Deeply disturbing information on combining longevity supplements

[Ulf]

In a fascinating video posted by RapAdmin on gemfibrozil, dr Brian Kennedy says that when you are taking one antiaging supplement, you are at the edge. When you take two, you are the off the edge. You have no idea what is happening. He brings it up 22 minutes into this video, preset to start then.

Prof. Brian Kennedy at Rejuvenation Startup Summit 2022

At a conference in August Brian Kennedy gave further details. He said that when more than one supplement is given to mice the most common result is that the supp with the weakest effect is nullified. The effect of the strongest supp stays the same.

Scary is the second most common result which is that the effects of the supps cancel each other out.

The third most common, and rarest, result is that the effects are additive. I had assumed this was the most common result and if he is correct my supplement world is turned upside down.

I hope somebody on the thread can convince me this is not correct, or give another perspective!

Brian Kennedy told me there is nothing published on this and it is all on mice.

He also told me that he believes all this is true even if different pathways are used to reach the same target. He seemed to agree that if supps don´t share the same target, the risk should be less or nullified. But this may be of scant consolation since the more I look the more everything seems to be related:

Our talk departed from the mTOR signalling pathway and my use of Ca AKG, an mTOR inhibitor. As I research my supp stack, I realize that “All roads lead to mTOR”. In the crosstalk between signalling pathways, almost all my supps interact with the mTOR pathway: Besides AKG, they are taurine, curcumin, CoQ10, quercetin, carnosine, zinc, melatonin, tadalafil and reishi, They all inhibit mTOR except one that mainly activates mTOR.

With rapamycin on hold for me, Ca AKG is my current no 1 longevity supp, that I will be using for seven months as per the average in that trial, before retesting my AKG level. Should I really stop all others, taking them one by one sequentially, perhaps two a year? Or could the fact that the supplements also have other targets than mTOR mean that these are unaffected by (negative) interaction between supplements? Could the fact that my AKG level is so low mean that supplementing it will somehow avoid interaction risks with other mTOR inhibitors?

I have no idea. I would love a long talk with Brian Kennedy or some other person with deep knowledge, about each of the supps. Having grabbed him three times at the conference for snippets of talk between others wanting his attention, I balk at reaching out again.

For the time being, I am only taking the three supplements that are the dearest to me.

To help me arrive at a conclusion, I have put in writing the connection of each one to mTOR. This in the hope that the connection would prove to be weak but the more I look the stronger I find the connection to be in most of them. If wanted I can post them.

[KarlT]

It would be difficult to disagree with the opinion of an expert in the field especially since he covered all the bases by saying that multiple supplements could work together or against each other.
The recent Attia podcast with Dr K and Dr S, make it clear to me that the experts are a long way from understanding how mtor exactly works and what all the upstream and downstream effects are.
If you’re taking a lot of supplements you’re almost certain to both stimulate and inhibit mtor. My understanding is that the Rapa inhibition of mtor is rather strong and probably wins out.

[DeStrider]

Matt Kaberlein did a terrific study on C. Elegans where different drugs were tested alongside Metformin to see how they affected lifespan. Most were additive, but not in a 1:1 fashion. Some were multiplicative. And in some cases, different compounds which had both increased lifespan separately caused a decrease in lifespan.

Also look at multivitamins. They have a large number of different supplements yet they do not cause shortened lifespan.

I agree that if you combine a bunch of MTOR inhibitors, you’re probably going to be negating the effects of many.

[John_Hemming]

The problem is that without knowing what mechanisms you are trying to increase or reduce it is hard to work out what might happen from a combination.

[JKPrime]

Makes sense. Interactions between supplements and medications especially unregulated ones are unclear. More supplements and more unpredictable interactions. Perhaps in the future we could model all these interactions through AI to eliminate the risks and understand benefits. But we are not there yet. So fewer supplements and meds you can take to an achieve your goals the better.

[Joseph_Lavelle]

Thank you for this. I am going to dive into this question. Until I get a satisfactory answer I am going to cycle my supplements each week. No supplements on rapa day +0 (I already do this). Only take supplements on rapa day +1-4. No supplements on rapa day +5-6. I will continue with medications as prescribed.

