New Evidence for Free Radical Theory of Aging Suggests
Antioxidants Extend Life
by David Jay Brown
Caenorhabditis elegans is a type of nematode that normally lives for about three weeks. These microscopic roundworms can live for up to twelve weeks, however, when mutations are engineered in certain genes that control a period of slowed-down metabolism in their life cycle, called the dauer state. In this state they can move around and respond to their environment, but they are sealed up (front and back) and cannot eat. This ability to extend their lifespan has been of interest to longevity researchers, but, because humans do not have a dauer state in their life cycle, skeptics have claimed that it probably has little relevance for extending human life.
The recent discovery of a new catalase gene in these tiny creatures, however, provides additional evidence for the free radical theory of aging, which proposes that one of the primary reasons cells age is the damage to DNA caused by free radicals and reactive oxygen species.1 New evidence for this theory is important because free radical and oxidative damage can greatly affect human health and longevity.2 This newly discovered gene controls the production of catalase, an endogenous (produced by the body) enzyme that neutralizes reactive oxidants and protects cells from oxidative damage.
Free radicals are atoms or molecules that contain at least one unpaired electron (in most stable chemical species, the electrons are paired). This makes them chemically unstable and allows them to react readily with other compounds. In so doing, free radicals and other reactive oxidants can cause extensive damage to cells and tissue, impairing the immune system and leading to infections and various degenerative disorders, such as cardiovascular disease, joint disease, and mental decline. Perhaps worst of all, they can damage the DNA in our cells and put us at risk for cancer.3
Figure 1. The nematode C. elegans in reproductive embrace.
Many researchers believe that the havoc that free radicals and other reactive oxidants wreak on our bodies is the basis for the aging process. These dangerously reactive chemicals can be caused by exposure to radiation and toxic compounds, but they also result from necessary and seemingly harmless metabolic processes, such as the breaking down of stored fat molecules for use as an energy source, or simply from metabolizing oxygen. In other words, free radicals are generated from simply eating food and breathing air.
Dr Martin Chalfie and his colleagues at Columbia University recently discovered a new gene for a catalase in nematodes. Catalases promote the decomposition of hydrogen peroxide, a strong oxidant. They are found in the blood and most living cells of animals, including humans (they are also found in breast milk). If this particular gene is disabled in the normal, nonmutated nematode, the catalase that it codes for is diminished, resulting in significant cellular damage. When this same gene is disabled in the genetically mutated nematode (which has an extended lifespan), the nematode incurs not only the same cellular damage but loses its life extension capabilities. This strongly suggests that catalase is necessary for extending the life of the nematode.
"What that says genetically," Dr Chalfie stated, "is that this particular catalase is a necessary component - perhaps not a sufficient one, though, because we haven't proved that yet - for the extension of lifespan in this animal. If you can control the catalase gene, then that can have a profound effect on how long the worms will live. We've shown that animals that do live longer have more catalase activity and that this particular catalase is greatly increased in those animals."
A newly discovered nematode gene neutralizes free radicals thereby protecting cells from oxidative damage and slowing down aging.
I asked Dr Chalfie how the discovery of this gene might affect our understanding of how to lengthen human lifespan. "I think," he replied, "the first thing we have to ask is, is there an equivalent gene in any animal other than this nematode? Is it in humans? So far, by looking at the publicly available human DNA sequences, we have not found it. I suspect that we will get a definite answer for this after the human genome sequence is completed in the next three to five years. Then we'll know whether there is, in fact, a catalase like this."
But whether or not there are any human genes that can be engineered to extend life, Dr Chalfie's discovery of the role that catalase plays in nematodes lends strong plausibility to the free radical and oxidative damage theory of aging. Dr Chalfie believes the most important implication of his discovery is that, "It gives support to the idea that a major contributor to aging, at least as we see it in this worm, is oxidative damage. This is an important controlling aspect for the aging of this animal. It's not only free radicals that cause the damage, it's also reactive oxygen species, of which hydrogen peroxide is one.* They're often called oxygen radicals, but that's a misnomer. So here's an enzyme that controls reactive oxygen damage, and when you disable it, the animals live shorter lives. They appear to age more rapidly, and the genetic mutations that normally extend lifespan no longer do so. This suggests that it's the action of this enzyme that was important for that lifespan extension."
