There’s one additional crucial phenomenon that I think needs to be better highlighted here, which is natural selection for cancer as an organism ages.
Cancer isn’t best understood as a manifestation of genetic damage that the body is unable to remove or repair. That’s what causes individual cancer cells to emerge and survive. But that alone does not guarantee that the damaging agent (the cancer cell) will replicate itself. Damage and failure of disposal alone only leads to local blockage.
Cancer goes beyond this to propagate itself throughout the organism. It evolves, developing drug resistance, the ability to colonize new “soils,” and better evade the immune system with time. This is a feature that, as far as I know, is unique to cancer. And it depends on the mechanism of natural selection.
By contrast, lipofuscin, transposon-caused DNA damage, and protein plaques seem mainly to accumulate, causing local dysfunction. It’s deadly, but it’s ultimately a passive force.
Hence, I think that “selection for cancer” deserves to be mentioned as a “further up the chain” core pathway of aging. This is an active, antagonistic force actively working to defeat our efforts to cure it.
Eh, yes and no. I’m definitely on board with selection pressure as a major piece in cancer. But for purposes of finding the root causes of aging, the key question is “why does cancer become more likely with aging?”, and my current understanding is that selection pressures don’t play a significant role there.
Once a cancer is already underway, selection pressure for drug resistance or differentiation or whatever is a big deal. But at a young age, the mutation rate is low and problematic cells are cleared before they have time to propagate anyway. Those defences have to break down somehow before cancer-selection-pressures can play any role at all, and it seems like the rate-limiting step (i.e. the step which accounts for the age-related increase in cancer) is the breakdown of the defences, not the time required for selection itself. Once cancer is underway, the selection process operates on a faster timescale.
it seems like the rate-limiting step (i.e. the step which accounts for the age-related increase in cancer) is the breakdown of the defences, not the time required for selection itself. Once cancer is underway, the selection process operates on a faster timescale.
Maybe there are multiple aging clocks.
Some run independently.
In other cases, clock A ‘triggers’ clock B.
Cancer selection might be triggered by the ‘primary aging clock’ you’ve proposed. Once that happens, you now have two clocks running simultaneously. However, the ‘cancer clock’ could still be potentially triggered even in the absence of the ‘primary aging clock.’
Then the empirical question becomes when in the life cycle the ‘cancer clock’ starts ticking. Is it always running in the background, but DNA damage from other sources makes it speed up over time? Or, in the absence of the ‘primary aging clock,’ would the ‘cancer clock’ stay off for most people, most of the time, barring exposure to some potent carcinogen?
There’s also a possibility of hard-to-specify combinations of physical and mental damage that are self-perpetuating, and operate independently of DNA damage. Each year, perhaps people face a risk of trauma that triggers a cycle of progressively self-destructive behavior, a ‘behavioral dysfunction clock.’ That’s speculation, just meant to illustrate the idea.
It still seems conceptually important to focus attention on the ‘primary aging clock’ as a hypothetical target. I agree with you that it’s plausible the ‘primary aging clock’ is the bottleneck. So this is more a move from “there’s one aging clock” to “there might be more than one aging clock, but one of them is a lot more responsible for diseases of aging than the others.”
A new bigger cluster of cells emerging that divides forming.
What happens once such a cluster is formed.
I think it’s plausible that 1) happening more frequently in older people is due to a weaker immune system as the largest factor.
As 2) happens and a tumor develops more mutations it activates telomerase production (which results in the cancer keep on growing), develop drug resistence, create some attack surfaces for the immune system and also remove attack surfaces for the immune system.
The interaction between the immune system and a tumor is that every cells automatically presents subchains of it’s proteins on it’s sell surface as antigens. It’s the nature of a tumor that some tumor cells have protein sequences that differ from the other cells in the organism due to mutations. When the part of the sequences that’s mutated gets presented on the cell wall, the immune system can attack the tumor cells.