[Dexter_Scott]

Bad news for that creepy super-rich guy who is taking a bazillion longevity drugs and supplements at once.

[RapAdmin]

@DeStrider

Matt Kaberlein did a terrific study on C. Elegans where different drugs were tested alongside Metformin to see how they affected lifespan.

Yes - here is the slide I think you’re talking about:

On the last slide, Matt noted that there are in some compounds, synergistic effects both postive and negative. In this slide Metformin is the the “control” - with consistent positive results when used alone (this is in worms) of between 5% and 15%.

Some drugs show synergistic effects with significant increases in lifespan (of the worms in this study) but some show no effect, and sometimes there is a toxic combination effect where the outcome is much worse than the two drugs individually (those are the green bars that extend down the furthest in this graph below).

It just reinforces that we still don’t know how all these drug / drug interactions will work out inside our bodies. I’m hoping that Matt and Ora Biomedical will share with the public all the data on combinations of drugs and supplements that show either no beneficial combination effects, or toxic effects… The toxic effect combinations below are the green bars that go downwards below the Zero effect line. It looks like about one out of every 10 or 15 combinations resulted in some toxicity and negative impact on lifespan. (the good news that in this group about one in 4 seem to have a positive boost over and above the individual compound effects).

I’m reaching out to one of the co-founders of Ora Biomedical to see if they may have some new data they can share with us.

[RapAdmin]

@Dexter_Scott

Bad news for that creepy super-rich guy

But - he’s doing a ton of blood testing and other types of testing, so he (perhaps unlike most of us) should be able to catch any negative repercussions very early on… and change his supplement regimen.

[Ulf]

Great if you can make the dive, be prepared to stay under for a while, this is deep! I thought I had it all figured out with stacks of newly purchased highest quality supplements… But better informed than happily uninformed. Helps me prioritize meds very strictly.

[Joseph_Lavelle]

I don’t hope to find “the answer” but rather certain guardrails and ways to minimize risk. I’m sure that one step is to reduce my exposure to supra physiological doses of exogenous chemicals. I’ll be setting up interviews with people who are in a position to offer wisdom.

[DeStrider]

So, in a way, we should all be very thankful for Bryan Johnson. If there is a negative combination of drugs or supplements that can be detected by biomarkers or scans, he’ll be the canary in the coal mine.

I truly appreciate what Bryan is doing for the rest of us. Thank you!

(Practicing some gratitude here )

[Joseph_Lavelle]

But will he alert the world to his failure? I’m not counting on it.

[DeStrider]

I think he would alert the rest of the world to it. Why not?

[KarlT]

If something goes wrong, I’m very curious how he figures out what the cause is.

[Joseph_Lavelle]

No one can know what he will do. I am saying that i will not putting my health in his hands.

[scta123]

@Joseph_Lavelle

i will not putting my health in his hands

But what is he doing differently than all of us? He is just trying to optimize nutrition, exercise and sleep and corresponding biomarkers using scientifically proven methods.

[Ilya_M]

I don’t think that many combinations were tested properly. And we already know from ITP that rapamycin worked best in combination with acarbose.
And soon we will have more information on combinatory approach from Aubrey’s RMR.

I listened to Russian longevity podcast, where Mikhail Batin said that what we should do is to train AI to predict the result of different drug combinations and gradually improve it’s ability to predict. This is the key to combinatory approach.

[John_Hemming]

He won’t however engage in the scientific debate. If he were to participate in this forum I would have more respect for his approach.

There is always a challenge for people to learn when they are making assumptions that are wrong or their analysis is wrong. If people don’t get involved in discussing issues particularly scientific issues they cannot learn from that process.

[DeStrider]

Who knows? Maybe he is engaging via an alias here. His doctor has visited before. This is a hub of scientific knowledge and debate about longevity. A veritable breeding ground for the things he desires.

I think it would be foolish if he or a representative of his was not at least lurking here.

That’s what I would do.

And then I would hire someone who is knowledgeable in longevity to scour these forums for actionable items.

No need to directly engage in the debate while others do it for you.