To rapamycin or not to rapamycin — that’s the question

#1

Hi all,

I’m 64 years old, very healthy, and I seem to have inherited good genes. My father was born in 1928, so he’s now 97 and still mentally sharp, never took any medications, and only his legs have given up on him.

I’ve lived a very disciplined life myself:

  • daily exercise (cycling, yoga, strength training),
  • 16-hour daily fasting plus one 24-hour fast each week,
  • healthy mediterranean diet (no processed foods, moderate alcohol),
  • 3 sauna sessions per week for 25 years, plus year-round cold plunges in my swimming pond
  • stable weight since age 18, no chronic issues, no medication.

I’ve been monitoring this group for two years, hoping to find a rational risk/reward reason to start my rapamycin journey — but I’m not making any progress. The decisions (or indecisions) of high-profile people like Eric Verdin, David Sabatini, Peter Attia, and Bryan Johnson don’t help either.
To be honest, I’m also scared to start taking it — I hate risk and not being in control of what’s happening in my body.

So here’s my question:

If I’m already doing everything that naturally keeps mTOR activity low (fasting, exercise, moderation), is there any meaningful benefit left to gain from rapamycin?

In other words:
Would rapamycin in my case add a few percent of marginal benefit, or is it simply redundant — an attempt to mimic what my current lifestyle already achieves?

I’m genuinely open-minded — I just need a clear mechanistic or empirical justification, not faith.

Thanks,
Jaak

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#2

I will let others give you much more detailed answers, but I’ll share my personal experience.

I only workout 3 days per week, but I’m WFPB, I don’t eat for 12-16 hours per day, I don’t drink much, I’m a healthy weight, I was doing Prolon FMD once a quarter for several years…

I was nervous I might implode after taking my first pill…. Well, within short order, my lifelong insomnia vanished. POOF!!!

My sleep was still not perfect, but I turned into a different person (I have since added more things to help, and now I’m the poster child for great sleep). My husband witnessed my drastic change, so he wanted to start taking rapa, too… note, he has no noticeable effects.

I realize it’s most likely the sleep that makes me feel like a new person, but either way, rapa was the cause of this transformation.

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#3

Jaak, if I were you I would not take it. You seem healthy and also lucky to inherit great genes. I take Rapamycin to trick my immune system into accepting my transplanted kidney as my own. It works well for that purpose. I wouldn’t take it if I didn’t have my chronic condition.

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#4

Hi Jaak,

I have the following thoughts:

  1. Rapamycin seems pretty safe. There is the PEARL trial of people taking the 3-6mg/week doses and there are no adverse events. There’s also a big survey of 300+ “recreational” users (i.e. us) and there is no association with adverse events. So on the “risk” side of your equation, I believe it’s fairly low. So personally I don’t see much cause for fear. Arguably Rapamycin is better studied than 16h or 24h fasts. If you don’t consider those to be risks, then I don’t think Rapamycin is any riskier. I’ve attached an interesting study which shows that fasting in humans is not all simply good news. Any intervention we take has some risks and benefits, and most of it is faith based.

12e6ab02-a2f1-596b-6971-4b48f3bd6f46.pdf (2.7 MB)

  1. On the “benefits” side, there is not that much evidence of Rapamycin benefits in humans. However, Rapamycin has extended lifespan of countless species - some of which are similar to us, and many which are evolutionarily distant. To me, that says it hits some conserved mechanisms and it’s likely to also apply to us. Of course, some people believe that humans are already outliers and we won’t get the same benefits. But there’s no evidence either way, so it really is a leap of faith.

If you’ve spent 2 years researching, then you’ve read all the same things that we have, so there really isn’t any clear mechanistic or empirical justification.

  1. Have you taken care of other major risk factors? Your dad is alive at 97, which is awesome, and your lifestyle sounds great. But what about lipids, HbA1C etc? I don’t mean to sound like an ass, but you can be a healthy and fit, active 64 year old and still die from a myocardial infarction at 70. There are certain conditions that can happen no matter how fit you are, and dealing with them would be 10x more important than deliberating over Rapamycin.

  2. In your post you made two statements: “never took medications” and “no medication”, almost as if it’s a badge of honour. I think medications are a tool, and using them isn’t an admission of weakness, or an admission of an inferior lifestyle or anything else. Maybe that’s something to consider?

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#5

Thanks for your reply — our topic is indeed incredibly complex, with so many unknowns.

My goal (like many here) is to make it to 100 while still living rather than just being alive. My father is in great shape for 97, but in my opinion, he’s unfortunately no longer “living.”

So my question is: how do I maximize my chances of reaching that goal while limiting the risk of making a bad or unnecessary choice?

I feel more trust — and peace — in targeting mTOR naturally through exercise and short fasts (16h daily, plus one 24h fast weekly) for evolutionary-biological reasons rather than pharmacologically with rapamycin.

