There was an in depth discussion about this drug with a longevity researcher on a recent episode of the Tim Ferriss podcast, in case anyone wants to dive deeper.
"you can take Rapamycin now. It is an existing drug"
No: your doctor can prescribe it for you if it's indicated, or when there's good evidence that you need what it can do more than the side effects you'll suffer.
It's just like a gun: useful in some situations. But unlike guns, it's not you who decides.
The bigger story with rapamycin is that the mechanistic target of rapamycin (mTOR) plays an absolutely crucial role in major diseases of modern civilization. One of the ways to inhibit mTOR for free is to simply stop consuming nutrients for extended periods of time.
I did caloric restriction for a year and eased into it gradually until I was eating two small meals a day. I had no ailments but weighed upward of 230 lbs, 104kg. In a year I went down to near zero body fat and weighed 150lbs/68kg. Unfortunately for my build and frame that made me look sickly so I started eating again and Ive settled around 165 and working to put on a little muscle. Overall I'd say I did this whole thing over two years without much effort. Though yes, getting over the hunger pangs is very hard but once over them you quickly learn to ignore them.
True but after I went very low-carb, I found fasting to be much easier when it had always been very hard for me previously. I know it's more complicated than "carbs cause hunger pangs ~8 hrs later" but my N=1 experience sure feels that way.
No, there definitely seems to be a "there" there. I went zero carb for 6 months and I was able to continually fast for 24-44 hours at a time, always with zero hunger pangs after the initial "break-in" period, which seems to be about 2-3 weeks. Sadly I don't think the zero carb life is "doable" for me personally, because giving up pasta and pizza is a huge ask. Honestly I would rather die 10 years earlier than live a life with no pizza or carbonara.
If you want to sell me on the health effects you should be able to list them. If it made you feel better but not in an objectively measurable way that's great, but that's not a health effect.
If that's the mechanism by which the anti-aging effect takes place that would be promising for a lot of things, because many things, including Caffeine, exercise, and traditional caloric restriction inhibits mTOR, so there's lots of options, but as the person I originally responded to pointed out, for some reason Hacker News will always choose fasting.
That is a very shallow perspective. Fasting causes large, measurable phase changes in cellular function (eg autophagy). You can question whether it actually works or not, but there's a very plausible mechanism for why it would work that isn't simply related to calories-in-calories-out weight loss.
I think it's fair to say that we don't have to do something just because there's a plausible mechanism for a benefit. If there are clear and obvious health benefits that are far beyond what you see with a regular calorically restricted diet, I haven't heard them well explained.
The points listed there include heart health and the prevention of diabetes and obesity, which are very clearly things traditional caloric restriction also help with. For the other claims I don't see any comparison with traditional caloric restriction (I can't access the source paper).
I think we are talking past each other actually - I read your question "how did it make you healthier?" as in "how did it act to make you healthier?" and now I think you were saying "how did you determine it made you healthier?". Ambiguity of English strikes again...
So many chronic diseases in first world countries these days are downstream consequences of metabolic disorders. That is why it's so commonly recommended.
It’s simple, but not easy. Intermittent fasting is an easier way to start compared to traditional fasting. Imo it’s still better than other diets due to its simplicity.
> One of the ways to inhibit mTOR for free to simply stop consuming nutrients for extended periods of time.
What is an extended period of time in this context? I happen to consume all my meals within seven hours every day and only drink water in between. Would that help?
(Not doing this for health reasons, it is just a habit.)
A good measure is whether or not you feel that empty, churning feeling in your stomach. Another good measure is if you're into the idea of eating something like plain cabbage or oats.
I have no personal experience with this, so I must have read I somewhere. Usually in the first hours your get hungry, which eases off after some time. After that, you can until you are hungry again.
This [1] study was pretty thorough on different fasting lengths. They tested 1422 patients for fasting lengths between 4 and 21 days, with a maximum calorie consumption of 200-250kcal and a moderate-intensity lifestyle program.
It concludes that all fasting lengths are beneficial, and are likely going to result in a) reduction in weight and waist circumference, b) beneficial effects on blood lipids, regulation of sugar and other blood-related parameters, including lower blood sugars and higher ketone body levels, c) an increase in physical and emotional well-being and absence of hunger, d) a high probability of decrease of pre-existing health-complaints, e) very limited chance of side-effects.
To build on this post it is further beneficial to understand the importance of the interaction between clock genes and nutrient intake timing for optimal results
This gives zero evidence a threshold has been reached for enzyme activation.
There is evidence of effects after 72 hours of fasting [1]. But we also know of counter-effects around 24 hours, when glucose released by the liver breaking down amino acids from muscle wasting (EDIT: autophagy) partially reactivates mTOR [2]. It could be massive or minimal benefits through 24 hours, we don't know, benefits which reduce between 24 hours and some other number, and then increase until, or until right before or well through 72 hours.
> some evidence that exercising during the fast helps minimize the loss of muscle
The original point was autophagy reactivates mTOR. This isn’t a linear system. It could be that a 20-hour fast downregulates mTOR more than a 30-hour fast. (We know it works at 72 hours.)
As added information: metformin, a common anti-diabetic drug, is a inhibitor of mTOR. It potential adverse effects are less severe than rapamycin but are still significant. Specifically, long term usage can cause renal damage. Its mechanism of action has yet to be fully elucidated.
Can you source this? I believe you and I wanted to look into it. I googled this and I did not find anything explicitly saying renal damage. I did find many articles saying it's not safe to take if you already have renal disease but nothing saying that it causes it.
I even found articles that says it doesn't cause renal failure. I'm sure what you said is some real study just not popularized yet.
Ages ago, I had a colleague who was deeply into hacking of his mTOR pathway. Among other things, this included a permanent calorie deficit and removal of all protein from his diet.
I don't know if he's still alive. Maybe it was working a bit too well, I recall he looked like an extremely tall 13 year old with anorexia.
Pool your money with others and order in bulk from Asian or Sourh American suppliers. No questions asked. There are specific subreddits/forums for this kind of stuff.
Could you point me to some of those subreddits/forums? A quick search didn't yield anything but I'm probably not familiar with the specific terminology they would use.
