Those are excellent points! You’d take it out of my cold dead hands, but he had me doubting myself!
In the video, he pointed out it was fast tracked through the FDA so we don’t have all the normal safety data.
I don’t know if it made the AI summary, but in the video he noted Hazel worked with his mentor
And WHOA those prices!!!
I had not viewed the video and not much was in the summary - so I want back and listened to the section on SS-31 peptides and though it was interesting and more helpful than just the summary in this area.
Matt obviously knows quite a bit about the SS-31 peptides, given that his mentor was someone who worked closely with Hazel on the early research on SS-31 in mice many years ago. Matt brings up good points… there is no indication that SS-31 will have any impact on lifespan. He does admit that if the mouse studies translate to humans, we could expect some benefits in bio-energetics (muscle energy) and frailty reduction. He then balances that agains the risks of grey market peptides. And it’s true we don’t know the long term effects in humans (but thats going to be the case with most newer peptides or drugs given the relatively short phase three clinical studies).
The counter is that there actually have been quite a few human clinical trials with SS-31 with no side effects seen other than the injection site pain. The key issue in the equation (for me) is the safety/purity issue of the SS-31 peptide you’re using. If it’s well tested and quality verified, then the risk is only in the peptide itself (not the contaminants, etc. that could be in the peptide). And given the results seen so far, I would still be interested in trying it.
Here is the full transcript of the section where Matt discusses the SS-31 peptide. I think its worth a read, for anyone interested in this peptide:
Matt Kaeberlein:
SS peptides I’m going to put in the “avoid” category unless you have mitochondrial disease. I don’t think there’s any evidence in healthy people. And by the way, that’s not a supplement. That’s a prescription medication. So that’s the one that I was saying doesn’t really fit into the supplement category.
I know a lot of people are excited about peptides in general. A lot of people are excited about SS peptides. I say avoid. And I feel pretty strong on the avoid here. Again, not because I know anything dangerous about SS peptides, but I think there’s a few reasons not to go out and start taking SS peptides from a purely risk-reward perspective, unless you have some sort of mitochondrial disorder, and then that’s a different conversation.
So, just to make sure everybody really understands what we’re talking about here, SS peptides are in fact not a supplement. They are sort of a prescription medication, and they land in this gray area where doctors can prescribe them. As we’ll talk about, the SS peptide most people are going to be taking is SS-31 (or Elamipretide) that was just recently granted accelerated FDA approval. So a doctor can now prescribe SS-31, but it falls in this gray area of the peptides where some people are getting them from compounding, some people are getting research grade off the internet. It’s just kind of ugly and messy right now.
So what do we know about SS peptides from a data perspective? They’ve been around for 20-plus years. SS-31 in particular. I actually was around a lot of the early SS peptide work at the University of Washington because Hazel Szeto, one of the “S’s” in SS, collaborated extensively with my mentor, Peter Rabinovitch, on SS-31 work looking at mitochondrial function in mice. Peter, by the way, is one of the greatest people who I’ve ever had the opportunity to work with. As I said, he was a mentor of mine, and I’m just super grateful for all of the support he gave me throughout the years. Also a fantastic scientist.
And they did a lot of work in mice, treating mice with SS-31 and looking at: where does it go? How does it work? What are the effects on health span and lifespan? And so I think what we’ve learned through Peter’s studies and lots of other studies that Hazel did is SS-31 indeed localizes to mitochondria. It can interact with cardiolipin at least in some contexts. It can reduce mitochondrial fragmentation, reduce reactive oxygen species production, and increase ATP production or energy production. But the idea that SS-31 or any of the SS peptides are general “mitochondrial boosters” supporting mitochondrial function is just sort of a massive oversimplification of the biology. It’s very context dependent.
And my recollection of the mouse data that Peter’s lab and others did was that SS peptides can sort of remodel the mitochondrial proteome, improve some aspects of mitochondrial energetics, potentially improve muscle function in aging mice, but didn’t increase lifespan. So again, it’s one of these situations where maybe a few health span metrics are improved, but it doesn’t seem to be, at least in those experiments, a general longevity drug or general geroprotector. Having said that, if it had similar effects in people without any side effects, that might be something to consider. Maybe it would be beneficial for frailty in people as they’re aging.
