The
Oxygen Irony
Oxygen, the life force found in every breath, also is one of the human body’s
most destructive invaders.
Oxygen. It is the stuff of life—the backbone of water, the critical component in the air we breathe. It is what allows humans to grow, to thrive and to survive.
But oxygen has a dark side. Think rust. Think the white flesh of an apple, exposed to the air. Now think about the same sort of thing happening to the tissues of your body, day in and day out, with every breath you take.
“Oxygen—can’t live with it, can’t live without it,” quips Michael Lieber, M.D., Ph.D., a pathologist at the USC/Norris Comprehensive Cancer Center.
Oxygen is a relatively small element—number eight on the Periodic Table, for those who remember their high school chemistry. It is also highly reactive and electrically charged. Electrically charged atoms strive to become neutral, to have a particular number of electrons in their outer shells. Each atom of oxygen, with six electrons, needs two more to be complete. That is why it will eagerly combine with any electron-donating atom—hydrogen, for instance—whenever it is given the opportunity.
In the human body, of course, it is given that opportunity on a breath-by-breath basis. Each time a cells burns its oxygen fuel to create energy, it also creates freewheeling oxygen atoms known as oxygen free radicals.
Therein lies the problem. Oxygen is not discriminating about what other molecular structures it might destroy in its quest to become electrically whole. If there are electrons to spare in a protein molecule, or in the fats that make up a cells’ membrane, or even in the DNA that is crucial to the functioning of our cells and our bodies, it will grab them and change them. This constant cellular wear-and-tear due to the ravages of oxygen is so pervasive that it has been given a name: oxidative stress. And like its psychologically based cousin, oxidative stress can wear down a body over time.
Indeed, the biological consequences of this sort of electron scavenging can be found at the root of the normal process of aging. But it also has a part in cancer. Heart disease. Parkinson’s disease. Name the condition, and somewhere down the line, oxygen free radicals are likely to play a role.
USC boasts an unusually high number of talented researchers in the field of oxidative stress and its medical repercussions. Here are just a few of their stories.
Crippled chromosome
Human cells are exquisitely vulnerable to DNA damage, says Lieber, the Rita and Edward Polusky Chair in Basic Cancer Research at the Keck School of Medicine of USC. Cells taken out of the organism in which they live and viewed under a microscope will show that 5 to 10 percent of them will have at least one broken chromosome.
Normally, all double-stranded DNA breaks are repaired by a process called NHEJ, for non-homologous DNA end joining. In the NHEJ pathway, explains Lieber, the ends of the broken DNA strands are trimmed and rejoined to one another.
But the NHEJ pathway does not always function at full capacity. A paper published by Lieber, M.D./Ph.D. student Zarir E. Karanjawala and USC/Norris Cancer Center researcher Chih-Lin Hsieh, Ph.D., found that in cells where the NHEJ pathway is disabled or missing, the number of cells with at least one chromosome break goes shooting up to 60 percent.
What causes all of this breakage? In a recent issue of the journal Current Biology, Lieber and Karanjawala point their finger at oxygen.
Originally, says Karanjawala, they had wondered if the damage might be coming from some environmental source, perhaps from background radiation. But when they began to look more closely, he says, they found it was in the air we breathe. “We found that if you vary the oxygen levels in which cells are grown, the breakage levels of the chromosomes vary as well—the higher the oxygen level, the more breakage you’ll see,” says Karanjawala.
“Oxygen rips through our cells like a bullet,” Lieber adds. “And our bodies are being riddled with these bullets every day whether we like it or not.
“Now, the sorts of double-strand DNA breaks we were looking at are hard to repair. Even if you put the two ends together the best you can, you usually lose a couple of nucleotides along the way. And so every time we get an oxidative free radical hit, which happens several times per day per cell, we lose a little info. Every time it hits your DNA, you wind up with a little less genetic information than you had when you started the day.”
The solution? Frankly, says Lieber, there may be none. “We need oxygen to survive, but ultimately, it’s also probably what kills us.”
Energy crisis
Enrique Cadenas, M.D., Ph.D., professor and chair of the Department of Molecular Pharmacology and Toxicology at the USC School of Pharmacy, believes that the stresses of oxygen can also be blamed for depleting cells of their energy sources and thus kick-starting any number of neurodegenerative diseases.
The villain in this case, he says, is nitric oxide (NO). NO acts as a neurotransmitter and chemical messenger in the brain, but is just as reactive as any lone oxygen atom—and, he believes, encourages the production of oxygen free radicals, which lead to a variety of brain disorders.
Specifically, Cadenas is investigating the role that elevated levels of NO might play in the development of Parkinson’s disease, a condition in which the cells that produce the neurotransmitter dopamine are killed off in large numbers. With the help of a $2 million grant from the National Institute of Environmental Health Sciences (NIEHS), Cadenas is investigating the chain of molecular events that destroy the dopamine cells. His hypothesis is that the free radicals spawned by NO do major damage to the dopamine-producing cells’ mitochondria, which are the energy sources in all cells. If the mitochondria fail, the cell simply does not have the ability, the energy, to survive.
“The increase in nitric oxide, the increase in free radicals, the changes in the levels of dopamine—all these things change the mitochondria’s ability to function,” says Cadenas. “That causes an energy deficiency in the cell, which triggers the activity of enzymes that activate cell death.”
