David suggests we consider two key questions: (at 8:30 minutes)
- Are we taking enough rapamycin? (to achieve what we want)
- Are we already leading a lifestyle / following dietary habits, that are inhibiting mTOR
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Good interview.
Sabatini mentions some interesting stuff on future developments @ 26:34 (I might not be 100% quote correct)
“I do think there are interesting targets upstream of mtor. So that the sensing, nutrient sensing pathway. We originally thought was dedicated to mtor, that is was a very linear pathway. Nutrients, sensors, mtor.
But we now realize is that, that nutrient sensing pathway actually talks to many other proteins besides mtor.
Mtor is probably the most important to be fair. So if you really want to get closer to mimicking the impact of lower nutrients, you really can’t go after mtor itself, you have to go things upstream. So I think that is one very promising opportunity, and that’s something we are interest in looking at now. It’s hard because the targets in that pathway are not like mtor, which is a kinase. Which we know how to inhibit kinases.
Some of these other proteins we don’t know how to inhibit. So that’s the mtor space, and I’m excited to try to go after that.”
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Until then seems be another argument to also CR (at least sometimes) and for occasional fasting (and perhaps for shorter feeding windows each day)?
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https://www.nature.com/articles/s41392-023-01608-z/figures/3
Reduce glucose. Also reduce leucine and arginine.
Increase AMPK.
Low energy levels during glucose deprivation activate AMPK [81,82,83] through the phosphorylation of liver kinase B1 (LKB1) [84]. AMPK directly phosphorylates TSC2, increasing TSC2 GAP function [85]. In addition, AMPK phosphorylates mTORC1 component Raptor, increasing Raptor-14-3-3 binding and inhibiting mTORC1 [86]. During glucose deprivation, DNA damage response pathways lead to the inhibition of mTORC1 through the induction of tumor suppressor protein 53 (TP53) [87]. Other forms of stress, like hypoxia, result in mTORC1 inhibition. DNA damage and development 1 (REDD1) inhibits mTORC1 through TSC2, independently of AMPK [88,89].
How to increase AMPK.
AMPK: Metabolism & Insulin + Ways to Activate - SelfHacked.
- Exercise
- Caloric restriction
- Decrease inflammation
- Cold exposure
- Lipoic acid
The blog above also enumerates supplements to increase AMPK, among them, curcumin, bergerine, hydroxytyrosol (from olives), EVOO, fish oil, ginseng, and more.
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Another publication on AMPK activators.
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That’s what Sabatini seemed to allude to, CR.
However (If I recall correctly or not), in that podcast at another time, he did mention something about having enough vitamins (and maybe minerals, not sure) if one is doing CR.
So, who knows what supps/meds someone might need to use if doing CR to get max benefits.
He might have been thinking of doing a mixed approach like CR, occasional fasting, exercise, and use various supplements + medicines. It might depend on various health factors of the animal.
Or maybe those protein targets he mentioned will be so powerful of an intervention that CR/fasting won’t have to be used much if one can stay in a healthy weight range.
@JuanDaw Good info.
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I watched the video but, I don’t know if it is my declining memory, I can’t remember great actionable info in addiction to what we already know.
Sabatini didn’t speak about the well-known role of the mechanical signal in muscle cells mTOR activation.
He did mention that Rapa causes only a partial inhibition of mTOR, so it seems that, contrary to some sources mentioning an ON/OFF effect, mTOR would act more like a dimmer.
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I’m 63y and think i’m living a healthy lifestyle (Quality food, Exercise 15h+/week, 16:8 IF + 24hfast/once-a-week, No stress(retired), Good sleep, Less than 40drinks/month…)
At 9min I hear Sabatini saying that I may be doing enough mTor inhibition…
Furthermore, if I do start, he has no idea “how much” I should take to have an impact
Starting Rapa is a big step to take (do no harm principle)
I guess I can stay on the fence a few more years hoping to get more insight (starting at 2/3rd lifespan may get me most of the benefits?)
When he says that, I think he’s talking about caloric restriction. Caloric Restriction (with optimal nutrition) is something that has been researched a great deal in the past 40 years, and entails eating significantly less than what we eat “ad libitum” (when we want). The best results of CR in model organisms is typically about 40% to 60% of what these animals eat normally. I’ve tried CR with the meals from Roy Walford’s book “The 120 Year Diet”, and actually paid to have a service provide me the low calorie meals so I knew I was eating the target number of calories: Beyond the 120 Year Diet by Roy L. Walford, MD | Hachette Book Group
When I was on this diet (I think I was on it for a total of 6 to 9 months - this was many years ago) - I lost about 25lb and was very thin, I was cold all the time (had to wear a sweater in summer in California), my libido went through the floor, and I was hungry all the time. Some people can tolerate this… but its not what I consider to be a good life. Its very hard to maintain long term. I suspect only a few percent of the population can follow CR at this level for any significant length of time.
