8 ms·

Anti-aging is a hard problem, Rapamycin is most certainly not the most powerful anti-aging drug from my best understanding, it just targets 1 of 7 or 8 critical

Anti-aging is a hard problem, Rapamycin is most certainly not the most powerful anti-aging drug from my best understanding, it just targets 1 of 7 or 8 critical areas that are implicated in the aging formula. If you want to start down the rabbithole (SENS talks can be trusted and are good, well-backed by science, etc etc. Have been derailed by some drama recently, but still, they've really done a lot) then you can start by going to the rejuvenation roadmap: https://www.lifespan.io/road-maps/the-rejuvenation-roadmap/ https://www.lifespan.io/road-maps/the-rejuvenation-roadmap/ A little further (Aubrey de Grey, from SENS originally): https://www.ted.com/talks/aubrey_de_grey_a_roadmap_to_end_aging?language=tt https://www.ted.com/talks/aubrey_de_grey_a_roadmap_to_end_ag... If you want to lose 4-5+ hours (minimum -- think TVTropes level of rabbithole addiction here), then here is your next free joyride. It's a fun one, I've been pretty interested in it as it's continued to have developed. Have fun reading the saga: https://www.reddit.com/r/sleephackers/comments/ohfetn/turnbuckle_longecity_mitochondrial_fissionfusion/ https://www.reddit.com/r/sleephackers/comments/ohfetn/turnbu...

