I think the benefits of adding EPA to statins depend on the individual lipid panel. If triglycerides are not elevated then there are probably no CVD benefits (ignoring the other potential benefits you mentioned).
In my N of 1 case, my already bad triglycerides (2.3 mmol/L or 200 mg/dl) were elevated even further by starting statin therapy (Atorvastatin). My doctors kept increasing the dose but the triglycerides either got worse or stayed just as bad. It wasn’t until I added 4g per day of Omega 3 (algae oil since I am vegan) that my triglycerides have now more than halved from their starting point pre-statins.
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Same thing. I was amazed at how effectively adding fish oil smashed my high triglycerides.
LukeMV
#165
I actually do recall that as well. Could have to do with the fact that berberine inhibits the activity of the enzyme CYP3A4, so maybe supplements that also do this could be contraindicated (quercetin is one that comes to mind). Just an educated guess…
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Pat25
#166
Who knows. This reminds me of a paper claiming some of the benefits of D-glucosamine are negated by (certain) antioxidants. I will cite it below.
There may also be some reasons to be cautious about combining antioxidant supplementation with CR. Quite some papers after all suggest the importance of hormetic effects and metabolic adaptions.
Concerning antioxidants, of course there is also the 2009 publication of Ristow et al. “Antioxidants prevent health-promoting effects of physical exercise in humans.” Albeit it has been up for debate.
And we can’t be sure ROS does not function as a signaling factor for rapamycin to initiate autophagy, and how antioxidants may affect that. Some publications suggest that ROS may play a role in this process.
All in all I disagree with the notion that combining a lot of ‘interventions’ is a good idea, and that we could somehow extrapolate what the net effect is. Albeit I’m also guilty of it, I do think there is too much tendency to resort to confirmation bias and wishful thinking. However that’s my opinion, and after an ad hominem attack of CT when I expressed my concern about combining many interventions, I’m not sure whether I want to get into that again.
Treating T2D, cardiovascular disease etc through polydrug use, would likely also give a (very) different outcome than tossing in all sorts of drugs and supplements, while believing (/hoping) one doesn’t negate the effect of the other.
https://www.nature.com/articles/ncomms4563
Antioxidants prevent GlcN-mediated life span extension
Mitochondrial ROS signalling in nematodes15,24 and, in particular, mitohormesis15,25 suggests that a low-dose, transient increase in ROS formation promotes metabolic health and life span26,27,28, thereby questioning the free radical theory of ageing29. To test whether the increase in ROS (Fig. 1i,j) is essential for a GlcN-mediated extension of life span, we repeated the initial life span experiment (Fig. 1b) in the presence of the antioxidants butylated hydroxyl anisole (BHA) and N-acetyl-cystein (NAC), respectively. Although neither BHA (Fig. 2a) nor NAC (Fig. 2b) had a detectable effect on C. elegans life span in the absence of GlcN, the life span-extending capabilities of GlcN were nullified in the presence of BHA or NAC (Fig. 2c,d). This indicates that the transient increase in ROS (Fig. 1i,j) is required for the extension of life span caused by GlcN, thus providing additional support for adaptive ROS signalling26,30 or mitohormesis27,28 or both.
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Well, that’s a matter of perception. I certainly didn’t regard any of my responses as ad hominem. But then again, vigorously pushing back and challenging views should not be seen as a personal attack. Substantive, backed by arguments, citing studies (as in the post above wrt. antioxidants) are highly appreciated, whereas argument free jeremiads don’t bring us closer to the truth. Being on this site by self selection means it’s a group of people who are consciously taking r i s k s, so that is already baked in, polypharmacy entails risks, and those risks should be carefully evaluated and discussed what is definitely not needed and can naturally expect vigorous pushback is an argument free statement to the effect that polypharmacy is risky. We already know that. As I analogized before, in a group of voluntary astronauts nobody wants to hear that space travel has risks without a cogent discussion of a concrete flaw in the mission, because generalized risk all astronauts are acutely aware of, thanks. This is a site frequented by self selected risk tolerant adults who have longevity as their mission… a risky mission, as the drug which inpired the very name of this site, rapamycin represents a risk and a gamble not proven longevity drug in humans.
There are other sites which focus on health from a naturalistic perspective that eschews pharmaceuticals, and there general cautions against polypharmacy are congruent with that mission. Here, on a rapamycin-named site, many of us start with the premise that intervention, which necessarily involves risks, is imperative, as doing no intervention and eschewing drugs, and combinations of drugs represents a resignation to a death not postponed.
By all means, let’s discuss risks, including the risks of polypharmacy in concrete terms and specific drugs, and I will always be an enthusiastic participant, being, as I see it, one of the more conservative and cautious drug/supplement advocates. I also feel it’s important to push back against nonspecific and therefore not useful cautions and naturalistic fallacies - on this site.
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Pat25
#168
I don’t feel like getting into a discussion again, CT. And let’s not pollute this thread. If your posts in that thread had been in line with what you claim in your current post, I wouldn’t have even remembered it, let alone brought it up. It was an ad hominem attack. (Another member was kind enough to ask you to take it down a notch). Let’s just ‘agree to disagree’ here.
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 
.
Needs to be grown in special anaerobic vessels. Not possible for the average person.
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Absolute risk is still miniscule for healthy individuals. Don’t be too concerned with relative risks.
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LukeMV
#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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AnUser
#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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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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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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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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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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LukeMV
#178
I completely stand by what I said here
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To move the needle on improving health requires doing something unusual.
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AnUser
#180
Looks like polypharmacy is back on the menu boys!
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LukeMV
#181
Iconic video! “Yeahhh buddy”
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Jonas
#182
Peter Attia does not take many supplements. He, however, does not look great for a 51-year-old.
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