#62

It’s been discussed on this forum. I think it came out around mid 2024. I’ll hunt for it later if you can’t find it. I have to run for a podcast recording.

#63

Found it, understand it now, agree with @DeStrider, though the graph perhaps mostly shows how variable the metformin control outcome alone is, and therefore the huge error on any other single peak.

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#64

That’s a very reasonable question. A mindful strategy would be to resist the urge to add on every supplement that seems interesting and restrict yourself to either one or a very small number of drugs or supplements with the strongest evidence and/or largest effect sizes. That’s what Kaeberlein recommends in this discussion of supplement combinations with Kennedy. If you wanted to go further, you could prioritize cases where combinations are known to have favorable effects in mice. Kennedy also suggests adding only one thing at a time and giving yourself an extended time period to see how your system reacts to it, then dropping it and adding another one individually before trying all three. You should also do your best to drill down into mechanisms before even trying a combination (like the ambiguous effect of AKG on mTOR), and test what you can (though @CronosTempi is right that there’s often nothing you can test).

That’s a good example, and it’s particularly compelling since you see something similar with metformin.

This is technically a good example, but not very representative of the challenge we face with longevity drugs and supplements: (a) the connection between the drug and the effect that the combination improves (lower blood glucose) is more mechanistically clear and direct than the relationship between e.g. AKG or mTOR inhibition and life extension, which makes it harder to predict interactions, and (b) the effect can easily be measured and confirmed, so you know if their effects are additive, subadditive, or have negative synergy.

This is similar on point (b) to GLP1-RAs + SGLT2is, above.

This is not a good example: the GlyNAC lifespan study is garbage.

… in fruit flies. Trametinib + rapamycin has been reported to have an additive effect in mice, but the controls are short-lived, so it’s not clear that trametinib adds anything to rapa alone, as Kaeberlein illustrated here. Fortunately, it’s being tested in the ITP.

… in C. elegans and flies. The same study found no additive effect of metformin and rapa, which is additive in mice in the ITP.

This is based on a poorly-done observational study (not a clinical trial (although it was nested in a clinical trial population) or a rodent lifespan study) in just 857 diabetic men. It didn’t collect a lot of the standard personal characteristics one would expect from such a study or adjust for them, the methods are in various ways obscure (like, how did they identify men with ED who were not taking PDE5i?), and the nominal effect sizes are larger than seen in actual TRT and statin trials.

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#65

I don’t disagree with your analyses of the combinations I listed off as examples (except perhaps GlyNAC but that’s besides the point). You’re clearly very knowledgeable on these topics.

We can pick apart whether those examples I listed really are additive or not, but I think it’s more important to point out that they also don’t cancel each other out, which is what we are discussing here.

Do I think some longevity combinations probably cancel each other out? Yes, I do. I do recall Brian Kennedy mentioning that AKG and berberine didn’t work well together. I don’t know why that is but I could speculate it could be related to the CYP3A4 inhibition of berberine (completely guessing here). I just hesitate to make blanket statements in general.

I have listened to all those Brian Kennedy videos you mentioned by the way and I have to point out that always love to hear what he has to say.

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#66

I tend to agree with Brian Kennedy on this area generally, but to me this highlights the need to regular blood testing as you increase the complexity of your supplement protocol.

If course there is the chance of missing something going seriously out of wack in areas you are not tracking and that are important.

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#67

I probably do more testing than anyone else on this forum with weekly bloodwork. I regret not starting testing earlier. I don’t think weekly is necessary. However, as things can vary really quickly (see my thread on a test after a fast) and the values are not always that reliable more testing gives more obvious conclusions.

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#68

…

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#69

Yes more monitoring and testing is important, and for me, the strategy for 2025 contunue to be not to take to many supplements.

This thread makes me consider how to incorporate known physiological facts, that I can relate to biohackers as well as to ”regular” older patients. (BTW I dislike the term bio-hackers). I prefer the term health span and lifespan optimizers.

It is well documented that the effects of combining more than three medications are not fully understood, even among medical professionals and researchers.

Medications are developed based on biological responses observed in specific populations. Consequently, the effects of these medications on individuals can vary widely, often following a distribution curve among a populations that might be similar to a normal distribution. This means that while some individuals may experience very positive responses, others may suffer from severe side effects. Therefore, a careful risk-reward assessment is always necessary.

Unintended side effects are common, and determining the correct dosage can be challenging. It is not uncommon for a well known and approved medications, prescribed on the approved indications, due to side effects, to be replaced by a similar medication that will provide the benefit without sideffects.

Older persons are particularly vulnerable to overmedication, especially if they take multiple medications simultaneously. When elderly patients are prescribed 10-15 medications, monitoring is very iportnat and required to avoid adverse effects due to age related biological functions, like to name only one, reduced kidney function.

