Is Rapamycin Dead? (Kaeberlein)

#29

Photos need to be taken under controlled circumstances if you want to obtain useful information.

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#30

As another data point, I take rapamycin the day before a GLP-1. I worry about the slowed gastric emptying affecting how the rapa works. The day before the next GLP-1 dose seems like the time gastric emptying is back to baseline, so I take my rapa then. I have not noticed the rapa interacting with the GLP-1. I was on the GLP-1 for about a year before starting rapa.

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#31

At what doses?

#32

Why Rapamycin likely has no effect or only a minor effect on human longevity:

  • Mainly proven in lower-order species: It is an intervention with robust life-extending effects primarily in lower-order (less complex) species.
  • Lack of Mendelian randomization evidence: In humans, one would expect Mendelian randomization to show that mTOR-inhibiting mutations are life-extending. However, there is no such evidence, making me think it doesn’t exist. In contrast, there is strong genetic evidence that LDL-suppressive genes reduce lifetime heart disease risk and extend human lifespan.
  • Lack of observational evidence: In human cohorts utilizing rapamycin, the therapy isn’t associated with longevity or rejuvenation. Even metformin and several other antidiabetic drugs are associated with life extension in their respective patient cohorts. The fact that no analogous evidence exists for rapamycin makes its efficacy highly dubious.

How can humanity make progress here?

  • Focus on genes that have a direct causal effect on human lifespan based on Mendelian randomization studies. We will never run a 30-year RCT (and even if we did, it would be too late for current middle-aged people). The closest thing to a 30-year RCT is Mendelian randomization. We must double down on it to find genes that truly make a difference, and then find a way to test them indirectly (via observational studies) or directly (via interventions).

The key to solving this conundrum is to focus on humans; please do not get fooled by mice studies. Less than 5–10% of drugs that work in mice ever get approved for human use.

#33

We both take a GLP1 every day, Rapa once a week, 6 mg my husband and 3 mg me, have done this Rapa regime for several years, husband does 3 months on and one month off, I keep mine going . We are in our 80s and feel much younger. No colds or flue for at least 15 years . We golf 3 times a week, eat only organic , wild Alaska salmon, grass fed meat and eggs etc we have our own gym, a PEMF mat, we do 35 grams Vitimin C IV monthly and have ozone insufflation 3 or 4 times a month . Our little dog has half a gram of Rapa a week also for the last 2 years and her labs are perfect other than she has always had a heart murmur

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#34

I think the LLM summary here is wrong, it’s underplaying the data we have on higher order animals. The marmoset study is probably the most powerful indicator that we’ll see good results in humans… we are very close to marmosets in many ways (we’re both primates after all). I’ve been speaking with Adam Salmon, the researcher who is running this study at UT southwestern, and he’ll have more details later this summer it seems. So we’ll have even more data soon.

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#35

I think marmosets study would be great to see. As it’s yet unpublished, it’s hard to make claims.

Btw what I wrote was purely my opinion (written in the style of LLM). It wasn’t an LLM’s opinion or data.

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#36

Since, almost universally across species from worms to primates, rapamycin provided life extension results, it is one of the few, if not the only, interventions that I am not skeptical of. What is still up for debate is optimal dosing and timing.
On the N=1 side, I have been taking high-dose rapamycin for over 5 years and have received many health benefits. Life extension remains to be seen.

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#37

not really LOL. You’re well into your 80’s and were supposed to be dead at 78, so I’d say you’ve already got some life extension benefit. To be fair I’d like to see someone in their 90’s and using Rapa to be sure of the life extension benefit.

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#38

7.5-10mg tirz. 3-6mg rapa.
I do more or less depending on goals.

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#39

re: Rapamycin or other drugs to extend human lifespan. One point that differs from humans vs dogs, cats, monkeys, mice, worms, etc. is that humans have already drastically improved their lifespan over the past 100 years or so. If we hadn’t done it via vaccinations, food supply, infant mortality, etc. then maybe Rapa and others would show similar results as other animals.