Mistletoe 3y ago
I can’t tell if this Turnbuckle protocol is going to be one of the most revolutionary things I’ve read or going to be like when Napoleon Dynamite puts on Uncle Rico’s time machine from the internet and shocks himself.
- tysam_and 3y ago
  Likely if it works, it'll be one piece of the puzzle. It's not all that hard to try to be honest. Some people have reported absolutely massive changes, some small, some little to none. One or two said decrease but there seemed to be maybe some valid external factors for that. That's about the distribution one could expect if mitochondrial damage was at play and there was an effective solution for it. Not everyone is going to respond well, likely the older the better if it actually is doing what it says on the tin.
  - reducesuffering 3y ago
    That's about the distribution one could expect for placebo too.
    - tysam_and 3y ago
      Could be. Longecity I've found to be an odd mix of people who are rather combative about whether things work or not and who are way too in-depth (in a good way) about their personal experiences about what worked or not. At the very least, it's intriguing and out of all of the thousands of pages of medical literature I've read over the past half decade or so it's been one of the more interesting sagas to follow.
      - drBonkers 3y ago
        I have an intuition that if we are to find a solution it is more likely to first sprout from fringe experimentation, such as from Longecity, than the academy.
drBonkers 3y ago
What do you make of all that in the last link? At a cursory glance, it seems like the biohackers may simply be poisoning themselves on "fission" days and riding the rebound— eventually habituating to the fission supplements (a la arsenic eaters) so they feel less bad on the fission days (which they attribute to mitochondrial repair).
- tysam_and 3y ago
  Thanks for taking a gander! It is a very curious thread indeed (especially as you go deeper and deeper into its depths). Might I ask what makes you feel it is poisoning? It is safe doses of well-known supplements (and works for other swaps in their classes -- like apigenin, sulfuraphane, etc). Curious to hear though the thoughts on the poisoning line.
  - drBonkers 3y ago
    > Might I ask what makes you feel it is poisoning? I definitely didn't mean to imply that I necessarily believe its poisoning. Apparently the neurotic and anti-interventionist in me reared its head when reading the thread. I didn't recognize any of the supplement names, and so I didn't realize they all had reasonable safety profiles (individually?). I think my point still stands though. From what I saw, the outcomes were deemed positive as a function of subjective reports of well-being, without controls. It seems plausible the protocol is having any range of effects (from negative to null to positive)— I just didn't see anything other than placebo-uncontrolled anecdata. This is not to discount their efforts! I am truly interested in the subject.
    - tysam_and 3y ago
      I think these are very good points! I understand what you're saying better now. :) <3
- vidarh 3y ago
  Having lifted weights regularly for years, it's profoundly weird for me to see someone reporting doing curls to failure for even just that period of time without improving their results. While I get the person in question just used that as some curious proxy measure, it makes the whole thing seem counterproductive...
safety1st 3y ago
So in the science of fitness, there's a lot of woo, but there are a few really clear wins. One such example in weight lifting is supplementing creatine. It's well researched, fairly inexpensive, the performance improvements are significant and well documented, and it's very safe with side effects being mild and rare. Once you're actually doing the exercise and nutrition part more or less right, it's hard to argue against supplementing creatine. It's used by the vast majority of professional bodybuilders and most experienced weight lifters. Is there anything similar in the science of anti-aging? Where (A) The body of research is large, well established, and mostly uncontroversial; (B) The benefits and safety profile are good; (C) The majority of people who are serious about this stuff use it/take it/do it.
- xiphias2 3y ago
  By far the most important thing in anti aging that checks all boxes is excercise and getting nutrition right (no excess fat). Most of the interesting stuff happens when you focus on just A part: Yamanaka factors are both super powerful, established as reversing the probably most important hallmark of aging and super dangerous (causes cancer) at the same time. What's promising is the pace of research: in 20 years there's a good chance to have real safe anti-aging available, but we still need to survive until then.
  - tysam_and 3y ago
    I really appreciate this comment a lot. Feels like it hits the nail on the head. I've seen some of the discussion about/around the Yamanaka factors and it feels like an anime plot point, honestly. I need to look more into them and understand them a bit better. They're the ones implicated in stem cells returning back to pluripotency, right (and then the long deep dive about DNA damage/repair/what the heck is happening in the disparity between repairing damage for reproduction vs the everyday repair, etc...)?
    - xiphias2 3y ago
      You're half right, they are only resetting epigenetics (for example DNA methylation that is important in cell specialization), not DNA. Altos Labs being funded is both a blessing and a curse, because it funded the best researchers in this area with hundreds of millions of dollars (5-10x their salary in what they were making as university professors), but since it was founded, there are much less publications available.
reducesuffering 3y ago
They're recommending Nicotinamide Riboside which has been implicated in increasing cancers. My heuristics researching supplements, nootropics, longevity, are that the lab-created substances are more often than not, new and poorly studied, leading to eventual realization of more harm than they treat. Most recent, to me, was Alpha-GPC causing strokes.
- tysam_and 3y ago
  Like all things, it's about balance. In this case, NR was recommended as a cheaper alternative to NMN, I believe, though one can take Nicotinamide and Ribose separately IIRC (ribose is expensive either way, lol. Tastes great though, a very, very fancy sugar indeed). As far as cancer goes, basically half of the solutions here will cause cancer. That doesn't mean they're bad. Anything involving the body is extraordinarily nonlinear, so extrapolation is extremely hard in a variety of circumstances. You can find a study involving almost everything you consume and take linking it to a variety of things, it's just whether or not it's relevant to people in the doses and in the duration that they take them. Especially on the cancer side of things, that's just a very delicate matter to be handled. Cleaning things up in theory should reduce the risk of cancer overall, even if ingredients on their own at some dose could cause issues. A lot of these compounds have been around for or have been studied for 40-50 years or so. Some of the long-term effects are harder to pinpoint, but I'd be careful in seeking too much caution (in the same way I'd encourage someone not to go headlong throwing stuff into their bodies for no good reason). It's really easy to find nonlinear red lights for almost anything in medicine, in my (albeit limited) personal experience.
  - analognoise 3y ago
    This sounds like the chemical reasoning of homeopathy to me.
    - tysam_and 3y ago
      Not necessarily. I can give an analogous example. Lengthening telomeres is a naive strategy some chase for longevity. You can think of telomeres as aglets for DNA -- they shorten as you get older. So inhibiting that shortening is good, right? Well, that does extend life, in a way, but it also slows down DNA repair and makes that a harder thing to access, because now damaged DNA has longer end-caps on it too. So of course a few years after the whole "Just take telomere lengtheners!" headline wave, another headline wave of "Telomere lengtheners actually can worsen aging!" is a decent followup to expect (something like this happened IRL IIRC). You can make a similar analogy with stem cells and a limited stem cell pool (do you deplete the pool early, assuming it no longer regenerates at this point, for a boost of apparent vitality, or ration it over the course of a lifetime?) Homeopathy on the other hand assumes a bizzare, quantum-like "memory" in molecules that has not been shown to be accurate by science, but excels as being a placebo effect. These are quite different phenomena. It's another way of saying "the dose makes the poison", though in this case, it's "the dose has varying and highly state-dependent effects within a strongly chaotic dynamical system".
voldacar 3y ago
Is there anything in the works that can break down lipofuscein or advanced glycation endproducts? Those always seem under-discussed.
- tysam_and 3y ago
  I try to keep up with the AGE breaker development, I thought there were at least one or two labs/companies trying to develop them. I think IIRC that the crosslink breakers (referring to AGE above for those OOTL) mainly struggle from delivery being difficult? Because many of the AGEs we care about can end up in some bizzare, hard-to-reach places? I think? I don't think this is directly related but there was one therapy for cellulite that just had an enzyme that dissolved collagen. I just learned that they (sadly, in the long run for the research field in that area) had to shutter that after only two years or so, apparently due to the bruising and discoloration of skin long term (https://investor.endo.com/news-releases/news-release-details/endo-cease-production-and-sale-qwor-collagenase-clostridium https://investor.endo.com/news-releases/news-release-details...). I guess I can only feel so bad as they were marketing pretty heavily to people who were rich enough to pay for the cosmetic surgery out of pocket, and were as well in a category of middle-aged "luxury" buyers (from the official website -- I don't think the wayback machine will show the pictures [warning, very butt focused], but perhaps for the better, the saved version has the desktop and mobile transcript. Confetti for a medical drug advertisement website. Incredible: https://web.archive.org/web/20210124142605/https://www.qwo.com/ https://web.archive.org/web/20210124142605/https://www.qwo.c...) Lipofuscein I'd love to learn about, I have not heard of that before.
  - voldacar 3y ago
    Interesting stuff, glad to see that the research is continuing in this area. I'm thinking about experimenting with topical alagebrium just to see if it does anything. I recall a study in mice that found a very significant effect on skin wrinkles in aged animals. And it's lipofuscin, I mistyped it. Basically oxidized junk molecules that never seem to get broken down and just accumulate within the cell with age. Interestingly, piracetam seems to have a positive effect on this in rodent brains.
api 3y ago
The reason why anti-aging is hard is that humans are already very long lived for a large high metabolism mammal. As a result it's likely that evolution has already picked most of the low hanging fruit in humans. We're already optimized for decent longevity. This is why you see so many promising longevity studies in mice that don't replicate in humans. Mice are not particularly long lived compared to humans, so it's much easier to extend their life spans.
deleted 3y ago
[deleted]
TeaBrain 3y ago
There may be better anti-aging drugs that have yet to be tested or discovered, but Rapamycin currently has the best data backing it up. It is the only drug which has consistently increased both median and maximum lifespan across organisms, for both males and females, across many trials. It has also been shown to increase lifespan when given to organisms after they have reached their middle age, which is not common. The Interventions Testing Program (ITP) by the NIH, which has been testing substances for their effects on lifespan for over 15 years, is regarded as the gold standard for testing possible lifespan increasing substances. Rapamycin has outperformed every other substance they have tested, by a wide margin. There is only one other substance they have tested that has shown a median and maximum lifespan increase, for both females and males, that being acarbose. The greatest lifespan increase observed in any of the trials was seen with the combination of rapamycin and acarbose. All of the substances that NIH ITP have tested with their results listed, as well as the interventions they are testing now: https://www.nia.nih.gov/research/dab/interventions-testing-program-itp/supported-interventions https://www.nia.nih.gov/research/dab/interventions-testing-p... List of the substances they have tested with charts showing the relative increase in lifespan: https://phenome.jax.org/projects/ITP1 https://phenome.jax.org/projects/ITP1
camel_gopher 3y ago
“I can do more for you if you just eat right and exercise” - Dr. McCoy from “The Omega Glory” ST:TOS

