Rapamycin: The unlucky history of an anti-aging drug

> A number of studies assessing adherence to diabetes medications in patients with type 2 diabetes have reported that metformin has the lowest adherence rates when compared with other OAAs.

(A) The body of research is, in general, large and uncontroversial.

(B) The safety profile is good. The benefits for diabetics are certainly large. Probably no drug has been studied for anti-aging effects as extensively as creatine has been for fitness applications, so I'm not sure anything can fulfill that criteria. But it seems like the present research on metformin supports a variety of positive effects for non-diabetics with more on the way.

(C) I wouldn't know whether the majority of people who are serious about anti-aging use it but it does get mentioned a lot.

Pretty positive endorsement overall!

Do you mean "don't eat excess fat" or "don't have excess fat on your body"? It's not clear to me from the context.

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...)?

It's pretty obvious older people who have kept their fitness (cardio & strength, not just one of the two) up and their weight down their entire lives have profoundly higher quality of life.

That requires a totally different lifestyle from the standard "geek lifestyle" though.

Nutrition is difficult to get right because of the contradictory and plain harmful information that we have been receiving for so long.

For example: is fruit juice "healthy"? Not really, when you consider that you are far more likely to consume way more fruit that you otherwise would, and a lot of fiber content is removed. We are unlikely to eat 10 oranges in a row, but that's easy in juice form. That's without extra sugar - if sugar is added, then it's just a soda with added nutrients. And the problem with that is that fructose is only metabolized by the liver (turning into triglycerides), with a mechanism that's comparable to the one used to metabolize alcohol.

We have been told that fat is bad. Due to consumer demand, the industry start removing fat content. But then things taste horrible, so the solution was to add sugar.

So now we are worse off: not only we are consuming a lot of sugar (75% of all products in the supermarket have sugar, including 'salty' ones), but we haven't even attacked the problem that prompted fat removal (increase in heart conditions) in the first place. Fructose in particular turns into triglycerides, and gets stored as fat(with uric acid as byproduct, with way more free radical formation than glucose, and it even uses up ATP). It didn't address the heart issue, and actually made it worse. People have become far more obese than when they ate fats, as fats (plus fiber) make you feel full for longer. It also screws up hunger hormones and sugar is addictive by itself.

Or let's take bread. White bread is starting to get considered harmful, but then the alternative that's pushed is whole bread. It matters very little. If that's all we ate, we could have some bread, as our ancestors did. But in combination with all other crap, it's way too much sugar.

If you eat cereal for breakfast, some rice and beans for lunch with a glass of orange juice you have already exceeded dietary sugar limits by a lot. And that's a far, far healthier diet than what's done in the average household.

Whereas if you had an avocado for breakfast, meat and vegetables for lunch you would be in a far better shape (literally and figuratively) even if the second diet had more calories. Calories are not all the same, and calories contained in food are not the same as calories absorbed (or stored). We accept that, when we fuel our car, a bunch of energy in the fuel will be wasted. Somehow, when we count calories, we assume we'll absorb them all.

The end result is that we are prematurely aging (due to all the oxidative stress), getting diabetes, non alcoholic fatty liver disease, high blood pressure, gout, cardiac problems. Possibly even Alzheimers (research ongoing, but there's growing evidence) and a few types of cancers. Also oral health in general. Basically, most of the mortality these days is directly or indirectly linked to sugar and insulin resistance in general. 88% of Americans have some form of metabolic dysfunction.

> no excess fat

Too much fat is usually the symptom of a disease (generally metabolic illness). Just fat, by itself, can be ok(also depending on where it is) – there are fat people who are otherwise healthy (a tiny minority, but they exist). And there are people that are thin but otherwise unhealthy (TOFI, Thin on the Outside, Fat Inside). What commonly happens is that we get sick first (insulin resistance) and then we get fat. For most people, being obese is the symptom, not the cause.

Diabetes does not strike out of the blue, although if you ask most people, they got "surprise" diagnoses. You check your glucose levels, and they are normal. You keep checking them for a few years, they are normal. Then "out of the blue" they are outside limits, and you get a diagnosis of pre-diabetes (or full blown diabetes). What was missed all these years was that your body was fiercely fighting against the glucose increase by raising the amount of insulin produced. But there's only so much the body can make (and also the cells will be resisting that), at some point, the combination of not being able to increase production plus resistance will be too much to overcome. Insulin measurements are not part of standard bloodwork yet, but at least they are now including A1C.