If a tumor mutates in a way to shut down the process of antigen’s being presented on it’s outside, other immune system processes are there to kill those cells.
One theory would be that the primary aging clock is reduced thymus size. A smaller thymus means a weaker immune system and it’s plausible that this is the primary reason cancer develops more often in older people.
Interesting! Can you give me some background on where those ideas come from? I haven’t specifically studied cancer biology yet so I don’t know if this is something an intro textbook on the subject would cover, or whether they’re to some extent your original ideas?
The fact that immune function is worse in older people is standard knowledge and johnswentworth wrote a post about the thesis that the thymus might be a central factor here.
The fact that cancers have to mutate to activate telomerase production to be able to constantly replicate seems to me like a cancer 101 thing. There might be some cancers that happen in stem cells that actually produce telomerase naturally but it’s necessary for normal cells.
A decade ago, cancer vaccines were targeting single targets and usually proteins that are developed in the fetus but not in adults. The personalized cancer vaccines currently in development are about sequencing the cancers of a patient and then creating vaccine’s to targets a bunch of different mutations. I got that knowledge from an explanation about cancer vaccines.
This process of antigen presentation is done by MHC (Major Histocompatibility Complex)-molecules.
Lastly, as complete abrogation of antigen presentation can lead to natural killer (NK) cell-mediated tumour killing, we also discuss how tumours can harbour antigen presentation defects and still evade NK cell recognition.
Here it seems that it’s possible for a cancer to mutate in a way where it has some antigen presentation defects and still avoid NK cell recognition but it doesn’t seem to be the standard case.
One distinguishing factor of cancer cells is that they either have to present antigens of their mutations on their cell walls or fail to present some antigens that normal cells present on their cell wall.
Given cancer patients NK cells is one way of cancer immunotherapy that’s currently studied. There’s recent research on artifical NK cells.
There’s the general issue of biology usually being complex and there being a lot of unknowns, so when I say it’s plausible that reduced immune function is the most important reason for more cancers in old people, I’m not claiming that we currently have evidence for that thesis but that what we know is compatible with the thesis.
There’s one additional crucial phenomenon that I think needs to be better highlighted here, which is natural selection for cancer as an organism ages.
Cancer isn’t best understood as a manifestation of genetic damage that the body is unable to remove or repair. That’s what causes individual cancer cells to emerge and survive. But that alone does not guarantee that the damaging agent (the cancer cell) will replicate itself. Damage and failure of disposal alone only leads to local blockage.
Cancer goes beyond this to propagate itself throughout the organism. It evolves, developing drug resistance, the ability to colonize new “soils,” and better evade the immune system with time. This is a feature that, as far as I know, is unique to cancer. And it depends on the mechanism of natural selection.
By contrast, lipofuscin, transposon-caused DNA damage, and protein plaques seem mainly to accumulate, causing local dysfunction. It’s deadly, but it’s ultimately a passive force.
Hence, I think that “selection for cancer” deserves to be mentioned as a “further up the chain” core pathway of aging. This is an active, antagonistic force actively working to defeat our efforts to cure it.
Eh, yes and no. I’m definitely on board with selection pressure as a major piece in cancer. But for purposes of finding the root causes of aging, the key question is “why does cancer become more likely with aging?”, and my current understanding is that selection pressures don’t play a significant role there.
Once a cancer is already underway, selection pressure for drug resistance or differentiation or whatever is a big deal. But at a young age, the mutation rate is low and problematic cells are cleared before they have time to propagate anyway. Those defences have to break down somehow before cancer-selection-pressures can play any role at all, and it seems like the rate-limiting step (i.e. the step which accounts for the age-related increase in cancer) is the breakdown of the defences, not the time required for selection itself. Once cancer is underway, the selection process operates on a faster timescale.
Maybe there are multiple aging clocks.
Some run independently.
In other cases, clock A ‘triggers’ clock B.
