#356

Many of the things in my list of molecules are clearly included in very and many valuable ways throughout the book in the context where they are relevant (cardiovascular health, brain health/dementia, sleep, etc, etc, etc).

Let’s just agree to disagree if you have a different view of the book and Dr Attia overall as it pertains to the value of molecules as one part of a longevity playbook / quiver. Not sure anyone is getting any value from our continued back and forth. Feel free to have the last word if you want, this is likely my last post on this sub-topic.

For context, the reason for my first comment is that Dr Attia and his big team and resources have been one of the best sources around prescription and not prescription based supplements for me personally and I felt it would be a shame if anyone new to the field or not familiar with Dr Attia think that they only could learn about exercise and sleep from him.

His advice on molecules specifically has been a main driver and reason for that

  • my Apo B is now massively lower
  • my homocysteine had come down a lot
  • my Omega 3 Index is in better shape
  • my sleep is better
  • my gut is more optimized, and
  • that I’m trying out an SGLT inhibitor this month, then trialing acarbose.

If anyone else can be helped by his insight, his teams research and his recommendations re molecules even to a small fraction of how it has helped me, I hope they are not discouraged to see his wealth of resources also on molecules (as well as on exercise and other topics)

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#357

Neo, you always give very nuanced answers. I hope some day to be able to give answers like you.

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#358

Approach to Supplementation
I enjoyed reading this discussion thread and seeing the many different perspectives, all of them well reasoned. Without going into detail, my approach is more one of broad base than minimalist, with one important difference.

Model
With the exception of rapamycin (which I’m putting on hold for the moment) and metformin, my model is to take low doses of substances at levels that are generally higher that might be obtained from a diet but lower than is generally recommended as a healthspan enhancer. I take these supplements indefinitely until a consensus research trend suggests otherwise.

As an example, I supplement my intake of most of the well researched polyphenols (all types) at doses close to what I might get from my diet but only with great diligence and not for all of them combined. I used to take megadoses of some supplements but have backed off in recent years. I used to take 2,000 mg./day vitamin-C, sometimes more for example, but now take 1,000 mg. or ess per day.

The one exception to my general decision-rule is supplementing where I believe or know I have an outsize risk. I take a specialized prostate supplement for BPH, and DIM for E2 balance.

Evidence
Having taken supplements diligently for more than 50 years, I have no way of being sure that they are helping me. An article of faith is involved beyond the research. I have two observations that support inferring that they are beneficial in an outsize way. On a few occasions, I have not taken supplements for more than the day or two break I have always taken one or twice a month. On those occasions, my overall energy and sense of well being drops significantly. However, the explanation could be more one of habituation than long term benefit. Placebo is a possibility as well but much less likely over these decades. Also, I am a low placebo reactor. The second reason for inferring benefit might be stronger. The men in my family line from grandfather, to father, to uncles, to cousins (maybe 10 in all), have a remarkably consistent profile of health, fitness, energy and wellness. So far, my profile is at least a standard deviation and maybe two above the others. Everyone in the family has observed this exception.

Sources
My go-to sources for guidance are the NIH and other research stacks, Life Extension researchers, Kamal at Examine.com, and ConsumerLab.com. Increasingly, I’m finding the three AI LLMs I use to be a useful time saver. It is fairly easy to work around their shortcomings once you get the hang of it. More than once, an LLM has dug out an inference I missed due to its strength of considering all available sources more-or-less simultaneously.

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#359

FWIW: I recently switched from berberine to dihydroberberine because it has higher bioavailability than berberine and a longer half-time.

“Results from this study demonstrate that dihydroberberine, irrespective of what dose is delivered, achieves greater area under the curve as well as peak berberine concentrations when compared to oral ingestion of berberine or placebo”

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#360

I saw some stuff that said much of what berberine does comes from the microbiome, so is it possible you’re better off if it’s not absorbed?

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#361

I searched for more information on this and couldn’t come up with a good answer (specifically if this conversion process is what benefits the gut microbiome). What I found out is that berberine is converted to dihydroberberine by a healthy gut microbiome (but not if you take an antibiotic) and that this form is much more absorbable to cross the intestinal tissue where it is then converted back to berberine to enter the blood. This process depends on oxidation and will be terminated by the presence of Vitamin C, so don’t take them together (true for both forms of berberine).
" Vitamin C, a strong antioxidant, was then added to the reaction solution. As shown in [Fig. 4c], the dhBBR-to-BBR reversion was almost completely terminated by vitamin C, suggesting that the oxidization reaction is crucial for the dhBBR-to-BBR reversion in intestinal tissues."
“Human studies have clearly shown that individual gut microbiome differences predictably determine differences in the metabolism and absorption of berberine.”