Mistletoe 3y ago

I can’t tell if this Turnbuckle protocol is going to be one of the most revolutionary things I’ve read or going to be like when Napoleon Dynamite puts on Uncle Rico’s time machine from the internet and shocks himself.

tysam_and 3y ago
Likely if it works, it'll be one piece of the puzzle. It's not all that hard to try to be honest. Some people have reported absolutely massive changes, some small, some little to none. One or two said decrease but there seemed to be maybe some valid external factors for that. That's about the distribution one could expect if mitochondrial damage was at play and there was an effective solution for it. Not everyone is going to respond well, likely the older the better if it actually is doing what it says on the tin.
- reducesuffering 3y ago
  That's about the distribution one could expect for placebo too.
  - tysam_and 3y ago
    Could be. Longecity I've found to be an odd mix of people who are rather combative about whether things work or not and who are way too in-depth (in a good way) about their personal experiences about what worked or not. At the very least, it's intriguing and out of all of the thousands of pages of medical literature I've read over the past half decade or so it's been one of the more interesting sagas to follow.
    - drBonkers 3y ago
      I have an intuition that if we are to find a solution it is more likely to first sprout from fringe experimentation, such as from Longecity, than the academy.

drBonkers 3y ago

What do you make of all that in the last link? At a cursory glance, it seems like the biohackers may simply be poisoning themselves on "fission" days and riding the rebound— eventually habituating to the fission supplements (a la arsenic eaters) so they feel less bad on the fission days (which they attribute to mitochondrial repair).

