Combination of Rapamycin and Acarbose significantly Extends Lifespan | Hacker News Reader

Combination of Rapamycin and Acarbose significantly Extends Lifespan

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Like the joke says, if you're a mouse and still have cancer, diabetes, or Alzheimer's, you need a new agent.

I am currently undergoing gene therapy to turn into a mouse. All my problems are solved.

Previous links and discussions on Rapamycin and Metformin:

Rapamycin, drug used in cancer therapy, emerges as powerful anti-aging remedy [1]

Rapamycin extends life span and health span of male mice and Daphnia magna [2]

Drug typically used in cancer therapy emerges as potential anti-aging treatment[3]

Diabetes Drug Metformin Reduces All-Cause Mortality and Diseases of Aging (2017)[4]

Metformin for cancer prevention, longevity: popular in Silicon Valley[5]

[1] https://news.ycombinator.com/item?id=32660669

[2] https://news.ycombinator.com/item?id=33058322

[3] https://news.ycombinator.com/item?id=32648886

[4] https://news.ycombinator.com/item?id=27486841

[5] https://news.ycombinator.com/item?id=19472942

My understanding is that Metformin's mortality reduction effect is only present in younger people. I don't have a source handy, but I take it for diabetes and was reading about its other positive effects a few years ago. Perhaps someone can chime in with additional information.

I'm interested in how ultra-low-dose (or "sparse" regimens) affect things (before you get triggered by homeopathy, I'm not making regard to that here..tho doesn't mean in some cases it can't be effective). For example, ultra low dose minoxidil (a blood pressure drug) reverses hair loss in many people (not if you're totally bald, but in thinning areas) at dosages where it's "on-label" effect (lowering blood pressure) doesn't even occur. I wonder how ultra-low-dose (or sparse, like "1 timer per quarter") metformin affects things.

I can't recall the compound now, but I recall seeing something the other day about: "encounter with compound X just one time permanently strengthens immune system" or something. I think it was also in mice. I'm not even sure it was "immune system".

Also want to note that: our current pharmaceutical industry of (mostly) single molecule therapies is just one slice of the pie. In the future, we will probably have access to therapies that seem really sophisticated: not just "concoctions" (of multiple compounds in one therapy, which currently we are not sophisticated enough to explore sufficiently so the space of possible interactions that are therapeutic remains unknown); but also more "active" therapies, that include some vector (like virus, protein molecular machine, funghi, bacteria) that help to deliver / manufacture the therapy to just the right: time, location, amount our body needs.

And rather than being a specialized minority, they will be the majority. I think the space of molecules that are effective when delivered "systemically" is not as large or contains as many "silver bullet therapies" as the space of therapies that is effective when delivered precisely.

Rapamycin side effects don't look great tho: https://en.wikipedia.org/wiki/Sirolimus#Adverse_effects

I prefer drugs that are: well-tolerated, cheap, already have a long history of use for conditions X, Y and Z, and then discovered as an off-label therapy (maybe in combination) for something else. As a heuristic it may not always work, but I think a good sign / rule-of-thumb might be "on the WHO list of essential medicines"

You won't do it at the same doses as cancer treatment protocols .

I've been doing rapa for my mood issues stemming from inflammation for some years now and low doses similar to the doses seen in recent studies for age longevity with no apparent side effects .

Would be interested in your experience with fluorometholone eye drops. On-label for itchy eyes, but off-label seems to rapidly (onset ~ 60 seconds) reduce brain inflammation temporarily leading to mental quiet. Can't use too much tho as the steroid will dull the immune system in your sinuses increasing infection risk.

I have never used it but just like you explained Steroids will have that effect

You can join the discord server run by joshua leisk and mention fluorometholone and I'll find you so we can see what might best work for you

https://discord.gg/2HwvnxEn

I don’t know how to ask this neutrally, but how did you (and a doctor?) come to use an anti cancer medication for mood stabilization?

A large amount of rapa was bought during a group buy

It was devided up between people who couldn't afford or get it

To be clear its not specifically an anti cancer med it's an immune suppressant. It targets mtor so it's great for autoimmune disease

The group I belong to specifically are people that have diseases that couldn't be treated either because of financial reasons or because docs wouldn't prescribe meds off label so we resort to such methods .

So no actual medical professionals involved. Got it. Please start your comments with that, though. You do you, but last I remember I’ve never seen a single person who desperately tried to live long actually live long.

I'm not doing it to live long . I have an autoimmune disease that's killing me .

I can't afford the meds so this is the only way I can keep being alive

I wish you to be able to have access to it now and in the future.

