The mitochondria are a subcellular organelle (a sort of cell within a cell) that break down sugar to generate energy molecules used throughout the cell. Clay F. Semenkovich, MD at the Washington University School of Medicine and colleagues report that failures in mitochondria due to aging are suspected of causing atherosclerosis and heart disease.
The research team genetically engineered mice to have especially leaky mitochondria in their blood vessel cells. It found that although normal mice very rarely acquire atherosclerosis, the mutant mice all developed the disease, even when fed on a low-fat, low-cholesterol diet. The results of the experiment appear this week in Nature.
They speculate that an increased flow of reactive oxygen damages the blood vessel's walls. The body then mounts an immune response to repair this damage, and scientists have already established that cells trying to fix arterial damage can create problems. These immune cells attract a form of cholesterol that sticks to arterial walls, forming plaques.
Mentally I file this under "Totally Unsurprising". Mitochondria have their own DNA for some of their proteins. Some gerontologists (e.g. Aubrey de Grey) theorize that the mitochondrial DNA (mtDNA) acts as a sort of Achilles Heel in cellular metabolism and cellular aging. Very reactive chemical compounds get generated in mitochondria by breaking down sugar and some of those compounds occasionally break loose and fly into the mtDNA causing damage. So mtDNA might accumulate damage at a much faster rate than DNA in the nucleus.
The increased rate of mutational damage to mitochondrial DNA eventually disables some of the genes that a mitochondrion needs to generate energy. Given that many other mitochondria in a cell could step in to make up the shortage of energy from a single damaged mitochondrion one might not expect damage to one or two mitochondria to make much difference. But note how the article talks about reactive oxygen generated by old mitochondria. The same mutations that cause mitochondria to stop breaking down sugar properly also are suspected of causing mitochondria to generate lots of free radicals. Those free radicals cause inflammation that, through some additional steps, cause hardening and clogging of arteries.
So what to do about this? As one of his Strategies for Engineered Negligible Senescence Aubrey de Grey proposes development of gene therapies to move mtDNA genes into the nucleus where they won't get damaged by mitochondrial metabolism.
This gives us a wonderful opportunity: rather than fixing mitochondrial mutations, we can obviate them. We can make copies of those 13 genes, modified in fairly obvious ways so that the TIM/TOM machinery will work on them, and put these copies into the chromosomes in the nucleus. Then, if and when the mitochondrial DNA gets mutated so that one or more of the 13 proteins are no longer being synthesised inside the mitochondria, it won't matter -- the mitochondria will be getting the same proteins from outside. Since genes in our chromosomes are very, very much better protected from mutations than the mitochondrial DNA is, we can rely on the chromosomal copies carrying on working in very nearly all our cells for much longer than a currently normal lifetime.
This project needs a lot of work, though, even though it sounds simple. The 13 proteins of interest are actually quite difficult for the TIM/TOM machinery to process even when we "tell" it to do so, so we still need to work on making that part easier. But there has been good progress in this area in the past couple of years.
This latest report does not prove that mitochondrial aging is a major cause of plaque build-up in arteries. However, it is certainly consistent with this theory.
The development of gene therapy to fix the problem with mtDNA mutation accumulation still lies many years in the future. Semenkovich is looking for ways to change the amounts of omega 3 and omega 6 fatty acids available in cell walls in hopes that the inflammation response can be reduced so that perhaps the development atherosclerosis will be slowed.
"It would be interesting to figure out how to take essential fatty acids, get them into the vessel wall and see if you could treat atherosclerosis that way," said Semenkovich.
More omega 3 fatty acids from fish might help and I hope Semenkovich succeeds in his investigations. But I'd much rather have gene therapies that would rejuvenate artery and vein wall cells or cell therapies that would replace existing cells with younger and healthier cells.
|Share |||Randall Parker, 2005 May 25 10:37 PM Aging Studies|