Berberine Modulates Gut Microbiota

Research in rats fed a high-fat diet (HFD) shows that the prevention of obesity and insulin resistance driven by berberine supplementation is partly mediated by structural modification of the gut microbiota, which helps to alleviate inflammation by reducing exogenous antigen load in the host and elevates short-chain fatty acid levels in the intestine.9 Berberine increased Akkermansia spp. abundance in HFD-fed ApoE-knockout mice, decreased HFD-induced metabolic endotoxemia, lowered arterial and intestinal expression of proinflammatory cytokines and chemokines, increased thickness of the colonic mucus layer, and increased intestinal expression of tight junction proteins (related to restoring the gut barrier integrity).10 Additionally, in these HFD-fed ApoE-knockout mice, berberine treatment significantly reduced atherosclerosis.

As many now know, metformin has similar modulating effects on the microbiome, also increasing the abundance of beneficial commensal organisms Akkermansia spp.11 In fact, berberine and metformin have been shown to similarly shift the gut microbiota in animal models.12 Interestingly, in HFD-fed rats supplemented with berberine or metformin, the diversity of the gut microbiota was significantly decreased by both metformin and berberine treatment; while both increased SCFA-producing bacteria (berberine increasing the SCFA-producing bacteria to a greater extent than metformin). Berberine treatment has been shown to promote the production of butyrate in the gut microbiota, which may account for its effect on blood lipids and glucose. Importantly, pretreatment of animals with antibiotics abolished the effect of berberine on butyrate production.13

https://www.lifestylematrix.com/blog/post/berberine-and-the-gut-microbiota-a-bidirectional-relationship

https://www.nature.com/articles/srep12155

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WiseAthletes podcast episode on Heart Health
#362
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#363

Yes, but I don’t thinks it’s in the 5% of the science here that you consider factual.
…And I’m truly shocked that you made a post that didn’t mention AboB or LDL. That must have been hard…

Edit: I had a dream that I gave your ear a yank and all 3 of your eyeballs spun around and finally came to rest showing 3 "ApoB"s, Then you opened your mouth and a whole cascade of statins came pouring out.

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#364

Nice find on the vitamin C issue @ng0rge. When I was taking berberine, it is likely that one or more supplements containing vitamin C were in the mix. Do you have a reference for this?

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#365

I am curious what certain celebrities and the super-wealthy are taking.

Today, A picture was published about Robert Murdoch who is 93 and about to marry a 67-year-old women. He doesn’t look like he walks 10,000 steps daily or goes to the gym.

This is making me wonder if there are any “secret” drugs that they are taking.

There are others such as Joan Collins who is still in remarkable shape at 90 and claims she never had Botox, etc.

Another remarkable example to me is the difference in the apparent energy levels between Donald Trump and Joe Biden. Biden has been a lifelong proponent of exercise. Yet Biden appears much more frail than Trump.

“Biden begins his mornings with a workout that often includes lifting weights, and he meets regularly in person with a trainer. During the 2020 campaign, he biked regularly on both a traditional bike and a Peloton”

Pictures of Trump on the golf course look like he is overweight and in need of a diet and more exercise.

Back in the 1950’s there were many celebrates rumored to be taking Gerovital H3 (not the current successor products) The Gabor sisters were thought to be taking it and they looked good well into old age. Zaza Gabor lived until 99 years old.

The secret ingredient of Gerovital H3 was procaine hydrochloride.

“Procaine is most often used as an anti-aging agent for conditions such as dementia, age-related decline in memory and thinking skills, quality of life, and many others, but there is no good scientific evidence to support these uses.”

“Some clinical trials in the mid-to-late 1970s suggested that Gerovital H3 acts as a weak, competitive, reversible MAO inhibitor, and so may have some antidepressant value, but otherwise has a negligible effect on disease”

“From the 1950s until her death in 1988, Aslan promoted Gerovital H3 with great success. In the 1960s and 1970s her Romanian clinic, the Parhon Institute, became a mecca for celebrities seeking treatment, and an upscale tourist attraction. The New York Times referred to Gerovital’s “jet-set aura”, noting that Aslan had been covered in “society columns where such public figures as Nikita S. Khrushchev, Konrad Adenauer, and Ibn Saud have been listed among the multitudes said to have taken the drug.” As late as 1988 an advertisement by the Romanian National Tourist Office lauded “the picturesque and exciting cities, scenic delights, famous resorts (including Gerovital H3 treatment centers), cultural and historic treasures that await the traveler to Romania.”[2]”

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#366

It’s a quote from the nature.com link that I posted, I think down in the middle somewhere. And I would think beyond vitamin C, that it would apply to other strong antioxidants.

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#367

Evidence on berberine supplementation is growing and largely positive. I added a link to a decent summary below (apologies if it is already on this site). It is not unreasonable to be cautious about taking berberine. To my knowledge there are no long term case controlled studies focused on the full range of its possible effects. By comparison, there are decades of such studies on metformin.

For the time being, I stopped taking berberine because there have been few (perhaps no) case controlled studies on its overall impact on the intestinal biome. A scientist I trust who specializes in this type of research believes that gut responses could be highly individual, perhaps favorable for some and unfavorable for others. These possibilities are not facts, merely factors related to conjectures that have not been ruled out to consider in building a personalized risk/benefit equation. Related, I believe we have more objective human data on berberine than we have on rapamycin.

