Cell death due to oxidative damage is considered to be one of the major causes of aging and chronic degenerative diseases. Oxygen free radicals react with everything in sight inside of cells and wreak havoc with normal cell function. When the mayhem reaches a critical level, the cell literally commits suicide and dies; this is known in the scientific world as apoptosis (pronounced A-POP-TOE-SIS). When enough cells do it, whole organs fail, and eventually, the grim reaper gets his quarry.

So, what are those radicals (chemically speaking, not the political ones)? Where do they come from? What’s their connection to longevity? Let me try to explain.


Energy from food – the fuel of life

The cell is full of enzymes that are ready and willing to perform all the functions that are vital for life. Enzymes need a source of energy in order to perform their function. This energy is supplied by ATP (Adenosine Tri-Phosphate), a molecule that stores energy and releases it upon demand to the enzymes. Quite similar to gasoline providing the energy to your car engine.

The energy stored in ATP originates from our diet-carbohydrates, fats, and proteins. These dietary components are broken down by enzymes to smaller and smaller units and finally, the end product, pyruvic acid, enters special structures inside the cell, called mitochondria, the powerhouses of the cell.

In the mitochondria, a process called oxidative phosphorylation, or oxphos as the cognoscenti call it, takes place. This process is similar to what the gas hose does. It delivers energy, in the form of electrons, from the food-derived pyruvic acid to an intracellular molecule called ADP (Adenosine Diphosphate). This results in ADP being converted to ATP.


How can this normal process cause damage?

Again, let’s consider the fuel pump. Consider what would happen if there was a huge pressure buildup in the gas station storage tank, but the gasoline at the end of the hose can come out only as a slow trickle. Eventually, the pressure in the hose builds up to such a level that the hose springs a leak.

A very similar situation occurs in our cells. If we eat a diet that is rich in calories, we may have created a situation where there is excess fuel. When the “pressure” builds up in the oxphos chain inside the mitochondria, it simply cannot process all of the excess fuel and it springs a leak, so to speak. This leak occurs primarily at a complex of molecules called, quite unimaginatively, Complex A. The leak is in the form of reactive oxygen radicals, or ROS. These molecules are the culprits in a lot of what ails our aging population.

Are there any drugs that can plug the mitochondrial leak? The short answer is no. A lot of research is being done and a lot of claims are being made in this arena, but, in fact, nothing is currently available. Several foods and food supplements can help sop up and neutralize some of the ROS after they are released, but none can stop the leak.

Is there a natural way of relieving the pressure in the oxidative phosphorylation “hose” that would allow us to avoid the leaking of ROS? In fact, there is. If we use the energy from ATP at a very rapid rate, then electrons (energy) would flow very rapidly down the oxphos chain in order to replenish the ATP molecules. But we cannot just wish for ATP to be consumed rapidly, we need to accelerate the processes where it is being used. In short, we need to be physically active; we need to exercise!

Actually, exercise works in several ways to reduce ROS formation. In addition to increased utilization of ATP formed in each individual mitochondrion, exercise also increases the number of muscle cells and each muscle cell has its own mitochondria to “take care” of the nutritional energy supply. Also, if we exercise on a regular basis, with time, there will be an increase in the number of mitochondria per cell. All this explains why, by building up the muscle mass, the basic metabolic rate (BMR) is increased. What that means is that even at rest more calories are burned.


A bit of evolution

Now that evolution is kosher again in Kansas, I’ll give you the evolutionary perspective of it all. Oxphos is one of the most ancient mechanisms of life on earth. When the atmosphere started accumulating oxygen over a billion years ago, the primitive organisms that adapted to utilizing oxygen for their energy needs obviously had a survival advantage. All organisms evolved a pretty good balance between consumption and utilization of energy. So did humans, until about 100 years ago. Our downfall was that all of a sudden (in evolutionary terms), we were given a relatively huge supply of food and at the same time markedly reduced our activity. Result: Not only did we become fat, but we also sprung the ROS leak.

So here is the molecular basis for what we knew all along: In order to live long, you need to reduce your caloric intake and exercise.

Dov Michaeli, MD, PhD
Dov Michaeli, MD, PhD loves to write about the brain and human behavior as well as translate complicated basic science concepts into entertainment for the rest of us. He was a professor at the University of California San Francisco before leaving to enter the world of biotech. He served as the Chief Medical Officer of biotech companies, including Aphton Corporation. He also founded and served as the CEO of Madah Medica, an early stage biotech company developing products to improve post-surgical pain control. He is now retired and enjoys working out, following the stock market, travelling the world, and, of course, writing for TDWI.