As a thought experiment mostly for testing my own understanding, suppose we could do a bulk culling of transposons in all of an elderly human’s stem cells (or all cells). If I understand correctly, this post’s main hypothesis (DNA damage <-> ROS feedback loop) would imply the following should happen:
Senescent cell fraction quickly (within days or months) starts reverting to its healthy level.
Atherosclerosis heals on its own because ROS production reduces to its healthy level meaning the plaque equilibrium returns to the young level.
Similarly, vascular stiffening reverses for the same reason AG works temporarily.
Alzheimer’s remains unclear without further understanding but we can guess this might help.
Sarcopenia same story as atherosclerosis and stiffening.
Lens and elastin fibers continue to build up, so we’ll all be blind and wrinkly but otherwise healthy...
The one thing I’m less clear on is where immune system aging fits into this. I feel pretty confident that a treatment like this wouldn’t cause the thymus to spontaneously grow for example but am more uncertain about some of the other aged immune system phenotypes. It seems plausible that reducing the load on the immune system would allow it to regain some of its ability to deal with infectious diseases for example.
Yup, exactly right. This would be the most direct possible test of the hypothesis.
Re:thymus, this study found that a mitochondrially-targetted antioxidant prevented thymic involution, so there is at least some evidence that thymic involution is caused by the same core pathways. Though the timing of thymic involution is pretty suspicious, when compared to the other core-pathway diseases.
As a funny aside, a few months ago, I had the thought “removing all transposons would be a nice somewhat pointless but impressive demonstration of a civilization’s synthetic biology mastery.” I guess the “pointless” part may have been very wrong!
This suggests an interesting way to test the theory. JCVI had their “minimal cell” a few years back: they took a bacteria with an already-pretty-small genome, stripped out everything they could while still maintaining viability, then synthesized a plasmid with all the genes and promoters but with the “junk” DNA between them either removed or randomized (to make sure there was no functionality hiding in there which they didn’t know about), and grew the bacteria with the synthesized plasmid. More recently, they have a project to do something similar with yeast.
Once this sort of project scales up to mammals, I expect they’ll try it with mice/rats, and removing transposons is an obvious step. One prediction from the transposon theory of aging is that, when they do so, they’ll find that their mice are far longer-lived and have near-zero rates of cancer, heart disease, etc.
You don’t need to go through that much work. When we want to study what happens when a certain protein isn’t expressed we usually don’t remove the relevant gene from the genome but do gene knockdown via siRNA.
If we know all the active transposons we can create a DNA string that codes for a lot of siRNA for all the transposons we are concerned about and only need to do one injection into the genome.
The technology is there. If nobody has done the experiment it’s just the matter of talking anybody with a lab that cares about mice lifespan to run it (and maybe for a grant giver to spend a few hundred thousand).
If it’s true that transposons are more central to aging than a lot of the people in the field think, this would likely mean that it’s harder to fix aging invivo than many people in the anti-aging field want to think. There are also no clear medical interventions you can do with the knowledge.
As far as the size of the actual sum for the experiment goes, I don’t have the expertise to reliably estimate the cost and you would need to ask someone with more knowledge on how to do genetic engineering for that.
One thing I wonder about here is whether or not having a certain amount of “garbage” in the DNA is not actually a good thing. My understanding is that material transfers due to chromosomal overlaps as well. As that would be a purely random process there’s no guarantees that transfers occur at the beginning and end of the used/functional gene segment. Having some amount of meaningless sections seems like it would reduce the probability of the legs of the chromosomes overlapping at dangerous locations.
As a thought experiment mostly for testing my own understanding, suppose we could do a bulk culling of transposons in all of an elderly human’s stem cells (or all cells). If I understand correctly, this post’s main hypothesis (DNA damage <-> ROS feedback loop) would imply the following should happen:
Senescent cell fraction quickly (within days or months) starts reverting to its healthy level.
Atherosclerosis heals on its own because ROS production reduces to its healthy level meaning the plaque equilibrium returns to the young level.
Similarly, vascular stiffening reverses for the same reason AG works temporarily.
Alzheimer’s remains unclear without further understanding but we can guess this might help.
Sarcopenia same story as atherosclerosis and stiffening.
Lens and elastin fibers continue to build up, so we’ll all be blind and wrinkly but otherwise healthy...
The one thing I’m less clear on is where immune system aging fits into this. I feel pretty confident that a treatment like this wouldn’t cause the thymus to spontaneously grow for example but am more uncertain about some of the other aged immune system phenotypes. It seems plausible that reducing the load on the immune system would allow it to regain some of its ability to deal with infectious diseases for example.
Does this fit with your understanding?
Yup, exactly right. This would be the most direct possible test of the hypothesis.
Re:thymus, this study found that a mitochondrially-targetted antioxidant prevented thymic involution, so there is at least some evidence that thymic involution is caused by the same core pathways. Though the timing of thymic involution is pretty suspicious, when compared to the other core-pathway diseases.
As a funny aside, a few months ago, I had the thought “removing all transposons would be a nice somewhat pointless but impressive demonstration of a civilization’s synthetic biology mastery.” I guess the “pointless” part may have been very wrong!
This suggests an interesting way to test the theory. JCVI had their “minimal cell” a few years back: they took a bacteria with an already-pretty-small genome, stripped out everything they could while still maintaining viability, then synthesized a plasmid with all the genes and promoters but with the “junk” DNA between them either removed or randomized (to make sure there was no functionality hiding in there which they didn’t know about), and grew the bacteria with the synthesized plasmid. More recently, they have a project to do something similar with yeast.
Once this sort of project scales up to mammals, I expect they’ll try it with mice/rats, and removing transposons is an obvious step. One prediction from the transposon theory of aging is that, when they do so, they’ll find that their mice are far longer-lived and have near-zero rates of cancer, heart disease, etc.
You don’t need to go through that much work. When we want to study what happens when a certain protein isn’t expressed we usually don’t remove the relevant gene from the genome but do gene knockdown via siRNA.
If we know all the active transposons we can create a DNA string that codes for a lot of siRNA for all the transposons we are concerned about and only need to do one injection into the genome.
The technology is there. If nobody has done the experiment it’s just the matter of talking anybody with a lab that cares about mice lifespan to run it (and maybe for a grant giver to spend a few hundred thousand).
If there’s any reason to suspect grant-givers to be uninformed on the topic, or biased against it, crowd-sourcing a sum of that size sounds possible.
If it’s true that transposons are more central to aging than a lot of the people in the field think, this would likely mean that it’s harder to fix aging invivo than many people in the anti-aging field want to think. There are also no clear medical interventions you can do with the knowledge.
As far as the size of the actual sum for the experiment goes, I don’t have the expertise to reliably estimate the cost and you would need to ask someone with more knowledge on how to do genetic engineering for that.
Good point, this also suggests that Genome Project-Write is an important project.
One thing I wonder about here is whether or not having a certain amount of “garbage” in the DNA is not actually a good thing. My understanding is that material transfers due to chromosomal overlaps as well. As that would be a purely random process there’s no guarantees that transfers occur at the beginning and end of the used/functional gene segment. Having some amount of meaningless sections seems like it would reduce the probability of the legs of the chromosomes overlapping at dangerous locations.