So what do we actually know though about SS peptides in people? So, as I mentioned, Elamipretide was recently approved by the FDA—that’s SS-31—for Barth syndrome. But it wasn’t a sort of full approval. It was this accelerated approval path. And that’s because Barth syndrome is a rare childhood mitochondrial disorder where there really aren’t any other treatments available. So, it got this accelerated approval based on the fact that it’s for a severe disease without any alternative treatments, and there was a reasonable expectation that it might work.
So what hasn’t been shown is that SS-31 actually has efficacy for Barth syndrome or for anything else, at least not in the context of an FDA approval process. So we don’t know—it’s gotten this accelerated approval. We don’t know whether it actually works for this indication or for any indication for that matter. There are some other ongoing studies in humans and I think we just have to kind of wait and see. And I know a lot of people are frustrated with the FDA clinical trial process. It takes too long. I get all that. And you really want to know what the safety profile looks like and whether there’s a reasonable expectation that this is going to work for what you want to use it for.
Nonetheless, a lot of so-called “self-proclaimed longevity doctors” have started prescribing SS-31 for use in their patients. And you know, I’m sure they’re starting to get case reports, information about whether SS-31 has benefits, what the side effects look like, but it’s really hard to know what’s real and what’s not real at this point.
So, for that reason, I’d say the reward part is pretty questionable. Like maybe modest benefits for mitochondrial function. There was one study that I’m aware of in healthy older people where there were some indications of improved mitochondrial bioenergetics. That’s kind of what we know I think for healthy older people in SS-31 at this point. So that’s the potential reward. Maybe modest impact on mitochondrial function, maybe best case scenario, modest protection against frailty maybe, but not a lot of indications this is going to be a big effect size intervention. Certainly not compared to something like exercise.
And then what is the risk? Again, we really don’t know because we don’t have, as far as I know, any long-term studies in people. And there’s a few reasons to think that there could be some risks. First of all, we don’t really know the dosing for what we’re trying to use it for. Again, not a lot of data in people, and most of that comes from mitochondrial disease. So, we don’t know the dose. We know we are putting a foreign peptide into mitochondria. And so anybody who understands mitochondrial biology will recognize that there are some reasons to think you want to be careful about putting something into mitochondria that isn’t normally there. Doesn’t mean it’s going to have detrimental effects. Doesn’t mean it’s going to cause problems, but often it is the case when you put foreign proteins or peptides into the mitochondria, it creates a stress response that can be net detrimental. So we want to be a little bit careful about that.
And then I think outside of the SS peptide itself, and this is true for a lot of the peptides that are out there in general, there’s real reasons to be careful about purity and contamination in the peptide preps themselves. For reasons that somewhat due to lack of regulation, somewhat due to opportunism by people of questionable ethics, you might say there’s a lot of people selling peptides of uncertain purity. And so if you get it from a compounding pharmacy, that’s better than buying it from a random person on the internet who’s selling research grade peptides. But even peptides from compounding pharmacies have been sometimes found to have impurities that can lead to problems like allergic reactions.
So, I think you just want to be real careful when you think about the risk-reward with peptides in general, especially peptides that are not FDA approved, especially peptides that are research grade, and with peptides that we don’t have a ton of data, especially human data like SS-31 to understand what the safety profile looks like. I feel pretty good about putting SS-31 and SS peptides in general in the avoid category for now. They are super interesting, super promising biologics. I’d just like to see a bit more data.
