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.
The mtRNA hypothesis also suggests some new strategies for delaying the aging process. 1. Find a way to remove mtDNA from an organism’s body. 2. Create a vaccine so the body’s own antibodies would collect newly generated mtDNA fragments.
These would not be easy. (1) Aubrey de Grey has proposed moving the mitochondrial DNA to the nucleus. It sounds so simple when you say it that way, but it must be done in every mitochondrion in every cell of the body, and biochemists are very far from knowing how to do this. Even if they succeeded, we have no idea whether the products of this DNA would find their way back to the mitochondria. (2) It’s possible to create antibodies for any short stretch of DNA, but there are 16,600 base pairs in the mitochondria, and any short segment from anywhere within that could appear as a damaging fragment.
If Barja’s theory about mtDNA migrating to the nucleus proves to be a major cause of aging, then we will have a major challenge. The next step is to test the theory.
(1) is to be tested in human clinical trials of Leber’s, by Dr Marisol Corral-Debrinski, whose work on mtDNA transfer to nuclear DNA was supported by SENS and shared back (and constitutes a major approach to mitoSENS).
According to what Nick Lane says in his book, this is not an option.
Nick Lane has several books (which I have not read), which book are you talking about?
Particularly Power, Sex, Suicide.
Would not mtDNA fragments be ‘seen’ as a waste product and so be dealt with like any other cellular waste? Don’t cells have mechanisms that collect waste products and remove them harmlessly?
In principle, this is what you would expect. But cells don’t read the theory books, and we have to look at what happens in real life.
Have you looked at the role carbon dioxide plays in mortality in relation to free radicals?
People at altitude live noticeably and statistically significantly longer than those at sea level. It seems it is because they retain more CO2 (Bohr-Haldane effect). As you know co2 allows blood cells to bind free radical products for disposal by the liver/kidneys. The CO2 also increases oxygen delivery to cells allowing for greater oxidative metabolism which would increase cellular and systemic repair along with further co2 production.
Moderate exercise, by increasing mitochondrial activity and oxidative metabolism can increase circulating co2 and reduce circulating free fatty acids (Most importantly, those containing free double bonds)
People at altitude also have lower circulating oxygen levels so there is less oxygen for ROS to interact with.
Anecdotally I feel my best (Most energetic and relaxed) when my O2 saturation is at about 92% suggesting high levels of circulating co2.
You mention bats above – Don’t a lot of bats live in caves where CO2 levels are generally a lot higher than outside? Which bats were you referring to? It would be worth looking at where the bats from those studies reside.
Also bats due to their high energy production produce copious amounts of CO2.
Could carbon dioxide production be the link here?
I got these references from here:
What are your thoughts?
Thank you – this is a lot to think about, and I want to do some reading before I respond. I’m at an anti-aging conference in England, and just coincidentally I had lunch today with a man who told me about the importance of CO2 as well.
Excellent! I look forward to your thoughts!
Could we have an agent that turns mtDNA fragments into “recognizable waste”..?
And on: “The punch line: long-lived animals have fewer double bonds in their unsaturated lipids, so they are less vulnerable to ROS corrosion.” Is this not the exact contrary of what we have been told for the last 10/20 years? (so now we dump the virgin olive oil and turn to two days old and used frying oil?) I’m slightly confused.
But we’ve seen this often before. A new “idea is born” and we take years to adapt, only to find THEN that it really is no better (lucky when not worse) than before (caffeine was one of the “victims”)
Hi, Phil –
I don’t yet understand your hypothesis about “recognizable waste”. Tell me more.
You have to distinguish between the lipids that your body uses and the lipids that are healthy to eat. Nevertheless, from other evidence I believe that saturated fats are not bad for you. But re-using frying oil is not healthy – I think there’s universal agreement on that.
Interesting; but I have been looking at the Ketogenic diet which is medium chain fatty acids like coconut that is even better than animal fats. I read that the dna nucleus is protected by a protein fat ring and the mdna is not. Does the fat actually protect the dna from invasion from the mdna? Would more fat be the answer so that not only the nucleus dna would protected but the mdna would be ‘corralled’ with fat also?
Another interesting item touched here is the fact that our ancient historical civilizations originated in what is now know as areas of very low gravity as much as 40% difference. One might see these areas as hot beds of human development which could imply that our cellular mechanism functions best in low gravity.