You can order these drugs in bulk from chemical vendors for research purposes (i.e. non-human use). Chemscene, to name just one, sells Rapamacyn at 1440 USD for 5g.
EDIT: I clearly don't recommend you buying this and taking it by the way. You're never quite sure about the purity nor about how to dose this effectively as a layperson without access to a lab. It's also possibly completely illegal, depending on your local laws.
Yeah. By the time you're looking at stuff in the milligram range it becomes quite problematic to ensure consistent doses. I would be confident that I could get an *average* of 1mg/day but I would not be confident I could ensure every day was in .9mg to 1.1mg.
I'm not taking Rapamycin due to costs and immune system concerns, but when researching this niche (specifically, I'm interested in senolytics) I have found this forum with this list of doctors https://age-reversal.net/physician-directory/
[1] - "The figures are staggering: out of 35,000 children in care, more than 2,000 were physically or sexually abused by priests between 1936 and 1999" (Ireland alone)
[2] - French Church abuse: 216,000 children were victims of clergy - inquiry
My understanding is that simple plasma dilution (plasmapheresis) has the same or better results. Though some of the sources I saw said that a centrifugal plasmapheresis machine is better than the membrane-based machines.
For context, there have been other periods in history when young men were as focused on their apperance as women, used makeup and obsessed about how they were seen.
Social media gives an outlet for this to those who are not wealthy, but none of it is fundamentally new, it was just confined to those who were able to do it.
Maybe, but I'd be careful about generalizing that kind of thing. Even stuff like consistently applying sunscreen is heavily dependent on class membership, i.e. it's "just what you do, obviously, any time you're going to be outside at all, of course we always have sunscreen on-hand and our kids have been taught to apply it as routinely and consistently as tooth-brushing—wait, why are you asking, doesn't everyone do that?" in some circles, while in other (larger) circles they only break it out for beach or lake days, if at all.
I expect the described behavior is similarly unevenly distributed.
genuine question: why would someone want to live longer than the average?
Edit:
I ask because I personally don't see a reason to stay alive while people I love are dying, I don't see a reason to stay alive in an already fucked up planet, while we empty all the resources, etc. But you guys are so smart, intelligent and clever, why even bother.
It's not only "living longer" as a whole organism, but also your individual organs living longer (that ultimately impact aging). Take ovaries for example: Menopause causes major health problems (osteoporosis, cardiovascular disease, etc) for women and women now spend on average more time post-menopause than pre. There's a good writeup about this problem and the companies researching it here: https://spannr.com/articles/oviva-therapeutics-raises-11-5m-...
This isn't just about extending how long you live but also the reduction of disease. That's something that seems highly promising about some of these treatments
It's generally not maximizing lifespan people are interested in but rather maximizing health span which is the period of time you are healthy and able to operate at a high level. If done correctly you die with minimum time spent disabled.
If I could have a thousand years to read and study deeply and just write and think, I would take it.
Yes my loved ones will die and that will make me sad. I'll grieve and move on. My life is not theirs - their death does not mean an end to what I am doing.
Flip the problem. If you could bestow a friend/family member with a thousand years, even knowing you will die, would you?
One of the ancient greek prophets declared the apocalypse would happen in 9 generations. She was quite wrong. Most doomsday prophets are (well, probably all but the last one).
"""
The scientists have tested different time windows of short-term drug administration in fruit flies and found that a brief window of 2 weeks of rapamycin treatment in young, adult flies protected them against age-related pathology in the intestine and extended their lives. A corresponding short time window, 3 months of treatment starting at 3 months of age in young, adult mice, had similar beneficial effects on the health of the intestine when they were middle-aged.
“These brief drug treatments in early adulthood produced just as strong protection as continuous treatment started at the same time. We also found that the rapamycin treatment had the strongest and best effects when given in early life as compared to middle age. When the flies were treated with rapamycin in late life, on the other hand, it had no effects at all. So, the rapamycin memory is activated primarily in early adulthood”, explains Dr. Thomas Leech, co-author of the paper.
"""
And here I am wondering what the cutoff is for middle age...
When somebody asks about what is the next big thing, I always think on anti-aging. If you think that you don’t want to live forever, imagine that today when you arrive home you find a note saying that you will die exactly 1531[^1] days from today. How would you feel?
With that said, I would stay away from miracle drugs, because no two human beings have the same physiology. But that’s not an unsolvable problem.
[^1]: It’s a random number to “erase hope”. Not knowing when we are going to die keep us slightly hopeful and perky, our mind away from the problem.
I would argue that a miracle anti aging drug would work well for the majority of the population, much like NSAIDs work well for the majority of the population. Bonus points for being cheap and easy to synthesize.
Honestly, at peace lol. I don't really care about living.
My primary desire for living atm is keeping my family safe, providing for them, etc. Beyond that, i am living just because i am - and i enjoy life as much as i don't want to _not_ enjoy time i'm here anyway.
I think this is a great example of "what's good for the individual, is bad for humanity as a whole". Imagine we'd discovered a drug that adds 100 years to a persons natural life. Now imagine this drug was discovered 100 years ago. J.D. Rockefeller and the likes would still be alive and influencing politics. I can't even begin to think how much humanity would stagnate after such an invention.
See also the Planck principle: "A new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die and a new generation grows up that is familiar with it"
People don't need life-extending drugs to hold onto power or ways of doing things, that's what dynasties are for. And if in a democracy somebody like J.D. Rockefeller gets a voice that is too loud, then the democracy is flawed and we the citizens are ultimately at fault.
The idea that you could just take a pill one time and be "protected from aging" or something sounds ludicrous. Would be interested to see people reproduce these results and have them supposedly transfer over to humans. Humans are a much longer time scale.
I always go back to the SENS concept of having several different problems to solve related to built up damage, cells that won't die, etc.
The basic hypothesis is that cells operate in two modes, one storing up stuff in times of plenty, and a second mode which uses up the stores and cleans up, active during lean times. mTor is supposed to be the chemical signal which indicates which mode to act in; it's inhibited by both fasting and rapomycin.
