Scientists at the Karolinska Institute have found that changes in the "powerhouse" of cells, the mitochondria, play a key role in aging. The findings are being published in this week's issue of the journal Nature.
Mitochondria, which provide energy to cells, have their own set of DNA. Mutations of mitochondrial DNA increase with age, but until now no one knew whether this is a result of aging or a cause of aging. New research findings now indicate that the latter is the case.
Mice with a deficient capacity to correct mutations in mitochondrial DNA acquired an increased number of mutations and proved to age considerably earlier than normal. They lived an average of 10 to 12 months compared with the normal 2 or 3 years. These mice also developed several typical signs of premature aging, such as osteoporosis, weight loss, hair loss, anemia, reduced fertility, and heart muscle disorders.
The findings reveal fundamental biological mechanisms that lie behind the aging process. This knowledge paves the way for the possibility of slowing down aging and treating pathological changes that arise in connection with aging by protecting mitochondrial DNA from damage.
Mitochondria are organelles that exist inside all eukaryotic cells (most complex life forms including humans have eukaryotic cells) and function to break down sugars to produce energy. Mitochonida have their own DNA for a small subset of their proteins. The Swedish team introduced a mutation to break a repair mechanism for the DNA in mitochondria in order to study how important accumulation of damage to mitochondrial DNA is to the overall rate of aging. The results suggest that damage accumulation to mitochondrial DNA is as important as some scientists have argued for years.
Starting at young adulthood (24 weeks), the mice began to show symptoms of premature aging, including weight loss, hair loss, curvature of the spine, osteoporosis, and enlargement of the heart. They lived an average of 48 weeks, and all had died by the age of 61 weeks. Normal lab mice can live up to two years. Designing the experiment and carrying it out took a painstaking four years, Larsson said. ''I now know why no one had done it [before]," he said.
Why does the accumulation of mitochondrial DNA damage accelerate aging? One obvious possibility is that the DNA damage knocks out genes needed for energy production and hence cells begin to malfunction due to a lack of energy. But another quite plausible possibility is that the mutations knock out steps in sugar metabolism in a way that leads to the generation of lots of free radicals. In this model (suggested by Aubrey de Grey - more about him below) the cells that have defective mitochondria become toxic free radical generators for all the cells around them. In essence, a fairly small number of cells become mini-toxic waste sites. Someone call in the Environmental Protection Agency. This sort of thing should be forbidden by tough pollution law enforcement.
University of Cambridge biogerontologist Aubrey de Grey argues that the presence of 13 of the mitochondrial genes actually in the mitochondria makes those genes something akin to an Achilles Heel for human aging. These 13 genes are vulnerable to free radical damage from free radicals generated as a side effect of the main purpose which mitochondria serve breaking down sugars for energy. Aubrey argues that development of gene therapy to move mitochondrial genes into the nucleus could remove a major cause of aging my protecting those genes from the free radicals generated by breaking down sugars for energy.
The mitochondrion is therefore a really essential part of the cell. Lots of other parts of the cell are essential too, though, so why have a whole SENS page on it? The answer in: unlike any other part of the cell, mitochondria have their own DNA. This means that they can stop working as a result of mutations. Because the DNA is in a different place than the rest of the cell's DNA (which is in the nucleus), we need a different system to combat the inevitable accumulation of such mutations.
As usual, we're lucky - evolution has done the hardest part of this for us already. Mitochondria are very complex -- there are about 1000 different proteins in them, each encoded by a different gene. But nearly all of those genes are not in the mitochondrion's DNA at all! -- they are in the nucleus. The proteins are constructed in the cell, outside the mitochondrion, just like all non-mitochondrial proteins. Then, a complicated apparatus called the TIM/TOM complex (no kidding...) hauls the proteins into the mitochondron, through the membranes that make its surface. Only 13 of the mitochondrion's component proteins are encoded by its own DNA.
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.
Aubrey has repeatedly argued for funding of experimental work to move genes into the nucleus of a mouse cell to then be used to clone and raise mice that have all their mitochondrial genes in their nuclei. The effect might be the opposite of the experiment reported above. Rather than shortening life the mice might live much longer. Such a result would lend further support for the argument that mitochondrial DNA gene therapy should be developed as a rejuvenation technique.
Is the movement of mitochondrial genes into the nucleus doable? In a debate from November 2003 with Richard Sprott of the Ellison Medical Foundation Aubrey pointed out that in a yeast strain a single mitochondrial gene was moved into the nucleus 15 years ago.
The third thing we have to fix is what are called mitochondrial mutations. Mitochondria are special machines in the cell that have their own DNA. They only encode thirteen proteins of their own. All the other proteins that make up the very complicated mitochondria come from the nucleus. So the way to obviate, rather than eliminate, mitochondrial mutations with respect to aging is to make copies of these genes and put them in the nucleus, suitably modified so that they still work.
That sounds pretty damned ambitious, just said boldly like that. Right up until you hear that it was actually done successfully fifteen years ago—only for one of those thirteen genes, and only in yeast, but it was done and there has been more progress in mammalian cells with two more of those proteins in the past couple of years. So we are moving fast here.
This latest report provides support for the camp that argues for the development of gene therapies to repair mitochondrial DNA damage as a method to roll back aging and rejuvenate the body. See Aubrey's publications page and the section Obviation of mitochondrial mutations for more on the subject of what to about mitochondrial DNA damage accumulation as a cause of aging.
|Share |||Randall Parker, 2004 May 27 04:53 PM Aging Studies|