Cadenas is seeking the answers to just how all of this fits together. “If you can isolate a mechanism,” he explains, “then you can target drugs to the mechanism in terms of prevention or repair. What is the damage to the mitochondria? What is the specific free radical? If you can intercept this free radical, you can prevent dysfunction.”
In addition to the NIEHS grant money, Cadenas is being helped in this search by a gift from the L.K. Whittier Foundation—a gift of $2.3 million to the USC School of Pharmacy to establish a Research Center for the Prevention of Age-Related Diseases. Cadenas is co-director with Roberta Diaz Brinton, Ph.D., professor of molecular pharmacology and toxicology at the School of Pharmacy. The new center will focus on how free radical damage to the mitochondria can lead to neurodgenerative disease.
The long-range goal of the research being conducted at the center, Brinton says, is to identify critical sites of vulnerability in the brain and to develop therapeutics that will prevent the sort of neurodegeneration characteristic not only of Parkinson’s disease, but of a number of widespread conditions such as Alzheimer’s—as well as the decline in cognition often associated with aging. Finding out about the process and identifying interventions will enable patients to sustain a level of cognitive function that is essential for successful aging, explains Brinton. “Our goal is to discover sites and mechanisms of mitrochondriel damage and then develop strategies to prevent the damage.”
She adds: “The L.K. Whittier grant will enable us to make strides to conquer one of the most significant health challenges of our generation—that of preventing Alzheimer’s and other neurodegenerative diseases.”
Time flies
Antioxidants—found in a variety of forms including vitamins E and C and beta-carotene—are thought to protect the body’s cells from the damaging effects of oxidation by neutralizing oxygen free radicals. And if a study from researchers at USC and the University of California, Irvine, published in the June 2002 Genetics, is right, they might also play a role in retarding the aging process.
To test this theory directly, the researchers created transgenic fruit flies that had an extra copy of either of two antioxidant-producing genes known as superoxide dismutases or SOD. They arranged to control whether the extra gene was on or off, like a light switch. In control fruit flies, the researchers left the extra SOD genes inactive. Unsurprisingly, these flies lived a normal life span.
In the experimental flies, the researchers activated the extra copy, causing the flies’ cells to produce far more antioxidant enzymes than normal. These flies enjoyed a longevity boost of up to 40 percent, says lead researcher John Tower, Ph.D., an associate professor of biological sciences in the USC College of Letters, Arts and Sciences’ molecular and computational biology program. And the magnitude of that boost was exactly proportional to the amount of extra SOD production.
“It demonstrates that antioxidant activity is a rate-limiting factor for fly lifespan,” he says.
The researchers further proved that this lifespan extension was not being bought at the price of a more sluggish or less-active life. Tower’s co-investigators at UC Irvine showed that the long-lived flies used just as much oxygen over the course of their lifetime as their normal-living brethren.
“There was no negative effect on metabolism from the SOD over-expression,” Tower says. “So we’re extending life span without some kind of trade-off or deficit in the creatures’ metabolism.”
Does this mean we should all start taking antioxidant supplements every day along with our vitamins?
“From what my colleagues tell me, dietary antioxidants haven’t proven very effective,” says Tower. “Is it because they aren’t making it into our cells? Is it because the body senses the increase and down-regulates its own endogenous production in response? No one is sure why yet.”
Saved by soy
The devastation wrought by oxygen free radicals is undeniably immense. But also undeniable is the fact that the human body manages to survive this assault—for decades upon decades. Antioxidants, which act as a sort of cellular mop, sopping up as many of the charged oxygen radicals as they can before they ping into something important, are one defense the body employs.
But there are other ways to protect the body from oxidative stress, notes Alex Sevanian, Ph.D., professor of molecular pharmacology and toxicology at the USC School of Pharmacy. Soy, for example. Soy, says Sevanian, can have an antioxidant activity, but its most crucial role in combating oxidative stress is a bit subtler. “Soy compounds change the biochemistry and physiology and behavior of tissues, making them more adapted to handling oxidative stress,” Sevanian explains. “It’s a metabolic response.”
Sevanian has been focusing on the damage that oxidative stress does to the cardiovascular system. “For instance,” he says, “inflammation is considered a form of oxidative stress, and when it occurs in places where it’s not supposed to be for a protracted time, it causes injury. Atherosclerosis [the accumulation of plaque in the blood vessels] has a very strong inflammatory component.”
Soy, he explains, works by helping to suppress inflammation by suppressing the production of the so-called superoxide radical, which is the most prevalent form of oxygen radical found in the circulatory system. It does this, it seems, not only by decreasing the expression of the enzymes that make superoxide, but also by increasing the production of nitric oxide. Nitric oxide (NO) in the brain may be suspected of all sorts of shenanigans, but in the cardiovascular system it is generally a good guy, says Sevanian.
“The end result is that if you can increase the balance in favor of more NO and less superoxide, you favor an antioxidative process,” he says. “The flip side of that is [if you have] more superoxide than nitric oxide you get a pro-oxidative, inflammatory process.”
Keeping the cardiovascular environment antioxidative is what soy does best. But don’t start stocking up on soy extracts quite yet. “There are three kinds of isoflavones in a soybean,” says Sevanian. “Individually, as they’re found in the extracts, they’re not effective.”
As scientists learn more and more about the mechanisms by which oxygen, that ubiquitous gas, does its radical damage in the body, we will all be better able to stave off its ill effects. Still, the ultimate cure-all for oxidative stress is likely many years—if not decades—away. In the meantime, don’t hold your breath.
Matthew Blakeslee contributed to this article.