March 2008

Is aging directly related to DNA damage?

Aging has been linked to mitochondrial DNA (mtDNA) damage.
Photo: Administration on Aging.

Wallace: Aging is definitely related to DNA [deoxyribonucleic acid]¹ damage. But certainly, DNA damage, in and of itself, is not the whole answer. DNA is a molecule inside a cell that is involved in maintaining information. The cell itself is assembled from that information.

Just like the blueprints of a house are used to build a house, there are really two ways of looking at damage to the cell, which you can equate to a house. You can have damage to the structure of the house, but the blueprints could help with repairs. However, you could have so much damage to the house that having blueprints wouldn’t be worth using for the repairs. In another situation, you could have a house that is in pretty good repair, but without blueprints, even a small change is devastating because you don’t have a reference to fix a problem. The loss of cells in aging could be due to a direct hit on the important informational blueprint, such as a DNA molecule but the loss could be from such overwhelming damage to the house itself, that even having the blueprints isn’t enough to make a difference.

You study mitochondrial DNA—what is special about mitochondria?

Wallace: The mitochondria², as is commonly said, are the power plants of the cells, and that is exactly right; they make the energy that is necessary for the cells of our body. The food that we eat is a source of our energy. Then, the air that we breathe is used to burn the food that we eat inside the mitochondria, and that is used to make heat and then energy to perform the work that we wish to do.

We eat fats and carbohydrates, specifically carbohydrates such as sugar. You can think of your mitochondria as little fireplaces; but instead of giving off light and heat, they are giving off heat plus they are trapping the light in the form of ATP [adenosine triphosphate],³ which is a small molecule that carries energy to the body to use for different things.

What happens to mitochondria as we age?

Wallace: The mitochondria are unique because they have their own DNA (labeled mtDNA) and that DNA is the blueprint to determine how energy is generated and used. So, as we age in the process of making energy, the mitochondria also make what is called in the popular literature oxygen radicals.⁴ The oxygen radicals are just like smoke; they will damage their environment. You can imagine, say, the city of Los Angeles with its 20-some power plants—each power plant is bringing in coal, which reacts with oxygen and the incomplete combustion is coming off as smoke. So, if you burn really dirty coal, you make a lot of smoke, and you kill all of the people in Los Angeles.

What you have done is you have made energy, but you have defeated the purpose—mitochondria have the same important compromises in their process. They have to make enough energy to get our cells energized to do the work we want them to without making so much dirty smoke that it poisons the cells and the whole system dies. The mitochondria is constantly struggling between the process that is making energy, which makes the smoke, and the smoke, which intoxicates the cell. The consequence is that the cell then has to use the information in its DNA to repair this damage. So, there is that kind of interplay between the necessity of eating and converting that energy and the byproduct of damaging oxygen radicals. Oxygen radicals over a long period of time can accumulate and ultimately kill off its agent —i.e. your body.

How mtDNA mutate? And, what does that mean for human health?

Wallace: DNA is simply a tape of information like the tape on a tape recorder, and the information is organized in a linear form, so you can read it from left to right, top-down. That information, instead of being positive and negative charges like on a tape, has four states, and we just call them A, G, C, and T.⁵ The linear array of A,G,C, and T, in whatever order, conveys the information about a cell, how to make it function, and how to make it do the things you want it to do. Now every time a living thing duplicates itself—reproduces—it has to duplicate its information as well. If you want to build two atomic power plants, you don’t run back and forth with the same blueprints, you photocopy the blueprints, and hand them to the next builder who is going to build another power plant. So, in the same way, if you are going to make another human being, you are going to have to duplicate the information, and that is, in fact, what sexual reproduction does. You are bringing the information into a new conception, in this case a zygote—a new baby.

Duplicating these AGCT’s involves over 3 billion of them, and they have to be read without an error, all three billion in 24 hours — the equivalent of a person trying to read 23 sets of Encyclopedia Britannica and typing out all the letters without an error in 24 hours. Well, you aren’t going to do it right. It is impossible to make a system with that much information completely without errors. So in the process of duplicating the information to make a new cell, or to make new mitochondria, an error can occur by simply mistyping it. This is called a replication⁶ error, and many of the errors that accumulate occur that way. When you make a change to the original information in the sequence on an audiotape, you might get a high note instead of a low note, and that is what we would call a mutation. If the mutation is particularly problematic for the cell, then it can cause that cell to be sick, leading to disease.