I have friends with such diseases and wenn I read the line "I can't afford the meds", it always punches me in the belly.

I'm not sure why you didn't take the time to read the comment you replied to, but still, if we modify your statement a little:

> I’ve never seen a single person who desperately tried to live long actually live long

to I’ve never seen a single person who desperately tried to live longer actually live longer it changes from something you can't believe to a statement we know to be false because we see people achieving it every day, and that's what @jokowueu is attempting to do, and good luck to them.

The vibe I get off of Aubrey de Grey is not here’s a man who wants to live forever, so much as here’s a man afraid of dying. And these days he’s starting to look like an origin story for a lich. He’s 5% ghoul and climbing. He needs Buddhism, not anti cancer drugs.

Once in a great while I see a movie character who wants to see how the story ends. Most of the rest and most of the real humans want to cheat death, which is a very different sentiment.

I know someone who played Russian Roulette once and is still alive. Getting lucky and risk taking have been best friends since the dawn of time.

Side effects don’t hit everyone and they don’t hit everyone the same. I’m on the absolutely lowest dose of a prescription drug because I react strongly to it. First dose had a really unpleasant side effect, lower dose got rid of that one but another developed later. It wasn’t particularly bad, I just found it upsetting. Lowest dose still gets most of the benefit without the side effects. For me. I know of someone with panic disorder who has a long list of drugs they can’t take at all because “feels funny” is enough to trigger an attack. We suspect vagus nerve issues of some sort.

Better than dying of old age though.

Metformin doesn't look so hot either: https://www.science.org/content/article/rare-genital-defects...

I think at this point not putting "in mice" in an article title like this is just dishonesty.

I just went straight to the comments looking for "in mice", not disappointed

I "yelled" IN MICE right after reading the title, went to check the article, and sure enough...

But yeah, it seems 100% deliberate because most people wouldn't probably care after reading the title. It's academic clickbait techniques.

To be fair, there is little choice for any such study to be done on anything else but mice, because of their short natural lifespan.

Even if there were human volunteers willing to test on themselves various cocktails of chemicals, such a study would take many centuries.

Also on monkeys any study would take much too long.

So until aging in mice is well understood, any tests on monkeys or humans are pointless.

It is unlikely that the aging mechanisms differ in an essential way between mice and humans. If the aging in mice were understood, finding how it functions in humans would need far less work than for discovering how it functions in mice.

The problem wasn't that the study was done on mice, it was that this piece of information out was left out of the title. I agree with the OC that its deliberatively deceptive, unless of course this article was in 'The Journal of Mice' in which case it would be ok.

Your last point needs to be emphasized more. The core mechanism of aging is likely to be very similar across species as aging affect all tissues, organs, etc.

I think so too. And particular drugs that work in mice might not work in humans, but what those drugs tells us about aging in mice will help us understand aging in humans.

AFAIK, the question of why our lifespan is so different from other mammals is still open. And one quite possible answer is still that our aging happens by a slightly different mechanism.

The lifespan of humans is not completely different from other mammals.

The lifespan of humans is less than twice that of our closest relatives, and probably there is no coincidence in the fact that about the same ratio exists between the maturity age of humans and that of apes.

Aging in humans does not seem to have any qualitative difference, it just happens slower, like also the maturity.

So, compared to the most similar animals you can find, we still age half as fast. That's pretty unusual if you ask me.

Besides, the apes in general age in an unusual way. All take too long to mature compared to their lifespan, and all have too long a lifespan compared to their size (the mammals have a rough correlation between lifespan and size). Yes, we are merely at the extreme of that weirdness, not in a new category of weirdness. But it still means we are different from mice in some way.

It is unlikely that the aging mechanisms differ in an essential way between mice and humans.

[citation needed]

A citation is needed for the contrary statement.

Aging has appeared hundreds of millions of years ago in the ancestors of all multicellular animals and it manifests in the same way in most of them.

There is no known reason for aging in a way to be replaced by aging in some other way, like e.g. respiration through gills may be replaced by respiration through lungs, especially when we discuss some closely related mammals which have not diverged significantly in their way of life.

There are a few animal groups where more significant alterations in aging appears to have occurred, e.g. which have an unusually long lifespan, but whatever has changed seems to be restricted to those small groups.

There are no great divisions between animals where you could say that one group has a modified aging, like they might have a modified digestive system, enabling them to use a different food.

So until a contrary proof, the most plausible supposition is that aging happens in the same way in all multicellular animals, with minor differences, caused e.g. by more efficient cellular repair mechanisms in some of them, or by a "programmed death", i.e. suicide, which happens in many animals after reproduction, or in some colonial animals before a season when there will not be food for all of them.

