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So telomeres shortening has a useful purpose in preventing runaway cell division right? So wouldn't artificially increasing their lengths increase cancer incide

by im3w1l 6y ago

So telomeres shortening has a useful purpose in preventing runaway cell division right? So wouldn't artificially increasing their lengths increase cancer incidence, unless combined with other interventions for fighting cancer?

dfischer 6y ago
Bret Weinstein has much to say about that. I have been meaning to revisit his conclusions. Sorry I don’t have a more specific answer but I do remember very interesting things brought up by him.
- didgeoridoo 6y ago
  Indeed — Weinstein’s claim (that I don’t have the expertise to validate) is that an enormous amount of biomedical research is performed on a subset of mice from a single breeding facility in Maine. These mice have abnormally long telomeres as compared to wild mice. This means they can take remarkable amounts of cellular damage before apoptosis (cell death) is triggered. The downside is that, by forestalling even desirable apoptosis, these mouse cells frequently end up cancerous. If true, Weinstein says, this means that any compounds tested on these mice will necessarily look less damaging than they should, at least in the short run, because these mice have extensive regenerative capabilities. This might explain how certain drugs that cause heart damage (e.g. Vioxx) got approved — they looked safe in these super-mice, and human safety testing was too brief to catch the damage being done.
  - alextheparrot 6y ago
    I’m only vaguely familiar with Weinstein’s claims, but you might find the following news article about some research I remembered going to a talk to about 5 years ago [0]. There’s a lot of proposals in the stem cell community like this, though I lack the insight to vet whether that’s happening in practice. > About 80 percent of experimental drugs fail in human clinical trials because they are unsafe or ineffective, with some 30 percent found to be toxic in people despite promising results in animal studies Effectively, a huge percent of drugs are failing out in clinical trials — so a few false negatives where the phenotypes aren’t measured correctly or are on an incompatible time scale seems pretty expected. I haven’t seen anyone showing that “fixing” lab mice would’ve resulted in different animal trial results — is Bret claiming this? [0] https://madison.com/wsj/news/local/health_med_fit/tissue-chips-could-replace-animal-studies-uw-madison-researchers-say/article_8ee0cee1-57a6-5858-8d96-1b15c7387a7a.html https://madison.com/wsj/news/local/health_med_fit/tissue-chi...
    - mlyle 6y ago
      > I haven’t seen anyone showing that “fixing” lab mice would’ve resulted in different animal trial results — is Bret claiming this? No one may have shown it, but it seems extremely unlikely to me that we are testing things in animals in the absolute optimum fashion to minimize failure in later human trials. It would be quite extraordinary if we happened to so luckily arrive at the ideal model organisms and procedures. Presumably all the protocols we could use are not equally good, and good criticism of existing protocols towards improving their utility is important.
      - alextheparrot 6y ago
        This may be a conservative view point, but showing that it would increase the translatability of mice trials to humans seems like a prerequisite for the criticism to change anything, though. No one is saying that our current animal trials are optimal, one of the professors in the news article I linked is quoted as saying the exact opposite "The animal models used to understand the safety and efficacy of drugs are flawed". It just is the case that retraining, to draw analogy to computational models, our model animal is not free because the evaluation of its performance after that change is much more complex and expensive than an ROC curve produced from labeled data.
        mlyle 6y ago
        Sheesh. Well, sure. But even beginning to prove anything like this would be an extraordinarily expensive trial itself: what are you going to do, repeat trials for 100 substances in mice to see if you get a better alignment with later human results across potential substances than you do with current practices? So instead, we talk about it, consider imperfect arguments, and do experiments that are somewhat silly until we start to become convinced that we've likely spotted some of the causal factors. That's what convinces us to eventually do the work that will show it.
DoreenMichele 6y ago
Telomere length in these studies gets used as a proxy for "cells acting young" or "cells acting old." Telomere length tends to shorten as you age and it gets looked at as a proxy for de-aging your body at the cellular level.
- im3w1l 6y ago
  My mental model is this: Old cells have DNA mutations. Short telomeres tell the cells that they are old and should take it slow and be careful not to accumulate more mutations (senescence). Any simple treatment like oxygen therapy, will be unable to fix DNA damage. It has mutated already and thats that. What it might do is to "lie" to the cell. "You are perfectly healthy", when it actually isn't. This has benefits, such as more rapid healing of injuries, and it has drawbacks such as cancer.
  - DoreenMichele 6y ago
    I think it's much more likely that old cells just have an accumulation of crud, like a house that is old and doesn't get cleaned enough. We don't really have a good definition of "aging" because we don't really know what causes the body to give out after a certain amount of time has passed.
    - im3w1l 6y ago
      If a "cruddy" cell divides, then the two new cells will each have less then the original one.
      - deleted 6y ago
        [deleted]
- codecamper 6y ago
  Yes exactly. The article is hype. The factual, reality answer is clearing senescent cells.
  - 6y ago
Aerroon 6y ago
I don't know whether artificially increasing the length of telomeres increases the incidence of cancer, but cancer usually upregulates the creation of telomerase. Telomerase is part of an enzyme complex that lengthens telomeres.[0] In other words, most (almost all?) cancers end up lengthening their telomeres themselves. [0] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4915101/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4915101/ The background section seemed to give an overview of this, however, I don't know how good this information is.
erichocean 6y ago
> wouldn't artificially increasing their lengths increase cancer incidence Yes, this is well-established in other species.

