5 ms·

Thanks for the review. Surprised not to see any mention of interleukins and metformin. [Warning - metformin linked to birth defects] https://www.nature.com/ar

Thanks for the review. Surprised not to see any mention of interleukins and metformin. [Warning - metformin linked to birth defects] https://www.nature.com/articles/s41586-024-07701-9 https://www.nature.com/articles/s41586-024-07701-9 The more I learn about molecular biology/oncology, the more skeptical I am of longevity research. The pathways are usually broad hub genes that shouldn't be touched. E.g. Myc is an oncogene. As a rule of thumb, any time you see "reprogramming," be skeptical. Gene therapy for neurodegenerative diseases should not be considered longevity.

abhishaike 2y ago
thanks for reading! i could’ve covered the metabolic/immune stuff in deeper depth…might make a part two for this all, i was pretty opinionated on what to add in, there is a lot more to the field
api 2y ago
Life extension in humans is difficult because we are already long lived for a high metabolism large mammal. That means evolution has probably already tweaked the obvious knobs. It doesn’t mean it can’t be done, just that it is not likely to be as easy as pushing a few chemical buttons or turning something on or off.
- kurthr 2y ago
  Why would evolution "tweak the obvious knobs" for something well beyond our breeding age 100-500-5000 years ago? The best argument is that those same tweaks affect child bearing/survival performance in the same direction. Since sickle cell and other diseases were selected for, it seems unlikely all of them go the same way.
  - marcus_holmes 2y ago
    This. If anything, evolution would seem to select for lower longevity so more breeding sooner (assuming that if we live longer we would put off breeding until later, which may not be true, and if it is, is probably only true with contraception). And, of course, the oft-repeated "anything that happens after reproduction is irrelevant to evolution". Which isn't 100% true (it takes a village to raise a child, after all).
  - brigadier132 2y ago
    For humans I can speculate generational knowledge is much more valuable since we can communicate using language.
    - sdwr 2y ago
      Yeah, this, paired with a social scorekeeping system that literally kills old people if they are less useful (lonelier -> general health problems)
  - sjducb 2y ago
    Grandparents contribute to the survival of their grandchildren. Evolution has selected for long lived grandparents. The same thing happened in elephants and whales.
    - hirenj 2y ago
      This is my favourite bit of research regarding the grandmother effect - linking pathogen evasion to neuroprotective activities in old age, all at the molecular level, in an evolutionary context. https://pubmed.ncbi.nlm.nih.gov/35809046/ https://pubmed.ncbi.nlm.nih.gov/35809046/
    - roenxi 2y ago
      True in the sense that evolution does select for populations with grandparents, but not entirely obvious in the sense that it is optimising the long lifetime of those grandparents. You don't need a lot of grandparents lying around in the community evolutionary speaking, they take resources to maintain. And there might be a limit to how long knowledge is useful for that evolution has sniffed out and calibrated lifespans to. Human life seems to go through 3-4 phases (roughly youth, middle age and old age). The role of each of those is distinct and fairly clear, but it isn't easy to pick why evolution settled on specific numbers of years.
    - aziaziazi 2y ago
      GP used to live within their family, caring of kids and helping with vegetable garden. Their modern “living” in hospices, hospitals, far away neighborhood or vacation resorts have a minor effect on survival on their grand children. Probably negative effect for some pension systems.
      - Lutger 2y ago
        By the age we currently stop being 'useful' as members of clan human, i.e. retirement, our forefathers in an evolutionary sense could already have been (great) great grandfathers. Our life as a pensionado or geriatric patient is already a form of life extension, an extra age compared to the stages we used to go through. Evolution doesn't mean only what is useful stays, it is only when selected for under evolutionary pressure that things are forced to go a certain way, and only after many generations. The uselessness of old age will only affect evolution if A) there will be a society that is mad enough to really 'do something about it' and B) such a society will eventually outcompete other ways of life and its values start to dominate. I can imagine a politics where money spend on welfare and healthcare for elderly is minimized to such an extent that life expectancy starts dropping significantly. In a way, the US has something like such a 'make money or die' politics and indeed, life expectancy there is quite a bit lower than would you would expect from such as prosperous nation. Can be economically effective. But it competes which economies where people are productive at an older age, being more focused on staying healthy and significantly less stressed.
  - n4r9 2y ago