Of course, even that is complicated, as Valter Longo keeps reminding us: “16:8 is a bad idea — don’t skip breakfast!” But I choose to ignore him.

Maybe there is an added benefit to taking rapamycin, but I suspect I’m an outlier mammal with an outlier profile — ~2 hours/day of cycling, yoga, strength, and hiking. Nobody really knows what dosing regime would make sense for someone like me (as David Sabatini points out).

I do yearly bloodwork (in May). Some results are great — HDL 123 mg/dl, triglycerides 42 — and others less so: LDL 140. I’ve chosen not to treat the LDL, given no family history of CVD.

I admit I’m biased toward staying off medication and supplements and prefer the “natural way” as long as my bloodwork doesn’t mandate action. For example, my vitamin B12 stays around 700 ng/L and vitamin D above 40 ng/ml through diet and long winter sun holidays.

Still, I remain open to more evidence — just cautious — because, as you said, every intervention is partly a leap of faith

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#6

My approach to rapamycin is less binary. After all, you don’t have to decide “all or nothing”, you can test, titrate, or pause at any time.

I assume you’ve looked at, and follow all the research: Rapamycin Frequently Asked Questions (FAQ)

The downside is quite minimal for most people - you might get a mouth sore, you might get slightly raised lipids, etc.

And while most of the benefits are, the research suggests, likely to accrue over time there are also many people who get immediate benefits. More energy, elimination of any aches or pains that frequently come with higher exercise regimens, etc.

mTOR inhibition is a really hard thing to calculate or measure… we can’t do it clinically yet. So we really don’t know if lean, high exercising, moderate food intake people are vastly different, or minimally different, from rapamycin users.

I think the biggest variable here is “risk propensity”. Some people are comfortable with more risk, others with less risk. From looking at my friends and others who decide to try or not try rapamycin, I think this is the largest factor that decides which side you fall on.

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#7

You’re better off taking care of the low-hanging fruits first: control your high LDL to help reduce CV risk, and reduce your HbA1c/insulin/glucose if they’re too high. I assume your BMI is within a healthy range, and your lean mass is adequate. Rapamycin is the cherry on top, and in fact won’t help you much if your LDL and glucose are out of control.

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#8

Hahaha… in a quote presented by Mikhail Blagosklonny, "If you wait until you are ready, it is almost certainly too late ".

You’re not getting any younger waiting. :wink:

Haven’t this forum’s members convinced you at all.

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#9

I took a very low dose of Rapamycin once every few weeks and got mouth sores so bad l could hardly eat. Now I get scared just looking at the package.

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#10

I agree with @relaxedmeatball especially in regard to traditional risks.
Having no family history of CAD is relatively meaningless in regard to risk, and assuming good genes in the family predict outcome is a problem - as it probably only is 15-20% of the outcome with the rest being lifestyle.

Now having a great lifestyle runs in families, and individuals assume it’s genetics when that is the minor part.

I’d be super comfortable with your assessment of being low risk and not treating your lipids if you grabbed a CCTA with Cleerly analysis and it was all clear and got an MRA head/neck and this was all clear including no white matter changes.

I have several patients with great family histories, great lifestyles and lipids that really aren’t bad that have extensive and unexpected disease on this assessment.

I also have a good number who have pretty high lipids and get this assessment and have no vascular disease I can find and have made it into their 70’s. I still recommend they take some low dose lipid medications, but I also tell them that objectively I cannot make a strong argument for that as their phenotype is markedly more important.

There are a lot of factors that go into forming vascular disease - I have my list that I optimize:
ApoB + Lp(a) + 9p21 + Apo E4 are the low hanging ones to consider on the lipid/unexpected risk side.
Omega 3 index
Homocysteine
Insulin sensitivity
Vitamin D level and Vitamin K2MK7

If these are not good, my pre-test probability of disease when I test is quite high.

Additionally, malignancy is a wild card - and surveillance of this including MRI yearly plus all recommended screenings are important.

Sarcopenia/Osteoporosis/Trauma

Infections/Immunizations

Optimize these a few more low hanging fruit … and only then should we be thinking about doing the clever things, like rapamycin is my current approach.

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#11

These are not necessarily mutually exclusive :grin:. Optimize but move all the levers together, walk and chew gum is my approach, but I may have slightly greater risk tolerance :sweat_smile:.

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#12

Oops.

So yeah, you’re missing the wood for the trees here. Don’t even think about Rapamycin until you’ve dealt with this, or at least get an all-clear by CTCA scan if you don’t want to lower the LDL-C with medications. @DrFraser is talking 100% sense here.

Just to put this into context: you’re looking at an off-lab use of an unproven medication with unknown benefits, but ignoring something which is the cause of death in 1/4 of people.

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#13

I recommend you read this thread, but start here at this post and recent story Cardiovascular Health 2025 - #1083 by RapAdmin

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