To learn more about the implications of Dr Chalfie's discovery, I spoke with Dr Bruce Ames, an expert on oxidant damage and antioxidants at the University of California, Berkeley. Dr Ames said the discovery was important because, "It confirms the idea that aging in animals results from accidental damage to DNA, like that caused by free radicals, and not from a genetically directed clock. I don't think aging is built in, as with telomeres, where you have a certain number of ticks and then you die. I think it has more to do with wear and tear, and that mitochondrial decay has a lot to do with it. I think the evidence for the free radical theory of aging is getting much stronger."
In addition to catalase, a number of important free radical scavengers occur naturally in the body, such as superoxide dismutase, methionine reductase, and glutathione peroxidase. However, these enzymes are not enough to arrest the free radical damage that is imposed upon our cells virtually every moment, so antioxidant supplementation is advisable.
Some examples of nutrients that act as antioxidants are Vitamin A, Vitamins B1, B5, and B6, and Vitamins C and E; other tocopherols, such as tocotrienol; beta-carotene and other carotenoids, such as lycopene; the amino acids taurine and cysteine; alpha-lipoic acid; and the trace minerals selenium and zinc. Many of these compounds can work synergistically to neutralize free radicals and other oxidants.
Many researchers believe that the havoc free radicals wreak on our bodies is the basis for the aging process.
Melatonin, the hormone that many people use as a supplement to help them sleep at night, has also been shown to be a powerful antioxidant. The components of certain herbs, such as green tea, marijuana, and ginkgo biloba, have been shown to have these properties as well. Then there are the food additives BHT (butylated hydroxytoluene) and BHA (butylated hydroxyanisole) . . . and the list goes on.
According to Dr Ames, "If you don't get enough of Vitamins C or E, it's like irradiating yourself. Oxidant byproducts of normal metabolism - notably superoxide, hydrogen peroxide, and hydroxyl radical - are some of the same mutagens produced by radiation. Ingesting a diet with inadequate antioxidants, such as Vitamins C and E, mimics radiation exposure. Oxidative damage to DNA and other macromolecules appears to play a major role in aging and degenerative diseases associated with aging, such as cancer."
Many antioxidants are found naturally in sprouted grains and in fresh fruits and vegetables. Dr Ames states that "The quarter of the population eating the fewest fruits and vegetables has double the cancer rate - for most types of cancer - compared to the quarter eating the most fruits and vegetables. Antioxidant and other micronutrient deficiencies may explain much of why this is so, as inadequate intake of these substances can cause broken chromosomes and lead to cancer.
We can arrest and possibly reverse damage caused by free radicals by using a broad spectrum of antioxidants.
"Much of the population does not get enough of the required antioxidants and other essential micronutrients from fruits and vegetables. To maintain the maximum possible protection from the constant onslaught of free radicals and to prevent chromosome breakage, it is necessary to eat at least five portions of fruits and vegetables per day. We can also minimize damage by taking multivitamins as insurance. It may be desirable to take Vitamin E in addition, as it appears difficult to get the optimal amount of this antioxidant through diet alone."
At present we can't do anything about our own levels of the antioxidant catalase. However, we can do something about arresting, and possibly even reversing, some of the damage caused by free radicals by using a broad spectrum of antioxidants. These antioxidants may be able to do a lot to ensure that we remain healthy.
What excites Dr Ames most about his own work, he told me, is that "We're making progress in rejuvenating old rats by feeding them normal mitochondrial metabolites, such as acetyl carnitine and lipoic acid. This restores mitochondrial function to a large extent after just a few weeks. It also lowers oxidants to the level of a young rat and increases ambulatory activity. It's really amazing. They become lively old rats. They get up and do the macarena. I'd like to get that into people."
* Reactive oxygen species are the entire class of highly reactive molecules derived from the metabolism of oxygen. Scientific interest in reactive oxygen species and oxidative stress is growing very rapidly. A Medline search on these terms brings up 177 citations between 1976 and 1984. Between 1996 and the present, the figure increased to 5,756.4
- Taub J, Lau JF, Ma C, Hahn JH, Hoque R, Rothblatt J, Chalfie M. A cytosolic catalase is needed to extend adult lifespan in C. elegans daf-C and clk-1 mutants. Nature May 1999;399:162-6.
- Beckman K, Ames B. The free radical theory of aging matures. Physiolog Rev April 1998;78(2):547-81.
- Ames B. Micronutrients prevent cancer and delay aging. Toxicol Lett 1998;102-103:5-18.
- Gilbert D, Colton C, eds. Reactive Oxygen Species in Biological Systems: An Interdisciplinary Approach. Plenum, New York, 1999.