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Mitochondrial genome refurbishment

Live long enough to see your half-baked ideas realized..
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Aging is complex and poorly understood, but at least one component of it is probably the degeneration of mitochondria - the little diesel engines of your cells. Mitochondria have their own DNA, and over the years this becomes damaged (more rapidly than the DNA in the cell's nucleus, because of all the oxidative reactions that happen in mitochondria) and the mitochondria become moribund. Your cells lose their pazzazz.

Now, mitochondria are basically symbiotic bacteria. And bacteria can be infected by their own type of virus, called 'phage. 'Phage work by injecting their DNA into the bacterium. Ergo, it should be possible to design a modified 'phage that would put new DNA into your old mitochondria - a sort of mitochondrial genome upgrade.

So, regain the energy of your youth! (Parallel research programme: beat Alzheimer's, so you can remember what to do with all that youthful energy).

Basepair, Mar 11 2005

Mitochondria and aging http://www.healthan...ntent/topics4_3.htm
Overview of potential role of mt's in aging. [Basepair, Mar 11 2005]

[link]






       Mitochondrial gnome refurbishment......   

       <annoyingsnigger> Sne sne sne</annoyingsnigger>
DesertFox, Mar 11 2005
  

       Oooh you YOU, you!
Basepair, Mar 11 2005
  

       I like the idea that bacteriophages might recognize mitochondria, and that they could thus be genetically engineered. + for that alone. The idea that cells age because of mitochondrial wear is also interesting, and plausible. Do you have a link?
bungston, Mar 11 2005
  

       This is a bad idea, because....   

       1) There's no way of getting a phage into the mitochondria. You'd have to get it into the (Eukaryotic) host cell first and phages don't do that. Even if they did work on Eukaryotic cells, the viral DNA would have to penetrate the walls of the Mitochondria after penetrating the host's, and since it loses the protein coat as it enters the cell....   

       2) Mitochondria can't be all that important to the aging process because they don't get "younger" when we reproduce. Unlike cells, which undergo mitosis and recombination as part of the reproductive act, mitochondria just get handed down from the mother to the child. (If you're a guy, your mtDNA is screwed, evolutionarily speaking.) Fetal DNA is as "old" as the mother's DNA as far as its genes go. Hell, that means ALL mtDNA is REALLY, REALLY old.
Madcat, Mar 11 2005
  

       There's no such thing as a bad idea.
JesusHChrist, Mar 11 2005
  

       Madcat - I'd thought of the problem of getting a virus that'll get into both eukaryotic and prokaryotic-like cells. What we need is a Trojan Horse virus. basically, you make a phage genome but you package it in vitro with eukaryotic viral coat proteins. This infects the eukaryotic cell. The phage genome encodes the packaging proteins necessary to re-package it as an active phage to enter the mitochondria. With a nifty bit of coding, you could (hopefully) ensure that the phage-coat-encoding genes were inactive in the mitochondrion (by suitable choice of promotors perhaps). The phage would also encode, of course, a fully active mitochondrion.   

       As for the relevance of Mt's to aging, there is a lot of evidence to suggest that they are at least one of the factors. I honestly don't know why maternally- inherited mt's don't degrade over the generations, but presumably they are reproductively priviledged in the same way as the oocyte and sperm genomes are (since, by the same token, the genomes of reproductive cells are as old as the species)? . In any case, it is well documented that old mitochondria (I mean, those from an old person) have a higer level of DNA damage than those from a younger person.   

       I'll find a link on the mitochondrial business for you and Bungston...
Basepair, Mar 11 2005
  

       An example link re Mt aging has been added, but run a Google search and you'll find others. If you have access to the journals I can dig out some references (probably from Cell). There's also some work whereby they made transgenic mice with a defective mtDNA-repair enzyme; these mice accumulated mtDNA damage faster than normal mice and also aged faster. Of course, this is not equal to saying that better mitochondrial maintenance extends lifespan, but it is suggestive.
Basepair, Mar 11 2005
  

       /Hell, that means ALL mtDNA is REALLY, REALLY old/. Think about that. Your entire current bodily supply of mitochondria was not packed into the egg that became you. Yes, you got mitos from your ma. But you make new ones as you grow.
bungston, Mar 11 2005
  

       [Bungston] - there are two questions getting confused here, I think. Certainly your mitochondria reproduce along with your cells, so their DNA is not "old" in that sense. But Madcat's point (I think) was that there is a direct descent of mitochondrial DNA through the generations, and therefore it (I mean, its sequence) cannot be degrading (mutating) significantly over time.   