Completely drop added sugar. Reduce sugar in all forms, added, "natural", it doesn't matter. A sane amount of fruits is ok for their other benefits. Increase the amount of fat and fiber. Hydrate. And then drop processed foods in general. That's how we survive until 'anti-aging' is available.

https://pubmed.ncbi.nlm.nih.gov/19741313/

To be clear, no one is arguing that Creatine causes hairloss, simply that it exacerbates hairloss in people with so called androgenetic alopecia.

I recall a study that was set to try and replicate these results, but I worry that it was impacted by COVID. If anyone else can find it, I'd be very interested to see it.

Honestly hard to say, because that doesn't immediately "disprove" it either....

Health aside, it is hard to stress how much better I feel on ketones, relative to carbs.

(see the rating + probability of positive effect charts here. [Warning, this is another insane rabbit hole of research to fall into!]): https://troof.blog/posts/nootropics/

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.

If something else is helping the tumors grow faster than the body can kill them naturally - then it's going to result both more severe tumors AND more tumors in general (as we discover them, since we usually don't know about tumors that form and get destroyed by the body naturally).

Not everyone needs NR necessarily (or any of the other forms), but it does seem to get more important as we get older and our ability to manufacture NMN goes down (IIRC that's the main target that's limited here?)

For now, I'd rather bet on very clean air, very clean water, fasting, organic vegetables, green tea, omega 3 fish oil, well monitored sleep, and lots of exercise for longevity.

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.

There is definitely "real" randomness, DNA replication errors are truly random because they are caused by quantum molecular effects. You can characterize them statistically and reduce their incidence, for example by controlling the diet or shielding the body from UV, but you can't measure those causes, only observe their effects. At best you could correct them, starting from a known-good-copy, as indeed cell biology already does.

Sure, that's entropy, but that's only necessarily true at the level of the whole system, energy inputs can and do reduce local entropy.

> The best you'll get is extended life

Sounds good, let's start there. 'True' immortality may or may not be a pipe dream, but it doesn't matter if it is. Almost nobody is talking about living absolutely forever, but looking at ways in which greater longevity can be achieved. I'd bite your hand off for another couple of decades on top of whatever my current 'allocation' might be, I don't give a crap if we've "conquered death" or not, but if we can find ways to give the average person more time, that seems like a win.

> Better that those resources go to something more productive, like healthcare.

How is this not healthcare?

There seems to be this backlash against any talk of life extension, that other things matter more, that it's somehow frivolous, or just morally wrong to seek to live longer. It feels to me entirely arbitrary as we already use all sorts of interventions to help people live longer, and to be healthier for more of that time. This is good and wise and virtuous. But some folks seem to have this weird switch in their heads when extending life gets mentioned, that suddenly they're uncomfortable and the whole thing is not to be discussed by preference.

And I wonder if it's because they don't want to admit to themselves or others that they are terrified, but have rationalised away their fear as "meant to be, can't be changed". Such talk of extension makes them uncomfortable.

Anti-aging science is basically the most audacious preventative program out there. It is not really about "immortality" (even if this level of success were to be reached, one can always kill themselves, no biology will give you immunity to fast flying bullets), but an attempt to prevent or at least delay onset of a host of chronic diseases that are synonymous with aging.

"but the problem is that it gets rolled up with immortality"

Then don't contribute to that problem by insinuating that anti-aging is something different from healthcare. It is not, it is literally about extending healthspan, at least at this point. Rejuvenation means making people live longer by improving their metabolism etc.; how it is not healthcare in the best sense of the word (protecting health instead of treating already extant diseases)?

"Everything dies, or breaks down, or decays."

And yet you can keep your room tidy for long decades even if the entropy of the universe as such increases.

We have a lot of self-repair mechanisms, that is why we live longer than our relatives like dogs and mice. "The universe" does not dictate to us whether to get cancer or not; some species (like whales) seem to be very resistant to cancer and it is absolutely thinkable that we could acquire this ability too, if we happen to learn enough about metabolism. Etc. etc.

Human death at 80 isn't a result of laws of physics, any more than murine death at 2,5. It is a case of biological dysregulation that can possibly be fixed or at least improved, much like we improved other things about ourselves. Few of the HN crowd would proclaim wearing glasses to fix your vision to be unnatural. What we are looking for in anti-aging are "glasses for the body".

