Dr. Joan Mannick — mTOR’s Role in Aging

#1

During this episode of Longevity by Design, Dr. Joan Mannick explains how mTOR influences the aging process. She explains that this evolutionarily conserved protein is involved in several cellular functions in the body and acts on longevity-promoting pathways like autophagy. Dr. Mannick also discusses the connection between mTOR and the immune system, sharing her research on how low-dose mTOR inhibitors can upregulate antiviral immunity, creating an opportunity for more targeted vaccines for older adults. After extensive research on mTOR across many species, Dr. Mannick shares impressive insight into how mTOR inhibitors like rapamycin can promote longevity.

Joan Mannick has started a company (Tornado Therapeutics) to develop new rapamycin-like drugs. For Tornado, rapamycin is a competitor product, so you should expect Joan (a founder and major shareholder in Tornado) to be a little biased against rapamycin, though she is very positive on the mTOR inhibitors generally and clearly identifies rapamycin as the most proven longevity drug by a wide margin.

Joan is generally more conservative than some of the rapamycin-focused researchers we follow closely. She doesn’t recommend anyone take any longevity-oriented drugs or supplements until more data is gathered. She anticipates it will be 5 years before we have really good clinical data on whether mTOR inhibitors can significantly slow an age-related decline in a human system (e.g the immune system) or organ. And given that the only groups that have the financial incentive and funding to do good clinical testing on mTOR inhibitors she is effectively saying that the biotech companies developing these new patented mTOR inhibitors will likey be the only groups to have this type of data.

And so, in half a decade we might know, with high certainty levels, if 65 or 75 year old immune systems benefit from the Tornado mTOR inhibitors. This is still, sadly, a long way away from knowing its affect more broadly on aging. So, it remains to be seen whether the new Tornado rapalogs will provide longevity benefits as great as rapamycin does (as shown in mice), what new side-effects the Tornado drugs will have, and whether the cost/benefit ratio of the drugs (when compared to rapamycin) will be compelling for end users.

Whatever the case, it will likely be many years before we find out. Research on rapamycin’s impact on longevity has been going on for almost 20 years now, so its going to take a decade or more for the research on these new mTOR inhibitors to get anywhere close to that of rapamycin. At the same time, given the lack of human clinical trials being done on rapamycin (due to lack of funding), its doubtful right now whether we will ever seen well-powered human clinical trials for rapamycin in aging; we will have to instead rely upon animal studies or (it is hoped) well-designed studies with next-generation biomarker clocks. Brian Kennedy, Andrea Maier at the National University of Singapore are working on the later type of study with rapamycin in people.

Obviously new and improved mTOR inhibitors are a good thing for the market and we hope Tornadio is successful, and that they price the drug at a level most people can afford.

Related Reading: Cambrian Biopharma Announces Plan to Develop New mTOR Inhibitors, Tornado Therapeutics led by Joan Mannick

Also, here (below) is a very recent update from James Peyer, founder of Cambrian BioPharma (the parent company to Joan Mannick’s company Tornado Therapeutics) in a BioWorld Insider podcast posted yesterday: Cambrian carves out a new niche as it works to keep people from getting sick

When the CEO of Cambrian Biopharma watched his grandfather fail every cancer treatment and eventually pass away, he came to a realization that now forms the backbone of his company. James Peyer said, the more he learned about cancer, the more convinced he became that approaching cancer as a disease was wrong. He said we shouldn’t wait until people become sick to do something. Peyer has described his own company as focused 15% on moonshots and 85% on longevity innovation.

The firm is developing multiple anti-ageing therapies, all of which are at the preclinical stage, very early. He built Cambrian with a unique business model, one that fits the new field of geroscience.

Lee: Talk to me about your pipeline. I want to make sure I understand because it sounds like, if I understand correctly that each pipeline candidate would have its own company…?

James: That’s right. We have 15 different drugs under development at Cambrian currently held across 10 different pipeline companies. Some even have more than one and it’s more based around a group of shared mechanisms. For example, we have two rapamycin analogs that are in development entering IND-enabling work now and both of those assets live in our pipeline company, Tornado Therapeutics. It’s not one-to-one, but our 10 subsidiary companies are developing 15 drugs.

Lee: Got it. So are the rapamycin candidates the most advanced ones?

James: As far as we’ve announced, yes.

Full interview transcript below:

BioWorld-Insider-Podcast-Episode-25-transcript.pdf (103.0 KB)

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James Peyer (Cambrian Biopharma) Has A New Treatment To Extend Life, Plus A Possible Landmark Weight-Loss Drug (Forbes)
#2

Just listened to this and agree that Joan is quite risk averse. I think most on this site believe the rewards seem to outweigh the risks, given the doses most are taking (5-8mgs a week).

It would be interesting to hear a debate between Joan and Matt K about this. The reasons given in this presentation for not taking Rapa (or a derivative) seem a little superficial, especially when there is a significant body of data available already, albeit in a different subset of people (I.e. organ transplant recipients).

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#3

There is a significant amount of date regarding Rapamycin. There is a paucity of data. A handful of rodent studies is it. Having spent 35 years in the biotech industry I can tell you 99% of drugs that looked effective in animal models didn’t work. Maybe Rapamycin is in the 1% but we are a long long way from that conclusion.

