Top 5 - Which Currently Available Longevity Interventions Do You Think Are the Best

#388
  • Air pollution is now the second leading risk factor for death worldwide behind high blood pressure, and ahead of tobacco and poor diet.

This is not even cutting edge stuff. Here’s a paper from 2010:

https://www.ahajournals.org/doi/10.1161/cir.0b013e3181dbece1

PM2.5 causes systemic oxidative stress, endothelial dysfunction, autonomic imbalance, and low-grade vascular inflammation

And aside from death, around 30% of childhood asthma is attributable to car exhaust NO2.

Up to 23 million annual asthma emergency room visits globally are attributable to ozone, and 5–10 million attributable to PM2.5.

And for cancer, PM2.5 was formally classified as a Group 1 human carcinogen way back in 2013. 370,000–450,000 lung cancer deaths per year are due to PM2.5, which is about 15–20% of global lung cancer mortality.

And more worryingly, https://pubmed.ncbi.nlm.nih.gov/37020004/ showed that PM2.5 promotes EGFR-mutant lung adenocarcinoma in never-smokers. It can explain around 15% of the lung cancers in never-smokers.

There are also links to diabetes: https://www.thelancet.com/journals/lanplh/article/PIIS2542-5196(18)30140-2/fulltext That’s a paper about data from 2016, showing ~3.2 million T2D cases per year are attributable to PM2.5.

For kids, air pollution is associated with 2.7–3.4 million preterm births per year, and ~16% of low-birth-weight infants globally (https://www.sciencedirect.com/science/article/pii/S0013935123024416)

I suppose as somebody interested in longevity, you’re worried about dementia. Well https://www.bmj.com/content/381/bmj-2022-071620 showed that every 2 μg/m³ long-term PM2.5 increases all-cause dementia with a HR of ~1.04.

The evidence seems to weigh air pollution much more strongly than those. And especially water. If you live in a first-world country, your water is just fine. I asked Claude to integrate the findings, and it reckons that total deaths from chemicals in drinking water (lead, arsenic, PFAS etc) are responsible for 3-5% as many deaths as air pollution. Even if you take in total unsafe water (like bacterial contamination, poor sewerage etc), then it would be 20% of air pollution.

It also gives a nice explanation:

Dose and duration. You inhale ~11,000 liters of air per day versus ~2 liters of water. Even at modest PM2.5 concentrations, total delivered dose of particles and adsorbed toxicants to the alveolar surface is enormous, and the alveolar–capillary barrier is ~0.5 μm thick with no first-pass metabolism. Ingested chemicals pass through gut epithelium plus hepatic first-pass clearance, and most are excreted.

We can actually do some basic maths:

  • Resting/sleeping adult: ~5–6 L/min
  • Light activity (sitting, light office work): ~12 L/min
  • Moderate activity (walking, housework): ~25 L/min
  • Heavy activity (running, cycling): ~50–80 L/min

So let’s use 15 L/min as a representative number. Based on USA average levels of 9µg/m^3, it means yearly exposure of ~50mg/year. If you live in Dehli, that is 500mg/year.

During a wildfire, PM2.5 levels can rise to 300µg/m3, which will give you 4.5mg per day

The particles are tiny and don’t weigh much, so a better way might be to think about particle number. In the USA, that would be 10¹¹ to 10¹² ultrafine particles per day deep into your lungs.

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#389

low dose naltrexone would be my go to here

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#390

Would you say the same thing about Urolithin A? It seems to me that we have way more data of higher quality and over a longer period of time on rapamycin than UA. (On top of that, as sirolimus is an Rx drug, supply chains are controlled, and you’re more likely to get a safe product than random UA supplements.)

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#391

Yes. I would definitely say that UA is highly experimental. We have longer running and more clinical data on rapamycin and likely a much larger experimental user base from which to draw useful information. No comparison really.

I’m not sure of the connection you had in mind between two substances because they differ so starkly in the consequentiality of their mechanisms of action. Rapamycin operates as a “master regulator” at the apex of the nutrient-sensing pyramid, whereas Urolithin-A (UA) functions as a narrow downstream targeted intervention. Rapamycin affects almost every tissue type and multiple metabolic pathways (glucose, lipids, and protein turnover) simultaneously whereas UA effects mitochondrial quality control but does not reset the entire cellular growth program in the same way rapamycin does. The risk/reward equations are materially different.

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#392

There might be effects of UA we don’t know. Your comment on rapa is factually correct (“It is not impossible that a currently unknown problem will emerge in which we learn that it harms and perhaps even shortens the life of some early adopters.”). Then everyone has a different risk tolerance threshold and can decide for themselves. What I find weird is taking UA. Applying the same criteria, I don’t see how you can say “Rapa is risky, I don’t take it” but “UA is worth trying”.