Cancer selection might be triggered by the ‘primary aging clock’ you’ve proposed. Once that happens, you now have two clocks running simultaneously. However, the ‘cancer clock’ could still be potentially triggered even in the absence of the ‘primary aging clock.’
Then the empirical question becomes when in the life cycle the ‘cancer clock’ starts ticking. Is it always running in the background, but DNA damage from other sources makes it speed up over time? Or, in the absence of the ‘primary aging clock,’ would the ‘cancer clock’ stay off for most people, most of the time, barring exposure to some potent carcinogen?
There’s also a possibility of hard-to-specify combinations of physical and mental damage that are self-perpetuating, and operate independently of DNA damage. Each year, perhaps people face a risk of trauma that triggers a cycle of progressively self-destructive behavior, a ‘behavioral dysfunction clock.’ That’s speculation, just meant to illustrate the idea.
It still seems conceptually important to focus attention on the ‘primary aging clock’ as a hypothetical target. I agree with you that it’s plausible the ‘primary aging clock’ is the bottleneck. So this is more a move from “there’s one aging clock” to “there might be more than one aging clock, but one of them is a lot more responsible for diseases of aging than the others.”
Cancer was two levels that are quite distinct.
A new bigger cluster of cells emerging that divides forming.
What happens once such a cluster is formed.
I think it’s plausible that 1) happening more frequently in older people is due to a weaker immune system as the largest factor.
As 2) happens and a tumor develops more mutations it activates telomerase production (which results in the cancer keep on growing), develop drug resistence, create some attack surfaces for the immune system and also remove attack surfaces for the immune system.
The interaction between the immune system and a tumor is that every cells automatically presents subchains of it’s proteins on it’s sell surface as antigens. It’s the nature of a tumor that some tumor cells have protein sequences that differ from the other cells in the organism due to mutations. When the part of the sequences that’s mutated gets presented on the cell wall, the immune system can attack the tumor cells.
If a tumor mutates in a way to shut down the process of antigen’s being presented on it’s outside, other immune system processes are there to kill those cells.
One theory would be that the primary aging clock is reduced thymus size. A smaller thymus means a weaker immune system and it’s plausible that this is the primary reason cancer develops more often in older people.
Interesting! Can you give me some background on where those ideas come from? I haven’t specifically studied cancer biology yet so I don’t know if this is something an intro textbook on the subject would cover, or whether they’re to some extent your original ideas?
What I wrote isn’t very original.
The fact that immune function is worse in older people is standard knowledge and johnswentworth wrote a post about the thesis that the thymus might be a central factor here.
The fact that cancers have to mutate to activate telomerase production to be able to constantly replicate seems to me like a cancer 101 thing. There might be some cancers that happen in stem cells that actually produce telomerase naturally but it’s necessary for normal cells.
A decade ago, cancer vaccines were targeting single targets and usually proteins that are developed in the fetus but not in adults. The personalized cancer vaccines currently in development are about sequencing the cancers of a patient and then creating vaccine’s to targets a bunch of different mutations. I got that knowledge from an explanation about cancer vaccines.
This process of antigen presentation is done by MHC (Major Histocompatibility Complex)-molecules.
Searching a bit gives me https://pubmed.ncbi.nlm.nih.gov/33750922/ for the thesis about complete stop of antigen presentation:
Here it seems that it’s possible for a cancer to mutate in a way where it has some antigen presentation defects and still avoid NK cell recognition but it doesn’t seem to be the standard case.
One distinguishing factor of cancer cells is that they either have to present antigens of their mutations on their cell walls or fail to present some antigens that normal cells present on their cell wall.
Given cancer patients NK cells is one way of cancer immunotherapy that’s currently studied. There’s recent research on artifical NK cells.
There’s the general issue of biology usually being complex and there being a lot of unknowns, so when I say it’s plausible that reduced immune function is the most important reason for more cancers in old people, I’m not claiming that we currently have evidence for that thesis but that what we know is compatible with the thesis.