> "Yes, and so do you," said Harry. "I want to live one more day. Tomorrow I will still want to live one more day. Therefore I want to live forever, proof by induction on the positive integers. If you don't want to die, it means you want to live forever. If you don't want to live forever, it means you want to die. You've got to do one or the other... I'm not getting through here, am I."

It would be interesting to see how society will change when we can make ourselves permanently healthy. Maybe people who want to die will start taking extreme risks like sky-diving or Russian roulette but the above quote stands imo. If you don't want to live any more sounds to me like you have a psychological problem. I don't mean that 80 year olds, that have a dozen physical problems and struggle to do anything and therefore want to die because life is unbearable, have a psychological problem but if you're young, healthy and still find no pleasure in living then maybe you should see a therapist. Maybe the psychological part of living forever needs to be solved too

Most people don't want to die. I want to learn more, and indulge curiosity for another day. I want to laugh and love and see my family forever longer - I don't think I'd ever wish to leave my loved ones, and I will unsurprisingly mourn their loss. I assume I'm not particularly special in any of this...

I think the sudden onset of immortality (especially concentrated on the wealthy) will be catastrophic for society. Imagine Bezos or a Kardashian or someone politically motivated like Murdoch/Soros but immortal? Imagine them being able to spend (and grow) generations of wealth... for generation?

For the rest of us, the cost of an opportunity to be immortal will be massive because of course it can be. People today save for retirement, but one day they may save for immortality - or perhaps take out insane loans to fund it. Imagine real estate prices when banks can offer 100y mortgages to a class of rich immortal workers? Imagine trying to advance in your career when someone can get a senior job and work for hundreds of years, especially if they need to fund their 100y mortgage or their immortality procedure - Millennials already complain that boomers won't retire and open up the higher-rung jobs.

Immortality would upend society, and likely exacerbate social tensions, but it could also be a great reset in social expectations. Maybe it'd encourage everyone to take a long-term view of their actions. eg. Climate change would impact everyone, so no one would be "too old to care".

That's what anti-aging is.

So you can imagine that rather than see another sunset, you'd die?

You can imagine a state of being where you become so jaded, so incurious, that nothing can pique your interest any more, that interpersonal relationships would be better off terminated with biological death than continued, that learning, travel, discovery all lose their meaning and value?

Honestly, as with many of these comments, I feel it says more about your present life than those who would like to live longer or indefinitely.

And I certainly know people in their 70s who are not ready to settle down and be fitted for a coffin yet, even if their bodies are starting to seriously disagree. I don't imagine they would turn down the chance of a few more decades of relative fitness.

>Just a never-ending cycle of expensive, likely painful, time-consuming all-consuming patches on the body to delay the inevitable.

So I take it you never visit a doctor or dentist? After all, going to the doctor to get that mole checked for cancer, or getting your teeth drilled to prevent an infection that kills you is unnatural.

Even if you don't consider yourself important to the world, surely you are important to yourself. At least I as an atheist consider my limited time alive here— conscious and healthy— to be infinitely valuable to me personally as it's really all that I have. And I think if your life isn't valuable to you in the same way, there's something wrong. Hence, extending it is a worthwhile goal.

Longevity research is difficult and it's not as if a breakthrough improving our lifetime by an order of magnitude is around the corner. So, I see little risk in ambitious research that'll probably only yield humble results anyway, at least until we're reaching 200 years old.

And telling other people when they should die is sorta messed up. Ignore these anti-aging medications, should people be cut off other medicines at a certain point? What's the difference?

The entire medical (and dental) profession is all about keeping you from dying when you're "supposed to". You're supposed to die in your teenage years of a tooth infection, or in your 30s or 40s of cancer, or any random age of an injury.

People in rich countries live much longer (and healthier) than people in poor countries because of access to modern medicine.

So apparently you think people shouldn't have access to any medical services?

I feel miserable just trying to imagine why a person would think this way. I'm grateful I don't have this kind of psychology.

The rest of us will support the relevant research, and use the results to remain young or to be young again, possibly lasting for millennia.

> Time is the great equalizer

Yes, totally, we all get to live exactly the same amount of time, so it's perfectly fair. Also that fixed term life deal is the perfect amount of time by definition, so we should never, ever try to change it.