#2932

I think you need to try some medications to determine if they give you any side effects. For instance, I was horribly intolerant to statins, but my body handles bempedoic acid and ezetimibe just fine.

My biggest worry at this point was that LabCorp botched my last test and scared the crap out of me (My LDL went from 81 to 122). It’ll be nice if my LDL goes to 50 due to BA and Ezetimibe and a LabCorp testing error. :wink: I’ll get my ApoB retested this summer, and I’ll bring my BA and Ezetimibe when I travel.

3 Likes
#2933

I think it’s interesting to try to put some numbers on the relative cvd risk impact of the various factors so we can consider apo b in context.I think these support the argument that we should focus more broadly than apo b.

My personal view is that we don’t have very good long-term intervention study data for all cause mortality data or side effects for lowering apo b to very low levels with current pharmaceuticals.

By contrast we can optimize diet, blood glucose, k2, blood pressure, evoo, fish, exercise, fibre with low side effect risk and each one of these can give a comparable beneficial CVD impact (to say, lowering apob from 65 to 40). The diet and lifestyle interventions also have many other benefits for all cause mortality, dementia, cancer, healthspan etc

Whether to target very low (sub 50 mg/dl) apob with pharma will vary by the individual. For some it will be sensible, but for me, reducing my apo b from 65 to 40 with pharma long term doesn’t seem worth the risk at the moment given that I can prioritize the other factors, because if I do, I believe I can reduce my long term (30 year) risk of atherosclerosis to a very low level.

Apo b. Based on mendelian randomization studies apob 40 vs 65 equates to about a 24% lower risk of cad

Hba1c “A 1% increase in absolute concentrations of glycated hemoglobin is associated with about 10-20% increase in cardiovascular disease risk”
Glycated hemoglobin as a marker of cardiovascular risk - PubMed.

Med diet. “The results of the analysis showed that sticking closely to a Mediterranean diet was associated with a 24% lower risk of cardiovascular disease ,”
https://www.bmj.com/company/newsroom/mediterranean-diet-may-cut-womens-cardiovascular-disease-and-death-risk-by-nearly-25/%23

Blood pressure. A 25% reduction in cvd risk is associated with approx 30mgHG lower systolic bp

Intake of fatty fish (≥1 mean/week) was associated with a 50% reduction in risk of primary cardiac arrest.

Issues of Fish Consumption for Cardiovascular Disease Risk Reduction - PMC(%E2%89%A5,risk%20of%20primary%20cardiac%20arrest.

Vitamin k1 and k2. “people who eat a diet rich in vitamin K have up to a 34 percent lower risk of atherosclerosis-related cardiovascular disease”

Exercise “people who engaged in 150 minutes of moderate-intensity leisure activity per week had a 14 percent lower risk of coronary heart disease than those who reported no exercise”
Can Exercise Prevent or Reverse Heart Disease? | Healthline?

Fibre increasing dietary fibre by 14g reduces cvd risk by about 18%

EVOO " Higher baseline total olive oil consumption was associated with 48% (HR: 0.52; 95% CI: 0.29 to 0.93) reduced risk of cardiovascular mortality ."
https://www.researchgate.net/publication/262489294_Olive_oil_intake_and_risk_of_cardiovascular_disease_and_mortality_in_the_PREDIMED_Study#:~:text=Higher%20baseline%20total%20olive%20oil,%25%20and%207%25%2C%20respectively.

Curious what people think of all this. A question that springs to mind is: for someone with apob of say 65 mg/dl, which is likely to reduce 30 year atherosclerosis risk the most: a standard dose of psk9i or metformin?

I obviously don’t know the answer, but my guess would be metformin.

6 Likes
#2934

That’s your decision to make, I don’t understand why you keep asking a similar question when Neo has already decided for him what makes sense. Instead of asking questions you can just say that you’ve decided the risk vs. reward isn’t in favor of the intervention for you. I have not seen you explain why. You have to think for yourself. You are actively making the decision to not do anything about it, so what’s the reason why?
Why does Neo has to tell explain his reasoning, and not you, yours?

I don’t want to hear anything except the part where you explain why the risk is higher than the reward for you. If you haven’t thought about it before well now you can.

First you have to figure out what the expected reward is, then what the expected risks are. Once you’ve established that in an accurate way, you can compare them both. It’s likely you are wrong on at least the reward side.

