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Mitochondria and Aging

Douglas C. Wallace

interviewhighlights

Aging has lately been linked to mitochondrial DNA (mtDNA) damage.

  • Mitochondrial DNA provides energy to the cells; when damaged, they do not provide the energy they need to help you function properly and you get sick.
  • Damaged mitochondrial DNA in genetic diseases is similar to damaged mitochondrial DNA seen in older humans, only the damage presents itself much sooner.
  • Humans are programmed to overeat—to “store up for winter,” but by overeating, mtDNA produces oxygen radicals that damage our bodies.

March 2008

Is aging directly related to DNA damage?

Aging is definitely related to DNA damage, but DNA is not the only issue.

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?

Mitochondria are the power plants of the cells.

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.

The food we eat is used to generate that energy.

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?

mtDNA also produce oxygen radicals.

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.

Fighting oxygen radicals is a constant battle.

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?

DNA gives information about a cell.

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.

Mutations can occur when duplicating the information.

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?

Mitochondrial genetic diseases zap your energy.

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?

Mitochondrial diseases show the same symptoms as aging.

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?

Manipulating mtDNA shows promise.

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.

Lab animal tests have been successful.

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?

The study with primates is called caloric restriction.

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.

Animals with restricted calories are healthier.

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?

Humans are hard-wired to seek calories in our diet.

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.

Dr. Douglas Wallace is the Director of the Center for Molecular & Mitochondrial Medicine and Genetics, University of California at Irvine. He is one of the nation’s leading genetics researchers, helping to discover how defects in inherited genes contribute to neurodegenerative diseases such as Parkinson’s and Alzheimer’s. Through his research, Wallace has shown that defects in mitochondrial genes are major contributors to degenerative diseases, cancer and aging. A recent study of his, published in the Proceedings of the National Academy of Sciences, shows a link between mtDNA mutations and prostate cancer. He’s using that link now to test non-toxic drugs to kill prostate cancer in mice. Dr. Wallace was interviewed at the 2007 annual meeting of the American Institute of Biological Sciences. http://www.ucihs.uci.edu/pediatrics/faculty/genetics/wallace/wallace.html

Mitochondria and Aging

More from Dr. Wallace:

Mitochondrial DNA and aging

Mitochondrial DNA and Eye Problems

A new study finds that the mitochondrial (mt)DNA in the retinas of patients with age-related macular degeneration (AMD) contained more single-nucleotide polymorphisms (SNPs) within the control region of the geneome compared to normal retinas. Read more:
http://www.myvisiontest.com/newsarchive.php?id=876

Mitochondrial DNA Clarifies Human Evolution

An ActionBioscience.org article examines the origins and migration of modern humans.
http://www.actionbioscience.org/evolution/ingman.html

Laboratory specializes in human mtDNA testing

The Paleo DNA Laboratory of Lakehead University in Thunder Bay, Ontario is a leading laboratory for mitochondrial DNA testing. They also have interesting news and links.
< http://www.ancientdna.com/ >

For Scientists and Students—MITOMAP

This website is a database of human mitochondrial genomes, describing different sequences, polymorphisms, and more. There are links to other databases, as well: http://www.mitomap.org/

read a book

For more in depth knowledge about mitochondrial DNA and aging, read Dr. Wallace’s e-Book, Mitochondrial DNA in Aging and Disease, available on the Internet.

The Children’s Mitochondrial Disease Network (UK)

A non-profit help group. The site contains information and news.
http://www.emdn-mitonet.co.uk/index.htm

United Mitochondrial Disease Foundation

The organization provides support and information to people afflicted with mitochondrial diseases.
http://www.umdf.org/site/c.dnJEKLNqFoG/b.3041929/

nwabrlogosmall.png

Teaching Resources from the Northwest Association for Biomedical Research (NWABR)

The Northwest Association for Biomedical Research (NWABR) strengthens public trust in research through education and dialogue. Its diverse membership spans academic, industry, non-profit research institutes, health care, and voluntary health organizations. Through membership and extensive education programs, it fosters a shared commitment to the ethical conduct of research and ensures the vitality of the life sciences community.