I suspect that to get the same sort of benefits you get from rapamycin (the same level of autophagy, mTOC1 inhibition, etc) - I suspect (but can’t prove) that you need to do this type of diet modification. I also don’t think that David Sabatini has any information on what dose might match what level of caloric restriction (they are not exactly the same, but there is a lot of overlap). Right now its all pretty unclear because we have no way to measure autophagy or mTORC1 levels in clinical testing - so we really don’t know, and probably won’t know for another decade.
I do virtually all the same things as you and I also take rapamycin (for the past 5 years) and all I can say is I feel a lot better when I’m on rapamycin. No aches and pains, more energy, better skin and oral health, better sleep… so for me at least, the answer is to do both; good diet, lots of exercise, low stress, and rapamycin. But I know a few other people who practice CR and choose differently and thats fine too.
My approach is to do both, do lots of monitoring and testing (blood tests and Dexa) to track progress and blood levels, etc. As long as everything is trending in the right direction and I feel good, I’ll follow this plan. If anything changes, I’ll re-evaluate.
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Yes, he was talking about “Reducing Food Intake” (not clear whether he meant CR?) but also about “Exercise”
Here is what he said:
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Yes - I suspect it will be at least 5 years before we have a reasonable idea about how much rapamycin would equate to what percent decrease in calories, in terms of autophagy generation, mTORC1 inhibition, etc.
As I understand it autophagy doesn’t really kick in substantially until the 2nd or 3rd day of a fast, so I suspect that the caloric reduction that David Sabatini is alluding to is substantially more that what most people would want to do.
See below. If I take rapamycin every week (8mg, say), I suspect that its likely similar to doing a 2 or 3 day fast every week. I doubt most people would want to actually do that, to get the same level of autophagy via fasting. Sure, as David suggests, some people may be doing that already, but I don’t think its what most people prefer to do.
If you are doing time restricted feeding (e.g. 16/8), I suspect that the amount of autophagy is minimal. I’ve seen no science to support the idea that you get significant autophagy that way.
How long do you need to fast for autophagy?
Depending on the individual’s metabolism, significant autophagy may take two to four days of fasting in humans. Autophagy is believed to begin when glucose and insulin levels drop considerably. Animal studies have shown evidence of autophagy after 24 hours of fasting, which starts peaking at around 48 hours of fasting.
Some studies have detected autophagy in human cultured neutrophils (the most abundant type of immune cell in the blood) after 24 hours. There are, however, no conclusive studies on humans that indicate an optimal period of fasting to achieve autophagy. However, do not attempt to fast to induce autophagy without discussing this method with your doctor.
How long do you have to fast for autophagy to occur?
Studies involving animals suggest that autophagy may begin between 24 to 48 hours of fasting. Not enough research has been collected on the ideal timing to trigger human autophagy.
Related:
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Brilliant answer, RapAdmin. As someone who actually did CR for over 8 years, and was aware of Walford’s book already back in the 80’s (first edition), CR has been on my radar for literally decades. I gave up CR for pretty much similar reasons, which I outlined in greater detail elsewhere on this site. It was not about “can I do it”, as I could (and have been incredibly lucky to have my wife share that journey - in fact, without her, I wouldn’t even try tackling it!) - it was in the most succinct way: about the quality of life, not just quantity.
In the end, rapa to me is just a more practical way of taking a crack at possible life/health extension, without having to upend my entire life in the real world of social context. CR has taught me a lot, lessons I have taken with me, even though I no longer follow CR as strictly defined. I don’t overeat. I pay great attention to quality of food. The question “are these calories worth the price” is second nature to me and something I ask myself practically with every meal. Nutritional bang for calorie buck.
However on some level, CR is nature at its most fundamental, implementable and pure. And yet, I also want to take advantage of that which has driven human civilization from the beginning: making things easier through technology - this is where rapa comes in. If I can have the advantages of CR without the effort, I want it. Same reason why I don’t hunt down my own food, but rely on the fruits of technological progress in making life easier and better. Rapa today, and hopefully something better tomorrow. I leave CR to those who like to hunt down, skin and roast their own wooly mammoth - I’ll be over there in the other corner gobbling down my rapa pills brought to me by the post office of India.
