One of the oldest and best-established theories of aging holds that we age because of oxidative damage. In the classic version, the body exploits high-energy chemistry based on oxidation for an energy supply at the cellular level, but this involves constant exposure to these high-energy species and the free radicals that are their by-products, species which can attack sensitive biomolecules. Damage to these molecules accumulates over a lifetime, so the story goes, and makes the body gradually less able to maintain its balance. I’ve argued against the general idea that aging is an accumulation of damage, because of evidence that it is an active process, closely regulated like everything else about life. But new to me this week is a version of the theory by Spanish physiologist Gustavo Barja, in which some of the same chemistry is described as an active program of self-destruction. Barja argues that the process of burning fuel to produce energy can be extremely clean or it can be rather dirty. It is the “leakage” of free radicals during the process that causes the damage of aging, and this leakage can be quite fast, or it can be almost nil. Leakage is tightly-regulated in a way that determines life span. This is a unique lens through which to view aging. What does it help us to understand?
An old and (I believe) discredited view of aging is that the body ages the same way a tool rusts or a car wears out over time – because damage accumulates with wear and exposure to corrosion. The best-established version of this theory is based on damage in the cellular energy factories, the mitochondria, and it is called the Mitochondrial Free Radical Theory of Aging, MFRTA. I visited last week with a man who has devoted his career to studying the chemistry of mitochondria, and he has come to believe that indeed mitochondrial chemistry has a lot to do with aging, but this is not just damage that accumulates as a side-effect of the energetic chemistry. He thinks that this damage is purposeful and programmed, and has written an updated version of MFRTA.
Everything that you have heard about free radicals, ROS (reactive oxygen species) and anti-oxidants derives from the MFRTA. Mitochondria are tiny energy factories. Hundreds of them in each cell of our body burn sugar and convert the energy to an electrochemical form, analogous to charging a battery. This is the Krebs cycle. The electrochemical energy (in the form ATP) is then used for nerve signals and muscle movements and manufacturing biochemicals – everything for which the body requires energy.
In the original version of MFRTA theory, there are unavoidable by-products of the highly-energetic chemical reactions that power our bodies. These are free radicals or ROS, and they corrode the body’s delicate chemistry. There are quencher chemicals – antioxidants that help mop up the toxic waste. These include SOD, ubiquinone (coQ10), and glutathione, catalase, and vitamin C. But they are not 100% efficient at preventing damage. It is the buildup of damaged biochemicals that is the root cause of aging.
One of the attractive things about the MFRTA is its connection to evolutionary history. Once upon a time, more than a billion years ago, mitochondria were infectious bacteria. They invaded the primitive cells at the time, lived as parasites, and killed the cell with their powerful oxidative toxins. Over a long period of time, the parasites evolved to be friendlier to the host, and the host evolved to exploit the energy products of the parasite. Every eukaryotic cell, including all multi-cellular life today, is descended from this ancient symbiosis. Modern mitochondria are performing in the service of the host cell, and have no will of their own. But they retain the capacity to kill the cell, and in fact can serve as executioners when they are signaled to do so. This is apoptosis, or programmed cell death.
Problems with the MFRTA theory include:
- Anti-oxidants don’t seem to extend life span when fed to animals or humans.
- Exercise dramatically increases mitochondrial activity, but it actually helps you live longer. (Exercise promotes longevity in animals, too.)
- In one dramatic experiment, worms that are missing both copies of the gene for the anti-oxidant ubiquinone lived ten times longer than “wild-type” worms in which this gene remains intact.
- Long-lived animals generally have less anti-oxidant defense than similar-sized short-lived animals.
- Damage to mitochondria hardly seems lasting, since hundreds of mitochondria are constantly recycling themselves, cloning themselves and even exchanging DNA with one another within the lifetime of a single cell.
- MFRTA seems to address the “how” but not the “why” of aging. If ROS damage can be avoided by some animals that live a long time, why have other (short-lived) animals not learned this same trick?
Barja update on MFRTA
Gustavo Barja addresses some of these objections in his up-dated version of the MFRTA. In Barja’s version, the leakage of free radicals is not unavoidable; rather toxic by-products are borrowed (co-opted) for a purposeful self-destruction. Thus he turns the weakness of MFRTA into a strength, noting that the rate of leakage is dramatically variable from one animal species to another, and in different tissues at different times. This must be purposeful, and the purpose (aging→ death) is modulated according to environmental cues.
During exercise, there is much more mitochondrial energy generation (of course) but the rate of free radical leakage is dramatically lower. There is actually less ROS damage, even with a far greater energy throughput. This low leakage rate persists when exercise is finished, and is responsible for some of the health and longevity benefits of exercise.
(I’ve mentioned in this column evidence that free radical generation from exercise serves as a signal to bring protective chemistry into play that slows aging. I haven’t yet figured out how to make this jive with new information that I learned from Barja, that ROS production is down during exercise.)
There is less free radical damage in a long-lived bat (40 years) than in a short-lived mouse (3 years), and it is because the rate of ROS production is lower in the bat. The bat actually has less free radical defense chemistry than the mouse, because less is needed, and this despite the bat burns so much more energy in flying than the mouse needs on the ground. This is a consistent pattern among long-lived species.
Long-lived animals also protect themselves by using biochemicals that are less vulnerable to ROS attack. In particular, double bonds are hot spots for chemical change. You’ve heard of saturated and unsaturated and polyunsaturated fats. “Saturated” means no double bonds, and “polyunsaturated” means many double bonds. Fat molecules (“lipids”) are essential parts of body chemistry, used to form membranes that separate one cell from another and one part of a cell from other parts. The punch line: long-lived animals have fewer double bonds in their unsaturated lipids, so they are less vulnerable to ROS corrosion.
A new and unexpected observation
Part of the problem with the MFRTA theory is that the damage is centered on the mitochondria, which are dynamic, “disposable” orangelles within the cell. Barja wondered how might it come about that mitochondria inflict permanent damage on the cell? Three years ago he found a clue. Mitochondria retain a bit of their own DNA, a relic from their historic origins as independent bacteria. Mitochondrial DNA (abbreviated mtDNA) is exposed to the ROS products of oxidative chemistry at close range, and is easily damaged. Sometimes the mtDNA is broken by the ROS.
What Barja found (in collaboration with labs of Juan Sastre and Maria Jesus Pertas) is that mtDNA fragments are released into the cell and even into the bloodstream. Some of these fragments find their way into the cell nucleus, and they can insert themselves into the nuclear DNA, where they might do great damage. There are many redundant copies of mtDNA, but only two copies of the nuclear DNA. Barja was able to detect sequences associated with mtDNA in samples of the nuclear DNA taken from tissues of young and old rats. There was consistently more mtDNA in the old rats than the young, and up to four times as much in some samples. This suggests that ROS damage occurring at the site of the mitochondria can transfer itself to the cell nucleus, and there it can persist and accumulate with age.
So here is a new twist on an old theory of aging. Could this out-of-place mtDNA be disrupting the normal activity of the nuclear DNA in regulating the cell? Could this be a means by which the mitochondria continue their ancient role as assassins?
Barja has shown that there is an association between mtDNA fragment and age. I have proposed to Barja that the next step is to see whether there is also an association with mortality. When two rats of the same age have different amounts of mtDNA out of place in the cell nucleus, is the one with the greater mtDNA likely to die sooner? Answering this question is a straightforward extension of Barja’s research, but such a study takes time; if all goes well, we’ll know in a few years.