Before you worry about how to get legitimate uncontaminated SS-31, you first have to ask why you’d want to. I looked at the evidence, and similar to Matt, I just don’t see it. First and foremost, let’s keep in mind that there is no evidence whatsoever that SS-31 is a longevity molecule - in fact, in mice it has failed (to extend lifespan). So, if it’s not a longevity molecule, perhaps it’s a healthspan molecule? Well, we have some results in mice mitochondria and the like, but it’s pretty equivocal insofar as you have to make a lot of assumptions that what it’s doing to the mitochondria is health promoting for people who don’t have mitochondrial disease. Even the FDA approval was an emergency one, where they’re willing to lower the standards simply because there is no other intervention and this at least has some hints it might work for a rare disease condition - but we’ve had little clinical experience here, and it may very well fail in even that once it is more widely used for its indication.
That leaves “healthy” people. As Matt has pointed out - there is no evidence whatsoever that SS-31 does anything in healthy people mitochondria that somehow enhances the mitochondria or represents a helpful kind of mitophagy. I mean, no disrespect to Hazel, but apart from prolific mechanistic speculation, there is no hard outcomes data in humans.
So you’re asking me to invest time and effort and twist myself into a pretzel to take a “possible” healthspan extender? Do you know how many interventions exist that can make a much better healthspan claim than SS-31 - you’d quickly lose count.
Meanwhile, worry about purity and dosing. There’s the SS-31 thread, where there’s literally a handful of posts about any possible evidence of benefits and the rest is worrying about how to score the right stuff and dose and adminstration routes and all that stuff around it. And I keep coming back to “bbbb bbbb bbut why take it in the first place, can we get back to that?”
I’m not saying you or anyone should not take a chance on SS-31 (or any other molecule), but you frequently reference ROI in time, money, effort and opportunity cost. And looking at the evidence, this ROI strikes me as absolutely abysmal. Based on the evidence - clear evidence - not vibes, authority, influencer or scientist personal enthusiasm, but cold hard evidence - I just don’t see this gamble, I wouldn’t bother staking 1 penny on this peptide. There’s a universe of other molecules out there that I’d sooner invest in. And quite frankly, I’m trying to - if anything - prune my stack. Adding this makes no sense - to me, but it might be very persuasive to you, because we all have our own situations to evaluate, which is why I rarely make unqualified blanket statements that a molecule is “good” or “bad”, because we all have our own profiles. However, I think it’s always useful to turn on a skeptical light with any drug, to make us evaluate again whether it really makes sense. Even with stuff that we already take. And so, I follow the rapamycin literature, because who knows, maybe one day evidence will turn up that makes me drop the rapamycin gamble. I try to do this with all my drugs and supplements. I regularly ask myself - does this drug still have a place in my stack? That goes triple for a prospective drug, an addition to the stack, like SS-31. For me - not saying for you or anyone else! - SS-31 is not even in the ballpark, city, world, solar system, galaxy. Of course, as usual YMMV.
You heard about lithium orotate almost 4 years ago from Rapamycin News. So it was not a hidden sleeper for us. The observational data at the time was was very promising.
Stay tuned to Rapamycin News for the latest in healthspan and lifespan interventions. No other website is even close if you want to be an early adopter. Sorry Mike, Attia, Huberman, et al. You impart only a fraction of the information published on this site. And, the information here is freely shared.
Most days I take 5 mg lithiumorotate. Some days I up the dose to 10 mg.
The provided transcript details an interview with Dr. Kim Brockenbrough, a cardiovascular radiologist, advocating for a paradigm shift in preventative cardiology: the transition from Coronary Artery Calcium (CAC) scoring and functional stress testing to universal Coronary Computed Tomography Angiography (CCTA) for asymptomatic individuals. The core thesis posits that CAC scoring fundamentally fails as an early diagnostic tool because it only detects late-stage, calcified atherosclerosis. It systematically misses low-attenuation, non-calcified (“soft”) plaque, which is the primary morphological substrate for acute plaque rupture, myocardial infarction, and micro-embolic vascular dementia.
