#102

Peter Attia mentioned in the MPMD podcast released recently that they are testing homocysteine and treating it because of this trial.

A total of 168 participants (85 in active treatment group; 83 receiving placebo) completed the MRI section of the trial. The mean rate of brain atrophy per year was 0.76% [95% CI, 0.63–0.90] in the active treatment group and 1.08% [0.94–1.22] in the placebo group (P = 0.001). The treatment response was related to baseline homocysteine levels: the rate of atrophy in participants with homocysteine >13 µmol/L was 53% lower in the active treatment group (P = 0.001). A greater rate of atrophy was associated with a lower final cognitive test scores. There was no difference in serious adverse events according to treatment category.

No that doesn’t seem to be the result :see_no_evil:

But there was a follow up post-hoc analysis study of VITACOG where that was the result. I’ll have to read these carefully.

3 Likes
#103

2010 trial. I don’t think these results have been confirmed in more recent trials, meta analyses and mendelian randomization. And for the association studies we have a u curve above. My two cents:

  • If your homocysteine is high it might be a reason to investigate and see what causes it to be high and address the root cause. For instance you might have low B12 and fixing that will fix Hcy. But if your homocysteine is high and you can’t find the cause, for instance if all your B Vitamin levels are optimal, then even though taking vit B will lower your Hcy, I think there’s zero evidence it will help.
1 Like
#104

Do you give zero weight to that Peter Attia thinks the risk/reward is still good in working to lower it? Not certain of benefit, but a lot of reasons to think it might help with with really bad stuff and the side effects and risks of our / his toolkit is very benign it seems (not talking of dosages of the b vitamins (and creatine, etc) that are crazy high)

The issue is again when things are not patentable as drugs you will not see a lot funding for clinical trials….

Seems like a “picking up a potential 1000-dollar bill in front of a kid on tricycle”

Those bets are good to take in my view - so think I’m with @AnUser here.

1 Like
#105

I give zero weight to what Attia thinks. I give weight to evidence. RCT + MR + association studies don’t show that homocysteine lowering is beneficial. So why would anyone focus on that when there are so many other things to focus on?

4 Likes
#106

Has Attia commented on that U curve? What are your homocysteine levels? What have you done to reduce it? Why isn't it part of PhenoAge or aging.ai clocks? - #97 by adssx

On the MR studies showing nothing?

Or did he just cherry pick a few papers and concluded that hcy lowering was important?

#107

Yes, it’s always about the risk vs. reward IMO.

It seems safe to take some methyl B12 & Folate, and possible some small doses of B6 and seeing how homocysteine moves. If the downside is basically nothing any upside is great (but at the same time might be a pascalian mugging, but at worst just time & cost).

He is targeting not above 8 or 9 homocysteine, so it’s optimal for association?

ACM is hard to detect if it’s that you mean.

No he said the paper I linked is the single paper they are pretty much using for their decision making.

1 Like
#108

Time and cost are massive factors. It’s the opportunity cost of focusing on something else instead.

If that study is correct then you also want to increase it for people that are too low. If he targets 9: fine.

Yes for ACM but no for CVD, AD, PD, etc. and we have MR studies for those with Hcy.

So there are dozens (hundreds?) of papers pointing to another direction but they focus on a small old trial that says otherwise. Why not, they might end up being correct and there might be a case for general Hcy lowering. But this case is not clear to me beyond addressing the root causes of high Hcy.

If I take my example: my Hcy was high (18 umol/L), B6 and B9 optimal. B12 close to the lower bound. So I supplemented with B12. B12 is now high => Hcy now around 12 umol/L. I don’t see additional benefit in doing anything about it.

3 Likes
#109

Is that correct? I had totally missed that and if so I’d weigh things here in a very different way.

#110

By “another direction” I meant “lack of benefits” (RCT + MR). However if you add the U curves for homocysteine and for the various homocysteine factors, there might also be detrimental effects (association studies though). I posted everything in this thread I think.

#111

image

Okay I’ll try this one to lower homocysteine, I’m doing a bunch of other things at the same time. It has P-5-P in it too (B6), that’s easy. But because I don’t want B12 deficiency I’ll still take 1 mg cyanocobalamin a week or so just in case and until I’m sure this will be enough.

3 Likes
#112

I was looking at something else and learned that methotrexate blocks the body’s use of folic acid. Indeed, administration of folic acid worsens leukemia, while a diet deficient in folic acid produces improvement: Methotrexate - Wikipedia

Why do I mention that? The ITP is testing methotrexate (amethopterin). So, they think that it might have life-extension properties. If so, what could this tell us about B9 supplementation? I don’t know: methotrexate is an analog of folic acid, so it’s quite complex. (That being said, there’s only one old paper in the DrugAge database that looked at amethopterin in rats: longer lifespan at high dose in females and shorter lifespan at low dose in males. For whatever reason they didn’t test the same dose in males and females?)