    What do you mean by "breeding age"? Women of course undergo menopause at some point. Men may have peak vigour around age 40, but can continue reproducing into their sixties or beyond. In modern forager populations in Africa and Australia, it's common for men to take wives at such an advanced age. See eg https://d1wqtxts1xzle7.cloudfront.net/46398103/s12110-000-1001-720160611-15509-1afrpfu-libre.pdf?1465652678=&response-content-disposition=inline%3B+filename%3DThe_patriarch_hypothesis.pdf&Expires=1722847016&Signature=I4seuZfUOOgji40VjRiEGFiKZA6YFn1dyZt-Gwaevz2I9NH5NeYDWKR0Qp4NTzu-Pvq-k~uzRYZXGsRLFc3Ba4nWlfCKbplDN4oWhIRmitriR3FDtqXn36scjakBgsWsOY3tq6KM6wTTrAVG7Za3Qj2c6hfbd4Xz6DY~7OPYiIz8dOSvM-slj2ZxB5Hv6TR3sE53k0DwBosGBm1NNSfZZ-kVJV2BtOKzp0vaq1-tj1X-lb6~IEfScdJhOSQ09v58FHXFgkM9GTJsaoSKZgqZg7RtDMMpQ9o8iF9xPKp8XM4486mNE~zXqkMct3pKBrs0EJ0qtgTgIXQsWTvw1xQCgg__&Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA https://d1wqtxts1xzle7.cloudfront.net/46398103/s12110-000-10... . I don't know about the overall hypothesis, but there's some fascinating data there about how old men can get whole still playing important tribal roles.
    - n4r9 2y ago
      Hmm, that link isn't working. Anyone interested should be able to access it by clicking the "PDF" link in the top right of Google scholar: https://scholar.google.com/scholar_lookup?title=The+patriarch+hypothesis&author=Marlowe+F.&publication+year=2000&journal=Human+Nature&volume=11&doi=10.1007%2Fs12110-000-1001-7&pages=27-42 https://scholar.google.com/scholar_lookup?title=The+patriarc...
  - abecedarius 2y ago
    Why is a good question, but if you draw a log-log plot of lifespan against mass for mammals, humans appear above the main curve. "That's unlikely by my model" doesn't change that.
- hinkley 2y ago
  I have long suspected that part of the solution to getting old will be delaying puberty. And in a world where there is more to know every year, that might not be such a bad thing for puberty to hit at 16 instead of 12-14. But 16 year olds think they will live forever, so I’m not sure how that would work.
- ren_engineer 2y ago
  from an evolutionary perspective the current human lifespan seems almost perfect >long enough for grandparents to help with kids and pass on valuable knowledge >short enough that new generations are able to adapt as needed to changing environments and throw out out of date information or cultural "technology" that is no longer relevant increasing human lifespan significantly seems like a nightmare, especially if only the richest have access. The saying "science advances one death at a time" and just the thought of political leaders being able to entrench themselves over longer times spans is awful. Seems like it would most likely lead to complete stagnation
pfdietz 2y ago
The doses of metformin taken are really quite high (1 gram/day, say). It's mostly excreted in feces; the dry mass of which might end up ~1% metformin. It's one of the most commonly detected drugs in waterways. It biodegrades, but slowly.
bboygravity 2y ago
You don't necesarily need gene therapy to "turn off" genes. You can just (temporarily) silence genes. Here's a podcast episode about just that (with the example of prion disease immunity): https://traffic.libsyn.com/secure/twiv/TWiV1127.mp3?dest-id=25528 https://traffic.libsyn.com/secure/twiv/TWiV1127.mp3?dest-id=... Also a fun related fact that I remember from Kurtzgesagt: whales should get tons of cancer (for being so huge), but they (almost?) never do. I'm convinced that there are feasible ways.
- amanaplanacanal 2y ago
  They figure out how to prevent cancer, but it makes you huge and your limbs turn into flippers.
  - mystified5016 2y ago
    A cure for cancer and a return to the oceans? My friend, this is a feature not a bug.
- Kalanos 2y ago
  all drugs "temporarily silence genes" by acting on the gene's target protein until the dose degrades. silencing typically refers to siRNA/RNAi. There are only 7 siRNA approved, all for liver diseases
caeril 2y ago
The craziest conclusion I've seen longevity experts narrow in on is the mTOR == cancer hypothesis. And the logic leaps are astounding: 1. Rapamycin inhibits expression of mTOR. (verified) 2. Rapamycin extends lifespan of cancer-encoded laboratory rats. (verified) 3. Therefore, activation of mTOR causes cancer. (???) 4. Therefore, stop eating protein. The leap from 2 to 3 is incredible. These guys aren't considering the possibility that Rapamycin might have other cancer-inhibiting properties via other pathways. They're just assuming that because the R in mTOR stands for Rapamycin, that's the only thing the drug does.
- Kalanos 2y ago
  I doubt step #1. When you downregulate mTOR, there are other supervisors of that pathway that help right the ship by upregulating it. It's naive to think "we can shut off one of the most critical pathways in biology"
rnewme 2y ago
Can you share more on "metformin linked to birth defects" - my wife is on it, and she's a pharmacist - she claims this has not been proven so far
- abracadaniel 2y ago
  Was curious as well. The only thing I’ve found is a study on men taking metformin suggesting a risk of sperm formation that could cause defects in male offspring.

