#169

Well we certainly disagree, and I definitely see it differently, and we can both find supporters and detractors. I stand by what I say, as do you, so I agree that we should agree to disagree :+1:.

#170

Needs to be grown in special anaerobic vessels. Not possible for the average person.

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#171

Absolute risk is still miniscule for healthy individuals. Don’t be too concerned with relative risks.

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#172

I don’t think I would panic about this either, however, I do not recall whether you’re using a GLP1 or not. If you are, you might be protected

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#173

It’s over anti-polypharmacy bros

A geroscientist debunked the harms of polypharmacy, using human, mice, genetic studies, etc:

Be careful about known drug interactions though (like altering metabolism of drug at CYP3A4).

The anti-polypharmacy hysteria has been a bit lackluster as its proponents never cite evidence.

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#174

From Kamil Pabil, the biologist focused on the science of aging:

Should you supplement 40 different compounds? Probably not because many of the compounds just by themselves already lack strong evidence. Would it be harmful to take 5 or 10 different supplements? I doubt it. In fact, most treatments are likely to be additive, albeit with diminishing returns.

和：

Personally, I am worried about liver toxicity from combining multiple hormetics / irritants / unspecific Nrf2 activators. Take, EGCG as a good example. There is quite a bit of evidence for liver toxicity at very high intakes. The same problem can happen with gastrointestinal irritants, because drugs and supplements are provided as highly concentrated pills that can lead to very high, non-physiologic concentrations of the substance. Historically, for example, potassium supplements were associated with deadly bowel perforations. Not because potassium is harmful, but because of locally elevated concentrations. This was largely resolved with delayed release formulations.

Sometimes mechanistic understanding can help us avoid side effects.

and

Drug-Drug interactions and clinical evidence

It is true that undesirable drug-drug interactions are somewhat common but do these drug-drug interactions shorten your lifespan? Do we even have a list of positive drug-drug interactions? I doubt anyone is keeping track of these. So that is certainly a bias. It is also important to point out that these are interactions among a random set of drugs. In the case of longevity supplements and drugs these have already been preselected to 1. be somewhat beneficial and 2. have low risk of interactions in the case of supplements (hence they are GRAS).

One can make the argument that polypharmacy is harmful but that is not a good outcome to look at. The number of drugs a person takes usually correlates negatively with their health status and this is almost impossible to correct for statistically (1). In clinical practice negative drug interactions are also often accepted because there is no alternative. Taking two or three immunosuppressants might increase your risk of cancer and infection but it is still better than a swift death through organ rejection.

Rational polypill approaches have in fact been quite successful, e.g. the recent PolyIran cluster randomized study with over 50 000 participants. A fixed combination of a statin, aspirin and two blood pressure lowering medications successfully reduced major cardiovascular events by 39%.
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)31791-X/abstract

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#175

Well, yes, I have long since been combatting exaggerated polypharmacy hysteria. Caution is of course indicated. I check and recheck the literature before I add a drug/supplement to my stack, looking for DDI (Drug Drug Interactions). And I monitor the effects carefully. But it doesn’t make me shy away from polypharmacy, for a very fundamental reason - it is highly unlikely that you are going to significantly affect aging by monotherapy, using just one drug. It is inevitable that you will need to address different aspects of physiology, modify one drug with another, ameliorate side effects, augment, and improve. There is no simplistic just one weird trick. That’s not how things work, and we’ve seen that play out when rapamycin was combined with acarbose, mixing and matching is absolutely inevitable.

Is adding more drugs/supplements increasing geometrically the complexity of effects? Absolutely. But so what? That’s baked into the challenge. If you want to land humans on the moon, you are going to have to build an unfathomably complex system, where the opportunity for things to “go wrong” is a huge challenge. But what’s the alternative? There are only two mutually exclusive paths. One is to give up on the challenge as too great. Second is to plunge in and do the best job you possibly can. Once you have accepted the challenge - attempt to extend your lifespan beyond its natural limit - you don’t need to hear jeremiads about the dangers of polypharmacy… no sh|t, Sherlock, it’s extremely fraught - it tells me nothing new, so unless you have a concrete caution about a concrete interaction, please spare everyone the pointless nattering.