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There is another tread running about “Autophagy” saying :
- “you see about the same autophagy in humans after 30 minutes of aerobic exercise as you see in 3 days of fasting”
I’ve been doing 16:8 IF with breakfast skipping for 5 years. Not sure it helps with health/longevity but it’s routine now. A few coffees each morning keep the hunger away.
Once a week I also skip dinner. Just before I have my regular 70km cycle tour. That evening I have a hungry feeling from 18h-20h and then it fades.
That night I need to put my socks on because otherwise my feet feel cold.
Next morning I do my daily Yoga & Strenght training. I typically feel “stronger” (ex. more push-ups) than other mornings (occasionally I feel weak for half an hour when getting out of bed that day)
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Which really shows that it’s not all just about autophagy. Aerobic exercise, or exercise induces autophagy, but exercise doesn’t extend max lifespan (it does extend mean), whereas CR definitely does, and rapamycin arguably too. CR s not just about autophagy, and it is only one of many mechanisms of action by which lifespan/healthspan is extended; and rapamycin’s effects are also not exclusively about autophagy. The signalling pathway of mtorc encompasses more, and downstream you have impact on proliferation, immune modulation and so on. Matt Kaeberlein likes to say that rapamycin effects are a small subset of CR effects, so in that case, CR certainly is more than just mtorc inhibition, and really this is probably also true, although clearly to a lesser extent in the case of rapamycin.
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Insulin by itself is a very poor secretagogue. 24.01
Rapamycin is a partial inhibitor of mTOR 26:02
If you really want to get closer to mimicking the impact of lower nutrients, you really can’t go after mTOR itself. 27:02
you have to go to things upstream.
@JuanDaw, I think the exact transcription is a little different, probably closer to the captions I see in the video:
- Leucine by itself is a very poor insulin secretagogue: meaning, leucine causes much less secretion of insulin than glucose. That’s in answer to the host asking why aminoacids spike insulin. By actionable info, I may construe the above like this. Protein alone cannot substitute the glucose-insulin signal. I subscribe to that. In my personal experience, maybe because I have low levels of circulating insulin (to be verified, I only made a single analysis), in lack of glucose signal (on a low, even moderate carbs diet) I go catabolic, no matter the amount of protein I can eat.
2)Rapamycin is a partial inhibitor of mTOR 26:02. Not a total inhibitor, otherwise the cell would be dead. Also, it means that mTOR can be partially inhibited, but does it mean it can be dimmed or that parts of the cascade are inhibited and others not, but which ones???
3)If you really want to get closer to mimicking the impact of lower nutrients, you really can’t go after mTOR itself. 27:02 you have to go to things upstream.
Here, Sabatini points out that mTOR is just one protein influenced by the nutrients signal and that there are others. So, hitting mTOR equals hitting a downstream target, missing some part of the big picture. Going upstream, that is lowering nutrients, encompasses a wider amount of pathways.
But Sabatini does not offer actionable info, because he says, there are other proteins involved which are no kinases, and we don’t know how to inhibit them.
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Or at least, he seems to whisper something, he says he has some ideas, but he keeps vague.
For example, going to things upstream, what exactly does it mean? Long-term CR (with all the mentioned drawbacks)? And which degree of CR? Or intermittent CR? And how intermittent and how severe?
Besides, things upstream would include Activation of AMPK which many of us already do by endurance exercise, plus inhibition of the PTEN protein by mechanical stress/resistance exercise, which many of us already do …
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Recently I listened to the Peter Attia podcast with guests Sabatini and Kaberlein, about 1 year ago.
Sabatini elucidates what partial inhibition is. It is an inhibition of the interactions of mTOR with most molecules, except the smaller ones. He compares the Rapa-FKBP12 complex to a boulder at the entrance of a cave. Due to irregularities in the shape of both boulder and cave entrance, something can enter, something small like for example ATP.
So Rapamacyn is a dimmer, but apparently a selective one, in that it partially inhibits mTOR activity but leaves some interactions with small molecules like ATP, which takes to which consequences?
He doesn’t say what mTOR does/activates/phosphorylates when partially inhibited by Rapa, and I do not know about it. Probably it keeps going with the basic growth and proliferation signals, necessary to survival.
The difference with the catalyst inhibitors of mTOR is that they inhibit mTOR completely, like and OFF switch, and this causes acute toxicity and death in lab animals.