Yes, and the closer the evolutionary relationship, the closer you would expect the biochemistry to be.

A result in yeast might not apply at all. a result in fish might be something worth investigating. A result in mice has a good likelihood of applying to humans. A money study would be a close match.

They've been studying Acarbose for awhile now

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8789153/

The problem with a lot of these longevity approaches is they "solve the problem" by reducing energy conversion, like acarbose, pulling people to a baseline and preventing stress adaptations.

Great for sitting around. The opposite of that for doing anything athletic, you'd never improve.

What does that mean, preventing stress adaptations? Does it mean that the body wouldn’t get stronger in training ?

Right. Some of these potential longevity interventions seem to have a catabolic effect. Not a problem if you're a mouse living in a safe, flat lab cage. But problematic for an elderly human at risk of falling down the stairs and breaking a hip due to sarcopenia.

Is it strong enough to actually cause that, or is it the kind of thing nonathletes won't notice?

Or is the life extension effect too subtle to be relevant at all outside a flat mousecage?

It's just a general trend. The strength of the catabolic effect will depend on the specific intervention and dose. The risk is greatest for non-athletes because they tend to be weaker to start with and more likely to experience disabling falls as they age.

That is really interesting. I hadn't heard that, but it makes a lot of sense.

There is some evidence that "aerobic exercise" itself produces an equivalent baseline energy deficit without the performance downside.

This guy[0] studies total average energy expenditure over time and demonstrates that an athlete undertaking intense regular exercise uses marginally more energy over time than someone sitting on a couch all day. The hypothesis being that the athlete is conserving energy by down-regulating baseline metabolic and inflammatory processes when at rest.

Disappointing news for "exercise causes dramatic weight loss" but encouraging news for "exercise is anti-cancer" (a correlation demonstrated many times I believe).

[0] https://www.science.org/content/article/scientist-busts-myth...

I have seen this study before, but I can't see how this gentleman's work disproves the huge body of health and fitness research that comes before it. It's an interesting outcome for sure, but the idea that it suggests exercise is a bad weight loss tool doesn't seem to reflect reality. The long term outcome of exercise is a changed body composition, which itself can contribute to changing metabolic rates.

I think it points to an interesting insight, something we have yet to uncover perhaps, but I don't think it disproves that exercise spends energy. Maybe all it's really proving is that we are very efficient at the chosen type of exercise in the study.

Exercise causes weight loss only in that as you want to get more fit you start watching what you eat, quality and quantity, more carefully.

As a lifelong runner I know I only burn 80 calories or less per mile, that's nothing.

However exercise does things that no supplement or drug can do, proper AMPK and cAMP activation, endorphin and endocannabinoid release.

I have just gotten my resting heart rate back down to pre-quarantine levels. I don’t know how many days I shaved off my lifespan from all that sitting around, but I’m a little bitter about it.

Guess we'll figure out how to make mice immortal sometime soon, and sadly realize that the drug cocktail doesn't work on humans. Then the meek mice take over the earth as humanity dies off...

Presumably the mice would still need humans to keep producing the drugs that keep them immortal. But if immortality was a genetic trait passed on to their offspring then we’d be in trouble!

This future is oddly more comforting to me than Skynet.

And dogs too!

https://dogagingproject.org/

Is there progress in the research to transition from human to mouse?

https://archive.ph/Uaeza

Please add the expected [in mice] mysteriously missing from the headline itself

Props to the authors for choosing the subheader: "This effect was shown in mice."

I remember there being a lot of noise a few years ago about resveratrol, and how red wine (but only of a certain grape) was the secret to long life. What happens if you make the wrong decision and go all in, drinking wine and gobbling grape seeds, while it turns about to be something else entirely and you missed the boat? There’s no end to it, especially as there are only two real solutions that work, extreme caloric restriction and young blood transfusions(i.e a personal “blood boy”, humorously depicted in HBO’s Silicon Valley).

rapamycin triggers the same effect as extreme caloric restriction. Neither of the solutions you mentioned have been scientifically verified in humans.

Longevity research itself hasn't been around long enough to verify ANY longevity hypothesis on humans.

… in spite of being around for millennia.

The scientific method came around 1600s. Statistics existed in 1662.

Science itself has not existed for a millenia.

Longevity research has, though. Philosophers stone, fountain of youth, these are the same things we seek today, through new means.

Doesn't count as research imo. It's more speculation and musings. Research requires actual science.

