Mechanisms of Aging: Free Radicals

Americans, who claim to be most freedom loving people in the world, like to say that there is no such thing as too much freedom. Indeed, freedom is a great thing when exercised within the framework of reasonable laws that protect people's lives, rights and property. Criminals, on the other hand, attempt to exercise an absolute, boundless freedom, harming their fellow citizens and society at large. And so, their love for freedom notwithstanding, Americans do what they must to protect themselves: they vote for tough anti-crime laws, urge politicians to put more police on the streets, and, of course, buy home security systems and handguns. The point is that while we need freedom, we also may need protection from too much freedom in someone else's hands.

One can find a very clear analogy between free radicals in our bodies and criminals in a community. Free radicals are chemicals with an unpaired electron, which are extremely and randomly reactive. Most chemicals in the body react with each other relatively slowly and within rules known as metabolic pathways. These rules are enforced by enzymes, which are special proteins guiding and facilitating chemical reactions. Not so with free radicals: those bandits react quickly and indiscriminately with whatever cellular structures are at hand, inflicting damage as a result.

How do free radicals get in our system? Unfortunately, they are an intrinsic part of most forms of life on Earth. All higher organisms generate energy by slowly burning (oxidizing) fuel, such as carbohydrates and fats, in special biological microreactors called mitochondria. The energy so produced is stored in the form of adenosine triphosphate (ATP), which is the universal biological energy currency. This nice little power-generating enterprise, however, produces highly toxic by-products: free radicals. As long as we breathe, free radical will be with us. Actually, many other things can produce free radical: X-rays, UV-light, ozone and so forth, but those can be largely avoided while breathing cannot.

Free radicals can react with essentially any structure in the cell. Free radical damage to DNA can lead to mutations, knocking out or disrupting the activity of genes, thus altering vital functions or even causing cancer. Cell membrane is especially vulnerable to free radicals because it contains unsaturated fatty acids, which are highly reactive. Free radicals make the membrane rigid, fragile and leaky, in other words, dysfunctional.

In the course of evolution, organisms developed the means to protect themselves from free radical damage. Several enzymes are involved in the inactivation of free radicals and their derivatives, namely superoxide dismutase (SOD, neutralizes superoxide radical), catalase (inactivates hydrogen peroxide) and glutathione peroxidase (participates in neutralizing lipid and other peroxides). On top of that, cells are protected by various antioxidants (free radical scavengers), including vitamins C, E, selenium, glutathione, melatonin and others. Despite such sophisticated security system, a few free radicals always manage to escape and cause damage. The damage is greater if antioxidant defenses are down because of stress, malnutrition, old age or illness.

The idea that free radicals may cause aging was first proposed in the fifties by Dr. Denham Harman. For quite a while it was considered a curious hypothesis. Eventually, scientists accumulated a large body of evidence in favor of this idea, turning it into one of the best-supported theories of aging.

The amount of free radical damage appears to be proportionate to the organism's metabolic rate, which is essentially the rate of burning calories. Metabolic rate of a rat is about 7 times that of a human. It is estimated that rats suffer about 10 times more free radical "hits" to DNA per cell than humans. This is likely to be one of the reasons why humans live much longer than rats. In fact, when metabolic rate of rats if lowered by severe food restriction, their life span increases dramatically.

Mitochondria, the cells power station, are particularly important to the free radical theory of aging. First, free radicals are produced mainly in the mitochondria because that's where the cell burns its fuel. Second, even though there are a lot more free radicals inside mitochondria than elsewhere in the cell, mitochondria is actually far less protected from free radical damage than the rest of the cell. For example, whereas DNA in the cell's nucleus is covered with protective proteins, the DNA in the mitochondria is largely exposed and very vulnerable. Discussing how such seemingly irrational design came to be is beyond the scope of this article. For now, let us just call it a cruel irony of evolution. (Or a designers oversight if you prefer.) Anyway, under the assault of free radicals of their own making, mitochondria tend to deteriorate faster than other parts of the cell. And since they are the primary energy producers, the call's 'entire economy' falls into recession. In fact, the so-called mitochondrial burnout is considered one of the key mechanisms of aging. (See our article on mitochondrial burnout.)

The are many lines of evidence demonstrating that free radical damage accumulates with age. For instance, a two year old rat has twice the number of oxidative lesions (lesions caused by free radicals) in DNA than a young rat. The frequency of mutations in human lymphocytes from elderly people is about 9 times greater than in the lymphocytes from infants. Werner syndrome and progeria, two human diseases that cause dramatically accelerated aging, are associated with a marked increase in oxidized (free radical damaged) proteins. Age-related pigments (clusters of molecular waste, such as lipofuscin) that accumulate in the cells with age are believed to be a product of oxidative damage to proteins and lipids. Up to a point, these pigments are relatively benign, but if their accumulation exceeds a certain level, they begin to stifle cells. The accumulation of waste pigments can be slowed by antioxidants.

