efficiency.

Whose brains benefit from aerobic exercise?

The Kramer study included 59 adults, ages 60 to 79. Half of this group exercised (a brisk walk at about 3 miles per hour) 3 hours a week, the other half performed non-aerobic exercises like stretching and toning. Only the aerobic exercisers showed brain benefit.

Since we know that cognitive functions begin a slow decline from about age 40, it may be that adults 40 and elders are the prime beneficiaries of aerobic exercise when it comes to improved brain function.   However, we cannot say definitively that younger people's brains do not benefit from aerobic exercise as that simply not been studied yet.

Resveratrol, aerobics, and the brain: bringing it all together .

As I discussed in my last post, we know that resveratrol does a number of good things with respect to cellular energy metabolism:

• It improves the efficiency of oxygen utilization in cellular organelles called mitochondria
• The improved efficiency of oxygen utilization in mitochondria leads to enhanced ATP production (ATP is the prime energy storage unit for cells)
• Enhanced ATP production facilitates increased physical endurance, at least in mice.

Aerobic exercise, on the other hand, leads to an increased number of cells and therefore, an increased number of mitochondria that produce ATP.  The endpoint is the same as resveratrol.  There is an increased amount of energy, stored as ATP, to fuel various cellular functions.  Thus, enhanced physical endurance and increased brain power.

The problem is, from a practical point of view, very large amounts of red wine must be consumed in order to consume enough resveratrol it to do any good. So, if you think you can drink your way to everlasting happy/healthy life--fuggedaboudit.   You would need to drink hundreds of glasses of red wine every day to consume the required amount of resveratrol. Most likely, rather than live forever with great endurance and expanded brain power,  you’d die of cirrhosis and alcohol-related mental problems.

Let's  consider now what aerobic exercise can do for us. We have now compelling evidence that it is good not only for the body but also for the mind (unlike exessive amounts of red wine). It increases the volume of muscle tissue, the efficiency of mitochondria and their number per cell. Likewise, it increases the number of neurons in the frontal lobes (as well as in the areas of the brain that control motor functions), and it increases the number and efficiency of mitochondria in those neurons.

Here is another  fact: many neurodegenerative diseases, like Alzheimer's disease and Parkinson's disease, are associated with mitochondrial loss of function. Could aerobic exercise slow down the progression of such diseases? We don't know the answer to this question yet, but it is an intriguing possibility.

What is the bottom line with respect to improved mitochondrial energy production?: The best way to develop high functioning mitochondrial energy production is via regular AEROBIC EXERCISE!  It may not be as palatable as drinking lots of red wine, but it is pretty safe, it can be fun, and it improve, not pollutes brain power.