#2935

Bempedoic acid is only active in the liver, it is hepatoselective. It is only converted in the liver to the active form.
I don’t know enough about it, but I would guess it has zero negative effect on parkinson and alzheimer’s as it only affects serum apoB/LDL since it is active in the liver. I don’t know where the genes relating to parkinson’s are related to increases in LDL. They might be active in the brain, increasing brain cholesterol as well. That makes me think if increasing serum apoA1 can help as it can pass the BBB and take over some roles of other lipoproteins and of course it shouldn’t be atherogenic.

1 Like
#2936

Thanks. Photobiomodulation is promising, but there are so many modalities to define (wavelength, power, area of the body, duration, and frequency of the treatment, etc.) that I think we’re far from knowing the optimal intervention. It might depend on the person as well. I use it, though, and I “feel” the benefits, but I want to see more data.

MB: it failed the ITP (–5% max lifespan, even though p = 0.60, it’s not amazing…), and it failed in one phase 3 trial for AD. However, we should be able to reach a conclusion very soon: the trial “Effects of Methylene Blue in Healthy Aging, Mild Cognitive Impairment and Alzheimer’s Disease (MB2)” that started in 2015 at the University of Texas is about to finish. So I’ll wait a few more months before painting my brain blue :stuck_out_tongue:

Thanks, all good then :wink:

I agree that mitochondrial health is essential. Actually, the authors of the PD paper I shared previously argue that PD is caused by pollutants that impair mitochondrial function. I didn’t know about Urolithin A and mitopure, here again, I’ll wait for more data :sweat_smile: “First do no harm”… So far, I’ve found that besides rapa, SGLTi, low-dose metformin, telmisartan, and GlyNAC seem to be safe bets to improve mitochondrial function. Many others seem promising (MB, dasatinib + quercetin, suvorexant, melatonin, pioglitazone, irisin, etc.), but again, more trials needed…

4 Likes
#2937

MB strikes me as something that can be used to increase ATP production, but that does not in itself improve the efficiency of mitochondria. Hence it does not strike me as something to take if you actually want your mitochondria to be more efficient. It is more of a temporary prop.

#2938

I had put this in the bucket of likely very safe - as it is in a lot of normal food. So would be low risk. What side effects to you think we should be careful about?

Re data, I think there are 300 papers or something, but have not got my head around the literature here yet. There are three threads her on the forum that you can look at if you want to familiarize yourself more.

#2939

Yes, maybe I should have said that I need to do my research on it first. In general, I want to see data about long-term use, but it’s hard with supplements, whereas with prescription drugs, you can just look at longitudinal data. I’ll look at Mitopure and continue the discussion there: Urolithin A (UA) One of 4 Promising Agents 2024 by Brian Kennedy of NSU

2 Likes
#2940

Another powerful one - with only positive “side effects” - that seem powerful for mitochondria if done over the years and decades is Zone 2, see eg below.

This might me more powerful for your mitochondrial health than (any) drugs…

Adding Mr Mitochondria @John_Hemming

IMG_6729
IMG_6729934×1015 60.6 KB

  • Exploring Metabolic Flexibility (18:33)
  • Determining the Causes of Mitochondrial Dysfunction (21:01)
  • Zone 2’s Optimal Stimulation of Mitochondria (45:29)
  • Lactate’s Impact on Mitochondria: Unraveling the Effects (50:46)
  • Inducing Mitochondrial Stimulation Through Zone 2 Training (1:17:31)
  • Strategies for Enhancing Mitochondrial Count (1:19:27)
  • Weekly Zone 2 Prescription for Robust Mitochondrial Health (2:07:24)
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#2941

Happily (?) this is a non-risk: remaining life expectancy after AD diagnosis is 5.8 years, and “Survival time from disease onset was also shorter in people with non-Alzheimer’s dementia, across types, compared with people with Alzheimer’s disease”. The numbers are not quite as “favorable” with PD, but it’s also more manageable with existing therpies and stem cell therapies are getting increasingly promising: “At 65 years, the life expectancy of patients with parkinsonism was reduced with 6.7 [95% CI: 2.4;10.7] years compared to controls. At 85, the difference in life expectancy was 1.2 [95% CI: -2.2;4.5] years compared to controls.”

#2942

I do not feel qualified to advocate for what medical decisions people should make, I’m a PhD and work in biotech, but I’m not an MD, so only feel comfortable asking questions or point to things to think about and say what I would do.

Having said that, I would not (a) take rapa and (b) have my Apo B jump from the 50s to 80s and then not also address the Apo B in a big way. That feels like a very inconsistent way to weigh the cost/benefit analysis of using pharmaceuticals - in one case one would be taking a leap of faith in the other case one would not be weighing a massive amount of data on the largest killer and disabler in the western world.