Lol, why do say that? I had the same impression of him.
It appears that people fall for his niceness is my theory about him. And no doubt he is a nice guy. It's just that his explanations lacked the rigor I generally look for.
A lot of his earlier work with resveratrol was extremely sloppy and it fell apart in time. I believe it's a lot of what gained him earlier popularity, and has effectively been debunked to a very large degree.
I don't think he _endorsed_ rapamycin or metformin. If he endorsed anything, I'd say it was NMN.
Everything people like Sinclair state should be taken with a grain of salt (as even his peers say he's guilty of making excessive claims) but it's forward-thinkers who change the world, not people following others' steps and afraid to take peek outside their box.
Maybe the guy will achieve something real in the field and maybe it'll be the next guy. No way to know. But I'm far from dismissing someone just because their opinions are not in line with popular knowledge. Boltzmann, Galileo, Copernicus and Wright brothers were discredited or ridiculed.
Dr. Peter Attia did a thorough summary several months ago of what we know about rapamycin as an anti-aging therapy. There are plausible reasons to think it might be safe and effective, but human studies are lacking. This is a promising area for future research.
Maybe I missed this, but 2 weeks in fruit flies and 3 months in mice probably translates into something much longer in humans, on the order of a year or two maybe, if not longer? That's a pretty long time to be on an immune-suppressing drug with pretty significant side effects.
It's still an important bit of information if it replicates, but I think it might not be as clinically practical as it sounds from the press release.
Not just the quantity of extended time, but the quality of that time matters too. Even if life wasn't extended a day but one had greater vigor/vitality/cognition it would still likely be a worthy pursuit.
I fast a lot, right now I do 36 - 72h every 6 - 8 weeks.
The hardest moment is right when your body is about to switch from using glucose to using ketone bodies for energy. After that the hunger, feeling anxious, etc stops.
The time it takes to get to that point (when feeling "bad" intensifies) and how long the transition takes can be influenced.
Primarily, by what you eat before you fast. In general, avoid eating carbohydrates, especially simple carbohydrates like sugar, fruits, past, bread, etc.
I usually eat more protein and fat before fasting.
Another "trick" during fasting is to cheat your stomach a bit by filling it with liquids - I drink lots of water and tea.
The main thing to remember - it will pass, and you will feel great after your body switches. Your mind will tell you that it will just progressively get worse the deeper you get into the fast - it's not true :)
I also use the tricks mentioned above. They are very useful.
Additional tricks:
- Use fiber supplements in your water sometime in the middle of your fast (simplest time is in the morning in lieu of breakfast). I use psyllium husk.
- Soup (or rather broth) is a fasting bff. Remember miso, herbs, spices, salt, do not have calories. Flavor your water liberally. Change up the consistency with stuff in it (green onions, seaweed). Change up the temperature (hot, cold, whatever). I even add psyllium husk to my soups to change up the texture and consistency just for the variety. Remember you can “eat” a lot of tasty stuff while still technically fasting.
- Actively (rather than passively) deplete your glycogen stores. Do a workout ideally including cardio, then do your best to immediately fall asleep to recover. I can sleep through anything, if you can too you’ll be in keto by the morning and no real feelings of difficulty.
- Remember to take a multi-vitamin daily while fasting. Make sure it doesn’t have sugar like those “vitamin C hangover powders” or “electrolyte water stuff like Gatorade”.
I've dabbled in fasting and found my ability to do it comfortably varies a ton day-to-day. Some days I'm craving food by noon and/or am very tired and practically can't think at all by 3PM (this is pretty bad on work days, obviously, but not really great on any day). Other days I can go from wake-up to lie-down without a single bite of food, and hardly notice a thing. I can't tell in advance which it's going to be, so rather than sticking hard to a fasting schedule, when I'm in the mood to do it I'll pick days to try, and if at some point it becomes clear I'm gonna wreck my whole day if I persist, I bail and eat a meal. Ends up being about 50/50, days that work out and days that don't, if I try a couple days per week.
Sometimes I can approach 48 hours before I start to feel bad, other times I can't even make it one day before I'm a mess and can hardly function. I'm sure the difference has to do with blood sugar timing and/or what I ate the day before or something.
1. There is some internal clock that we don’t yet understand but clearly exists. Specifically your digestive track proactively activates itself in preparation for food. Then if food doesn’t come, your stomach will “growl”. It takes a 1-3 months for your clock to readjust such that it doesn’t do that. After this you will not “feel hungry”. If you intermittently fast for a year or so, you will likely never again “feel hungry”.
2. Eating meals is a habit. Arguably more addictive than smoking. But like with any habit, it can be broken. This isn’t the feeling of hunger… rather a weird compulsion. If you stop fasting for a few months, this will need to be rebroken every time. I’m currently struggling to re-break it.
3. The social pressure to eat is real! This is the hardest to contend with.
> Also people who fast for a long time: How do you do that? I get super hangry and find it really a struggle past a certain point of not eating.
Different people have different responses to fasting.
It's always been very easy for me to fast by becoming "at peace" with the feeling of hunger for the first 2-3 days, and after that I don't even notice. But later in life something about my body changed and my response to fasting was much more severe and I was suddenly unable to fast for more than 1-2 days due to extremely strong urges to eat, irritability, etc. This happened for 2-3 attempted fasts around the age of 32. A year or two later, and fasting is suddenly "easy" for me again. To be clear, the first 2-3 days usually sucks regardless.
I suspect that I am generally very good at metabolizing fat. When I get blood tests while fasting, even if I haven't eaten anything at all in 7 days, my glucose is generally still well above the minimum of normal, even sometimes towards the high side. I suspect that if my blood sugar was low, I'd have much more difficulty. It does seem to take 2-3 days for my body to "switch" to metabolizing fat at a high enough rate to raise my blood sugar up.
I also suspect different people have very different reactions to low blood sugar.
Just as a note, for me one of the biggest determinants of a successful fast is control over my environment. If there are people in my home cooking great food every night at the same time, it's very hard. If I'm living alone and let my fridge get empty, it's much easier. I've also dealt with it by shifting my work hours to leave later and come home after my partner has finished dinner and cleaned up the kitchen. But this is orthogonal to the above issue.
