The Doctor Weighs In

We modern humans have a tough time curbing our appetite. The reason for that is that our primitive ancestors, leading a life of hunters/gatherers (or scavengers, as recent research suggests) did not have a steady, predictable supply of food. So our physiology has evolved to store calories when we could get them, in the form of fat. The need was to maximize conservation of energy (or calories), and an elaborate system has evolved in the gut and the brain to accomplish that.

This state of affairs served our species well until relatively recently. When the industrial revolution arrived about 200 years ago, farms became more efficient and produced more food, people became more affluent working in factories and offices, being able to afford the cornucopia of food and drink. At the same time work, and life in general, demanded less and less effort (or expenditure of calories).The consequences are evident today on every street of the industrial world. Unfortunately, our metabolism has not been able to adapt to this relatively recent change in lifestyle. Such things require an untold number of genetic mutations and take thousands of generations.

Is there nothing to be done about it?

The only way we can change our metabolism is through drugs. So far, all the heavily promoted and hyped diet pills, which are basically attempts to change our metabolism chemically, have been either very limited successes, or total failures. Fortunately, we are a species endowed with a high degree of awareness and the capacity to quickly adapt through changes in behavior. Remember Pavlov’s drooling dog? We are better. Being aware of what triggers our brain to send ‘hunger’ signals allows us to counteract them through behavioral strategies.

The biological clock

No, this is not really a ticking clock; but, biologically speaking, a lot more powerful. A clock is neutral, it just keeps time. There is no inherent functional meaning to 3AM or 3PM. It is us who invest it with the meaning of afternoon or early morning. The biological clock, on the other hand, doesn’t only tell time, it gives time a meaning. For instance, around 6 PM I get terribly hungry. Or around 6:30 AM I wake up regardless whether I got enough sleep or not. And when I travel across time zones, either to Europe or the Far East, my biological clock and my whole physiology still lives in California, and is totally screwed up.

We can see then, that this clock actually controls much of the brain function. One of these functions is the sensation of hunger. I am used to eating breakfast at a certain time of the day, and if I don’t get it I feel that something is missing, I am unhappy and miserable to be around, I can’t function at peak performance. If you think about it, the clock didn’t just control hunger, it controlled mood (great omelet--happy; it’s 11 AM and I haven’t had my breakfast yet--unhappy).

The nice thing about this all-powerful clock is that it can be trained to suit our whims. Try skipping lunch and the first few times will send you trawling for food the whole afternoon. But after a while, your need for lunch becomes less and less urgent until eventually you really don’t feel the need to eat in the middle of the day. But don’t carry it too far. I am reminded of one of my professors at UC Berkeley ( who will remain anonymous for obvious reasons), who studied the metabolic effects of calorie deprivation in the German cockroach (Blatella germanica; and I am not making this up). He slowly habituated the critters to a progressively lower calorie diet. One morning he came to the lab and was dumbfounded to find his meticulously habituated cockroach colony totally, irreversibly dead. Theories as to the causes ranged from the sublime to the ridiculous. To my simple-minded suggestion that they may have died of run-of-the-mill starvation, he responded plaintively,” but they have already got used to it…”.

Sight and smell

Why are the French such foodies? My theory de jour: it’s the presentation. When we walked in the market in Beijing and saw row after row of hanging Peking ducks at the butcher shops, I was mildly disinterested. But when they wheeled in the duck in a fancy restaurant the thing looked irresistably delicious and we devoured the whole thing. How do you think did Ray Croc make McDonald’s such a success? He stood outside a small hamburger diner and took in the smells. He immediately knew that he stumbled upon a winner, bought the restaurant and its formula for Freedom (aka French) fries and hamburger patties, and the rest is, as they say… fat kids with diabetes. Both the rhinencephalon (or the smell center) and the visual cortex communicate with the hypothalamus, the area in the brain that controls hunger, through extensive neural connections.

Don’t eat when you are cold

One of the important functions of our physiology is to maintain normal body temperature. For instance, the shivering response to cold is a way for the body to raise its temperature. Metabolism creates heat, and when we are cold the normal response is to eat more, and more frequently. That’s why we tend to eat more in the winter (and, alas, gain more weight) than in the summer. Can you imagine yourself being ravenous on a 100° day? All I can think of is crushed-ice margaritas.

What can we do?

The answer is: a lot. The biological clock and the relationship between smell, sight and hunger are all subject to habituation, or more plainly—to our will. This is literally the old 'mind over body', and all we need is the will and the persistence.

And yes, don’t forget to heat up the house before you sit down to dinner.