Personally I’d probably also try out different ways to manage down the Apo B of 58 further if I was back to that level.

30 year risk calculators are much better than 10 year ones, but my target in your shoes would be to live much longer than just into your 70s and would want to maximize ability to avoid strokes and heart disease in those later decades beyond my 70s too when risks could start increasing exponentially.

Remember that Apo B causal risk in many ways seems to be proportional to the area under the curve - so it not just your average level, but how many decades you multiply that level by and we may be on the path to behind extra decades and hence those scenarios need to be weighted too.

Do you think Apo B of 58/84 vs Apo B of say 30-40 would have any big difference on the risks of cardiovascular disease if you could live into your 90s, 100s, even 110s?

1 Like
#2943

Only unfiltered coffee.

3 Likes
#2944

Thank you for putting all these together.

For me the answer is that it is not do all the things in your list OR use generally safe, extremely well studied medicine to lower Apo B, but it is so all the things in your list and use such Apo B lowering medical tools.

Suffering a heart attack or stroke is extremely bad - and in the cases where one survives it can be extremely disabling. If you multiply that by that anyone whose lives long will start having exponentially increasing risks of this family of diseases for each extra 5 years they are allove the math is very different that just thinking about 10 or 30 year risks.

One question to you - how long (assuming in a healthy state) would you aim to live?

1 Like
#2945

@adssx @John_Hemming (who has discussed aspects of this) and others you might find this interesting

The Mitochondrial Nutrient Missing From Every Supplement?

#2946

I am on his list. I hadn’t previously seen MK-4 suggested. I do take MK-4 daily whereas I don’t take MK-7 daily - I take it when I wish to boost ATP. On an N=1 basis I have noticed a metabolic boost from Mk-7, but not Mk-4.

I take a higher dose of Mk-4 than Mk-7 as a rule. (when I take Mk-7 which I stopped to bring my metabolism back into balance). Today, however, is a Rapamycin plus Pomelo day. (4mg Rapacan and an oldish slice of Pomelo which I hope will still inhibit CYP3A4. I dropped the dosage slightly from my last 6mg without enhancer. I bought a new Pomelo at the weekend, but thought I should finish off a slice in the fridge rather than see it wasted.)

1 Like
#2947

I think Zone 2 fits with the idea of stress, but not too much. Zone 2 provides a stimulus, but probably does not go beyond Hif 1 alpha that much.

This is my page about comparing hypoxic stresses:

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#2948

@John_Hemming Are you sure that Pomelo inhibits CYP3A4?

#2949

I have seen studies it is as strong inhibitor as GFJ.

2 Likes
#2950

It has been discussed on this forum. Grapefruits are a hybrid between Pomelo and sweet orange. Pomelo has the same inhibitor in the juice as grapefruit.

2 Likes
#2951

I’d love to hit 200 :birthday:!
I suspect we agree on a lot of this, but I always find it useful to explore where I precisely disagree with thoughtful people and so here are some areas where i think we might disagree. I believe…

1 atherosclerosis is completely avoidable with apo b levels above 50. Apob is necessary but not sufficient for atherosclerosis.
2 And that apob of say, 30 isn’t a guarantee of no atherosclerosis. (MRandomization studies)
3. If inflammation is low, and oxidation risk highly reduced by exercise, evoo, fibre etc there is very little benefit and maybe no or negative benefit from reducing apob from 55 to 30.
4. I don’t think we should discount the downside risk of extremely low cholesterol completely either, just yet. The science isn’t settled and certainly not for a 30+ year period.
5. All pharma has potential side effect risks especially v. long term use. Psk9i are newish and I’d love to see more long term data. Statins are likely to have some (small) downside over v long term use.
6. Using pharma and optimizing lifestyle is possible but confidence in the pharma is likely to lead to worse lifestyle.
7. within 10 years we’ll have a much better understanding of the mechanisms of atherosclerosis including the role of inflammation and oxidation and therefore we’ll have better targets than apoB.
8. Someone who achieves say, apo b 65 with exercise, fibre, evoo, fish, nuts etc is likely to have a much lower risk of ascvd than someone who achieved it with say, a statin
9.edit: risk of atherosclerosis doesn’t increase exponentially with age for individuals with zero risk factors

Interested which of these you disagree with. I appreciate they are not solidly verifiable either way from the research base. And I appreciate that one could agree with all these and still opt to use pharma to get down to apob 30. But on balance and based on these points, i think it’s better to focus on keeping apo b down to the 50 to 65 range using lifestyle/diet measures which additionally reduce inflammation and oxidation. At least for now.

4 Likes