I have been taking rapamycin for many years now. It's obviously not ready for anywhere near the general public and is never something I'd suggest to someone at this point, but my own results have been wonderful and my blood panels and energy levels are great. If I had to guess, when properly used, this would probably add a full 5-10 years onto the lifespan of a lot of people. When combined with many other promising treatments, I think we could easily add 10-15 years onto most peoples' health+lifespans.
I'm a month into taking rapa and already I feel like it's having a noticeable effect. I'm curious what others on this threads dosage looks like. If you prefer to keep it private, you can email me directly (my email is on my profile).
I'm currently taking 2mg once a week on my rest day; I started with 1mg and after 1 month added another MG. I'll continue each month until I reach 8MG once a week, which is the dosage the doc I worked with in Texas to get my prescription recommended and most people seem to take.
Also - I would say that NMN + Rapa is a completely life altering combination for anyone 50+. I feel like I can lift harder and longer now than when I was in my 40's and things seem to be getting easier the farther into my rapa routine I get.
Also also - you can find rapamycin online / overseas under its other name - Sirolimus - and the cost is a little lower than getting a proper US prescription.
Nicotinamide Mononucleotide, an unregulated supplement.
Note also:
> We found that, when data from all organisms studied were combined for each compound, aspirin resulted in the highest percent increase in average lifespan (52.01%), followed by minocycline (27.30%), N-acetyl cysteine (17.93%), nordihydroguaiaretic acid (17.65%) and rapamycin (15.66%), in average.[0]
Though I'd consider whether flies and worms are good models for your human self.
Yeah as others appointed out it’s a nad+ precursor.
I feel compelled to comment though because anytime I read about how this stuff is only been tested in worms in mice… That automatically discount it’s worth as something to consider.
I’m gonna sah what I said before - I’ve played high-level hockey my whole life, I’m now 55 and I play against guys that barely washed out of their pro career.
When I stop taking nmn for two months my speed dropped from 20+ Mph to the mid teens.
A week after resuming my NMN supplementation my speeds are back in the 23-24 mph range
There’s just no way to fake it against players of this caliber. And to be clear I don’t know anybody even close to my age competing at this level.
I have been taking Rapamycin for 19 weeks and NR and Metformin (for anti-aging) for much longer and I can't see any difference. I'm 50+. I generally, however, feel excellent, as well as I remember when I was younger so long as I have gotten lots of sleep and don't have a cold. When I'm sick or tired I feel much worse than I did, however.
Clinical trials are expensive, and rapamycin can't be patented. My guess is that, some time in the future, a pharma company will produce and patent an analogue, and then there will be trials.
Who will fund it (it would be *very* expensive) when they have no hope of recouping the expenses? Consider: We have a likely candidate for a male birth control pill. It's considered quite safe, infertility (while taking it) is a known side effect. All that needs testing is whether it's reliable enough to be used for birth control. Unfortunately, there's a big headache with that--it does *not* stop sperm production so you can't test by having men jack off in a test tube and do a sperm count. Thus testing will be expensive. It's been known about for quite a while and nobody has funded it.
Amyloid beta may not cause alzheimer's disease, but you still don't want amyloid beta plaques in your brain. They may not themselves be causing damage but they are almost definitely a sign of damage to the brain, so anything that appears to increase them should be handled with extreme caution.
There seems to be a growing trend of generally healthy people looking for drugs/supplements to provide marginal improvements. I can't help thinking it's a sign of a vacuous and unfulfilling life. Instead of spending time and money on drugs to increase your life span, why not spend that time/money on actually living your life? I think this probably comes down to the general boredom that comes from not having a family and not having enough time off work to do anything else worthwhile.
> There seems to be a growing trend of generally healthy people looking for drugs/supplements to provide marginal improvements. I can't help thinking it's a sign of a vacuous and unfulfilling life.
Not sure I agree with your analysis. If I had a vacuous and unfulfilling life, I wouldn't strive to prolong it.
Just putting this out there, I am a PharmD and this is totally real and the traditional medical establishment is really behind. It is positive effects are beyond doubt - the argument against it is usually "we don't know what the side effects if 100m+ went on it for 20+ years". (which is also 100% true, but that's where patient autonomy comes in). Also, there are some questions about how much are really the positive effects.
Anyway, I am tinkering with something in that space - feel free to reach out if you want explore being a co-founder. (email in about)
As someone already said - rapamycin literature is mostly in cancer and transplant patients and with relatively high-doses. The risks are real, but my clinical judgement would lead me to believe that for at least some people the benefits would far outweigh the risks
What makes me scared about this is that it's immunosuppressive. The immune system is a very important part of the human body, and I worry that taking it could have terrible health impact after years of acting on your body lines of defense.
Your concern is correct. Suppressing the immune system is a 2-edged sword - a little suppression in the right setting, is extremely beneficial, but go overboard and it is harmful. That's why in a perfect world, we would have large human trials with different dosages and iterate until we can get the maximum benefit and the least harm.
The problem is, no one wants to do those trials because rapamycin is cheap and generic. Why would Pharma spend money on something that they can't patent? Also, these kind of trials have to go on for 10+ years at a minimum - which is cost-prohibitive even if it is patentable (not to go in the weeds, but long trials count in the period of exclusivity given to pharma patents).
I believe the right approach is to use it off-label, be upfront about the potential risks, and collect lots of data so you can improve as you go. Practical anti-aging so to speak.
Another approach is through the NIH grant pathway, but that has a lot of road-blocks as well.
> The problem is, no one wants to do those trials because rapamycin is cheap and generic. Why would Pharma spend money on something that they can't patent?
Same issue with psychedelics. However, they are so useful that people in the medical/therapeutic/academic fields are doing tons of research anyway.
Apparently big pharma is also trying to create their own psychedelics (there was an article about it on the front page of HN recently).
So far, the business seems like it will be on the assisted therapy side and everything that it entails. So more like services instead of products.
Why don't insurance companies fund some of this research? Honestly, I don't know.