Advanced Bioinformatics: Genetic Research
This curriculum unit explores how bioinformatics is used to perform genetic research. Students examine DNA sequences from different animal species, investigate the relationship between protein structure and function, and explore evolutionary relationships among eukaryotic organisms. Throughout the unit, students are presented with a number of career options in which the tools of bioinformatics are developed or used.
http://www.nwabr.org/curriculum/advanced-bioinformatics-genetic-research
Animals in Research
Through this curriculum, students are introduced to the complex topic of Animal Research using structured discussion, stakeholder activities, case studies, and the ethical frameworks used by those in support of, and in opposition to, this work. One of the goals of the curriculum is for students to support their own position on this issue through well-reasoned, fact-driven justifications in a classroom atmosphere of respectful dialogue.
http://www.nwabr.org/curriculum/animals-research
For the Greater Good
The “For the Greater Good” series is composed of five featured articles. Each article portrays one author’s personal stories of people and animals whose lives have been improved or saved by medical breakthroughs made possible by animal research. The Curriculum Guide includes a 5-lesson unit outlining the use of models in both science and ethics, and provides resources for exploring the use of animals in research.
http://www.nwabr.org/curriculum/greater-good

ActionBioscience.org lesson

The lesson “mtDNA: So What Did You Inherit from Mom?” has been written by a science educator to specifically accompany the ActionBioscience.org article, Mitochondrial DNA Clarifies Human Evolution by Max Ingman.
http://www.actionbioscience.org/evolution/ingman.html

Last Flight of Bomber 31

The objective is to identify which members of a family share the same mitochondrial DNA (mtDNA). http://www.pbs.org/wgbh/nova/teachers/activities/3002_bomber.html

Positively Aging

The curriculum currently consists of 346 activities designed to gradually move students toward a more future-oriented and empathetic mind set toward aging. The curriculum encourages student involvement in cross-generational relationships and family research.
http://teachhealthk-12.uthscsa.edu/

References and Notes

  1. From Wikipedia.org: Deoxyribonucleic acid (DNA) is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms. The main role of DNA molecules is the long-term storage of information. DNA is often compared to a set of blueprints, since it contains the instructions needed to construct other components of cells, such as proteins and RNA molecules. The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in regulating the use of this genetic information. For complete details, see: http://en.wikipedia.org/wiki/DNA (accessed January 27, 2008).
  2. From Wikipedia.org: In cell biology, a mitochondrion (plural mitochondria) is a membrane-enclosed organelle found in most eukaryotic cells. The word mitochondrion comes from the Greek μίτος or mitos, thread + χονδρίον or khondrion, granule. Their origin is unclear, but, according to the endosymbiotic theory, mitochondria are thought to be descended from ancient bacteria. These organelles range from 1–10 micrometers (μm) in size. Mitochondria are sometimes described as “cellular power plants” because they generate most of the cell’s supply of adenosine triphosphate (ATP), used as a source of chemical energy. In addition to supplying cellular energy, mitochondria are involved in a range of other processes, such as signaling, cellular differentiation, cell death, as well as the control of the cell cycle and cell growth. Mitochondria have been implicated in several human diseases and may play a role in the aging process. For complete details, see: http://en.wikipedia.org/wiki/Mitochondria (accessed January 27, 2008).
  3. From the Oxford University Press, via Answers.com, ATP is defined thoroughly at http://www.answers.com/topic/adenosine-triphosphate?cat=health (accessed January 27, 2008).
  4. For extensive information regarding radicals and specifically, oxygen radicals, see the Colorado State University Hypertext website. It is a website generated to keep information more up-to-date than static text books, as well as provide a more interactive experience. See http://www.vivo.colostate.edu/hbooks/pathphys/misc_topics/radicals.html (accessed January 27, 2008).
  5. The DNA double helix is stabilized by hydrogen bonds between the bases attached to the two strands. The four bases found in DNA are adenine (abbreviated A), cytosine (C), guanine (G) and thymine (T). These four bases are attached to the sugar/phosphate to form the complete nucleotide, as shown for adenosine monophosphate. From Wikipedia.org, see: http://en.wikipedia.org/wiki/DNA (accessed January 27, 2008).
  6. DNA is the carrier of genetic information. Before a cell divides, DNA must be precisely copied, or “replicated,” so that each of the two daughter cells can inherit a complete genome, the full set of genes present in the organism. For further details, see the “Genetic Encyclopedia” section of http://www.answers.com/topic/replication?cat=biz-fin (accessed January 28, 2008).

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