tysam_and 3y ago
Thanks for taking a gander! It is a very curious thread indeed (especially as you go deeper and deeper into its depths). Might I ask what makes you feel it is poisoning? It is safe doses of well-known supplements (and works for other swaps in their classes -- like apigenin, sulfuraphane, etc). Curious to hear though the thoughts on the poisoning line.
- drBonkers 3y ago
  > Might I ask what makes you feel it is poisoning? I definitely didn't mean to imply that I necessarily believe its poisoning. Apparently the neurotic and anti-interventionist in me reared its head when reading the thread. I didn't recognize any of the supplement names, and so I didn't realize they all had reasonable safety profiles (individually?). I think my point still stands though. From what I saw, the outcomes were deemed positive as a function of subjective reports of well-being, without controls. It seems plausible the protocol is having any range of effects (from negative to null to positive)— I just didn't see anything other than placebo-uncontrolled anecdata. This is not to discount their efforts! I am truly interested in the subject.
  - tysam_and 3y ago
    I think these are very good points! I understand what you're saying better now. :) <3
vidarh 3y ago
Having lifted weights regularly for years, it's profoundly weird for me to see someone reporting doing curls to failure for even just that period of time without improving their results. While I get the person in question just used that as some curious proxy measure, it makes the whole thing seem counterproductive...

safety1st 3y ago

So in the science of fitness, there's a lot of woo, but there are a few really clear wins. One such example in weight lifting is supplementing creatine. It's well researched, fairly inexpensive, the performance improvements are significant and well documented, and it's very safe with side effects being mild and rare. Once you're actually doing the exercise and nutrition part more or less right, it's hard to argue against supplementing creatine. It's used by the vast majority of professional bodybuilders and most experienced weight lifters. Is there anything similar in the science of anti-aging? Where (A) The body of research is large, well established, and mostly uncontroversial; (B) The benefits and safety profile are good; (C) The majority of people who are serious about this stuff use it/take it/do it.

xiphias2 3y ago
By far the most important thing in anti aging that checks all boxes is excercise and getting nutrition right (no excess fat). Most of the interesting stuff happens when you focus on just A part: Yamanaka factors are both super powerful, established as reversing the probably most important hallmark of aging and super dangerous (causes cancer) at the same time. What's promising is the pace of research: in 20 years there's a good chance to have real safe anti-aging available, but we still need to survive until then.
- tysam_and 3y ago
  I really appreciate this comment a lot. Feels like it hits the nail on the head. I've seen some of the discussion about/around the Yamanaka factors and it feels like an anime plot point, honestly. I need to look more into them and understand them a bit better. They're the ones implicated in stem cells returning back to pluripotency, right (and then the long deep dive about DNA damage/repair/what the heck is happening in the disparity between repairing damage for reproduction vs the everyday repair, etc...)?
  - xiphias2 3y ago
    You're half right, they are only resetting epigenetics (for example DNA methylation that is important in cell specialization), not DNA. Altos Labs being funded is both a blessing and a curse, because it funded the best researchers in this area with hundreds of millions of dollars (5-10x their salary in what they were making as university professors), but since it was founded, there are much less publications available.

reducesuffering 3y ago

They're recommending Nicotinamide Riboside which has been implicated in increasing cancers. My heuristics researching supplements, nootropics, longevity, are that the lab-created substances are more often than not, new and poorly studied, leading to eventual realization of more harm than they treat. Most recent, to me, was Alpha-GPC causing strokes.

tysam_and 3y ago
Like all things, it's about balance. In this case, NR was recommended as a cheaper alternative to NMN, I believe, though one can take Nicotinamide and Ribose separately IIRC (ribose is expensive either way, lol. Tastes great though, a very, very fancy sugar indeed). As far as cancer goes, basically half of the solutions here will cause cancer. That doesn't mean they're bad. Anything involving the body is extraordinarily nonlinear, so extrapolation is extremely hard in a variety of circumstances. You can find a study involving almost everything you consume and take linking it to a variety of things, it's just whether or not it's relevant to people in the doses and in the duration that they take them. Especially on the cancer side of things, that's just a very delicate matter to be handled. Cleaning things up in theory should reduce the risk of cancer overall, even if ingredients on their own at some dose could cause issues. A lot of these compounds have been around for or have been studied for 40-50 years or so. Some of the long-term effects are harder to pinpoint, but I'd be careful in seeking too much caution (in the same way I'd encourage someone not to go headlong throwing stuff into their bodies for no good reason). It's really easy to find nonlinear red lights for almost anything in medicine, in my (albeit limited) personal experience.
- analognoise 3y ago
  This sounds like the chemical reasoning of homeopathy to me.
  - tysam_and 3y ago
    Not necessarily. I can give an analogous example. Lengthening telomeres is a naive strategy some chase for longevity. You can think of telomeres as aglets for DNA -- they shorten as you get older. So inhibiting that shortening is good, right? Well, that does extend life, in a way, but it also slows down DNA repair and makes that a harder thing to access, because now damaged DNA has longer end-caps on it too. So of course a few years after the whole "Just take telomere lengtheners!" headline wave, another headline wave of "Telomere lengtheners actually can worsen aging!" is a decent followup to expect (something like this happened IRL IIRC). You can make a similar analogy with stem cells and a limited stem cell pool (do you deplete the pool early, assuming it no longer regenerates at this point, for a boost of apparent vitality, or ration it over the course of a lifetime?) Homeopathy on the other hand assumes a bizzare, quantum-like "memory" in molecules that has not been shown to be accurate by science, but excels as being a placebo effect. These are quite different phenomena. It's another way of saying "the dose makes the poison", though in this case, it's "the dose has varying and highly state-dependent effects within a strongly chaotic dynamical system".