1 Like
#113

It says in wiki:

Folic acid is commonly co-prescribed with methotrexate to minimise the risk of adverse effects.[23]

An Perplexity seems to think this too.

#114

I think it’s given for autoimmune diseases. Not sure for leukemia. And it might be given to avoid deficiency (that is for sure bad). I don’t have an opinion on this. Just: the body is complex, test for B6, B9 and B12 before supplementing with those. I guess this is a general rule for any supplementation: measure before/after and adjust. (See also: Megavitamin-B6 syndrome - Wikipedia )

1 Like
#115

I think it’s going to take too long time and there’s so many confounding factors with N=1 and multiple things happening at the same time anyway. I think it’s better to just go for it if it seems safe. Once reached stable levels can try discontinue at some point.

B-vitamins are water soluble so there’s more leeway, and the Jarrow supplement has 1.6 mg B6 much lower than the UL of 16 mg/day, 10-12 mg/day. The point of the supplement is to lower homocysteine, and B6 is not available for measurement for me.

Measure all biomarkers and stats, optimize all at the same time as much as possible I think seems simpler and better.

#116

Yes, 1.6 mg is very likely safe (Unless your B6 level is already very high?) By the way, the upper limit is 10 mg/day, according to the UK NHS.

1 Like
#117

I think I now understand why the ITP is testing methotrexate: Late-life dietary folate restriction reduces biosynthesis without compromising healthspan in mice 2024

This paper, authored by Kaeberlein and Kennedy concludes:

Folate is a vitamin required for cell growth and is present in fortified foods in the form of folic acid to prevent congenital abnormalities. The impact of low-folate status on life-long health is poorly understood. We found that limiting folate levels with the folate antagonist methotrexate increased the lifespan of yeast and worms. We then restricted folate intake in aged mice and measured various health metrics, metabolites, and gene expression signatures. Limiting folate intake decreased anabolic biosynthetic processes in mice and enhanced metabolic plasticity. Despite reduced serum folate levels in mice with limited folic acid intake, these animals maintained their weight and adiposity late in life, and we did not observe adverse health outcomes. These results argue that the effectiveness of folate dietary interventions may vary depending on an individual’s age and sex. A higher folate intake is advantageous during the early stages of life to support cell divisions needed for proper development. However, a lower folate intake later in life may result in healthier aging.

4 Likes
White Blood Cells and Folate (B9)
#118

It feels like to me this and other things they are doing aren’t going to push things further, such an intervention must have marginal benefits since it’s merely using built in functions of the body (i.e stories of caloric restriction, protein restriction, mTOR inhibition, is similar), and we know the results of that by studying populations today.

I think people need to test synthetic substances no one’s heard about which aren’t merely turning up or down things the body can do in certain situations. I guess that’s what Altos labs and such are doing.

#119

I agree. It’s still interesting to know that B9 supplementation might be detrimental and shorten lifespan (if these results are confirmed and can expand to humans).

3 Likes
#120

Why? I skimmed through Dr. Joshua Miller’s video and didn’t see anything about riboflavin (B2). On the other hand, there’s a growing body of evidence pointing to potential benefits: Riboflavin and Neurocognitive Decline

Here’s Miller’s conclusion:

image
image1458×852 62.1 KB

Riboflavin (B2) is rarely tested. B2 deficiency seems common among individuals homozygous for the methylenetetrahydrofolate reductase (MTHFR ) 677C→T (TT): Your “MTHFR” Is Just a Riboflavin Deficiency 2019 (is this a good source?)

Interestingly, riboflavin supplementation at 1.6 mg/day (very small dose! Most supplements have 10x or 100x that) significantly lowers Hcy in these TT individuals (from 16.1 to 12.5 μmol/L) but not in other individuals: Riboflavin Lowers Homocysteine in Individuals Homozygous for the MTHFR 677C→T Polymorphism 2005

Similarly, riboflavin supplementation seems to lower systolic blood pressure in TT individuals but not others:

So, I guess if you have high homocysteine, test for B2, B6, B9, and B12 and check your genes (MTHFR), see which vitamins are low, and supplement accordingly to get them to the optimal level. Homocysteine will be lowerered as a result. The absence of such an individualized approach in homocysteine-lowering trials might explain the inconclusive results: for instance, if someone has high homocysteine due to low B2, giving them high-dose B9 might not help or even be detrimental? And vice-versa?

4 Likes
#121

Yes, the cheap approach that yields junk results seems common, because it is easy to data mine. There needs to be an actual study where levels are tested, and individuals are supplemented and show on retest therapeutic levels, then compare them to a placebo group with similar risks (e.g. homocysteine elevated or MTHFR mutation and homocysteine elevated.

Without doing this there is so much noise that one cannot show benefit, when there is likely benefit.

3 Likes