abhishaike 2y ago

thanks for reading! i could’ve covered the metabolic/immune stuff in deeper depth…might make a part two for this all, i was pretty opinionated on what to add in, there is a lot more to the field

api 2y ago

Life extension in humans is difficult because we are already long lived for a high metabolism large mammal. That means evolution has probably already tweaked the obvious knobs. It doesn’t mean it can’t be done, just that it is not likely to be as easy as pushing a few chemical buttons or turning something on or off.

kurthr 2y ago
Why would evolution "tweak the obvious knobs" for something well beyond our breeding age 100-500-5000 years ago? The best argument is that those same tweaks affect child bearing/survival performance in the same direction. Since sickle cell and other diseases were selected for, it seems unlikely all of them go the same way.
- marcus_holmes 2y ago
  This. If anything, evolution would seem to select for lower longevity so more breeding sooner (assuming that if we live longer we would put off breeding until later, which may not be true, and if it is, is probably only true with contraception). And, of course, the oft-repeated "anything that happens after reproduction is irrelevant to evolution". Which isn't 100% true (it takes a village to raise a child, after all).
- brigadier132 2y ago
  For humans I can speculate generational knowledge is much more valuable since we can communicate using language.
  - sdwr 2y ago
    Yeah, this, paired with a social scorekeeping system that literally kills old people if they are less useful (lonelier -> general health problems)
- sjducb 2y ago
  Grandparents contribute to the survival of their grandchildren. Evolution has selected for long lived grandparents. The same thing happened in elephants and whales.
  - hirenj 2y ago
    This is my favourite bit of research regarding the grandmother effect - linking pathogen evasion to neuroprotective activities in old age, all at the molecular level, in an evolutionary context. https://pubmed.ncbi.nlm.nih.gov/35809046/ https://pubmed.ncbi.nlm.nih.gov/35809046/
  - roenxi 2y ago
    True in the sense that evolution does select for populations with grandparents, but not entirely obvious in the sense that it is optimising the long lifetime of those grandparents. You don't need a lot of grandparents lying around in the community evolutionary speaking, they take resources to maintain. And there might be a limit to how long knowledge is useful for that evolution has sniffed out and calibrated lifespans to. Human life seems to go through 3-4 phases (roughly youth, middle age and old age). The role of each of those is distinct and fairly clear, but it isn't easy to pick why evolution settled on specific numbers of years.
  - aziaziazi 2y ago
    GP used to live within their family, caring of kids and helping with vegetable garden. Their modern “living” in hospices, hospitals, far away neighborhood or vacation resorts have a minor effect on survival on their grand children. Probably negative effect for some pension systems.
    - Lutger 2y ago
      By the age we currently stop being 'useful' as members of clan human, i.e. retirement, our forefathers in an evolutionary sense could already have been (great) great grandfathers. Our life as a pensionado or geriatric patient is already a form of life extension, an extra age compared to the stages we used to go through. Evolution doesn't mean only what is useful stays, it is only when selected for under evolutionary pressure that things are forced to go a certain way, and only after many generations. The uselessness of old age will only affect evolution if A) there will be a society that is mad enough to really 'do something about it' and B) such a society will eventually outcompete other ways of life and its values start to dominate. I can imagine a politics where money spend on welfare and healthcare for elderly is minimized to such an extent that life expectancy starts dropping significantly. In a way, the US has something like such a 'make money or die' politics and indeed, life expectancy there is quite a bit lower than would you would expect from such as prosperous nation. Can be economically effective. But it competes which economies where people are productive at an older age, being more focused on staying healthy and significantly less stressed.
- n4r9 2y ago
  What do you mean by "breeding age"? Women of course undergo menopause at some point. Men may have peak vigour around age 40, but can continue reproducing into their sixties or beyond. In modern forager populations in Africa and Australia, it's common for men to take wives at such an advanced age. See eg https://d1wqtxts1xzle7.cloudfront.net/46398103/s12110-000-1001-720160611-15509-1afrpfu-libre.pdf?1465652678=&response-content-disposition=inline%3B+filename%3DThe_patriarch_hypothesis.pdf&Expires=1722847016&Signature=I4seuZfUOOgji40VjRiEGFiKZA6YFn1dyZt-Gwaevz2I9NH5NeYDWKR0Qp4NTzu-Pvq-k~uzRYZXGsRLFc3Ba4nWlfCKbplDN4oWhIRmitriR3FDtqXn36scjakBgsWsOY3tq6KM6wTTrAVG7Za3Qj2c6hfbd4Xz6DY~7OPYiIz8dOSvM-slj2ZxB5Hv6TR3sE53k0DwBosGBm1NNSfZZ-kVJV2BtOKzp0vaq1-tj1X-lb6~IEfScdJhOSQ09v58FHXFgkM9GTJsaoSKZgqZg7RtDMMpQ9o8iF9xPKp8XM4486mNE~zXqkMct3pKBrs0EJ0qtgTgIXQsWTvw1xQCgg__&Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA https://d1wqtxts1xzle7.cloudfront.net/46398103/s12110-000-10... . I don't know about the overall hypothesis, but there's some fascinating data there about how old men can get whole still playing important tribal roles.
  - n4r9 2y ago
    Hmm, that link isn't working. Anyone interested should be able to access it by clicking the "PDF" link in the top right of Google scholar: https://scholar.google.com/scholar_lookup?title=The+patriarch+hypothesis&author=Marlowe+F.&publication+year=2000&journal=Human+Nature&volume=11&doi=10.1007%2Fs12110-000-1001-7&pages=27-42 https://scholar.google.com/scholar_lookup?title=The+patriarc...
- abecedarius 2y ago
  Why is a good question, but if you draw a log-log plot of lifespan against mass for mammals, humans appear above the main curve. "That's unlikely by my model" doesn't change that.
hinkley 2y ago
I have long suspected that part of the solution to getting old will be delaying puberty. And in a world where there is more to know every year, that might not be such a bad thing for puberty to hit at 16 instead of 12-14. But 16 year olds think they will live forever, so I’m not sure how that would work.
ren_engineer 2y ago
from an evolutionary perspective the current human lifespan seems almost perfect >long enough for grandparents to help with kids and pass on valuable knowledge >short enough that new generations are able to adapt as needed to changing environments and throw out out of date information or cultural "technology" that is no longer relevant increasing human lifespan significantly seems like a nightmare, especially if only the richest have access. The saying "science advances one death at a time" and just the thought of political leaders being able to entrench themselves over longer times spans is awful. Seems like it would most likely lead to complete stagnation