Wouldn't they want to get treatment costs down? Large HMOs, especially, have motivation to control treatment costs, and access to the patients, data, etc... to make it work.
Delivering care counts toward their margins, regulated by the ACA. I forget the exact number, but it is 80 percent to be spent on care, something like that.
The key thing is more care = more dollars = more in the bank.
One response to that legislation was insurers buying care providers.
> That's why in a perfect world, we would have large human trials with different dosages and iterate until we can get the maximum benefit and the least harm.
Off topic, but whenever I think about this, I find myself thinking that what the world really needs is next-level human/medicinal modeling. Imagine if human trials didn't have to happen in order to know the long-term effects (and in a fraction of the time)!
I'm sure. But it's data we don't even have right now. We don't even know every chemical that naturally occurs in the body, how are we supposed to predict how they could interact with novel chemicals? Some day, though, it may be possible. There was a point where people couldn't imagine these image generation AIs working
Yea, data collection is the key here. If we had unobstrusive sensors that people could wear and embed in their body, to continuously measure a multitide of biometrics, that would greatly empower bio-AI systems.
I'd imagine we'd have to have complete knowledge of the human body to completely replace human testing. There's a hell of a lot that we don't know, especially when it comes to why or how things work.
According to the abstract of the article, its effects, at least in that form of using it, were not immunosuppresive.
On the contrary, the protection of the intestine to aging effects was due to increased autophagy in the intestinal cells, which eliminated the defective cells, and by increased levels of antimicrobial lysozyme, and these effects persisted long after the initial treatment ended.
If you think about it, there are specific parts of our immune systems that are likely entirely maladaptive given modern civilization, where people are ~never exposed to parasites, animal venoms, etc.
We can turn those parts off, while leaving everything else on, and be better for it (no allergies, psoriatic arthritis, MS, Chron’s, etc.; and so none of the accelerated cellular senescence those conditions provoke in affected tissue.)
A lot of recent pharma is already focused on doing specific forms of this at low levels. Every other drug ad in the US is for an immune-receptor blocker of some kind. And the side effects of these drugs come down mostly to the fact that they’re too low-level — they stop these parts of the immune system from being called into action at affected sites, but they leave it active and “patrolling”, such that it attacks harder any tissues that don’t absorb the receptor-blocker well, and such that you get withdrawal effects of potential inflammatory crisis if/when it wears off.
Just deactivating the relevant parts of the immune system entirely, on the other hand, provides the same benefits these drugs do, but with none of the “now the rowdy enforcers have nothing better to do, so they go looking for trouble” drawbacks.
For the average human on Earth: sure, merely uncommon.
For the average person who lives in a city and rarely goes out into nature, and paranoid-ly avoids doing things like walking barefoot in dung or wearing shortsleeves in forests when they do: effectively never.
If you live within the malaria zone (and an awful lot of people do) being in a city isn't protection. And the main threat from short sleeves in the forest is things that want your blood, not parasite infection.
Deactivating parts of the immune system wouldn't be simpler than giving receptor blockers. Everything in the body is connected to one another, and whatever circulating immune signaling proteins are involved could have numerous other effects on other non-immune cells.
There's also no reason to think that the immune system is so easily split up between systems that respond to parasites, bacteria, and virii. While a human designer might think that way, in nature most things are messy and have tons of overlap. This is true of the immune system. For example you can measure C-Reactive Protein and use it as a thermometer for general systemic inflammation. But elevated levels could as likely be a cold as a particularly intense workout-- they'll both trigger strong immune reactions with lots of overlap in effect.
> There's also no reason to think that the immune system is so easily split up between systems that respond to parasites, bacteria, and virii.
Well, sure. We essentially have multiple "immune systems", with overlapping goals. (Sort of like having both an anti-virus and anti-spyware scanner installed, as well as a system integrity checker, secure-boot verification logic, etc.)
Some immune responses are good at stopping all sorts of things (e.g. xenoreactive antibodies, which attack both parasites, bacteria, and cancer cells.) I wouldn't suggest doing anything to these. Conveniently, these processes don't tend to cause many long-term health problems, save in edge cases (e.g. xenograft implantation.)
Other immune responses are more specialized. And — also conveniently — it's the reactions/systems that specialize in responding to things we see almost none of in "city living", that seem to do bad things for longevity.
Parasite-specialist immune cells (mast cells), for example, cause a lot of chronic inflammatory problems. We've been preventing mast cells from doing their jobs for a long time now — that's the point of taking antihistamines — with very little negative to show for it. I don't think it would be much of a stretch from there to a treatment for allergies that's just a siRNA that "NOPs out" the entire immune-response functionality of mast cells. (Or even a "permanent" treatment for allergies, via CRISPR gene edit to rub out the definition of mast-cell antigen recognition receptors from the body's vocabulary.)
And I would also say that it's not much of a stretch to hypothesize that people who had this done, would, under longitudinal studies, show increased longevity / QUALYs. "Never having an [even sub-clinical] allergic reaction" would do really good things for the body. At the cost of — for most people reading this — just having to avoid sashimi.
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[ 5.5 ms ] story [ 270 ms ] threadProbably Peter Attia?
There's also some free to read review articles (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814615/). No idea about the quality of the journal Aging or the field in general, though.
https://tim.blog/2022/07/30/matt-kaeberlein-life-extension-t...
However, you can take Rapamycin now. It is an existing drug.
No: your doctor can prescribe it for you if it's indicated, or when there's good evidence that you need what it can do more than the side effects you'll suffer.
It's just like a gun: useful in some situations. But unlike guns, it's not you who decides.
That is not simple for most people.
Changes in one's perception of local stimuli and focus abilities are almost impossible to convey to others.
What is an extended period of time in this context? I happen to consume all my meals within seven hours every day and only drink water in between. Would that help?
(Not doing this for health reasons, it is just a habit.)
Around day 3 or day 4 of a water-only fast or (the potentially easier but still effective option of) of a fasting-mimicking diet fast.