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#4

Hi Philly3458 - what I meant by data was in relation to the side effects….I.e. Rapa shouldn’t kill us :grinning:
Cheers

#5

Are you saying this about rapamycin? There have been approximately 40 studies in mice - here is a full accounting of them: List of all the Mouse Studies Showing Rapamycin Lifespan Extension

Also - the argument that many of the geoscientists make about rapamycin is that its worked in every species ever tested… yeast, flies, worms, mice, …

and that unlike typical biotech/pharma drug targeting efforts with artificially-created disease models in mice, aging is pretty similar across mammalian species - its not too hard to identify an old mouse, an old horse, an old dog, or an old human… (the phenotype is pretty similar) suggesting that mice aging is likely a more transferrable model than most mouse disease models used in biotech/pharma: Most mouse research doesn't translate to humans - why do we think rapamycin is different?

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#6

Your 1% may be pessimistic. Many drugs fail for safety reasons (which shouldn’t affect rapamycin which is already used un humans). And the translation of decent.mouse trials is much higher
(Translation of Research Evidence From Animals to Humans | JAMA | JAMA Network)
"where medical interventions were tested on animals and whether the results were replicated in human trials.

It showed that of the most-cited animal studies in prestigious scientific journals, such as Nature and Cell, only 37% were replicated in subsequent human randomised trials"

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#7

btw, I tend to look at things a bit different… I try something and if I am 100% convinced that I’m getting positive results then to me there is no risks. For example, I see 0% taking RAPA (6 per week) since I feel way better and more agile (literally I can climb two stairs at once as i used to when i was in my 20’s, and without rapa I usually do one stair at a time and need to watch my steps lol) . The only side effect has been Cranker sores but even those seem to be very rare now, I also thought i might have experienced muscle spasms but that has gone away also, so where is the risk? NONE for me! and the benefit seems huge!

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#8

It’s great to hear that you are getting those benefits @kansel :+1:t3::facepunch:t2:

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#9

Great to hear you’re getting good results, but I think we all need to be a little careful in extrapolating our good results… and thinking it means “no risk”.

I actually don’t worry too much about the rapamycin itself - it doesn’t seem to me that the rapamycin is likely to harm us directly. The risks are more subtle I think… possible increased risk of infection as we go higher in dosing, perhaps some negative changes in our bloodwork (e.g. lipids) that won’t harm you immediately but could cause issues and increases in risks (e.g. cardiovascular disease) over time… so for me at least, I always try to keep in mind that i need to keep checking the bloodwork, and tracking things, because negative trendlines need to be addressed.

I think there are risks with every medication, so I think its helpful to be cautious as we use rapamycin.

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#10

Does it mean that you may decide to decrease the dose of Rapamycin or add a statin or another medication in case of elevated lipids?

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#11

I would go as far as saying as rapamycin causes heart disease as a side effect, via increased lipids. Fortunately that can be managed safely and effectively with for example statins.

It would be very unfortunate if people didn’t do bloodwork of apoB, non-HDL-c, or LDL when they are taking rapamycin, or in general.

It wouldn’t make sense if there weren’t downsides to rapa, but the heart disease one can be managed and completely nullified. So it’s not something to worry about if you control it, as the lipid number is all that matters.

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#12

In my view you are incorrect, review;

All should review this presentation.

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#13

I’ve always had high cholestrol (and APOB), and they went higher when I added rapamycin. I’ve alternated off and on statins over the years… and yes, I’m back on now. And yes - I’m always testing things - tracking impacts on bloodwork, and adjusting things (trying to change only one variable at a time so I have an idea on the cause/effect relationship).

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#14

That makes sense. I am still nervous about the increasing risk of cardio- vascular disease caused by elevated lipids and in some cases, worsening glucose control. You take statins which is probably a right thing to do. Most of the cardiologists and neurovascular experts take statins.
As far as I understand some safety studies on humans should be coming out soon. Is that correct?

#15

You’re linking a 60 minute video to my claim that the lipid number is all that matters.
Why not write out your thoughts, that refute my claim, to the best of your ability?
Let’s not outsource thinking to others.

Someone talking in a youtube video on its own matters nil.
The first 7 minutes are not arguing against my claim, the least you can do is link the part which does.

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#16

In your view

A person posting on a forum is
of very little value mostly useless.

The two people in the link video are medical doctors, Lustig
is Professor emeritus of Pediatrics in the Division of Endocrinology at the University of California, San Francisco. What he has to say is highly valuable.

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#17

I meant as a citation, a youtube video as evidence on its own is useless. You need to find papers too, that’s why it’s more useful to write out your arguments and finding scientific papers to back up your position as well. The totality of evidence and the quality of that evidence matters.

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#18

Papers are useful, but so is a renowned doctor giving the benefit of his experience. Don’t get me wrong. I love reading papers. We all try to read these papers with varying degrees of success, but I don’t think anybody would have much success reading a few papers and formulating judgments in my profession. I suspect it is similar in the medical field.

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#19

While it is true that rapamycin has been associated with increased lipids, the claim that rapamycin causes heart disease as a side effect is not supported by the available evidence.

In fact, studies have suggested that TORC1 inhibition may have cardioprotective effects by reducing inflammation and oxidative stress in the heart, which are key drivers of heart disease. For example, a study published in the journal Aging Cell in 2019 found that rapamycin treatment reduced cardiac fibrosis and improved cardiac function in aged mice.

Furthermore, the claim that the lipid number is all that matters when assessing the risk of heart disease is also not entirely accurate. While elevated lipids are a risk factor for heart disease, they are not the only factor. Other risk factors such as hypertension, smoking, and diabetes also play important roles in the development of heart disease. Therefore, simply controlling lipid levels may not completely nullify the risk of heart disease in individuals

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#20

I think both of those statements are are accurate… I don’t want to repeat the cardiovascular disease thread discussion here, just saying that higher APOB trends are something I’m going to watch/measure and work to reduce. Nobody knows yet how the beneficial effects of rapamycin on the heart balance out against any possible lipid increases, in humans.

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