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#40

You’re mixing up two different concepts. One of disease or illness and death prevention (e.g. better prenatal care, vaccines, better food, etc. - you might call this "extrinsic mortality), compared with the basic biology of aging (or “intrinsic aging”).

A simple example is if you take a mouse out of the wild and put in him a lab environment you’ve probably doubled his expected lifespan compared to the wild type (because he no longer is likely to be eaten by predators), but his intrinsic aging rate hasn’t changed.

People have always had a max lifespan of around 120 years and people lived until 80 or 90 quite frequently in centuries before. Similarly, mice, monkeys, etc. have a natural limit on their age. What rapamycin and other longevity drugs seem to be doing (and what the researchers are focused on) is slowing the intrinsic aging of the animal or human.

Rapamycin’s demonstrated effect in animals is specifically on intrinsic aging / maximum lifespan , the one thing a century of vaccines and sanitation did not change. So rather than making rapamycin redundant, the current human situation (and medical therapies) leaves that mechanism largely untouched.

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#41

No. Completely, 100% wrong.

Mice and rats used in research, have had their husbandry steadily improved, (and obviously live longer than in the wild), with long lived strains developed (which didn’t even happen with humans - we didn’t develop a strain of long lived humans). And it is in these well cared for animals living in protected environments (lab environments are even more protective than free living humans), that we tested rapamycin and achieved substantial max lifespan extension on top, thus validating the efficacy of this drug. In fact, we are so attuned to avoiding the effects of poor genetics or poor hubandry, nutrition and environment, that we exclude all those limitations by insisting that only long lived rodents are used as controls, thus assuring that we are not comparing to subpar cohorts. That’s what Matt Kaeberlein’s 900 day mouse rule is all about.

And the same is true for companion animals such as dogs and cats. Veterinary science and pet care have evolved to the point where the longevity of our pets have reached new records. It is in this context that studies of longevity interventions including with rapamycin have been and are being conducted by scientists like Matt Kaeberlein on pets that share our environment.

And in general our knowledge and care for lab animals and zoos has grown dramatically in the last century where the animals are of course living incomparably longer than in the wild or in captivity compared to a bygone era. I think it’s safe to say that lab animals are cared for with greater attention to their health than the average human out there.

In short: no.

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#42

One thing that’s omitted here is that we DO have human data. It’s complicated by being in transplant patients, but the transplant literature is the closest thing we have to long-term human outcome data on chronic mTOR inhibition, and it’s not cited enough in my opinion in these longevity discussions. It supports a real anticancer effect. It does not cleanly support “sirolimus extends transplant patient lifespan” as a settled fact, but these are complicated transplant patients on many many medications and they are also on continuous immunosuppressive dosing, not the pulsed dosing, and they STILL have lower cancer rates. So there’s definitely a signal there in humans.

Sources

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#43

@splarme That’s certainly been my experience. I’ve been on Rapa for 6+ years and I’ve had a few where I didn’t feel my best, but I have maybe been actually sick twice.

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#44

I would like to see some anecdotal reports from people using Sirolimus who have managed to live beyond the average.
Is it too early to see this? Has anyone tried to find out?

Does anyone know how long a significant number of older people have been taking Sirolimus off label for longevity puposes, just want to get a feel for when we may see these anecdotal reports

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#45

Well, we have one in these boards that is 86 or 85 and going very strong. He’s been taking it for over five years. There’s couple other’s in their 70’s that swear by it and say they feel much younger and better than ever (could it be placebo, I don’t know).

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#46

Anybody that has been using Rapa for that long at this time is not normal. Probably doing 20 other things too and eating healthy. A great many people don’t do the sleep, eat and exercise. It’s a really tough job to figure out whether to take a drug or not and we won’t get anything at all from what we have now.

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#47

This is true. Most of us are taking a bunch of different things to have an additive effect because whether we live longer with more healthspan matters more to us than knowing which specifically helped us the most. It’s just human nature.

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#48

Placebo effect usually doesn’t last for years.

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