Some medications may remain on the list of prescriptions after their initial purpose has been fulfilled, especially as the patient ages and develops a new biological state that alter the response to previously prescribed medications. Sometimes when symptoms occur it is hard to know if they are symptoms due to age related decreased biological functions or a new intrinsic disease or if new symptoms/side effects are caused by medications or combinations of medications.

Sometimes older persons are prescribed medications by specialists in different fields, for instance neurology and gastroenterology, who may or may not be aware of each other’s prescriptions. Despite the best intentions, this can ofc lead to unintended negative effects. Even if the prescribing Dr are aware of the other’s prescriptions the professinal question is, under what circumstances will the family Dr or the gastroenterologist discontinue a medication prescribed by a neurologist?

For elderly patients taking 10 or more medications, it is advisable to periodically review, deprescribe and streamline the medication list, ideally done in collaboration between family physician, specialists and sometimes a pharmacist. By implementing reviews of prescribed medications, deprescribing practices, interprofessional collaboration, patient and family education, regular monitoring, and simplifying regimens, it is possible to reduce the risks associated with polypharmacy in elderly patients. But we dont live and an ideal world. In conclusion, when multiple medications are necessary, monitoring, testing and personalization is crucial.

I relate this reasoning to my ambitions to reduce my intake of supplements. Supplements have pleiotropic effects, and they might affect CYP3A4, liver function, kidney function, as well as cell metabolism. Doing nothing is not an option for me. So not only what Brian Kennedy put a light on, but also what we already know how multiple medications affect the older human body, makes me humble and want to reduce the supplements I take and therefore focus on the ones that provide the most important benefits. And 2025 I will also take a few “supplement holiday”.

We have the same goal but might apply different strategies. My strategy might not apply to others. I am looking forward to 2025 and to continue learning from this forum on our attempts how to best navigate the ocean of experiences and research related to health span and life span optimization. I have learned a lot on this forum, so thank you all, a Happy new year and ”live long and prosper”.

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#70

Twice a week I take a single Solgar VM 2000 multivitamin. The ingredients are below. This could in itself hit an arbitrary threshold as to limits of supplements. I am also happy to call myself a biohacker, but there is no reason for us to agree on the usage of that label.

Two (2) tablets provide: mg %EC NRV*
Calcium (as ascorbate, bisglycinate, carbonate) 128 mg 8
Vitamin C (as calcium ascorbate) 300 mg 375
Isolated Soya Protein Powder 200 mg
Vitamin E (200 IU, as D-alpha tocopheryl acid succinate) 134 mg μ-TE 1117
Vitamin B6 (as pyridoxine HCI) 10 mg** 7143
Thiamin (Vitamin B1, as thiamin mononitrate) 100 mg 9091
Choline (as bitartrate) 41 mg
Niacin (Vitamin B3, as nicotinamide) 100 mg NE 625
Inositol 100 mg
Riboflavin (Vitamin B2) 100 mg 7143
Pantothenic Acid (Vitamin B5, as D-pantothenate, calcium) 100 mg 1667
Magnesium (as oxide, bisglycinate) 32 mg 9
Iron (as bisglycinate) 10 mg 71
Betaine HCl 25 mg
Soya Lecithin 20 mg
Zinc (as oxide, bisglycinate) 15 mg 150
Manganese (as gluconate, bisglycinate) 2 mg 100
Boron (as boric acid) 1 mg
Copper (as gluconate, bisglycinate) 1500 μg 150
L-Ornithine HCl 6 mg
Natural Source Beta-carotene 5 mg
Taurine 5 mg
L-Glutathione 5 mg
Folic Acid (as pteroylmonoglutamic acid) 400 μg 200
Iodine (as potassium iodide) 150 μg 100
Chromium (as picolinate, yeast free) 25 μg 63
Vitamin B12 (as cyanocobalamin) 100 μg 4000
D-biotin 100 μg 200
Carotenoid Mix 13 μg
Selenium (as L-selenomethionine) 25 μg 45
Vitamin D2 (400 IU, as ergocalciferol) 10 μg 200

