Most mouse research doesn't translate to humans - why do we think rapamycin is different?

I know that the ITP studies are about as good as it gets in terms of mouse research, but the fact that the vast majority of mouse studies don’t end up panning out for humans is rather disheartening in the context of rapa.

A second question - why do we think that people on rapa for immunosuppression aren’t having better outcomes? We can point to mTORc2 inhibition but it seems like daily consumption is actually more in line with what we see in mouse studies where rapa is put in the chow. If daily consumption in a mouse leads to longevity, why aren’t we seeing greater longevity in humans using daily rapa? No, those people aren’t representative of the general population, but you’d think that we would see considerably better outcomes compared to tacrolimus etc. I know there’s some scant evidence of lower lymphoma rates, but it’s underwhelming IMO.

What sorts of arguments have you all heard against both of these points?

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Dosing in TRIAD is 0.15mg/kg once per week. Matt must be fairly confident he can hit his end point (based on the first trial) and, if he does, then that translates to 0.08mg/kg in humans.

why do we think that people on rapa for immunosuppression aren’t having better outcomes?
Possibly it is because they were very sick to begin with.

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See Richard Miller’s (of the NIA ITP Program) response to this very question in an interview by a Lifespan IO person:

Lifespan IO: Yes, we’ve had a lot of success in mice, but many drugs that work in mice do not work in humans.

Richard Miller: And many drugs that work in mice do work in humans. It would be silly to maintain that the percentage that work is zero, and it would be equally silly to maintain the percentage that fail is zero.

Most of the drugs that were developed for therapeutic effect in people were initially discovered by working on mice and rats. It would be nuts to say that every drug that extends lifespan in mice will do the same thing in humans, but the work in mice is a very important foundation.

Many of the pathways that are discovered, and maybe even some of the druggable targets that are first discovered, in the mice will serve in humans – maybe the same drug, maybe drugs of the same family, maybe drugs that target the same molecule, but through a different chemical grouping. It’s necessary to be neither insanely optimistic nor insanely pessimistic.

Lifespan IO: We do have a history of failures though, such as with Alzheimer’s, maybe because mice don’t really develop Alzheimer’s.

Richard Miller: Yes, that’s true, but it’s important to recognize the brains of people and the brains of mice have a lot of things that are not in common. In terms of aging, if I tell you that I have an individual right here in front of me, in my office, that has cataracts, bad hearing, weakened bones, a poor immune system, and a relatively low cardiovascular system, you would immediately recognize that individual as old, be it a mouse, a dog, a horse, or a person. But you wouldn’t know if that’s a seventy-year-old human, or a 25-year-old horse, or a three-year-old mouse.

So, the effects that aging has on mice and on humans are – not in every case, of course, but in most cases – recognizably quite similar. And that’s true for cells that divide, for cells that don’t divide, for structures like the bones and the tendons that are mostly extracellular material. It’s true for complicated circuits, like neuroendocrine feedback circuits, it’s true for cognition.

There are just so many aspects – not all, but so many aspects of aging in humans, mice, dogs, chimps, et cetera that are the same. So, it’s very reasonable to expect that the drug that could block aging effects in all of those tissues in mice might also do very similar things in people.

Lifespan IO: But different species die in old age for different reasons. For instance, around 80% of lab mice die of cancer, I think.

Richard Miller: The specific thing that kills the animal is of secondary importance when you’re studying the biology of aging. For instance, elephants die because their teeth wear down and they can no longer eat. When they’re 60 or 70, they have lost their last set of molars and they can’t chew food anymore. Mice, at least those that are used in aging research, indeed die mostly of tumors. People that eat a lot of fatty foods and watch TV, die mostly of atherosclerosis. In people that were alive a hundred thousand years ago, the most prevalent cause of death was probably breaking a bone and not being able to keep up with the group.

The point is not what is the specific cause of death in a specific environmental setting and in a specific species. The real question is what is it that postpones age-associated decline in bones, brains, the immune system, the sensory systems, the gut, and everything else for many decades in people, for a few years in mice, and for 20 years in horses. The factors that regulate the timing of the aging process, I would guess, is very similar in nearly all kinds of mammals.

Source:

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“If daily consumption in a mouse leads to longevity, why aren’t we seeing greater longevity in humans using daily rapa?”

With regard to metformin, Dr. Nir Barzilai’s slide has answered that question.

After five years, 90% of diabetics on metformin are still alive, versus 85% for non-diabetics not taking metformin.

Study below confirms the above.

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I have talked to the researchers about this with regard to rapamycin and the general response is that the typical organ transplant patient is very sick, and has been for a long while. They are also typically on many different drugs and again have been so for a long time. The net of all this is that its impossible to parse out the effects of a single drug in these scenarios.

You have to, for example, look at what specifically, causes a person to need a kidney transplant… so, for most people if you need a new kidney, you have likely had serious health issues for many years, if not decades… see below:

End-stage renal disease occurs when the kidneys have lost about 90% of their ability to function normally.