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

In my last posting, we discussed the adaptive response to lack of oxygen in wounds and in solid tumors. These are situations in which only a small area of the body is affected, while the oxygen supply to the rest of the body remains normal. There are situations, however, in which the whole body suffers from lack of adequate oxygen supply. The most common is emphysema , a chronic lung condition often related to cigarette smoking.

The structure of our airway

Our airway looks like a tree. The trunk, the main windpipe, is called the trachea. It branches into smaller caliber branches, or bronchi and those, in turn, give rise to progressively smaller branches called bronchioles. The last and smallest twig, the terminal bronchiole, opens into an air sack (alveolus) which looks like a tiny balloon. The alveolus is made up of a very thin wall enclosing an airspace. Thousands of these air sacks (alveoli) make up the lung.

When we inhale our chest expands, the lungs expand and air rushes into the alveoli. Oxygen is then taken up by the blood vessels (capillaries) that course through the walls of the alveoli and carbon dioxide is released from the blood into the alveolar airspace. When we exhale, the elastic alveolar walls contract, chest volume decreases, and carbon dioxide is expelled outside of our body. Think of a balloon letting out air through its elastic contraction.

What is emphysema?

To understand what happens to the emphysematous lung, think of a balloon that has seen better days before losing its elasticity. Air is not expelled as forcefully and completely as before; in fact a relatively large volume of air remains within the balloon.

When a disease process destroys the all important alveolar wall, several things happen. Adjacent alveoli whose walls are destroyed ‘merge’ into larger air sacks that are physiologically ineffective. The capillaries of the alveolar walls are destroyed as well. When this happens, the elasticity of the lung is severely compromised. The consequence of that is reduced air flow in and out of the lung as well as impaired oxygen delivery and carbon dioxide clearance. The patient ends up with low oxygen (hypoxia) and high carbon dioxide (hypercapnia) in the blood.

And the consequences are…

Quite devastating. I am sure everybody is familiar with the wheelchair-bound person with emphysema who must inhale oxygen from an attached tank. The reason for this should be clear by now: in previous posts we examined the role of oxygen in providing energy to the body’s cells.

Glucose is oxidized aerobically (with the help of oxygen), and provides energy in the form of ATP. When oxygen supply is limited, cells oxidize glucose anaerobic ally (without oxygen), a process that provides only a meager amount of ATP. This explains the lack of energy and limited exercise tolerance of people with emphysema. But wait, there is more!

The end product of anaerobic oxidation of glucose is lactic acid. Anybody who has done vigorous exercise knows the feeling of lactic acid accumulation in the muscles. Marathoners call it ‘hitting the wall’. Emphysema patients hit the wall after the slightest exertion. There are other complications that are out of the purview of this posting: low blood pH (acidosis) and heart failure, among others. But the root cause of all of them is low oxygen in the blood.

Who gets emphysema?

A lot of people-the numbers are truly alarming. The National Institutes of Health estimates that there are 12 million Americans with diagnosed emphysema, and an additional 12 million who have it, but haven’t yet been diagnosed.

Emphysema is the now the fourth leading cause of death in the U.S. and is expected to be the third leading cause by the year 2020. As mentioned above, the leading cause of the disease, about 80% of cases, are due to tobacco smoking. The other 20% (which translates to about 2.4 million people) is made up second-hand smoking, exposure to dust and air pollution, and a rare genetic deficiency disease (alpha 1 anti-protease deficiency).

One of the vivid pictures I still remember from my medical school days are the black lungs of two deceased people contained in a jar in the pathology lab. One lung belonged to a smoker; the other, to my great surprise, belonged to a non-smoker who lived in Los Angeles.

There is another chronic lung disease that is growing at an alarming rate due to air pollution: asthma, especially in children. The mechanism of this disease is different from emphysema, but biochemical outcome is the same: impaired airflow to the lung, low oxygen delivery to the tissues. Are there any lingering doubts about the dangers of smoking? Or air pollution?

What is being done about it?

It is amazing to me that we know the ravages of tobacco and air pollution down to the molecular level -- the science is irrefutable and beyond reproach. Yet, we had to fight the tobacco industry for many years to overcome their PR and the money they used to what amounts to bribery of our legislators. We continue to do less than is optimal to clean up air pollution. And, we still have a government that, rather than acknowledge science as a basis for public policy, uses the tactics similar to the tobacco and other vested industries to raise bogus doubts about the quality of the science and bullies scientists who simply report the facts.

Where is the outrage?

Dov Michaeli, MD, PhD