From a translational medicine perspective, the biological mechanisms described are highly accurate and align with contemporary intravascular imaging and histology data. HMG-CoA reductase inhibitors (statins) and PCSK9 inhibitors do induce plaque regression and stabilization, primarily by delipidating the necrotic core and increasing macroscopic calcification. Consequently, a rising CAC score in a patient on lipid-lowering therapy indicates therapeutic success (plaque stabilization), not disease progression. The transcript correctly identifies that relying on functional stress tests—which only flag >70% luminal stenosis—is a profound failure of preventative medicine, as the majority of acute myocardial infarctions originate from mildly stenotic but highly inflamed, vulnerable plaques.
However, the transcript presents significant epidemiological distortion and clinical selection bias. The assertion that 70% of patients with a zero CAC score possess soft plaque is highly skewed by a referred specialty clinic population; population-based cohorts demonstrate this prevalence is closer to 11–16% in asymptomatic individuals. Furthermore, while the mechanistic rationale for universal CCTA screening in 40-year-old men and 50-year-old women is compelling, it lacks Level A mortality-benefit data for purely asymptomatic populations without traditional risk factors, placing it in an aggressive, experimental tier of clinical practice.
| Specific Claim | Speaker’s Evidence | Scientific Reality (Current Data) | Evidence Grade | Verdict | Verified Status & Link |
|---|---|---|---|---|---|
| Soft plaque is more dangerous and likely to rupture than calcified plaque. | SCOT-HEART trial (2020) | Low-attenuation non-calcified plaque burden is the strongest predictor of fatal/non-fatal MI, outperforming CAC and stenosis severity. | Level B | Strong Support | Verified: Williams et al., Circulation 2020 |
| 70% of patients with a zero CAC score have non-calcified plaque. | Clinic’s internal data (first 100 patients of 2024). | General population registries (e.g., SCAPIS) show non-calcified plaque prevalence in CAC=0 patients is ~11%. The 70% figure represents extreme clinical selection bias. | Level E | Unsupported | Verified: SCAPIS cohort, Circulation 2021 |
| Statins and PCSK9 inhibitors “melt” soft plaque and increase calcification. | “LOCATE trial” (Germany, 2024) | High-intensity lipid-lowering therapy halts progression and induces regression of percent atheroma volume (PAV) while increasing plaque calcification (PARADIGM, GLAGOV, PACMAN-AMI trials). | Level A/B | Strong Support | Verified: GLAGOV Trial, JAMA 2016 / LOCATE trial source unverified in live search. |
| Stents and bypass do not prolong life more than medications in asymptomatic patients. | ISCHEMIA trial | Invasive strategy did not reduce the risk of ischemic cardiovascular events or death from any cause compared to conservative medical therapy in stable CAD. | Level B | Strong Support | Verified: Maron et al., NEJM 2020 |
| Testosterone replacement does not increase cardiac events if lipids are managed. | TRAVERSE trial | TRT was non-inferior to placebo regarding MACE over 22 months in hypogonadal men. However, the trial population was heavily medicated for existing CV risk factors. | Level B | Plausible | Verified: Lincoff et al., NEJM 2023 |
| Testosterone therapy in older men causes cardiac events. | TOM trial (2010) | The trial was prematurely terminated due to a significantly higher rate of cardiovascular adverse events in the testosterone group vs. placebo. | Level B | Strong Support | Verified: Basaria et al., NEJM 2010 |
The clinical outcomes discussed in the transcript are governed by specific intimal wall dynamics:
New episode:
He calls berberine basically not much different from metformin – basically an unregulated form of metformin.
Speaking of berberine, I was reading the other day that it has decent lipid-lowering effects, though of course not as potent as statins… And evidence not as strong (not as many large clinical trials).
He also mentions how the reason you see small clinical trials with supplements is not because people don’t know how to do high-powered studies. They do it just because it’s easier and they don’t have to go through the complicated and expensive process of getting FDA approval.
I think berberine is simply better than Metformin at everything. Better reduction in A1C, lower lipids, and better animal lifespan data. I think its effects on the microbiome are probably a large part of it. I think the results would be quite good if the ITP ever studied it. Yes, there is less data on it than Metformin but I am making an educated guess that when the dust is settled, it’ll be clear that berberine is better.