voldacar 3y ago

Is there anything in the works that can break down lipofuscein or advanced glycation endproducts? Those always seem under-discussed.

tysam_and 3y ago
I try to keep up with the AGE breaker development, I thought there were at least one or two labs/companies trying to develop them. I think IIRC that the crosslink breakers (referring to AGE above for those OOTL) mainly struggle from delivery being difficult? Because many of the AGEs we care about can end up in some bizzare, hard-to-reach places? I think? I don't think this is directly related but there was one therapy for cellulite that just had an enzyme that dissolved collagen. I just learned that they (sadly, in the long run for the research field in that area) had to shutter that after only two years or so, apparently due to the bruising and discoloration of skin long term (https://investor.endo.com/news-releases/news-release-details/endo-cease-production-and-sale-qwor-collagenase-clostridium https://investor.endo.com/news-releases/news-release-details...). I guess I can only feel so bad as they were marketing pretty heavily to people who were rich enough to pay for the cosmetic surgery out of pocket, and were as well in a category of middle-aged "luxury" buyers (from the official website -- I don't think the wayback machine will show the pictures [warning, very butt focused], but perhaps for the better, the saved version has the desktop and mobile transcript. Confetti for a medical drug advertisement website. Incredible: https://web.archive.org/web/20210124142605/https://www.qwo.com/ https://web.archive.org/web/20210124142605/https://www.qwo.c...) Lipofuscein I'd love to learn about, I have not heard of that before.
- voldacar 3y ago
  Interesting stuff, glad to see that the research is continuing in this area. I'm thinking about experimenting with topical alagebrium just to see if it does anything. I recall a study in mice that found a very significant effect on skin wrinkles in aged animals. And it's lipofuscin, I mistyped it. Basically oxidized junk molecules that never seem to get broken down and just accumulate within the cell with age. Interestingly, piracetam seems to have a positive effect on this in rodent brains.

api 3y ago

The reason why anti-aging is hard is that humans are already very long lived for a large high metabolism mammal. As a result it's likely that evolution has already picked most of the low hanging fruit in humans. We're already optimized for decent longevity. This is why you see so many promising longevity studies in mice that don't replicate in humans. Mice are not particularly long lived compared to humans, so it's much easier to extend their life spans.

deleted 3y ago

[deleted]

TeaBrain 3y ago

There may be better anti-aging drugs that have yet to be tested or discovered, but Rapamycin currently has the best data backing it up. It is the only drug which has consistently increased both median and maximum lifespan across organisms, for both males and females, across many trials. It has also been shown to increase lifespan when given to organisms after they have reached their middle age, which is not common. The Interventions Testing Program (ITP) by the NIH, which has been testing substances for their effects on lifespan for over 15 years, is regarded as the gold standard for testing possible lifespan increasing substances. Rapamycin has outperformed every other substance they have tested, by a wide margin. There is only one other substance they have tested that has shown a median and maximum lifespan increase, for both females and males, that being acarbose. The greatest lifespan increase observed in any of the trials was seen with the combination of rapamycin and acarbose. All of the substances that NIH ITP have tested with their results listed, as well as the interventions they are testing now: https://www.nia.nih.gov/research/dab/interventions-testing-program-itp/supported-interventions https://www.nia.nih.gov/research/dab/interventions-testing-p... List of the substances they have tested with charts showing the relative increase in lifespan: https://phenome.jax.org/projects/ITP1 https://phenome.jax.org/projects/ITP1

camel_gopher 3y ago

“I can do more for you if you just eat right and exercise” - Dr. McCoy from “The Omega Glory” ST:TOS