Without selecting the details in this there are species with negligible senescence.
A lot depends upon what you decide is “aging”. My view is that the main phenotypes of aging arise from the changes in acetylation.
There are, however, other causes of damage. For example DNA damage which can then be replicated. That, however, is not something I see as necessarily as signficant as the acetylation linked aging process. Similarly someone can have an accident at a macroscopic level and lose a limb or die. That is also entropy related.
I am not myself persuaded that LEV as a concept is that useful apart from fund raising for experiments although rational human beings should be willing to spend some money to improve their own health. The difficulty with research is the certainty of the link between expenditure and results.
DNA damage itself can be to some extent “fixed” by removing the cells that are damaged if they are causing an issue.
However, I think fixing acetylation (which arises from both mtDNA damage and SASP) will make a really big difference to healthspan and as a consequence a difference to lifespan.
Given your analysis what is the function of telomerase?
Thomas Seyfried argues much of cancer arises from cells using fermentation rather than OxPhos for energy production and it is metabolic (ie driven by mitochondrial status). Hence fixing the mitochondria can fix that. (which will still leave other cancers).
No more patching miles of ancient spaghetti rotting code, and start with a complete re-write.
I don’t think that is practical with the genome as things currently stand. At least nor your nor my genome.
I agree. The problem is that that is for the most part far beyonod our capabilities. We will need superintelligence to do that effectively. And by design we don’t just have to change the DNA and epigenetics, also a lot of other things that will not change by merely changing the DNA and epigenetics.
I tend to disagree with that. I think negligible senescence is not a good concept. I think that the organisms that are considered showing negligible senescence are still aging, we’re just not measuring the right things in enough detail for long enough to detect the entropic changes that are going on. But like so many things, this is a matter of definition.
This is very close to my belief. I would tweak it to 'it sets the optimal resilience against entropy that maximizes the survival fitness of the genes. The average lifespan that results from that.
The reason I think all this nuance is important is that evolutionary thought experiments might give insight into how likely it is that there are multiple programmed aging pathways vs just one primary or a few pathways. .Much depends on whether group selection pressures are the key driver of programmed agent versus evolutionary pressure at the individual level.
This is an interesting overview of the latest evidence:
I don’t think, however, that strictly it is entropy that results in aging. Evolution structures each species to have a balance where mitochondrial DNA is damaged at a particular rate. Interestingly prior to puberty and also in the central nervous system things operate to reduce the rate of damage.
There is in fact a dynamic equilibrium which operates, but which normally operates slowly in one direction.
However, at times it can operate in reverse and that is seen in some species.
An important point to note is that not all of the proteins in the electron transport chain are produced in the mitochondria, some (even hydrophobic ones which are harder to transport) are produced in the nucleus. My guess is that the genes for the ones which are more crucial to effective function are kept in the nucleus. Those which can tolerate damage and still function are made in the mitochondrion.
Yes the damage is slower at some time points and in some species, which is an example of evolution modulating the rate of aging. But the damage is still there. Entropy causes DNA damage in all species. Evolution doesn’t stop it fully, it just modulates the rate by making some species more robust at some time points. The way I view aging is that entropy is the ultimate cause of aging while evolution is a strong modulator of the rate.
Yes, some things can rejuvenate and reverse when the right genes are expressed or silenced. But the important point here is it’s only some things. A lot of things cannot reverse and as such are more directly at the whim of entropy.
Yes, I think this is accepted by many and it makes perfect evolutionary sense. The most important genes evolved to move to the nucleus to improve fitness of the animals.
I think you need to make a distinction between nuclear DNA damage and mitochondrial DNA damage. The latter can be removed from the cell. The former we are stuck with.
We, however, are used to a phentotype of aging and the proximate cause of that is mitochondrial DNA damage.
Beyond that the consequences of any nuclear DNA damage will need to be responded to in some way.
I don’t see a major distinction between nuclear and mitochondrial DNA in terms of damage in the end. Yes the rate of damage accumulation differs between them, and you can certainly say that mitochondrial DNA damage can be indirectly removed through mitophagy. But that’s not a full solution. When you remove mitochondria with mitophagy you will end up having to create new ones instead and while the new ones may be less damaged, many of them will have some mitochondrial DNA damage also. It’s not as if the body always has some backup mitochondria with perfectly undamaged mitochondrial DNA that it uses to create new ones. Some damaged ones will escape and be used for proliferation also, leading to gradual accumulaton of mitochondrial DNA damage despite mitophagy. In the end, both mitochondrial and nuclear DNA accumulate damage with aging that cannot be reversed fully with programming.
The mitochondrial DNA damage is a smaller problem though IMO. At some point in future we will proably be able to get mitochondrial transplants from healthy donors.
We don’t have to agree on these things. As I see it the quality of mtDNA rests in the efficiency of the electron transport chain. Sufficient mitophagy can result in the efficiency increasing rather than being maintained. That can be seen in species which can regress into a larval form.
Hence I see a really big difference between mtDNA and nucDNA.
I’m probably totally wrong about this, but I recall reading that we actually have far more potent DNA repair capabilities in our cells that are shut off, except for in sex cells. I think the system that shuts off the repair is the so-called DREAM Complex. I’m not sure how much mileage one would get out of somehow shutting it down, but it might be a lot (assuming it doesn’t cause cancer as a result). EGCG may temporarily weaken it through interfering with DYRK1A. I’m not sure if that has any effects on DNA repair – and, anyways, there might be other mechanisms through which EGCG can protect DNA.
I’m not sure what it would do for mitochondrial DNA, though.
Even if it’s not the answer, I’ve seen several other proposals to upgrade DNA repair. Clinical trials will take decades, though.
I partially agree with that. Increased mitochondrial efficiency reduces superoxide production which will tend to reduce mtDNA damage. However that’s only a small part of the solution IMO. Even a youthful super efficient mitochondria still generates superoxide and accumulates mtDNA damage.
Good points. I’ve heard of the DREAM Complex and I agree there is definitely some tradeoff going on here whereby if we had better DNA repair that would increase the risk of cancer so evolution has made it be not too good. If the cancer risk could be solved or all cancers cured then we might benefit a lot from increasing the efficiency of DNA repair in our cells.
DNA Polymerase gamma which replicates mtDNA is error prone so some mtDNA damage occurs without ROS. In fact there are those who are of the opinion that all transitions are replication errors and ROS only causes transversions and deletions.
At the same time at times replication can cause rNTPs to be incorporated rather than dNTPs this can also cause deletions to occur when next replicated.