Bulking Agents: microcrystalline cellulose, pea starch, alginate, dicalcium phosphate; Calcium (as citrate, carbonate, bisglycinate); Vitamin C (as L-ascorbic acid); Isolated Soya Protein Powder; Magnesium (as oxide, citrate, bisglycinate); Vitamin E (200 IU, as D-alpha tocopheryl acid succinate); Thiamin (Vitamin B1, as thiamin mononitrate); Pantothenic Acid (Vitamin B5, as D-pantothenate, calcium); Niacin (Vitamin B3, as nicotinamide); Riboflavin (vitamin B2, as riboflavin, riboflavin-5’-phosphate); Choline (as bitartrate); Anti-caking Agents: vegetable stearic acid, silicon dioxide, vegetable magnesium stearate; Inositol; Cross-Linked Cellulose Gum; Iron (as bisglycinate Glazing Agents: hydroxypropylmethyl cellulose, vegetable glycerin (from palm kernel oil and coconut oil); Betaine HCl; Soya Lecithin; Zinc (as oxide, bisglycinate); Vitamin B6 (as pyridoxine HCl); Manganese (as gluconate, bisglycinate); L-Ornithine HCl; Natural Source Beta-carotene; Taurine; L-Glutathione; Copper (as bisglycinate); Folic Acid (as pteroylmonoglutamic acid); Colour: Riboflavin; Iodine (as potassium iodide); Chromium (as picolinate); Vitamin B12 (as cyanocobalamin); D-biotin; Selenium (as L-selenomethionine); Carotenoid Mix; Vitamin D2 (400 IU, as ergocalciferol).

I have counted up the pills for tomorrow morning. That is 24 pills, plus the 31 ingredient solgar, plus probably around 30 melatonin pills of some form and over 10g of citrate powder dissolved.

Some days I add perhaps 12 additional HDAC inhibitors and maybe 12 Yang Qi AMPK activators and a couple of extra pills. Some times I take more than one pill for the same substance, however. Then there is food and drink. Within that perhaps chia seeds are the key health orientated ingredient.

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#71

I hate to say it, but doctors don’t always prescribe the optimal options for their patients.

Case in point - my mother, who had a heart attack, was prescribed 80 mg of Atorvastatin. This caused her to have severe muscle weakness and fatigue. The doctor suggested ceasing the statin. I then told her to ask for it to be replaced with 10 mg of Atorvastatin and 10 mg of Ezetemibe which would have a superior effect to 80 mg of Atorvastatin. The doctor agreed, but the doctor didn’t start with the optimal prescription and it was due to my research to find a better solution. Now my mother doesn’t have severe muscle pain and weakness (although a bit persists) and has better blood cholesterol values (Same LDL, Higher HDL).

Likewise the same issue regarding BP meds. My mother, who is also diabetic, was prescribed Losartan and I had to ask the doctor to change it to 80 mg of Telmisartan to get the pleiotropic effect on diabetes as well as continual BP control throughout the day. Losartan has a very short half-life.

Then there was the timing of medications. The doctor didn’t optimize when my mother was taking her meds so she took everything in the morning. This caused her to have depressed BP in the morning due to taking all of her meds at the same time. I then worked out a schedule which smoothed out her BP meds effects so she would have optimal BP all day instead of spikes and dips at different times of day.

The doctor had gone 80% of the way by prescribing the (almost) right drugs but failed to optimize their use and effectiveness. Unfortunately, I think this is quite common amongst doctors as many don’t know or care enough or are too busy to promote the optimal use of medications for maximal benefits. (My mother’s doctor takes the afternoons off on weekdays to play golf according to the nurse.)

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#72

I think the health sector is focussed on people being steady state organisms rather than in a dynamic equilibrium.

It is much harder to measure a dynamic equilibrium, however.

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#73

You are right, Chris. What’s worse is that often the doc (my doc, for example) merely checks off boxes without looking at the broader context. For example, my LDL has been going up every year, despite my great efforts at diet and exercise. I was on 10mg atorvastatin for the past 6 years. LDL levels go up with age, especially in the 60’s (I’m 66). As my LDL kept climbing (from LDL 70 in the first year of atorvastatin use, to LDL 146 this year), all he ever put in the comment section was “cut out saturated fat”, this despite my telling him that I’ve minimized my saturated fat intake already decades ago, and my only source of small saturated fat is from salmon/sardine ONCE a week, twice at most - my diet is pescatarian. Nonfat kefir or yoghurt 2 times a week. He has this info in his notes. Yet every year, the same “advice” to cut ou saturated fat, even though I’ve had the same diet for the past 20 years, and my LDL keeps climbing with age the past 5 years. Same with my blood glucose - “cut out extra sugar” even though I have not put sugar in my diet in literally 40 years. My blood glucose has been prediabetic for the past 10 years or so, slowly getting worse (A1c 5.9).

I don’t hold it against him, because he’s constrained by the SOC and what the insurance will cover. He can’t do prevention, only waiting until I’m frankly diabetic, and then he can spring into action and start prescribing meds as the protocol calls for.