That would be an N=1. Your statement is simply not the case.
I think it is. Let’s revisit this in five years when berberine data catches up to Metformin.
I thought we decided Imeglimin was the better metformin. Should I cancel my order and hit amazon? LOL
I don’t think anything is better for lowering glucose levels than metformin. My system just does not tolerate metformin. I take Imeglimin; it is second-best.
The main problem w/berberine IMO is its numerous drug interactions based on potent effects on multiple liver enzyme pathways, including but not limited to CYP3A4. For instance, it can completely screw up a once weekly rapamycin regimen by lengthening the effective half-life of the rapa and keeping one from ever reaching a trough in serum levels. I bled for hours from a simple tiny shaving cut due to its interaction with Plavix.
It’s better at everything except that it has fewer studies and human data, arguably lacking what’s most important.
This never gets old. The reason so many OTC supplements have such positive reception and reputation amongst consumers is exactly because we don’t have the kind of rigorous studies of them that pharmaceutical drugs are obliged to undergo.
I’ve said it before and I’ll say it again, a million times: I much prefer pharma drugs in my stack than any supplement for this very reason. Not only are extensive studies performed before regulatory approval, but you then have tons of clinical studies and an obligation to report any side effects over decades. None of this applies to supplements in the US. Not to mention when you buy a pharma drug, you are assured at least a minimum standard of quality and manufacturing - you know what you’re getting… you absolutely do not when buying supplements.
And that’s just the start of it. When researching a pharma drug, I can look at numerous studies and really follow possible interactions with other drugs and everything is well characterized with dosages specified. You have the information to make an informed choice (insofar as possible). But what do I do with some botanical extract that has a single dodgy small study somewhere claiming some benefit or other and zero other studies? There is no comparison. And if you mention a pharma drug, a botanical fan can always send you studies about side effects (because at least such studies exist), and then says “no side effects reported from the botanical”. Go figure.
The other day I had dinner with some friends. There was a guest and the discussion erupted over statins - I never participate, because it’s pointless. The guest was opposed to statins - instead they used “red yeast rice”… facepalm. There’s no sense in having such arguments. The discussion all focused on the evils of statins. I stayed out of it.
The berberine vs metformin discussion often has features of such. At least berberine has more studies behind it, but it’s still too woefully understudied to be making confident assertions about.
In some countries RYR has the statin removed.
Though, 1,000 to.1,500 mg are probably far less potent in terms of its effects on CYP3A4 than half a cup of grapefruit juice. And grapefruit juice’s effects will hang around for a while, taking several days to clear from the body from just one dose.
And a few grams (a teaspoon or two) of black pepper probably alao has a more potent effect than berberine.
I don’t think this is true. From memory, a single serving of grapefruit inhibits cyp3a4 in the intestine and therefore increases rapa absorption, but has little or no effect on liver 3a4 (and thus no effect on elimination/metabolism of rapa).
Google Gemini 3-thinking:
https://gemini.google.com/share/9a422f042c94
My question:
which has a more potent effect on CYP3A4, a half cup of grapefruit juice of 1,000 mg of berberine?
Its response:
When comparing the two, grapefruit juice generally has a more potent and clinically significant effect on CYP3A4 activity than 1,000 mg of berberine.
While both substances inhibit this enzyme, their mechanisms and the “depth” of that inhibition differ substantially.
…
The Bottom Line: If you are looking at which one will more drastically change how your body processes medication, grapefruit juice is the more powerful disruptor. It effectively “shuts down” the metabolic pathway in the small intestine for several days, whereas berberine’s effect is more transient and less absolute.
Please read what I said above in the previous post. You are completely missing the point, which is intestinal vs liver inhibition of cyp 3a4. Your comparison above would only be valid for someone guzzling grapefruit juice multiple times per day every day. People who use grapefruit with rapa only take it once with each weekly dose (in which case it only affects intestinal 3a4). Berberine is taken 2 or 3 times daily continuously and absolutely does affect both intestinal and liver 3a4.