Your mitochondria are a source of a whole lot of biochemical trouble as the years go by. Damaged mitochondria proliferate in some cells and, like damaged factories, pollute those cell with excess reactive oxygen species and free radicals produced as metabolic byproducts. Each damaged cell then tries to maintain itself by exporting more reactive oxygen species and free radicals from its cell membrane structures, spreading the damaging pollution far and wide in the body. See the Fight Aging! archives for a more detailed explanation:

Free radicals, and reactive oxygen species (ROS) in particular, play an important part in aging. These are (usually small) molecules lacking an electron needed for stability; they will steal an electron from the first thing they bump into. Like pulling a cog out from clockwork, stealing an electron from a protein or enzyme is usually not good for the finely-tuned biochemical machinery of our cells. The free radical might be rendered safe in the process, but it has left some form of chaos and damage in its wake.

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So you have the Rube Goldberg system outlined above whereby a few free radicals have caused a cell to become an ongoing, major exporter of free radicals into the surrounding environment.

Free radicals mean damage to molecules and cells, vital processes sabotaged one chemical reaction at a time. Over the years this adds it - it is a part of aging. Repairing or replacing damaged mitochondria is one way to strike at the root of this process, and a number of groups are working on that:

Today our team confirmed our previous preliminary data showing that we can achieve robust mitochondrial transfection ... This achievement has important implications for medicine: protofection technology works in vivo, and should be capable of replacing damaged mitochondrial genomes.

The SENS research program identifies a different and even more fundamental way forward: create a backup in the cell nucleus for specific mitochondrial processes that cause all these problems when damaged.

Mitochondria make energy from food available for cellular processes. To do this they need a small amount of their own DNA. For over 30 years mutations in mitochondrial DNA [mtDNA] have been suspected to be important contributors to aging. If we can incorporate working copies of that mtDNA into our nuclear DNA, the mtDNA will be rendered superfluous and any mutations it suffers will be inconsequential.

Another approach that's out there in the field is to target antioxidant chemicals to the mitochondria, where they can be effective in soaking up some fraction of the excess free radicals before they wreak havoc. Antioxidants in general don't seem to be terribly effective when simply thrown at our biochemistry. While making a difference, targeted antioxidants are clearly only a delaying tactic - as opposed to repair strategies that can be performed indefinitely:

Instead of gene therapy, Skulachev's group has found a viable biochemical strategy for effectively localizing ingested antioxidants in the mitochondria; clever. ... The life time of such mice increased by one third on average as compared to that of the reference group mice.

The concept of targeting chemicals to specific types of cell or specific cellular components is gaining ground in the broader biology and biotechnology research community. A great deal of money is flowing into this field of research. Here's a recent paper illustrating that many more people than just the SENS researchers are very interested in targeting mitochondria, and are actively engaged in engineering new methodologies:

Our approach is based on conjugating nitroxides to segments of natural products with relatively high affinity for mitochondrial membranes. For example, a modified gramicidin S segment was successfully used for this purpose and proven to be effective in preventing superoxide production in cells and [lipid] oxidation in mitochondria.

This is what medicine looks like at the base layer these days - a lot of organic chemistry, building molecules that tweak other molecular machinery in a particular way. Manipulating mitochondria to reduce their contribution to aging and age-related disease is a growth field; you'll be seeing a lot more of it in the years ahead.

Posted by Reason at January 16, 2008 9:22 PM | TrackBack (0)