       HOWever - my response to Madcat's point was that there is clearly a mechanism which protects (or screens out bad) mitochondrial DNA in the germ cells. So, the fertilized egg contains well-nigh perfect mitochondria. But the mitochondrial DNA in somatic cells does accumulate mutations and base modifications during the lifetime of an individual, and it's *this* damage which you might try to correct by mt genome replacement.   

       As with all aspects of aging, no-one really knows what the underlying mechanism is (and there are probably many), but accumulated mtDNA damage is one of a few very strong contenders.
Basepair, Mar 11 2005
  

       Just hope it doesn't mutate and kill all your mitrocondria. That would become the new definition of 'bad'.
my-nep, Mar 12 2005
  

       What an interesting thread. I wonder why there are not cancers of the mitochondria? Every other cell in the body can become malignant. Mitochondria must have some mechansims by which they determine that there is a need for them to reproduce. Why doesn't this go haywire sometimes such that the cell winds up packed with mitos?   

       I guess because such a cell would then die, and that is that.   

       I think mitos must have a mechanism for correcting DNA damage. Many such mechanisms exist in cells. I think mitos have their own DNA polymerase. Hmmm - in over my head here.   

       I think the argument that the phage would need to penetrate the cell is a pretty good one. The cell doesn't like stuff like that. Probably part of why the mitos moved in in the first place.
bungston, Mar 12 2005
  

       [Jesus H Christ] When my uncle was a kid he tried to immitate a cartoon- character superhereo who would throw around burning stones. He poured lighter fluid on a rock, held it in his hand, and then lit it. That was definitely a Bad Idea.
ignorantimmigrant, Mar 12 2005
  

       "Just hope it doesn't mutate and kill all your mitrocondria. That would become the new definition of 'bad'" [my-nep]. It certainly would. And it would sort of counteract the longevity benefits.   

       " I wonder why there are not cancers of the mitochondria?" [Bungston] That is a bloody good question! I guess (as you did) that it would be a self-limiting disease, confined to a single "host" - i.e. one cell. But maybe there are some diseases where mitochondrial numbers are not regulated....will have to look.
Basepair, Mar 12 2005
  

       Would it be possible to use increased mitochondria to ramp up the human metabolism? If it were possible, would that then cause a concomitant rise in the onset of aging, due to the increased number of toxins, free radicals and metabolic byproducts resulting from increased food intake?   

       Mitochondria have been linked to intelligence; could they make us a smart race of super-strong, really twitchy insomniacs (due to high metabolism)?   

       This kind of tinkering would need an extraordinary amount of testing before being used on humans.   

       Still, I would love this technology to exist. Faster, please!
justibone, Mar 12 2005
  

       I don't think tinkering with the normal levels or activities of Mts would be a good idea - they'll've evolved to something close to an optimum in a young body. But aging is non-evolved - evolution doesn't really give a toss once you've stopped reproducing. So, there's probably plenty of room to improve on what happens to us once we pass forty or so.   

       I didn't know that Mts had been linked to intelligence, except that their degeneration in brain cells may be one of the factors that adds to its general degeneration with age. But increasing their basal level of activity sounds like a bad thing.
Basepair, Mar 12 2005
  

       "This kind of tinkering would need an extraordinary amount of testing before being used on humans." [justibone] Yep, it certainly would. On the other hand, I think that it's generally more persuasive to test novel disease therapies on people who have the disease in its terminal form. In the case of aging, that's pretty much everyone :-)
Basepair, Mar 12 2005
  
      
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