So I gave up on my doc, and took my health into my own hands 100%. I dropped atorvastatin, and got on 4mg pitavastatin - two months so far, no side effects that I can detect, will get a lipid panel in March 2025, evaluate and see if I need to go on bempedouc acid +/- ezetemibe. I went on empagliflozin 12.5mg - been a month so far, dropped my morning blood sugar from 105-115 to under 100 consistently, highest was 99 on two occasions, the rest 88-95 range (I finger prick test daily first thing in the morning)… no side effects that I can detect so far, will get my A1c tested in March 2025 and evaluate future measures depending on results. Starting this coming Saturday 01/04/2025, once weekly (escalating weekly from 3mg to 6mg) I’m starting on rapamycin, in a month I’ll test my rapa levels after 48 hours post dosage, evaluate. If needed, I have telmisartan - I’m waiting to evaluate BP after all the other drugs take full effect.

I do all my own research, and all my meds come from India with no prescription.

If I had a responsive, knowledgeable and thoughtful physician, yes, I’d be more than happy to consult with and get prescriptions from a U.S. pharmacy instead of running risks with imports, but well, that’s not what I got. Regardless, ultimately my health is my responsibility and I will never relinquish it, no matter who the doctor is, the final decisions will always be mine. YMMV.

Unfortunately, in the U.S. doctors are very constrained by insurance. You can go concierge, but… often you’ll still get box checkers though with better personal interaction, and more time. Great doctors exist, no question… but it’s exactly the same as with any profession - great lawyer, great car mechanic, great cook, great trainer, great researcher - they’re all rare, by definition, because “great” anything is a rare occurrence. You can go on a long search doctor hopping and as Clint would say “do you feel lucky, punk?”, but life is short and choices have to be made. I’d just as soon rely on my own judgment and my own efforts - this way, good or bad, it is my responsibility 100%. I don’t look to blame or complain, I accept reality for what it is.

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#74

I guess if you don’t have a great doctor you need to pick up the slack and go the final distance yourself.

However this is a matter of life and death, and each decision could mean years of extra health vs an early death. This is high stakes here.

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#75

I don’t see it like a very actionable suggestions in humans living in an uncontrolled environment subject to frequent changes in conditions.
Also, for many supplements Kennedy’s suggestion would beg the question: what am I supposed to see, or analyze?

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#76

yes, The healthcare systems in the world are often systems built around "sick care” systems. And doctors education is focused on following routine treatments based on best evidence practices. This is, of course, many times good. But the system has flaws. The positive effects on an aggregated level come with a downside on the level of the individual. And yes sick care is really good if you have stroke or car accident. Under the cirumstances that you have acess to advanced care.

But doctors are often trained to adhere strictly to established guidelines and protocols, which can limit their flexibility in addressing individual patient needs. This adherence to routine treatments may overlook unique patient circumstances, leading to a one-size-fits-all approach that fails to consider personal health variations or preferences

The focus on evidence-based practices can sometimes overshadow the importance of patient autonomy, patient-centered care and shared decision-making. Patients can often feel that their values and preferences are not adequately considered.

The healthcare system itself can contribute to these obstacles through bureaucratic inefficiencies and a lack of coordination among providers. This fragmentation may lead to inconsistent care experiences, where patients receive conflicting information or inferior treatment outcomes due to poor communication between specialists. And often doctors have very limited time for each patient, and the system makes it impossible or at least very hard to allocate the time needed for a deep dive into a patient’s complex biology. As patients on our own or being a relative to a patient, we have more time to do deep dives, in the most recent research in a specific subfield of medicine that we are facing as patients.

While evidence-based practices are essential for quality care, the current sick care system’s rigid adherence to routine treatments often creates barriers that impede personalized patient care.

Not to mention the fact that a large bulk of a sick care system only becomes activated when a disease has reached the threshold where it presents obvious symptoms.

In the end, we are responsible to educate ourselves, make informed decisions. In my own case, I really miss working with a doctor who is open to person-centered proactive medicine as well as evidence based medicine. But also, I know all too well how the sick care system constricts Doctors in their work. fear of malpracticing and such. Not following the rules etc.

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#77

yes, this precisely! It sounds like good advice, and it ideally is, but I have tried doing so a hundred times, own health or research related, and almost every damn single time other things happened, like I got sick or whatever, that made any conclusions mere guesswork again. Talk is easy, real life…

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#78

I’m going to be a bit critical of this multivitmain. Too much B6 (which is risky long term), using Vitamin D2 instead of D3, too little magnesium and it uses the cheap oxide form anyway, wouldn’t want iron (unless deficient), no Vitamin K2, and a few other things I could be picky about.

It’s hard to find a good multi, but I think the two best ones are Naturelo (the one for men 50+) and Dr. Brad’s Microvitamin.

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#79

The B6 amount (10 mg) is probably OK. The maximum tolerated dose is between 12 mg (EU) and 100 mg (US): Vitamin B6 - Wikipedia

#80

Give repatha a try. It is synergistic with statins and bampedoic acid.

#81

I think B6 as pyridoxine should be kept below 50mg per day. I had an issue at 100mg per day. I only take VM2000 twice a week anyway and only one pill.