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#393

Whether here or elsewhere, I would suggest that inferring some kind of inconsistency in how someone else navigates choice points based on their adjudication of a complex set of facts and principles would require you knowing much more than you know. The decision literature is full of admonitions on this and it is why I would not call someone else out for what I might trivially and based on inadequate understanding see as an inconsistency in their application of principles.

Factually, I would also suggest carefully rereading the entirety of my comments and grasping the context. It remains scientifically correct to state, " It is not impossible that a currently unknown problem will emerge in which we learn that it harms and perhaps even shortens the life of some early adopters." It does not follow that I think one should not take rapamycin or that I will not again be taking it.

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#394

That’s a lot of words to say nothing.

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#395

This fallacy occurs when someone claims something is true simply because it has not been proven false, or claims something is false because it has not been proven true.

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#396

Hi @RobTuck. I normally stick to science here, but you touched on philosophy and seemed highly invested in the consistency of your reasoning process—so here we go!

First, I think this is a philosophical claim about limits of knowledge—not a scientific claim. More on that below.

Second, impossibility is a very low bar. You mentioned “decision literature”, so I imagine that you already know this. For example, it is not impossible that a sapient ballon who refers to itself as “Robert” resides on a planet outside of our solar system. Or, to use Bertrand Russell’s famous example, it’s not impossible that a teapot (too small to be revealed even by our most powerful telescopes) is currently revolving around the sun in an elliptical orbit.

In other words, possibility is the bare minimum for a claim. It’s not interesting on its own: the list of possible truths is effectively unbounded (i.e. nearly infinite). The interesting questions are around what’s probable, which is a much much smaller set than what’s possible. To quote Kahneman and Tversky’s foundational work establishing the modern sub-field of biases and heuristics, we are always making judgements under uncertainty.

It’s not impossible that rapamycin instigates a catastrophic epigenetic change in parents that only manifests after ten generations. But, to reiterate: possibility is the bare minimum for a claim. All true claims are possible, but most possible claims are not true.

As you pointed out, none of us know how you navigate “choice points based on [your] adjudication of a complex set of facts and principles”, but structuring your thoughts with “It’s not impossible that…” is a red flag that I invite you to reflect on.

So, what would a revised, well-structured (i.e. falsifiable), and scientific version of this claim look like? Something like this:

We do not currently have enough evidence to assess the probability of long-term harms in early adopters of rapamycin. In order to confidently rule out an unknown long-term harm, I would need to see [specific collection of evidence] that showed [success conditions] and didn’t show [failure conditions].

Structurally, this avoids the central problem with all unbounded negative claims, where the implicit demand for comprehensive evidence means that no amount of actual evidence can be sufficient (e.g. you can’t search every planet in the universe for that sapient balloon named Robert).

Practically, this puts the burden of proof (rightly) on you to argue why we should be concerned about unknown long-term harms in the first place. This is the step where you promote your claim from possible (uninteresting) to probable (interesting). Here, establishing a precedent of other drugs with late-arriving harms might be enough of a precautionary principle to warrant attention.

But this, then, invites a comparison of the data available at the release of those drugs vs. rapamycin, exploration into how well the mechanism of action was understood vs. rapamycin, how much preclinical data was available, etc.

Structuring a claim this way also means you have to specify what evidence would be sufficient to convince you. Which means the claim is now properly falsifiable. So, when @RapAdmin mentioned that:

this provides, not the gold-standard, but a substantial evidence base to interrogate for signals of harm. If you didn’t already have that background information, then finding out that a population of people have been consistently taking higher doses of rapamycin without unknown/unexpected harms should be a relief. Depending on your risk aversiveness, you may want long-term, randomized clinical trials in diverse populations, across multiple ages, exploring the dosing schedules and amounts used by early adopters. But, regardless, thanks to the structure of your claim—you would at least be able to update your confidence along the way.

And, crucially, well-structured, falsifiable claims make conversation so much more constructive. We’re all walking around with false beliefs in our heads—and I think engaging with the ideas of others (whether through reading or conversation) remains the best way to root them out.

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#397

I get all this @McAlister. I spent six weeks with Agassi when he was at Illinois. There is much to be said in response to your position but this is not the place for it. Obviously, something in the way I stated my position has engendered an interpretation unintended by me. Don’t you think this has gone far enough off point and tone. I do.

I always enjoy an informed argument on the philosophy of science. If you would like to tighten up your argument from that point of view and send it to me privately, I would be delighted to respond. Where you would want to begin is the common conflation of Popper’s falsifiability criterion. It applies to synthetic propositions about the world, not to analytic or logical claims. I already identified empirical claims which no one has impeached. Again, privately if you wish to engage more on the philosophy of science; publicly, let’s move on.