The body doesn’t just take the lipids in our diet and use them for lipid membranes. Like other food, they are digested, broken down into sugars, and reconstituted for whatever purpose the body needs. I’ve seen no evidence that lipids in the diet have anything to do with the quality of the nuclear membrane.
I don’t believe there are places on earth where gravity is 40% less than right here.
Carl Hauser at Harvard Medical School has been researching Systemic Inflammatory Response Syndrome (SIRS) caused by damaged tissues releasing mitochondrial DNA into the bloodstream. When mitochondria are within cell walls the body’s immune system leaves them alone, but when pieces of mitochondria escape the confines of cell walls it appears that the immune system recognizes the mitochondria’s bacterial DNA as an infection and mounts an inflammatory response. If that reaction is extreme it can lead to organ failure and death. Hauser has published several papers about it since 2010. Here’s an article that summarizes his hypothesis pretty well:
And inflammation has been shown to cause functional decline as we age:
This seems like it could be an important mechanism.
I find it hard to believe that our bodies are purposely committing suicide or that our mitochondria are murdering us. However, I recognize the need for apoptosis to eliminate cancer cells and other badly damaged cells, but that is different from suicide. Nevertheless, it is not necessary to prove one way or the other whether or not the body commits suicide. What we need to concentrate on is how to stop the aging. I believe most aging is a product of free radicals released in the mitochondria. Why don’t antioxidants solve the problem? Well most antioxidants are water soluble, and many are large molecules. Most likely the reason they don’t extend life is because they cannot penetrate the cell membrane of mitochondria, which is basically an alien bacterium. Even CoQ10 has a hard time entering a mitochondrium. ATP cannot even pass through the cell membrane of the mitochondrium, which is why we need to have creatine to penetrate the mitochondrial membrane to shuttle back and forth passing the high-energy phosphate into the cytoplasm to ADP to form ATP. I believe we need an oil soluble antioxidant such as C60 or BHT (butylated hydroxytoluene) which can penetrate the cell membrane of the mitochondrium. I take both of them daily, although there are conflicting reports that BHT causes (or prevents) cancer. I took BHT for about 20 years from the 1970’s to the 1990’s, but then it seemed to disappear from the health food stores. Recently I have started using it again when I found it available on the Internet. I am 73 now; if I live past 100, then I will let you know it is working. 😉
Through all of these studies, reports, and theories; we have to realize that the cell does know how to completely repair itself, otherwise the sex cells would not survive any longer than the soma cells. How old is the linage of the sex cells? These immortal cells have lived through it all for at least a billion years. So we should be able to extend the lifespan of the soma cells for an extra 20% easily. I expect some day aging will be a thing of the past, like smallpox. We will have to have more wars just to keep the population in balance. Of course they are already working on that. 😉
The signal from exercise to activate repair genes does not have to be free radicals. It could be pyruvic acid or just breakdown particles from muscle damage. (No pain, no gain).
A better way of visualizing free radical damage, instead of calling it corrosion (rusting), imagine epoxy glue getting loose in the cell. There cannot be anything good coming from free radicals; they are just chaos.
I don’t know what you mean by “doesn’t have to be” free radicals. Evidence is that it IS free radicals. For example, anti-oxidants can nullify the benefits of exercise. It’s not true that ‘there cannot be anything good coming from free radicals.’ You can extend the life span of worms 60% just by growing them in a medium with free radicals. Read this article by Hekimi.
I need to ask your pardon before I even write my comment. I’m a complete layman but have been following this and similar discussions and blogs for years. Sometimes I cannot NOT say what I think (especially when I have never read it before) so please forgive me if I’m disturbing the ‘silence’ invain..:
Could it not be that Apoptosis is a “quality check” at the end of the production line for new cells and it sorts out what would be substandard, but – as we grow older – the production gets so ‘sloppy’ it cannot meet quality criteria any longer and almost all new cells are dismissed – which is why we perceive Apoptosis as a killer when in reality it is there to maintain us healthy?
Thank you all and have a good day.
Thanks for contributing to the discussion, Phil. I hope you should never feel that your thoughts are unwelcome.
Most scientists in this area agree with you, that apoptosis becomes dysregulated with age, and something goes wrong. The reason I see it as a purposeful suicide mechanism has to do with a big picture which will be described at length in my forthcoming book. You can get a short preview here.