February 18, 2003
Mitochondrial DNA Mutation Common In Centenarians

A mutation in mitochondrial DNA appears to be linked to longer life expectancy.

Mitochondrial DNA is the portion of the cell DNA that is located in mitochondria, the organelles which are the "powerhouses" of the cell. These organelles capture the energy released from the oxidation of metabolites and convert it into ATP, the energy currency of the cell. Mitochondrial DNA passes only from mother to offspring. Every human cell contains hundreds, or, more often, thousands of mtDNA molecules.

It's known that mtDNA has a high mutation rate. Such mutations can be harmful, beneficial, or neutral. In 1999, Attardi and other colleagues found what Attardi described as a "clear trend" in mtDNA mutations in individuals over the age of 65. In fact, in the skin cells the researchers examined, they found that up to 50 percent of the mtDNA molecules had been mutated.

Then, in another study two years ago, Attardi and colleagues found four centenarians who shared a genetic change in the so-called main control region of mtDNA. Because this region controls DNA replication, that observation raised the possibility that some mutations may extend life.

Now, by analyzing mtDNA isolated from a group of Italian centenarians, the researchers have found a common mutation in the same main control region. Looking at mtDNA in white blood cells of a group of 52 Italians between the ages of 99 and 106, they found that 17 percent had a specific mutation called the C150T transition. That frequency compares to only 3.4 percent of 117 people under the age of 99 who shared the same C150T mutation.

To probe whether the mutation is inherited, the team studied skin cells collected from the same individuals between 9 and 19 years apart. In some, both samples showed that the mutation already existed, while in others, it either appeared or became more abundant during the intervening years. These results suggest that some people inherit the mutation from their mother, while others acquire it during their lifetime.

The mitochondria contain DNA that code for a subset of all the proteins that get used in mitochondria. Most of the genes for mitochondria are coded for in the nucleus. Those genes that are part of the miticondrial DNA (mtDNA) are more vulnerable to oxidative damage as cells age because the mitochondria produce a lot of free radicals as a side effect of how they do energy metabolism. The presence of mtDNA within mitochondria is rather like an Achilles Heel for how eukaryotic organisms are designed. Therefore a mutation in the mtDNA that affects longevity is not surprising.

Is news of this mutation useful for devising anti-aging therapies? Possibly. It might point to a method to slow aging by development of pharmaceutical means of enhancing mtDNA replication. However, the most optimal way to deal with the accumulation of damage to mtDNA would be a gene therapy that moved the mtDNA genes into the nucleus. Such a therapy would essentially move the mtDNA genes out of harm's way and therefore the genetic variations that help those genes survive better in mitochondria would become irrelevant.

Techniques to do gene therapy to a large portion of the cells in the body is probably the ability most needed to be able to turn back the biological clock on aged cells. While some cells and organs will some day be replaced via cell therapy and organ replacements there are parts of the body where replacement is really not a good idea. Most notably, the central nervous system defines who we are. Even if brain replacement was possible that would replace who we are with someone else. Gene therapy is most needed for brain rejuvenation so that the cells that constitute our brains can be made youthful again.

The abstract for the PNAS research paper that reports these results is available online.

Share |      Randall Parker, 2003 February 18 02:02 AM  Aging Reversal


Comments
Bob said at February 18, 2003 9:32 AM:

I have to wonder why we have never evolved those mtDNA in our nuclei. Is it possible they might cause some harm in the nucleus?

Randall Parker said at February 18, 2003 12:17 PM:

Mitochondria started out probably hundreds of millions of years ago as a microorganism with its own DNA that was absorbed into another organism and then gradually specialized just to do energy metabolism. Essentially, mitochondria are a prokaryotic symbiote living in a synergistic relationship with the eukaryotic host cell that surrounds it.

Some of the genes that were originally mtDNA encoded have over the many millions of years moved into the nucleus. But not all have made the transition. That's probably just due the fact that the needed chance event never happened.

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