pfdietz 2y ago

The doses of metformin taken are really quite high (1 gram/day, say). It's mostly excreted in feces; the dry mass of which might end up ~1% metformin. It's one of the most commonly detected drugs in waterways. It biodegrades, but slowly.

bboygravity 2y ago

You don't necesarily need gene therapy to "turn off" genes. You can just (temporarily) silence genes. Here's a podcast episode about just that (with the example of prion disease immunity): https://traffic.libsyn.com/secure/twiv/TWiV1127.mp3?dest-id=25528 https://traffic.libsyn.com/secure/twiv/TWiV1127.mp3?dest-id=... Also a fun related fact that I remember from Kurtzgesagt: whales should get tons of cancer (for being so huge), but they (almost?) never do. I'm convinced that there are feasible ways.

amanaplanacanal 2y ago
They figure out how to prevent cancer, but it makes you huge and your limbs turn into flippers.
- mystified5016 2y ago
  A cure for cancer and a return to the oceans? My friend, this is a feature not a bug.
Kalanos 2y ago
all drugs "temporarily silence genes" by acting on the gene's target protein until the dose degrades. silencing typically refers to siRNA/RNAi. There are only 7 siRNA approved, all for liver diseases

caeril 2y ago

The craziest conclusion I've seen longevity experts narrow in on is the mTOR == cancer hypothesis. And the logic leaps are astounding: 1. Rapamycin inhibits expression of mTOR. (verified) 2. Rapamycin extends lifespan of cancer-encoded laboratory rats. (verified) 3. Therefore, activation of mTOR causes cancer. (???) 4. Therefore, stop eating protein. The leap from 2 to 3 is incredible. These guys aren't considering the possibility that Rapamycin might have other cancer-inhibiting properties via other pathways. They're just assuming that because the R in mTOR stands for Rapamycin, that's the only thing the drug does.

Kalanos 2y ago
I doubt step #1. When you downregulate mTOR, there are other supervisors of that pathway that help right the ship by upregulating it. It's naive to think "we can shut off one of the most critical pathways in biology"

rnewme 2y ago

Can you share more on "metformin linked to birth defects" - my wife is on it, and she's a pharmacist - she claims this has not been proven so far

abracadaniel 2y ago
Was curious as well. The only thing I’ve found is a study on men taking metformin suggesting a risk of sperm formation that could cause defects in male offspring.