Common causes of end-stage kidney disease include:

  • Diabetes
  • Chronic, uncontrolled high blood pressure
  • Chronic glomerulonephritis — an inflammation and eventual scarring of the tiny filters within the kidneys
  • Polycystic kidney disease

People with end-stage renal disease need to have waste removed from their bloodstream via a machine (dialysis) or a kidney transplant to stay alive.

Source: Kidney transplant - Mayo Clinic

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I think Dr. Attia said it best about the effects of Rapamycin. This is my paraphrasing:

There are 84 trials on every kind of model organism from yeast to primates, and in every single trial on every single model organism, Rapamycin extended its lifespan.

That’s pretty darn good proof in my opinion.

And there are probably more than 84 trials by now. Each and every one has shown an increase in lifespan. That’s practically unheard-of success rate. So, yeah, I’m going to take Rapamycin.

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There are no rapamycin trials in primates demonstrating improved longevity. Even in dogs, longevity has not been used as an endpoint yet.

My point is, the question, at least to me, remains unanswered for rapa. But met has studies in its favor.

I’m not sure I understand how your response is addressing the question at hand. How is metformin relevant to this discussion?

Edit: just saw your second comment. Gotcha.

See post above yours. For info, I am not taking either.

There was a safety study of Rapamycin done on macaques. I would consider it a success.

rapamycin also prolongs life in normal mice as well as in yeast, worms and flies, and it prevents age-related conditions in rodents, dogs, nonhuman primates and humans.

Maybe I am extrapolating too much when I consider that it prevents age-related conditions in rodents, dogs, nonhuman primates and humans. But, to me that means a longer lifespan. I don’t have the time to wait until these individuals die to confirm that they indeed lived longer!

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Correct… 2026 is when we can expect the dog aging project / rapamycin results… Matt conveyed in the Webinar yesterday.

Most of us here prefer not to wait until then for better data. And even then, I’m concerned that the dosing may be too low to reach the 9% lifespan improvement that I think the study is powered to detect (the study is biased to minimize side effects for people’s companion dogs, not maximize longevity). See details on rapamycin/dog study here: Tech entrepreneurs pledge $2.5 million to Dog Aging Project / Test of Rapamycin in Dogs

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Ooh, good to know! Thanks for sharing, @RapAdmin

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I have talked to the researchers about this with regard to rapamycin and the general response is that the typical organ transplant patient is very sick, and has been for a long while. They are also typically on many different drugs and again have been so for a long time. The net of all this is that its impossible to parse out the effects of a single drug in these scenarios.

Well said. kidney transplant aren’t just on rapamycin, they are typically on 3-4 other potent immunosuppressant’s in conjunction with a small dose of rapamycin daily (1-2mg).

I follow a kidney transplant group and most of them are like on 3-10+ medications daily.

I have seen 1 guy in the group on 15 medications, hes taking 4 different blood pressure medications and some for cholesterol as well. Kidney function affects alot of different things. My grandma has stage 4 kidney disease and shes on blood pressure medication for it. She has to get a transplant in future if possible.

Here’s a typical day of the medication some transplant patients take. While they aren’t taking sirolimus they are taking everolimus which is similar.

Another kidney transplant on rapamycin and 2 other potent immuno medications:

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Does mouse research translate to humans? Not for metformin.

In the linked study by Richard Miller et al, on mice,

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/acel.12496

the paper states:

“Metformin alone, at a dose of 0.1% in the diet, did not significantly extend lifespan. Metformin (0.1%) combined with rapamycin (14 ppm) robustly extended lifespan, suggestive of an added benefit, based on historical comparison with earlier studies of rapamycin given alone.”

Yet, in human data, Barzilai’s slide shows that diabetics on metformin outlive non-diabetics.

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So will mouse research on Rapamycin translate to humans? That remains to be seen.

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I was listening to this “Translating Aging” podcast with Sebastian Brunemeier, of Healthspan Capital & ImmuneAge Pharma.

One of his statements was, I thought, relevant to your question on this topic. I encourage you to listen to the entire podcast, but here are this Longevity Biotech investor’s take on what makes a molecule’s success in animal models more likely to be relevant in humans:

“I would argue that if you have a drug that enhances robustness and resilience and extends lifespan, and it works in multiple different animal models and disease, contrived or not, that is a much stronger preclinical signal for efficacy down the road.”

In otherwords, if a molecule works in yeast, and e.elegans (worms), flies and mice, repeatedly for lifespan extension (and other disease or disabilities), then that is a much stronger probability of it work in humans… as is the case for rapamycin.

The key point here is that unlike most “mouse research”, the rapamycin longevity effect is very different; “Its not just mice”. Rapamycin has worked (extended life) in every type of organism it has been tested in, across a billion years of evolution. The probability of it not working in humans also, seems quite low. Humans diverged from mice (in evolutionary terms) about 75 million years ago; a small fraction of the billion years of evolutionary history that rapamycin has already been proven effective across. Of mice and men: how things got tricky when we split from Mickey

The argument is somewhat similar to that which Peter Attia makes:

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