#398

Btw we have a dedicated UA thread: Urolithin A (UA) One of 4 Promising Agents 2024 by Brian Kennedy of NSU - #393 by RapAdmin

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#399

I disagree with you about your original point and I also disagree with the argument that

this is not the place for it

In this forum we need to discuss things based upon the evidence that does exist. If you have a molecule with a long track record of being used and large numbers of case reports both negative and positive then although it is “possible” that there may be a negative effect that we are not aware of, that should realistically not be part of the reasoning for not making use of the substance.

This, obviously becomes different as dosing increases. Hence caution should be used if taking doses beyond those which are normally used.

Hence, where you say:

Factually, I would also suggest carefully rereading the entirety of my comments and grasping the context. It remains scientifically correct to state, " It is not impossible that a currently unknown problem will emerge in which we learn that it harms and perhaps even shortens the life of some early adopters. " It does not follow that I think one should not take rapamycin or that I will not again be taking it.

You are entitled to take that view as it is a view where you are making decisions about matters where you should have self actualisation.

However, I don’t think such arguments have a place on an evidence based forum.

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#400

Coming back to this a day later @John_Hemming, it seems clear that something I expressed (from evidence, an inartful expression) was interpreted to mean that I am against rapamycin and do not take it because of the risks. Someplace back in that thread and others, I believe I said that I’m not taking it at present because I did not have a good experience with it. I definitely did not intend to say that the drug does not present a sound risk/reward profile for people like us. To the contrary, I believe it does present a sound risk/reward profile and I plan to again initiate a regimen again once I have put some other issues behind me. The phrase that seems to have been most inflammatory to a few here, certainly the one most quoted, was a phrase I had initially considered deleting, not because of its tone, but because it is obvious perhaps to a point of triviality.

To clarify another strand of objection, I am very clear and always have been, in my understanding that some of the geroprotectives and related interventions I pursue are based on less evidence and therefore possess a less favorable risk/reward profile than rapamycin based on current evidence. On this point, the materiality of the downside risks and upside benefits modulate the personal risk equation each of us formulate.

One of your comments and a few of others give me pause with respect to how they navigate the is/ought and synthetic/analytic boundaries but these are the issues I had in mind when I suggested that they are not fruitful ground for this forum and that I would prefer to move on.

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#401

There might be effects of UA we don’t know. Your comment on rapa is factually correct (“It is not impossible that a currently unknown problem will emerge in which we learn that it harms and perhaps even shortens the life of some early adopters.” ). Then everyone has a different risk tolerance threshold and can decide for themselves. What I find weird is taking UA. Applying the same criteria, I don’t see how you can say “Rapa is risky, I don’t take it” but “UA is worth trying”.

I think in general most people are good at being risk-averse and treading cautiously when it comes to prescription drugs, even in the face of evidence that the drug will net them greater health.

For whatever reason, this skepticism/caution seems to go out the window when it comes to supplements (or nootropics, peptides, and natural products for that matter). FWIW I think this is somewhat warranted with things which play “housekeeping” roles and are non-toxic even in high doses. Even magnesium could stop your heart if you somehow took too much though, and if you somehow took too much glycine it could temporarily blind you and spike your blood ammonia. Antagonistic pleiotropy is more like the rule than the exception (or in the words of Phillip Anderson: More is different).

Popping bromantane and then discussing the potential neuro/cardiotoxicity of Adderall is hypocritical and naive. Absence of evidence is not evidence of absence, but unfortunately people treat it that way. Not necessarily people on this forum but UA is a bit of a double whammy too, because many succumb to the mind virus of natural product bias.

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#402

I’m actually reading your post while wearing a red light therapy mask at this very moment

#403

I’ve actually “overdosed” on magnesium before. I misread a study and chose a dose based on my amount elemental magnesium content instead of mg amount of a magnesium compound (taking into account the mineral/amino acid/etc in the total compound weight) and I had extreme muscle pain, difficulty breathing, basically about to pass out and sweating.

It took about 4 days for the dose to show symptoms, and about 2-3 days after this for me to realize what was happening. Once I stopped taking any magnesium it took 1-2 days for it to return to normal. Then I restarted magnesium glycinate at 1 capsule instead of 11, :rofl:

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#405

It would be interesting to know how much magnesium this was.

I need to type more because the forum otherwise rejects the corrected post. Corrected as to reply to.

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#406

11 of these a day:
https://au.iherb.com/pr/21st-century-chelated-magnesium-glycinate-90-capsules-100-mg-per-capsule/145057

One thing to note is it is bound to an amino acid instead of a mineral. I think magnesium citrate or oxide would have just caused diarrhea, but glycinate is better absorbed I think.

#407

That looks like 1.1g of magnesium in 11 pills. That does fit with the literature. The tolerable upper intake is 350mg, but kidney function is an issue as well.

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#408

The above comments by @RobTuck and @McAlister are certainly welcome here by me since I am new to this forum. Different viewpoints are good, Keep it coming!