And speaking of polypharmacy, I thought the idea behind the thread of “critique my stack” was excellent. I don’t think the execution was particularly inspiring, but that’s the limitation of the present format. I hope we could revive it or create a new one that is better focused. Because the challenge of polypharmacy is real, a challenge that this group - most members - absolutely does not see the option of not meeting. It is not for the faint of heart, but there is no alternative.

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#176

What bothers me is that although we hear of the dangers of polypharmacy, I have yet to see too many examples that are not overdosing.

The examples I have seen in C. Elegans where polypharmacy is negative is when you hit a given pathway too hard such as taking multiple drugs that turn MTOR down too much or in humans where you are taking too many or too much of similar polyphenols that cause liver damage. Just remember that even too much exercise or drinking too much water is bad for you.

I have yet to see examples of negative outcomes of hitting multiple beneficial pathways at just the right level. I think this is the key to polypharmacy. Hitting different pathways in a goldilocks fashion.

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#177

Of course we should do the best we can.

The setup for failure in this effort is how the easiest thing to do is the least likely to help and most likely to hurt. Supplements. One click and it shows up the next day. The reviews were good; what could go wrong? Add in pharmaceuticals from India (wait a bit longer).

All chemical interventions outside of nature will have side effects, known and unknown. So I put unnatural concentrations of chemicals found in nature and pharmaceuticals into the bucket of as little as necessary, as defined by measured deficits (or other biomarkers)

The harder path to health is working with our physiological mechanism to help it become the best version it can. That won’t create an unnatural lifespan, probably, but it will stop us from killing ourselves too fast with comfort and laziness and busyness.

Sure, use drugs to quickly fix problems caused by a lifetime of poor lifestyle but also fix the lifestyle to not need the drugs for long (or reduce the need). Once we have that part working, then work on unnatural longevity. Probably the best way to do that is to be alive and healthy when the real life extension programs arrive.

That’s my thinking. Polypharmacy isn’t worth arguing about because drugs are a crutch. Crutches are good while the bone is healing but bad if used to avoid relearning to use the leg.

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#178

I completely stand by what I said here

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#179

To move the needle on improving health requires doing something unusual.

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#180

Looks like polypharmacy is back on the menu boys!

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#181

Iconic video! “Yeahhh buddy”

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#182

Peter Attia does not take many supplements. He, however, does not look great for a 51-year-old.

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#183

I think he looks fine for 51 personally, not that looks necessarily always indicate someone’s health status.

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#184

Impressive stack.
Guessing the liver and kidney prescription pills he mentions are metformin and an ace inhibitor.
Omacor seems to be an omega 3 prescription. Sulindac (nsaid) prescription.
Cholesterol medication would probably be a statin.
supplements:
joint command: glucosamine/chondroitin/(maybe some herb extracts, msm, hyaluronic acid in it),
vitamin e, coq10, chromium, vitamin c, calcium/magnesium/zinc, multi mineral, humanofort, aspirin,
omega fat, echinacea, multi vitamin & mineral, saw palmetto, prostate health, advil.

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#185

If that’s all he takes, then he’s natty, no? Or are we only seeing part of his polypharmacy🤣…

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#186

I agree there are exceptions but “how we look” is a strong indicator of health status. It might not be a leading indicator but it is certainly a lagging indicator of health. It takes hard work to be very healthy and look bad. On the other hand, looking good is one of the rewards for getting healthy.

But faking it (appearing healthy) is the oldest game in town.

Sun exposure is a tricky bit. More sunshine obtained through outdoor activity is great for health but ages the skin. This is probably Attila’s issue. I’d guess he is pretty healthy and I also don’t think he looks bad for his age.

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#187

He, at least, did the Minicircle’s follistatin gene therapy which is a WADA prohibited substance so he is not a natty.

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#188

The peanut gallery thinks he looks older than he is. He is a handsome guy, though.

I am in the camp that someone’s health might be reflected in their body (they exercise and are not obese, for example), but I don’t think faces reflect health. I think genes (and spf!) are everything.

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