#22

This is an important post in the topic. Check also the very interesting time clip video with the Joan Mannick.

https://x.com/KristerKauppi/status/1857151201743372757

6 Likes
#23

What I meant with ‘messing with the immune system’, is using something with a proven increase infections or sepsis in RCT’s or observational trials – thus which might be the case for lower doses or longer use in rare circumstances.

Has anyone gotten sepsis from aspirin?

#24

I get Masterjohn’s newsletter, but haven’t seen the anti-rapa bit. I like reading him, and have gleaned a few actionable insights when it comes to supplementing, but as with any source, you have to understand their relative strengths and weaknesses.

Masterjohn is the posterboy for mechanistic reasoning where he is second to none in his deep dives, but mechanistic reasoning is famously treacherous and highly prone to mistakes. It’s fun to read, but for more serious pointers one should look to outcome studies, I think.

9 Likes
#25

The word you are probably looking for is an immunomodulator or more narrowly defined immunosuppressant.

However now that we defined it properly, there are millions of lives saved with immunomodulators/immunosuppressants.

Using immunomodulators (like any other Rx) irresponsibly is “always no bueno”

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#26

For me, the actual lifespan data across multiple animals stands much stronger than biomarker clocks.

But Bryan is a smart guy with a smart team, so it’s definitely worth considering.

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#27

I heard they hired professor Allan Lichtman after the election to turn the longevity keys.

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#28

I have a high genetic risk score for lupus, and if it’s on a spectrum with auto-immunity, which I can’t see why not, then I think I might benefit from rapamycin more than someone else. The same can be true for other autoimmune conditions or high genetic loading.

Question is will such a treatment be a net benefit considering:

  • skin/soft tissue infections
  • lipids
  • glucose
  • HR
  • HRV
  • other biomarkers
  • symptoms / feeling

I felt good taking rapamycin when I took it. So individualized medicine might be key here, including genetics because that tells you how much of each condition you might have. I don’t think it’s binary you have lupus or not lupus since it’s probably very polygenic (lots of levers +, -, and an accumulation of levers turned in a direction leads to diagnosis). Is that possible?

5 Likes
#29

yes. I have seen rheumatologists use terms like undeclared…

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#30

I wonder if age makes a difference.

Some interventions are not for the young and healthy. Like systemic senolytics before the age of 50 are most likely not very beneficial. But as we age it looks like killing excess zombie cells is beneficial. They may be beneficial for skin at an earlier age though

As the mTORc1 system ages might that be a better time to implement Rapa?

12 Likes
#31

I agree, the older one is and especially with medical conditions that rapamycin is purported to improve (periodontal disease, Alzheimer’s, etc.) the bigger the potential BENEFIT to potential RISK ratio.

Frankly, I don’t understand why a healthy 20 year or even 30 year old would want to use rapamycin… for me the benefit to risk ratio is very unclear for that cohort.

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#32

While I’m very happy that Bryan has shared some the interventions he has tried, it is far from the open source project he promised.

He makes so many changes (some justified and others not) with the vast majority not being available for scrutiny.

For example, it is the first time in 5 years that he has mentioned “hefty side effects” associated with rapamycin and only now he decides to come off. While everyone is an individual, is it the general experience of these forum members that the side effects of this intervention are hefty? (It hasn’t been my impression).

The rapamycin intervention where the clocks were tested were in 9 organ transplant patients taking a low dose of rapa. Also rapa extended lifespan in marmosets (primates) without affecting the epigenetic clock.

If you’re not getting any side effects from rapa it’s ballsy to discontinue the most evidenced longevity drug to date.

21 Likes
#33

Red line starts rapa+aca at 16 months, orange line at 9 months. From ITP

image
image1179×2217 125 KB

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#34

Good clip.

If that’s the case there might be a genetic difference (with or without combination of other drugs or supplements), when and at what extent rapamycin might inhibit mTORC2 for someone, and whether they need a much lower dose or discontinuing rapamycin specifically. Maybe everolimus works instead or some other mTOR inhibitor.

But first gotta establish mTORC1 vs. mTORC2 and effects on these side effects for sure? Or just trial and error now?

1 Like
#35

Absolutely. While useful for guiding investigation, rationalism is defeated by empiricism every time.

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#36

I subscribe to Deutsch that empiricism is false, but we are agreed that, at the moment, the lifespan data is a lot more informative than mechanistic theory.

1 Like
#37

Huh, it’s in mice. That’s near mechanistic theory.
If I remember correctly when mice eat onions their metabolism increases by 40% or something – we are not mice.

The effect something has on you, your biomarkers and stats, that you can know pretty much for sure and the effect that has. Also how you feel from it, but can be subject to placebo/nocebo.

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#38

Rapamycin has effect across animal models. The most similar to humans is the recent marmoset study - which is why that one is so exciting.

The theory is that rapamycin, by some mechanism preserved across all of these animals, reduces the negative effects of aging as measured by lifespan. Because it is preserved across animals, it may be preserved in humans.

According to that theory starting earlier will then have a greater effect, and the ITP tests of interventions started earlier having greater effect is evidence in support of that.

The alternative theory here is that biomarkers as measured by aging clocks are the best measurement of slowness of age related damage, and that because rapamycin pushes these in the “wrong” direction, rapamycin does not work in humans. I think that is a flawed theory which assumes we have a much greater insight into our biology, and aging clocks have a greater predictive power, than we and they do.

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#39

I didn’t mean aging clocks. Biomarkers like lipids, glucose, and stats like HR or HRV.

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#40

Assuming those are under control using other medications, rapamycin should still exert its pro-longevity effect depending on the dose and frequency.

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#41

Over nearly four years, I’ve experienced many of these side effects and they can be very problematic.

I have progressively changed my regime and since the turn of this year, I now take 5mg once monthly. This approach shows almost no side-effects, other than a slight headache on day one, and my body seems to have rebalanced the offsets based on my bloodworks and my general health.

The reason I persist is that I believe that Rapa based autophagy works and I find this extremely valuable.

“Autophagy is the conserved degradation of cells, miss-folded proteins and other detritus, that removes unnecessary or dysfunctional components through a lysosome-dependent regulated mechanism, and allows the orderly degradation and recycling of cellular components.”

16 Likes