If genuinely interested and not being tongue in cheek, there are a number of drugs and pathways that can be targeted to (in theory) extend lifespan in mammals. So as others have said- it may be that future therapies include a concoction of drugs and interventions to effectively increase lifespan in humans. If you’re curious about the subject Dr. David Sinclair does a lot content around this. He’s a researcher in the longevity field. He’s a little out there in terms of his personal beliefs but he does provide a lot of inform and context around all the current hot topics in longevity research.

Whenever these immortality drugs come up, I always envision some kind of old, rich guy who dedicated his life to becoming rich, finding out that all that money won't buy you a second youth when it's already too late to do all the things he wanted to do. Multi millionaires getting rich, forgetting to live, and then focusing their wealth on a pipe dream of living long enough to spend all their money.

Ever since the first days of medicine, people have sought to prolong life. I think the entire quest is misguided and a waste of the medical field's resources; finding the cure for cancer and other horrible diseases should have priority on making some chosen few live to 100.

Even if the drug does work on humans without making life worse through side effects, I think the end result will be quite dystopic. You end up with a drug the rich can afford quite handily, while the poor will need to work their asses off for decades longer. Unless the drug is free, this will only serve benefit the top 1% of the planet and the pharmaceutical companies selling these drugs. As mankind struggles to accept mortality, the pool of workers will grow, led by drug companies telling them just a few decades years of hard work will surely make them rich.

If you were drinking red wine for resveratrol you were not doing much research.

I want to add some nuance to this:

Resveratrol probably doesn’t do anything. This same research group actually studied it on mice. If you were gobbling it, you’re neutral. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3598361/

Young blood transfusions may work, but the research is certainly still thin. Interestingly, removing old blood seems to be the actual benefit, not the addition of young. Source: https://www.science.org/content/blog-post/young-blood-and-ol...

Extreme caloric restriction reduces lifespan, but there does seem to be a sweet spot of restriction that lengthens it.

None of these things are proven in humans however and we don’t really know the side effects. Do they give you dementia? Do they make you dumb? Unlikely, but we just don’t know.

To me it does look a bit comically like searching for the philosopher's stone as an ancient alchemist. If it's found within your natural lifetime you will be dead before the research is complete; by definition it will take longer than an average human lifespan. Mice only live a year so they are pretty quick and easy to study.

Or become a test subject and get lucky.

> If it's found within your natural lifetime you will be dead before the research is complete

I'm 30. If it takes another 30 years, I'll be 60. That's late, certainly, but I could still avoid a lot of health issues if I'm able to start taking something then. Most older people I know really start to degrade around their 70s and 80s, often after some sort of health incident or chronic issue crops up.

And if not, ok, well then some younger people in a generation or two will benefit and I'm happy for them.

I’m very confused. Rapamycin upregulates autophagy, which is a popular theory about strengthening the body by killing the weak cells. Ok. But it’s prescribed as an anti-rejection drug. Those two things don’t dovetail in my mental model.

Rapamycin is the word I keep hearing in 'health and wellness' communities online and on podcasts.

I think this guy is the most vocal about it

https://peterattiamd.com/rapamycin-risks/

https://twitter.com/mkaeberlein/status/1428740546177105922

Low effort post, but, it's almost as if we're working towards this end game: https://youtu.be/y5xcvAoKojo?t=223

dose: mice were fed a diet containing 14 ppm rapamycin (mTOR antibiotic) and 1000 ppm acarbose (diabetes drug) for three months

If you hate aging (who doesn't), SENS Foundation[0] is dedicated to engineering solutions to reverse it.

0. https://www.sens.org/

People in SENS kicked out Aubrey de Gray for a ,,grooming” email and took over control of the donations that were sent because of him. I do not condone his previous action, but I also think that kicking him out to take over millions of dollars was not an unselfish action.

He is in the process of setting up a new foundation where I expect most of the new donations will flow.

There was some drama[0], but did they really[1]?

I guess there's his twitter account[2]. Wow.

0. https://en.wikipedia.org/wiki/Aubrey_de_Grey#Sexual_harassme...

1. https://www.sens.org/about-us/leadership/

2. https://twitter.com/aubreydegrey

Rapamycin is a potent immunosuppressor... yikes.

Totally misleading headline

I get why people are facinated by this sort of research, but pick your favorite nasty person, such as Putin, and consider what it would mean to radically extend their life.

People in in Congress (an oxymoron) would be there even longer as they generally have to die to get kicked out. The longer they're there, the less they care about you and the more they'll care about their long lived fellow travelers.

Says more about the broken system(s) then the danger of long life's.

What systems are not broken?

Someone should inform the lab mice that they'll be living longer than before.

I don't think we should burden them in that way. It's hard enough being a lab mouse as it is.

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