Refining the Mitochondrial Free Radical Theory of Aging

Random damage to your mitochondrial DNA is a bad, bad thing in the long term - or so present theory has it. It happens all the time in your cells, however, as a natural consequence of the mitochondria doing their intended job of turning food into ATP, the universal fuel source used by your cells. The standard issue process by which food becomes ATP is called oxidative phosphorylation (OXPHOS); it generates damaging free radicals as a side-effect of its operation. Those free radicals won't get far before running into some other molecule and reacting with it, changing or damaging it in the process.

OXPHOS requires several key portions of your mitochondrial DNA to be intact and undamaged - or rather it requires the proteins that are created from those DNA blueprints. Now, if the needed portion of mitochondrial DNA is altered or destroyed by free radicals churned out by the OXPHOS process - well, no more OXPHOS for that mitochondrion. No more free radicals, either, and that's a more serious problem:

  • Sufficient free radical damage to mitochondrial DNA shuts down OXPHOS within that mitochondrion, as the necessary proteins can no longer be produced. The mitochondrion switches over to using a less efficient method of producing power, one that doesn't produce free radicals, but has to run at a much higher rate to produce the same level of ATP.

  • Mitochondria, like most cellular components, are recycled on a regular basis. Components called lysosomes are directed around the cell in response to various signals, engulfing and breaking down damaged or worn components. After the herd has been culled, surviving mitochondria within a cell divide and replicate, much like bacteria, to make up the numbers - this is called clonal expansion.

  • The signal to break down a mitochondrion is triggered by sufficient damage to its membrane: a sign that it's old, leaky, inefficient and needs to be replaced with a shiny new power plant.

  • BUT: if a mitochondrion has had its DNA damaged to the point of stopping OXPHOS, it will no longer be producing free radicals that can damage its membrane. So it will never get broken down by a lysosome. When the time comes to divide and replicate, it will replicate its damaged DNA into new mitochondria. None of those new mitochondria will be producing free radicals via OXPHOS, and so will not be recycled either.

  • One DNA-damaged, non-OXPHOS mitochondrion will eventually take over the entire mitochondrial population of a cell in this way. At that point, the trouble really gets started.

These cells entirely populated with damaged mitochondria start churning out large quantities of free radicals - through another, more forceful mechanism - into the body at large. That's a path to age-related degeneration and fatal conditions like atherosclerosis. The free radical theory of aging is based upon the harm done to tissues, structures and processes by these damaging biochemicals.

So how does this all get started again? Free radical damage to mitochondrial DNA? Possibly. There has been some debate of late as to how plausible this is as a mechanism, based on mutation rates, examinations of mitochondrial function in mice with many damage-induced point mutations in mitochondrial DNA, and so forth. With that in mind, I noted with interest a recent Nature Genetics paper:

What causes mitochondrial DNA deletions in human cells?

Mitochondrial DNA (mtDNA) deletions are a primary cause of mitochondrial disease and are likely to have a central role in the aging of postmitotic tissues. Understanding the mechanism of the formation and subsequent clonal expansion of these mtDNA deletions is an essential first step in trying to prevent their occurrence. We review the previous literature and recent results from our own laboratories, and conclude that mtDNA deletions are most likely to occur during repair of damaged mtDNA rather than during replication. This conclusion has important implications for prevention of mtDNA disease and, potentially, for our understanding of the aging process.

Deletion mutations are much more damaging than point mutations, and can result in a sequence of many genes being snipped out and lost. Thus a greater likelihood of losing one of the genes vital to OXPHOS. This paper presents an interesting nuance to the source of deletions - serious damage created as a result of errors in the processes that repair minor damage due to OXPHOS free radicals. Irony abounds throughout the mitochondrial free radical theory of aging.

To switch gears a little, I should note that the beauty of the Strategies for Engineered Negligible Senescence (SENS) approach to the mitochondrial free radical theory of aging is that it doesn't require medical engineers to understand why the damage happens. If we can successfully move genes that express the proteins vital to OXPHOS into the cellular nucleus, it then doesn't matter what happens to the mitochondrial DNA, OXPHOS will keep on working.

Similarly for wholesale replacement strategies - we don't need to know how the damage occurred to know that protofecting fresh, undamaged mitochondrial DNA into every cell will fix things for a while. "A while" being at least 30 years, given how long it takes the problem to become damaging to health.

Research is good - there is no such thing as useless knowledge, and every additional level of detail helps those building new therapies. But never feel as though there isn't enough to go on with already when it comes to engineering the repair of aging. Researchers know more than enough to be underway, and it's a tragedy that the field of aging repair - real rejuvenation medicine - is far less funded than present understanding merits.

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