How do the ROS and/or damaged molecules move between compartments, e.g. nucleus/cytoplasm/extracellular? I have seen very little on this, and consider it a major blindspot. I’m not sure if it’s a blindspot for the field or if I just haven’t found the right cluster of papers.
Man, I wrote up a whole summary of the mitochondria free radical theory of aging for you after reading this paragraph, then read the rest of your post and realized you already know about it. I’m surprised though that you still have questions about this, because the mechanism of export is described in Aubrey de Grey’s book. At least it’s described in his book “Ending Aging”. I haven’t read the other one, so I’m not sure if it contains less information.
A very quick description is that cells overtaken by clonal mutant mitochondria export electons from their cell membranes to keep themselves alive via the Krebs cycle (since the electron transport chain in mitochondria, which normally receives these excess electrons, is shut down).
The receptor molecule for these excess electrons is oxygen. These oxygen molecul\es with extra electrons are very powerful free radicals, and end up reacting with whatever molecule they bump into first. Unfortunately some decent fraction of these reactions are with low-density lipoproteins, which are then transported by the bloodstream to a much larger area of the body, and eventually deposited on blood vessel walls, contributing to atherosclerosis.
I’m glossing over a lot of details here, so if you want to read more about it, check out Chapter 5 of Ending Aging.
This book did come out in 2008, and I imagine quite a few new things have been learned in that time, so I’m not sure if this theory is still accepted. I’d be interested to know if there’s been any follow-up research.
I don’t know whether there’s any evidence that these molecules actually accumulate long-term. (Just because they’re not broken down doesn’t mean they’re not simply excreted.) I haven’t seen direct evidence, but I haven’t searched very carefully either, and I haven’t seen direct evidence against.
If I understand correctly, accumulation of A2E in the lysosomes of microglia in the retina is one of the main causes of macular degeneration. There is also a big section of Ending Aging dedicated to the topic of lipofuscin in general (non-digestible material that accumulates in the lysosomes of long-lived cells)
Final Thoughts
This is an amazing write-up. I am very surprised that De Grey’s book didn’t mention transposons. Is that new?
Regardless, it doesn’t seem like a stretch at all that they could play a key role in aging.
One thing I noticed was missing from your post: any mention of the role of information loss in the epigenome as part of aging. That seems to be Dr. Sinclair’s main theory for the root cause of aging. Sounds like that could actually be closely intertwined with transposon activity since transposons are repressed by methylation or histone structure most of the time.
And of course, since I am always thinking of genetic engineering, this whole post made me think that removing transposons from the human genome via genetic editing, should we find a way to do it safely without affecting desired function, would be a great victory against aging. Evolution has not and will not act in our best interest, and there is no better example of this than the existence of transposons. They are basically parasites within our genomes.
So, de Gray gave that mechanism for ROS export (which I think was one of his best contributions on the theory side of things, it was plausible and well-grounded and quite novel). It is a mechanism which can happen, although I don’t know of experimental evidence for whether it’s the main mechanism for ROS export, especially in senescent cells. And that also still leaves the question of ROS import into other cells—not so relevant for atherosclerosis, but quite relevant to the exponential acceleration of aging. Also, it leaves open the question of ROS transport between mitochondria/cytoplasm/nucleus, which is necessary to explain the DNA damage part of the senescence feedback loop.
Man, I wrote up a whole summary of the mitochondria free radical theory of aging for you after reading this paragraph, then read the rest of your post and realized you already know about it. I’m surprised though that you still have questions about this, because the mechanism of export is described in Aubrey de Grey’s book. At least it’s described in his book “Ending Aging”. I haven’t read the other one, so I’m not sure if it contains less information.
A very quick description is that cells overtaken by clonal mutant mitochondria export electons from their cell membranes to keep themselves alive via the Krebs cycle (since the electron transport chain in mitochondria, which normally receives these excess electrons, is shut down).
The receptor molecule for these excess electrons is oxygen. These oxygen molecul\es with extra electrons are very powerful free radicals, and end up reacting with whatever molecule they bump into first. Unfortunately some decent fraction of these reactions are with low-density lipoproteins, which are then transported by the bloodstream to a much larger area of the body, and eventually deposited on blood vessel walls, contributing to atherosclerosis.
I’m glossing over a lot of details here, so if you want to read more about it, check out Chapter 5 of Ending Aging.
This book did come out in 2008, and I imagine quite a few new things have been learned in that time, so I’m not sure if this theory is still accepted. I’d be interested to know if there’s been any follow-up research.
If I understand correctly, accumulation of A2E in the lysosomes of microglia in the retina is one of the main causes of macular degeneration. There is also a big section of Ending Aging dedicated to the topic of lipofuscin in general (non-digestible material that accumulates in the lysosomes of long-lived cells)
Final Thoughts
This is an amazing write-up. I am very surprised that De Grey’s book didn’t mention transposons. Is that new?
Regardless, it doesn’t seem like a stretch at all that they could play a key role in aging.
One thing I noticed was missing from your post: any mention of the role of information loss in the epigenome as part of aging. That seems to be Dr. Sinclair’s main theory for the root cause of aging. Sounds like that could actually be closely intertwined with transposon activity since transposons are repressed by methylation or histone structure most of the time.
And of course, since I am always thinking of genetic engineering, this whole post made me think that removing transposons from the human genome via genetic editing, should we find a way to do it safely without affecting desired function, would be a great victory against aging. Evolution has not and will not act in our best interest, and there is no better example of this than the existence of transposons. They are basically parasites within our genomes.
Great comment.
So, de Gray gave that mechanism for ROS export (which I think was one of his best contributions on the theory side of things, it was plausible and well-grounded and quite novel). It is a mechanism which can happen, although I don’t know of experimental evidence for whether it’s the main mechanism for ROS export, especially in senescent cells. And that also still leaves the question of ROS import into other cells—not so relevant for atherosclerosis, but quite relevant to the exponential acceleration of aging. Also, it leaves open the question of ROS transport between mitochondria/cytoplasm/nucleus, which is necessary to explain the DNA damage part of the senescence feedback loop.