It concludes that all fasting lengths are beneficial, and are likely going to result in a) reduction in weight and waist circumference, b) beneficial effects on blood lipids, regulation of sugar and other blood-related parameters, including lower blood sugars and higher ketone body levels, c) an increase in physical and emotional well-being and absence of hunger, d) a high probability of decrease of pre-existing health-complaints, e) very limited chance of side-effects.
[1] https://journals.plos.org/plosone/article?id=10.1371/journal...
How frequently and for how long must one fast to see this?
Did your overall calorie intake remain the same?
This gives zero evidence a threshold has been reached for enzyme activation.
There is evidence of effects after 72 hours of fasting [1]. But we also know of counter-effects around 24 hours, when glucose released by the liver breaking down amino acids from muscle wasting (EDIT: autophagy) partially reactivates mTOR [2]. It could be massive or minimal benefits through 24 hours, we don't know, benefits which reduce between 24 hours and some other number, and then increase until, or until right before or well through 72 hours.
[1] https://journals.plos.org/plosone/article?id=10.1371/journal...
[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390257/?_escap...
Fair enough, given it's voluntary [1]. It's biologically identical to wasting, however.
[1] https://en.wikipedia.org/wiki/Wasting
The original point was autophagy reactivates mTOR. This isn’t a linear system. It could be that a 20-hour fast downregulates mTOR more than a 30-hour fast. (We know it works at 72 hours.)
I even found articles that says it doesn't cause renal failure. I'm sure what you said is some real study just not popularized yet.
I don't know if he's still alive. Maybe it was working a bit too well, I recall he looked like an extremely tall 13 year old with anorexia.
EDIT: I clearly don't recommend you buying this and taking it by the way. You're never quite sure about the purity nor about how to dose this effectively as a layperson without access to a lab. It's also possibly completely illegal, depending on your local laws.
if you mean fasting, say that. "stop eating for a while" to most people would be skipping lunch.
your drive by non-chalant "stop eating" / "stop eating nutrients" is just not helpful commenting the way you are
Maybe it could help you.
That is : periodic blood transfusion from healthy young vegan donor.
It works very well. Rejuvenates ancient billionaires.
Surely it's superpopular among the oligarchs. Probably not the kind of thing you want in the news (vampires!).
The technical term is Parabiosis.
These guys offer the service : https://www.ambrosiaplasma.com/
[2] - French Church abuse: 216,000 children were victims of clergy - inquiry
1. https://www.justiceinfo.net/en/45133-sexual-abuse-church-map...
2. https://www.bbc.com/news/world-europe-58801183
https://knowyourmeme.com/memes/everyday-we-stray-further-fro...
It could be much worse. The bloodboy might pursue a career in advertising.
Not that I think prostitution should be illegal, but it's basically the same thing.
Teen boys are doing skincare routines.
So historically, I’d agree, but now that everyone can be a minor celeb in their own circle I think the youth are more focused on aging.
For context, there have been other periods in history when young men were as focused on their apperance as women, used makeup and obsessed about how they were seen.
Social media gives an outlet for this to those who are not wealthy, but none of it is fundamentally new, it was just confined to those who were able to do it.
Maybe, but I'd be careful about generalizing that kind of thing. Even stuff like consistently applying sunscreen is heavily dependent on class membership, i.e. it's "just what you do, obviously, any time you're going to be outside at all, of course we always have sunscreen on-hand and our kids have been taught to apply it as routinely and consistently as tooth-brushing—wait, why are you asking, doesn't everyone do that?" in some circles, while in other (larger) circles they only break it out for beach or lake days, if at all.
I expect the described behavior is similarly unevenly distributed.
Edit: I ask because I personally don't see a reason to stay alive while people I love are dying, I don't see a reason to stay alive in an already fucked up planet, while we empty all the resources, etc. But you guys are so smart, intelligent and clever, why even bother.
If you die, you're probably not healthy to begin with, or you die to very sudden trauma.
Do you want to live no longer than average, so lets call it no older than 75?
Yes my loved ones will die and that will make me sad. I'll grieve and move on. My life is not theirs - their death does not mean an end to what I am doing.
Flip the problem. If you could bestow a friend/family member with a thousand years, even knowing you will die, would you?
One of the ancient greek prophets declared the apocalypse would happen in 9 generations. She was quite wrong. Most doomsday prophets are (well, probably all but the last one).
I'd like to be healthy enough to help them when they are dying.
""" The scientists have tested different time windows of short-term drug administration in fruit flies and found that a brief window of 2 weeks of rapamycin treatment in young, adult flies protected them against age-related pathology in the intestine and extended their lives. A corresponding short time window, 3 months of treatment starting at 3 months of age in young, adult mice, had similar beneficial effects on the health of the intestine when they were middle-aged.
“These brief drug treatments in early adulthood produced just as strong protection as continuous treatment started at the same time. We also found that the rapamycin treatment had the strongest and best effects when given in early life as compared to middle age. When the flies were treated with rapamycin in late life, on the other hand, it had no effects at all. So, the rapamycin memory is activated primarily in early adulthood”, explains Dr. Thomas Leech, co-author of the paper. """
And here I am wondering what the cutoff is for middle age...
With that said, I would stay away from miracle drugs, because no two human beings have the same physiology. But that’s not an unsolvable problem.
[^1]: It’s a random number to “erase hope”. Not knowing when we are going to die keep us slightly hopeful and perky, our mind away from the problem.
My primary desire for living atm is keeping my family safe, providing for them, etc. Beyond that, i am living just because i am - and i enjoy life as much as i don't want to _not_ enjoy time i'm here anyway.
See also the Planck principle: "A new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die and a new generation grows up that is familiar with it"
https://en.wikipedia.org/wiki/Planck%27s_principle
[1]: https://dogagingproject.org/
I always go back to the SENS concept of having several different problems to solve related to built up damage, cells that won't die, etc.
The basic hypothesis is that cells operate in two modes, one storing up stuff in times of plenty, and a second mode which uses up the stores and cleans up, active during lean times. mTor is supposed to be the chemical signal which indicates which mode to act in; it's inhibited by both fasting and rapomycin.
Now we have vaccines that eliminate a specific form of cancer.
