7 replies to this topic

[Nate-2004]

Can Scientists Distinguished Damaged DNA and more importantly, mtDNA from Healthy?

 

If they can distinguish this easily, then can't they simply find drug targets specifically for eliminating damaged mitochondrial DNA? That way you just get a turnover of fresh healthy mitochondria.

 

This is not to go into Turnbuckle's idea of manipulating dynamics in order to achieve this but rather use a direct drug based, CRISPR based or nano robot means.

[QuestforLife]

There is the possibility that pieces of fragmented mtDNA contribute to inflammation in the body. But I'm not sure mutated mtDNA is important in human aging. Bacteria have got by for billions of years without aging, and even within eukaryotic cells can clearly share DNA when they need to. I expect that mitochondria become dysfunctional with age in humans because of the failure of other problems originating in the nucleus.

[Nate-2004]

No, mitochondrial DNA damage is one of the established causes of aging, here is a deeper explanation of what I'm talking about:

 

https://www.fightagi...-to-damage-you/

 

 

[QuestforLife]

No, mitochondrial DNA damage is one of the established causes of aging, here is a deeper explanation of what I'm talking about:

 

https://www.fightagi...-to-damage-you/

 

No it has not been established in any scientific papers that mitochondrial mutations are a cause of aging.

 

SENS postulate that allotropic expression of mitochondrial DNA may be beneficial by removing mtDNA away from the electron transport chain, where it can be damaged, but many others disagree. At this point in time it looks like evolution has come up with other mechanisms to deal with this damage, such as mitophagy - and this is supported by the fact that your need a stupid amount of mutations (50-80% of all mtDNA) in a cell to be mutated before you even notice anything wrong with the cell. That is not to say that alloptopic expression will not be helpful in aging, it might be - and it certainly will be for those with inherited mtDNA mutations, but it has certainly not been established as a cause of aging (no matter what Fight Aging claims).

[Nate-2004]

 

No, mitochondrial DNA damage is one of the established causes of aging, here is a deeper explanation of what I'm talking about:

 

https://www.fightagi...-to-damage-you/

 

No it has not been established in any scientific papers that mitochondrial mutations are a cause of aging.

 

SENS postulate that allotropic expression of mitochondrial DNA may be beneficial by removing mtDNA away from the electron transport chain, where it can be damaged, but many others disagree. At this point in time it looks like evolution has come up with other mechanisms to deal with this damage, such as mitophagy - and this is supported by the fact that your need a stupid amount of mutations (50-80% of all mtDNA) in a cell to be mutated before you even notice anything wrong with the cell. That is not to say that alloptopic expression will not be helpful in aging, it might be - and it certainly will be for those with inherited mtDNA mutations, but it has certainly not been established as a cause of aging (no matter what Fight Aging claims).

 

To quote:

 

 

• The signal to break down a mitochondrion is triggered by sufficient damage to its membrane: a sign that it's old, leaky, inefficient and needs to be replaced with a shiny new power plant.

   

• BUT: if a mitochondrion has had its DNA damaged to the point of stopping OXPHOS, it will no longer be producing free radicals that can damage its membrane. So it will never get broken down by a lysosome. When the time comes to divide and replicate, it will replicate its damaged DNA into new mitochondria. None of those new mitochondria will be producing free radicals via OXPHOS, and so will not be recycled either.

 

also:

 

ROS just can't travel far enough to explain how a corrupt 1% of our cells can cause a large fraction of the difference between being young and being old.

 

A more likely target for all the newly created ROS is cholesterol. Cholesterols, such as low-density lipoproteins (LDL) are used everywhere in the body and travel widely. If ROS reacts with nearby LDL - and there will always be nearby LDL - to form damaged, oxidized cholesterol, that damaged cholesterol can then be incorporated into and further damage biochemical processes throughout the body. For example, its effects on our arteries is well known:

Edited by Nate-2004, 15 February 2018 - 03:47 PM.

[QuestforLife]

So like I said, this was SENS' take back in the 2000s, but anyone who's been keeping up with mito research knows things have moved on since then. For example Aubrey's hypothesis that faulty mitos can evade mitophagy by not making any ATP is not plausible to my mind because this would show up as a low intermembrane potential and therefore WOULD be tagged for disposal (unless such mitos were fused with working ones, but that is dealt with by other means).

The wider question of 'would allotopic expression of mito genes be a good thing?' has yet to be answered conclusively either way. You would certainly improve the durability of the DNA being in the nucleus but would lose all the fine tuned response to changes in energy levels that mito to nucleus signalling currently gives you. I would put allotopic expression in the same pot as other futuristic gene editing techniques - we'll end up totally changing the human genome eventually, no doubt, but it's not going to part of the first genuine rejuvenation treatments.

[Nate-2004]

I'm *implicitly* ill informed if I'm asking a question as I did in my original post, there's no need to point that out  . People who are informed don't ask questions about that which they are informed about.

 

Given that the theory has been refined somewhat since 2007, would manipulating the dynamics of fission and fusion (as with Turnbuckle's suggestion) or finding ways to induce quality control resolve the issue of mitochondrial dysfunction that they think is associated with many age related problems? 

 

 

[QuestforLife]

Just so you know Nate, i didn't mark your post as ill informed.

My personal take is that Turnbuckles idea of increased fission and mitophagy is a very good stopgap until we figure out what the underlying reason is for mitochondrial dysfunction with age. I expect the answer is something along the lines of failure of tissue renewal - rising systemic inflammation (i.e. CD38) - metabolic and mitochondrial dysfunction.

Many of today's aging interventions: calorie restriction, exercise, rapamycin for MTOR inhibition, AMPK activation, are all intervening relatively late in the cascade of failure. That's my opinion, not fact. But I do think we're getting closer to understanding it all and putting the pieces together.