by im3w1l 6y ago

dfischer 6y ago

Bret Weinstein has much to say about that. I have been meaning to revisit his conclusions. Sorry I don’t have a more specific answer but I do remember very interesting things brought up by him.

didgeoridoo 6y ago
Indeed — Weinstein’s claim (that I don’t have the expertise to validate) is that an enormous amount of biomedical research is performed on a subset of mice from a single breeding facility in Maine. These mice have abnormally long telomeres as compared to wild mice. This means they can take remarkable amounts of cellular damage before apoptosis (cell death) is triggered. The downside is that, by forestalling even desirable apoptosis, these mouse cells frequently end up cancerous. If true, Weinstein says, this means that any compounds tested on these mice will necessarily look less damaging than they should, at least in the short run, because these mice have extensive regenerative capabilities. This might explain how certain drugs that cause heart damage (e.g. Vioxx) got approved — they looked safe in these super-mice, and human safety testing was too brief to catch the damage being done.
- alextheparrot 6y ago
  I’m only vaguely familiar with Weinstein’s claims, but you might find the following news article about some research I remembered going to a talk to about 5 years ago [0]. There’s a lot of proposals in the stem cell community like this, though I lack the insight to vet whether that’s happening in practice. > About 80 percent of experimental drugs fail in human clinical trials because they are unsafe or ineffective, with some 30 percent found to be toxic in people despite promising results in animal studies Effectively, a huge percent of drugs are failing out in clinical trials — so a few false negatives where the phenotypes aren’t measured correctly or are on an incompatible time scale seems pretty expected. I haven’t seen anyone showing that “fixing” lab mice would’ve resulted in different animal trial results — is Bret claiming this? [0] https://madison.com/wsj/news/local/health_med_fit/tissue-chips-could-replace-animal-studies-uw-madison-researchers-say/article_8ee0cee1-57a6-5858-8d96-1b15c7387a7a.html https://madison.com/wsj/news/local/health_med_fit/tissue-chi...
  - mlyle 6y ago
    > I haven’t seen anyone showing that “fixing” lab mice would’ve resulted in different animal trial results — is Bret claiming this? No one may have shown it, but it seems extremely unlikely to me that we are testing things in animals in the absolute optimum fashion to minimize failure in later human trials. It would be quite extraordinary if we happened to so luckily arrive at the ideal model organisms and procedures. Presumably all the protocols we could use are not equally good, and good criticism of existing protocols towards improving their utility is important.
    - alextheparrot 6y ago
      This may be a conservative view point, but showing that it would increase the translatability of mice trials to humans seems like a prerequisite for the criticism to change anything, though. No one is saying that our current animal trials are optimal, one of the professors in the news article I linked is quoted as saying the exact opposite "The animal models used to understand the safety and efficacy of drugs are flawed". It just is the case that retraining, to draw analogy to computational models, our model animal is not free because the evaluation of its performance after that change is much more complex and expensive than an ROC curve produced from labeled data.
      - mlyle 6y ago
        Sheesh. Well, sure. But even beginning to prove anything like this would be an extraordinarily expensive trial itself: what are you going to do, repeat trials for 100 substances in mice to see if you get a better alignment with later human results across potential substances than you do with current practices? So instead, we talk about it, consider imperfect arguments, and do experiments that are somewhat silly until we start to become convinced that we've likely spotted some of the causal factors. That's what convinces us to eventually do the work that will show it.

DoreenMichele 6y ago

Telomere length in these studies gets used as a proxy for "cells acting young" or "cells acting old." Telomere length tends to shorten as you age and it gets looked at as a proxy for de-aging your body at the cellular level.

im3w1l 6y ago
My mental model is this: Old cells have DNA mutations. Short telomeres tell the cells that they are old and should take it slow and be careful not to accumulate more mutations (senescence). Any simple treatment like oxygen therapy, will be unable to fix DNA damage. It has mutated already and thats that. What it might do is to "lie" to the cell. "You are perfectly healthy", when it actually isn't. This has benefits, such as more rapid healing of injuries, and it has drawbacks such as cancer.
- DoreenMichele 6y ago
  I think it's much more likely that old cells just have an accumulation of crud, like a house that is old and doesn't get cleaned enough. We don't really have a good definition of "aging" because we don't really know what causes the body to give out after a certain amount of time has passed.
  - im3w1l 6y ago
    If a "cruddy" cell divides, then the two new cells will each have less then the original one.
    - deleted 6y ago
      [deleted]
codecamper 6y ago
Yes exactly. The article is hype. The factual, reality answer is clearing senescent cells.
- 6y ago

Aerroon 6y ago

I don't know whether artificially increasing the length of telomeres increases the incidence of cancer, but cancer usually upregulates the creation of telomerase. Telomerase is part of an enzyme complex that lengthens telomeres.[0] In other words, most (almost all?) cancers end up lengthening their telomeres themselves. [0] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4915101/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4915101/ The background section seemed to give an overview of this, however, I don't know how good this information is.

erichocean 6y ago

> wouldn't artificially increasing their lengths increase cancer incidence Yes, this is well-established in other species.