Perhaps we will find a way to pack all the different treatments for the various SENS forms of aging into a single one-time pill.
Maybe it will just be self-replicating nanobots.
What a fascinating time we live in where we can actually start to make educated guesses about the viability and timeframe for these kinds of things.
[1] https://en.wikipedia.org/wiki/Lifespan_(book)
[2] https://lifespanbook.com/
It appears that people fall for his niceness is my theory about him. And no doubt he is a nice guy. It's just that his explanations lacked the rigor I generally look for.
Everything people like Sinclair state should be taken with a grain of salt (as even his peers say he's guilty of making excessive claims) but it's forward-thinkers who change the world, not people following others' steps and afraid to take peek outside their box.
Maybe the guy will achieve something real in the field and maybe it'll be the next guy. No way to know. But I'm far from dismissing someone just because their opinions are not in line with popular knowledge. Boltzmann, Galileo, Copernicus and Wright brothers were discredited or ridiculed.
https://peterattiamd.com/ama35/
It's still an important bit of information if it replicates, but I think it might not be as clinically practical as it sounds from the press release.
David Sinclair got me interested in this topic.
Also people who fast for a long time: How do you do that? I get super hangry and find it really a struggle past a certain point of not eating.
The hardest moment is right when your body is about to switch from using glucose to using ketone bodies for energy. After that the hunger, feeling anxious, etc stops.
The time it takes to get to that point (when feeling "bad" intensifies) and how long the transition takes can be influenced.
Primarily, by what you eat before you fast. In general, avoid eating carbohydrates, especially simple carbohydrates like sugar, fruits, past, bread, etc. I usually eat more protein and fat before fasting.
Another "trick" during fasting is to cheat your stomach a bit by filling it with liquids - I drink lots of water and tea.
The main thing to remember - it will pass, and you will feel great after your body switches. Your mind will tell you that it will just progressively get worse the deeper you get into the fast - it's not true :)
I also use the tricks mentioned above. They are very useful.
Additional tricks:
- Use fiber supplements in your water sometime in the middle of your fast (simplest time is in the morning in lieu of breakfast). I use psyllium husk.
- Soup (or rather broth) is a fasting bff. Remember miso, herbs, spices, salt, do not have calories. Flavor your water liberally. Change up the consistency with stuff in it (green onions, seaweed). Change up the temperature (hot, cold, whatever). I even add psyllium husk to my soups to change up the texture and consistency just for the variety. Remember you can “eat” a lot of tasty stuff while still technically fasting.
- Actively (rather than passively) deplete your glycogen stores. Do a workout ideally including cardio, then do your best to immediately fall asleep to recover. I can sleep through anything, if you can too you’ll be in keto by the morning and no real feelings of difficulty.
- Remember to take a multi-vitamin daily while fasting. Make sure it doesn’t have sugar like those “vitamin C hangover powders” or “electrolyte water stuff like Gatorade”.
Sometimes I can approach 48 hours before I start to feel bad, other times I can't even make it one day before I'm a mess and can hardly function. I'm sure the difference has to do with blood sugar timing and/or what I ate the day before or something.
1. There is some internal clock that we don’t yet understand but clearly exists. Specifically your digestive track proactively activates itself in preparation for food. Then if food doesn’t come, your stomach will “growl”. It takes a 1-3 months for your clock to readjust such that it doesn’t do that. After this you will not “feel hungry”. If you intermittently fast for a year or so, you will likely never again “feel hungry”.
2. Eating meals is a habit. Arguably more addictive than smoking. But like with any habit, it can be broken. This isn’t the feeling of hunger… rather a weird compulsion. If you stop fasting for a few months, this will need to be rebroken every time. I’m currently struggling to re-break it.
3. The social pressure to eat is real! This is the hardest to contend with.
Good luck :)
Different people have different responses to fasting.
It's always been very easy for me to fast by becoming "at peace" with the feeling of hunger for the first 2-3 days, and after that I don't even notice. But later in life something about my body changed and my response to fasting was much more severe and I was suddenly unable to fast for more than 1-2 days due to extremely strong urges to eat, irritability, etc. This happened for 2-3 attempted fasts around the age of 32. A year or two later, and fasting is suddenly "easy" for me again. To be clear, the first 2-3 days usually sucks regardless.
I suspect that I am generally very good at metabolizing fat. When I get blood tests while fasting, even if I haven't eaten anything at all in 7 days, my glucose is generally still well above the minimum of normal, even sometimes towards the high side. I suspect that if my blood sugar was low, I'd have much more difficulty. It does seem to take 2-3 days for my body to "switch" to metabolizing fat at a high enough rate to raise my blood sugar up.
I also suspect different people have very different reactions to low blood sugar.
Just as a note, for me one of the biggest determinants of a successful fast is control over my environment. If there are people in my home cooking great food every night at the same time, it's very hard. If I'm living alone and let my fridge get empty, it's much easier. I've also dealt with it by shifting my work hours to leave later and come home after my partner has finished dinner and cleaned up the kitchen. But this is orthogonal to the above issue.
I'm currently taking 2mg once a week on my rest day; I started with 1mg and after 1 month added another MG. I'll continue each month until I reach 8MG once a week, which is the dosage the doc I worked with in Texas to get my prescription recommended and most people seem to take.
Also - I would say that NMN + Rapa is a completely life altering combination for anyone 50+. I feel like I can lift harder and longer now than when I was in my 40's and things seem to be getting easier the farther into my rapa routine I get.
Also also - you can find rapamycin online / overseas under its other name - Sirolimus - and the cost is a little lower than getting a proper US prescription.
I read up ok it. It can literally cause cancer.
This website is known to the State of California to cause cancer.
Note also:
> We found that, when data from all organisms studied were combined for each compound, aspirin resulted in the highest percent increase in average lifespan (52.01%), followed by minocycline (27.30%), N-acetyl cysteine (17.93%), nordihydroguaiaretic acid (17.65%) and rapamycin (15.66%), in average.[0]
Though I'd consider whether flies and worms are good models for your human self.
0: https://pubmed.ncbi.nlm.nih.gov/34687363/
Even other vertebrates don't share the human cancer model, so people are absolutely jumping the gun assuming that this generalises to us.