If a mutation occurs in the mitochondria, is that different in any way?

Wallace: The mitochondrial DNA’s blueprints encode the wiring diagram for the electrical power of the house, and so if you disrupt the wiring diagram, then you don’t have the power. Then, you have the equivalent of a brownout inside the cell, which is what we call a mitochondrial genetic disease. All mitochondrial genetic diseases are energy-deficiency diseases, and they are commonly associated with things such as people feeling like they don’t have much energy; they have chronic pain; they have problems with seeing and their vision; they have problems with their heart; they have problems with their kidneys. All the kinds of tissues that need a lot of energy do not function well because the energy is not there.

Are those typical mitochondrial diseases that you just described?

Wallace: All the known genetic diseases, due to changes in the mitochondrial DNA, give the same kinds of symptoms that you see in aging and the elderly—you just see them earlier. Parkinson’s, for example, is a movement disorder. There are mitochondrial DNA mutations that can cause this in your 60’s, in your 40’s, in your 20’s, and even very severe ones when you are three; but they kill exactly the same cells and result in exactly the same effects.

Can you manipulate mitochondrial DNA, as you can nuclear DNA, to slow the aging process or age related disease?

Wallace: Right now, we cannot manipulate mtDNA in the same ways that people can manipulate the nuclear DNA; it is in a very different part of the cell, in a very different environment. So the same tools can’t be used, but the hope for aging and age related diseases by manipulating the mtDNA is, I believe, greater because now we have a better idea of why mtDNA becomes damaged and loses the content information in the blueprints. We think this is the result of the oxygen radicals. The oxygen radicals attack the mtDNA and damage the blueprints, so the approach we have been taking in our lab is to develop drugs that go into the mitochondria and take out the oxygen radicals. In that way then, the oxygen radicals won’t damage the mitochondrial DNA and won’t damage the structure of the mitochondria; then the mitochondria and its DNA will last longer. I think that there is a tremendous opportunity here.

We have produced a mouse in which we genetically put additional antioxidant defenses in its mitochondria, and the mice live longer and retain their mitochondria. We have also developed drugs that we can feed to animals, which allow them to live longer and protect their mitochondrial DNA. I think this is much more likely to be a productive approach, rather than some kind of genetic engineering.

Has this been tested with primates?

Wallace: Studies have been done with primates that used a caloric restriction approach but I think these studies are also related to the mitochondria. In our studies, laboratory animals were placed in confined environments and we give them all they want to eat. What resulted was kind of like a human being living in New York City, eating huge amounts of calories but not doing exercise to burn those calories. Getting back to the analogy of your stove or furnace, we are making a lot of smoke—the oxygen radicals. With that, we are increasing the damage rate to our mitochondria and our mitochondrial DNA.

An experiment with lab animals demonstrates this. We put a lab animal in a cage so she couldn’t get any exercise at all, and we gave her all of the food pellets she wanted to eat. Her natural instinct is to eat because she wants to store up food for when starvation might come—which will never happen. She keeps eating, eating, and eating. Eventually she had an excess of these calories, which would overload the furnace and make a lot of smoke. When you put another animal in the same restricting cage but only give it half as many calories, then your experiment is somewhat like the primate study. This second experiment is similar to when our ancestors lived in the forest and gathered and hunted because they were always limited for calories; that is why we want them so much. Our brain is wired to say we might not find calories tomorrow so we continue to overload our system with calories. The dietary restricted animal—rat, mouse, rabbit, cat all of them—do better at restricting calories not because they are being starved but because it is their natural state in the environment. The species that is out of whack is us.

You explained that a diet of fewer calories is good for healthy mitochondria. Yet your research focuses on medication that attacks free radicals, which come from overeating. Is that because you know we are always going to overeat?

Wallace: Human beings are evolutionary programmed to seek out sugar and fat and eat it because everything in biology is limited by energy except Homo sapiens. You need energy not only to maintain your body but also to reproduce, and the prime directive in all biology is that you have another generation; if you don’t have another generation, that lineage of species is dead. So, we are hard-wired to seek calories in our diet because that is what our ancestors needed to survive. When we invented agriculture, we produced so many calories we made ourselves sick eating them. We have a very high reproductive rate, and that is a positive outcome of having excess calories; but the end result is that we will live less well and be less healthy. And since nobody is going to stop eating because we are programmed to eat, then we have to get a drug that will at least offset the negative consequences of having too many calories.

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