#368

I have wondered this myself @desertshores . Biden and Trump are two of many examples of the range of differences that emerge later in life. Whereas Trump seems grossly out of shape and gets breathless when walking any distance, he does not appear at all frail. Biden, on the other hand, appears frail. An indeterminate part of Biden’s stiff gait might owe to his arthritic back and knee condition. There are other age related differences as well.

So far as anyone knows, neither of these people take special anti-aging drugs. One of my former mentors, who became a billionaire in his 70’s, was taking HGH and a formula of supplements customized for him by a longevity lab he funded. I looked at his formulation and it was surprisingly sparse. Even the B-vitamins were tailored to only a few specific ones based on his biochemistry. Later they dropped HGH. They also encouraged him to practice a time-restricted diet.

He lived to be a fairly robust 93, which I thought was not bad considering he very nearly died from advanced prostate cancer in the early 1980’s and didn’t begin his “health” regimine for another decade. Given what I saw in this one instance, it seems reasonable to think there highly customized longevity labs are marketing to and providing private services to billionaires.

In spite of some evidence that we can rise above them, there is no ignoring genes, IMO. My personal example of that is distance running. I ran 10Ks and marathons for several decades as an adult. I was pretty serious. In preparing for one race I can recall, I followed Frank Shorter’s exact training regimine for a year because he was going to be in the race and I thought it would be interesting to see if I could even keep him in sight during the race. I was not able to keep him in sight.

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#369

I see it now @ng0rge. Thank you. Even though the Nature article is experimentation and observation in test tubes, it identifies some interesting research topics that will likely follow from these obesrvations.

#370

I just read through the article you posted. Some selected quotes:

“Not only does berberine appear to produce significantly better results than metformin in blood glucose regulation, it also supersedes the benefits of rosiglitazone by improving fasting blood glucose levels.Recent clinical reports state that, in addition to the beneficial effect on the lipid profile, berberine increases the level of testosterone in men, which may reduce the risk of developing cardiovascular diseases.The effect of berberine, as well as its activity in combination with nutraceuticals, is undoubtedly beneficial in patients with a disturbed lipid profile. Consequently, it is interesting from the point of view of preventing the occurrence of cardiovascular diseases, because hypercholesterolemia is considered one of the most important cardiovascular risk factors.This may prove that berberine acts in a similar manner to some anti-diabetic drugs, such as acarbose and metformin, by modifying the gut microbiota and, thereby, altering the composition of bile acid and increasing the ratio between primary and secondary bile acids, which evince proinflammatory and cytotoxic effects.”

If you have links to negative outcomes with berberine or cautions about taking it, please post them. My main question at the moment is - does dihydroberberine provide the same gut benefits as berberine?
Another good example of this issue is curcumin. It has low bioavailabiliy so there are many alternative forms that are much more bioavailable, But curcumin also has beneficial effects on the gut microbiome. It’s not clear whether the alternative forms have the same positive effects on the gut. I’m particularly interested in bioavailability and have used and looked into liposomal encapsulation which is said to bypass both breakdown in the digestive tract and the effects of CYP3a4 in the liver. There are newer processes using nanoparticles and hydrogels being tested. Here’s a link:

https://ascendiapharma.com/newsroom/2022/07/28/liposome-vs-lipid-nanoparticle

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#371

I think it is perfectly reasonable to be a berberine enthusiast @ng0rge. In fact, it was a much earlier textual synthesis convinced me to add it to my regimen 500 mg. bid. This paper is an armchair review of a large number of studies and metanalyses. I like these kinds of papers for their stimulus value but it is also reasonable to keep in mind that the literature is scattered with papers of this type on different topics that were moved to the sidelines by comprehensive case-controlled research. Research on berberine is definitely on the rise as you can see if you plot the publication dates in the references.

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#372

Trump doesn’t appear frail only because he’s overweight. Any overweight person in older age looks “healthier” than any skinny person. However, the looks are deceiving. Its just an optical illusion. We know what being overweight does to the body.

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#373

Trump is also on 40mg of rosuvastatin to prevent strokes and heart attacks.

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#374

As a normal weight, reasonably fit person of the same general age as these two guys @LaraPo, I understand and agree with what you are saying. Trump also uses heavy spray-on tanning chemicals, makeup, and hair dye whereas Biden doesn’t appear to camouflage his looks. The fact that he doesn’t permits us to see the translucency of his skin as it grows increasingly thin due to age-related factors.

However, I would still say that Biden is more frail and unsure of his footing. I’m not talking about the occasional falls, which both have taken, but more of how he approaches and navigates obstacles on stage, etc.

Only some of this has to do with physiological age, where I would not think Trump to be younger. If I were underwriting life insurance policies, I would charge more for his. I don’t suppose any of this matters because neither of these two people appear to avail themselves of advanced longevity medicines.

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#375

I see what you are saying. Both need rapamycin like yesterday! The only thing is that it’s logically incorrect to say that Biden is “more frail” (more than who?) because Trump is not frail at all. He’s overweight.

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