But I'd imagine (and hope) that it's mostly laymen (and quacks in the supplement business) that are pushing the notion that the evidence is in?
I feel compelled to comment though because anytime I read about how this stuff is only been tested in worms in mice… That automatically discount it’s worth as something to consider.
I’m gonna sah what I said before - I’ve played high-level hockey my whole life, I’m now 55 and I play against guys that barely washed out of their pro career.
When I stop taking nmn for two months my speed dropped from 20+ Mph to the mid teens.
A week after resuming my NMN supplementation my speeds are back in the 23-24 mph range
There’s just no way to fake it against players of this caliber. And to be clear I don’t know anybody even close to my age competing at this level.
https://khn.org/news/a-fountain-of-youth-pill-sure-if-youre-...
The drug has been known for a long time but human trials always seems elusive
Human trials of this will likely never happen. At least not publicly.
Clinical trials are expensive, and rapamycin can't be patented. My guess is that, some time in the future, a pharma company will produce and patent an analogue, and then there will be trials.
https://neurosciencenews.com/rapamycin-amyloid-beta-20770/
https://en.m.wikipedia.org/wiki/Sirolimus
Not sure I agree with your analysis. If I had a vacuous and unfulfilling life, I wouldn't strive to prolong it.
Anyway, I am tinkering with something in that space - feel free to reach out if you want explore being a co-founder. (email in about)
What can you tell me about it?
The problem is, no one wants to do those trials because rapamycin is cheap and generic. Why would Pharma spend money on something that they can't patent? Also, these kind of trials have to go on for 10+ years at a minimum - which is cost-prohibitive even if it is patentable (not to go in the weeds, but long trials count in the period of exclusivity given to pharma patents).
I believe the right approach is to use it off-label, be upfront about the potential risks, and collect lots of data so you can improve as you go. Practical anti-aging so to speak.
Another approach is through the NIH grant pathway, but that has a lot of road-blocks as well.
Same issue with psychedelics. However, they are so useful that people in the medical/therapeutic/academic fields are doing tons of research anyway.
Apparently big pharma is also trying to create their own psychedelics (there was an article about it on the front page of HN recently).
So far, the business seems like it will be on the assisted therapy side and everything that it entails. So more like services instead of products.
Wouldn't they want to get treatment costs down? Large HMOs, especially, have motivation to control treatment costs, and access to the patients, data, etc... to make it work.
The key thing is more care = more dollars = more in the bank.
One response to that legislation was insurers buying care providers.
https://www.lifespan.io/campaigns/pearl-participatory-evalua...
Off topic, but whenever I think about this, I find myself thinking that what the world really needs is next-level human/medicinal modeling. Imagine if human trials didn't have to happen in order to know the long-term effects (and in a fraction of the time)!
It seems pretty safe anyway from my understanding…
On the contrary, the protection of the intestine to aging effects was due to increased autophagy in the intestinal cells, which eliminated the defective cells, and by increased levels of antimicrobial lysozyme, and these effects persisted long after the initial treatment ended.
Edit: it's an opinion article https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814615/
We can turn those parts off, while leaving everything else on, and be better for it (no allergies, psoriatic arthritis, MS, Chron’s, etc.; and so none of the accelerated cellular senescence those conditions provoke in affected tissue.)
A lot of recent pharma is already focused on doing specific forms of this at low levels. Every other drug ad in the US is for an immune-receptor blocker of some kind. And the side effects of these drugs come down mostly to the fact that they’re too low-level — they stop these parts of the immune system from being called into action at affected sites, but they leave it active and “patrolling”, such that it attacks harder any tissues that don’t absorb the receptor-blocker well, and such that you get withdrawal effects of potential inflammatory crisis if/when it wears off.
Just deactivating the relevant parts of the immune system entirely, on the other hand, provides the same benefits these drugs do, but with none of the “now the rowdy enforcers have nothing better to do, so they go looking for trouble” drawbacks.
For the average human on Earth: sure, merely uncommon.
For the average person who lives in a city and rarely goes out into nature, and paranoid-ly avoids doing things like walking barefoot in dung or wearing shortsleeves in forests when they do: effectively never.
There's also no reason to think that the immune system is so easily split up between systems that respond to parasites, bacteria, and virii. While a human designer might think that way, in nature most things are messy and have tons of overlap. This is true of the immune system. For example you can measure C-Reactive Protein and use it as a thermometer for general systemic inflammation. But elevated levels could as likely be a cold as a particularly intense workout-- they'll both trigger strong immune reactions with lots of overlap in effect.
Well, sure. We essentially have multiple "immune systems", with overlapping goals. (Sort of like having both an anti-virus and anti-spyware scanner installed, as well as a system integrity checker, secure-boot verification logic, etc.)
Some immune responses are good at stopping all sorts of things (e.g. xenoreactive antibodies, which attack both parasites, bacteria, and cancer cells.) I wouldn't suggest doing anything to these. Conveniently, these processes don't tend to cause many long-term health problems, save in edge cases (e.g. xenograft implantation.)
Other immune responses are more specialized. And — also conveniently — it's the reactions/systems that specialize in responding to things we see almost none of in "city living", that seem to do bad things for longevity.
Parasite-specialist immune cells (mast cells), for example, cause a lot of chronic inflammatory problems. We've been preventing mast cells from doing their jobs for a long time now — that's the point of taking antihistamines — with very little negative to show for it. I don't think it would be much of a stretch from there to a treatment for allergies that's just a siRNA that "NOPs out" the entire immune-response functionality of mast cells. (Or even a "permanent" treatment for allergies, via CRISPR gene edit to rub out the definition of mast-cell antigen recognition receptors from the body's vocabulary.)
And I would also say that it's not much of a stretch to hypothesize that people who had this done, would, under longitudinal studies, show increased longevity / QUALYs. "Never having an [even sub-clinical] allergic reaction" would do really good things for the body. At the cost of — for most people reading this — just having to avoid sashimi.
Which is suggesting Ashwagandha might a candidate for Rapamycin and Metformin mimcry.