The studies of long-lived mutants in various species provided some very convincing evidence of the link between aging and free radicals. It was found that mutations that knock out a single gene (called age-1) in a species of worm Caenorhabditis elegans produce a 70% increase in life span. It turned out that mutant worms had increased levels of two key free radical scavenging enzymes, superoxide dismutase and catalase. It was suggested that the gene knocked out by the mutations encodes an inhibitor of antioxidant systems of the cell. In another study, researcher used selective breeding to produce fruit flies (Drosophila melanogaster) that had twice the average lifespan. One important difference between regular and long-lived flies was a higher activity of superoxide dismutase in the long-lived kind.

In the early years of radiobiology, a field of science concerned with biological effects of radiation, researchers encountered a puzzling phenomenon. Low-level radiation treatments protected animals from higher exposures as well as many other stresses, such as mutagens, toxins and oxidants. Later, it was found that mild, temporary increase in free radical formation caused by radiation stimulates the cell's free radical-fighting systems (SOD, catalase, glutathione peroxidase), improving resistance to future damage.

Of course, having periodic X-rays in order to acquire a better stress resistance is a bad idea. But there seems to be a much simpler solution. Exercise is also a mild-to-moderate free radical inducer. Understandably, the more fuel you burn, the more oxidative by-products you get. A reasonable amount of periodic exercise will stimulate your own antioxidant defenses, which will remain enhanced long after the exercise is over. On the other hand, excessive exercise (the amount causing severe physical stress) may overwhelm you protective systems and accelerate aging. It would appear that exercise, like other elements of a healthy lifestyle is great in reasonable amount but may not be as great in excess.

People often ask: if free radical damage is one of the key mechanisms of aging then taking antioxidant supplements must have a major impact on longevity. The simple answer is: it's more complicated than that! Here's why. The cells maintain equilibrium between their levels of free radicals and the activity of antioxidant defense systems (a.k.a. oxidative equilibrium). But such defense can be very costly to maintain. Hence the body accepts a tradeoff between the level of damage it is willing to tolerate and the cost of maintaining antioxidant defense. (Like a city major who is willing to live with the manageable amount of crime rather than spend the entire budget on the police.) When you consume antioxidants, the body reacts by turning down its internal antioxidant systems. After all, why not spend less on defense when outside help is available. As a result, supplemental antioxidants do not reduce free radical damage as much as one would think.

Studies show that supplemental antioxidants generally do not increase maximal lifespan (the longest a species can live) in mammals. But antioxidants were shown to increase average lifespan (at least in rodents), i.e. how long a typical member of a species will live. This is consistent with the idea of oxidative equilibrium. When oxidative equilibrium is always nicely maintained, an organism has a chance to live out its species maximum lifespan. Supplemental antioxidants cannot alter that because they do not shift oxidative equilibrium. On the other hand, the more oxidative equilibrium is disrupted during an organism's lifetime, the shorter its actual lifespan. Indeed, in real life, our antioxidant systems are often pushed away from the perfect equilibrium. (They get flooded by large amounts of free radicals when exposed to UV-rays, toxins, cigarette smoke, radiation, stress and other harsh conditions.) This is one reason why most of us do not reach maximum possible human lifespan of about 110-120 years. Supplemental antioxidants might help push our average lifespan close to the potential maximum by providing reserve free radical scavenging capacity and thereby smoothing the disruptions of oxidative equilibrium.

Ultimately, though, the goal is to increase maximum lifespan, which requires shifting oxidative equilibrium to another level. Unfortunately, there are no proven practical ways to do that yet.

Another common question is: what antioxidant is best to take? This is generally a flawed approach. If you wish to protect your domain from unwelcome intruders, you do not put a fence on just one side of your property. There are many kinds of free radicals, such as superoxide, singlet oxygen, hydroxyl, alkoxyl and so forth. Different antioxidants tend to have affinity to different free radicals. Besides, you need both water-soluble and fat-soluble antioxidants in order to protect all parts of the cell. Hence, the optimal approach to consume a wide variety of different antioxidants.

While it may be possible to achieve broad antioxidant protection by combining various supplements, a simpler and more enjoyable first step is to eat a diet comprising a wide variety of fruits and vegetables. Many plant pigments, such as flavonoids, carotenoids, and anthocyanins, are known to be potent and versatile antioxidants. A diet with plenty of fruits and vegetables of varying color seems to provide the best all-round antioxidant protection. To ensure that your fruits and vegetables have all their antioxidants intact, make sure they are fresh and uncooked (or only minimally cooked) since heat inactivates most antioxidants. Additional supplements may be useful, especially under harsh condition, such as stress, illness or sun exposure. (Discussing individual antioxidants is beyond the scope of this article.)