adssx
#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.
AnUser
#111
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.
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adssx
#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?)
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AnUser
#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.
adssx
#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 )
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AnUser
#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.
adssx
#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.
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adssx
#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.
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AnUser
#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.
adssx
#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
adssx
#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:
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?
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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
adssx
#122
More good news for riboflavin:
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Association between riboflavin intake and the risk of all-cause mortality of patients with chronic kidney disease: A retrospective cohort study 2024: “After excluding potential confounders, lower intake of riboflavin was associated with the higher risk of all-cause mortality (Q1: HR = 1.33, 95% CI: 1.05–1.69). The similar association was also found in patients at mild/moderate stage (HR = 1.32, 95% CI: 1.05–1.66), in female (HR = 1.35, 95% CI: 1.01–1.81), with hypertension (HR = 1.37, 95% CI: 1.07–1.75), CVD (HR = 1.48, 95% CI: 1.08–2.03), and dyslipidemia (HR = 1.29, 95% CI: 1.01–1.66).”
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Riboflavin intake associated with decreased risk of all-cause mortality among adults attending NHANES 2005-2016 2023: “High intake of riboflavin was associated with a lower risk of all-cause mortality, and CVD mortality. In multivariable model adjusted for sociodemographic factors, lifestyle factors and chronic conditions, across the quartiles of riboflavin intake, the hazard ratios (HRs) [95% CI] for CVD mortality were: 1.00, 0.92 [0.63, 1.35], 0.79 [0.49, 1.26], 0.52 [0.30, 0.90] (p trend 0.027), respectively. The corresponding figures for all-cause mortality were: 1.00, 0.69 [0.55, 0.87], 0.74 [0.58, 0.94] and 0.62 [0.48, 0.80], respectively. The protective association between riboflavin intake and CVD mortality was further strengthened among those with a high intake of folate (quartiles 3 and 4) with HRs of 1.00, 0.49 [0.21, 1.12], 0.25 [0.10, 0.63] and 0.19 [0.08, 0.47] across quartiles of riboflavin intake (p for interaction 0.039). In conclusion, riboflavin intake was inversely associated with all-cause mortality, particularly CVD mortality. Riboflavin and folate synergistically decreased the risk of CVD mortality.”
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Riboflavin Intake Inversely Associated with Cardiovascular-Disease Mortality and Interacting with Folate Intake: Findings from the National Health and Nutrition Examination Survey (NHANES) 2005–2016 2022:" Compared to low level (quartile 1, Q1) of riboflavin intake, the hazard ratios (HRs) (95% confidence interval (CI)) for high level (quartile 4, Q4) were 0.53 (0.31–0.90) for CVD mortality and 0.62 (0.48–0.81) for all-cause mortality."
“The mean daily riboflavin intake was 2.1 (SD 1.0) mg ranging from 1.0 (SD 0.2) mg in the lowest quartile (Q1) to 3.4 (SD 1.0) mg in the highest one (Q4).”
As usual, association and not causality, but it’s good that it’s not a U curve.
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Good question. I have wondered why homocysteine lowering therapies don’t show clear benefits in clinical trials, especially since I have seen evidence of homocysteine directly harming the vasculature rathern than just being a marker of poor health. The study below indicates that maybe it’s not serum levels that are most important but tissue-bound or intracellular levels of homocysteine. Maybe most homocysteine lowering interventions mainly lower it in the serum but not so much in tissues. I’m not sure, but it’s an interesting theory. Here are a few relevant quotes:
“studies in animals and in cell culture suggest that Hcy has a vast array of toxic effects on the vasculature, with demonstrated roles in endothelial dysfunction, medial remodeling and adventitial inflammation. It is hypothesized that rather than serum Hcy, tissue-bound Hcy and the incorporation of Hcy into proteins could underlie the toxic effects of Hcy on the vasculature.”
" although B-vitamin supplementation successfully decreases serum Hcy concentrations, it is unknown whether it has the ability to decrease tissue-bound or intracellular Hcy. Current evidence suggests that Hcy elicits its negative effects directly in the vessel wall by inducing modifications to vascular cell function, and by irreversibly incorporating into cellular and extracellular matrix proteins (Fig. 2). These pathological changes induced by Hcy would likely be unaffected by serum Hcy-lowering treatments."
Source: Mechanisms of homocysteine-induced damage to the endothelial, medial and adventitial layers of the arterial wall - PubMed
6 Likes
adssx
#124
It seems that LifeExtension was right: Vitamin B12 Levels Association with Functional and Structural Biomarkers of Central Nervous System Injury in Older Adults 2025
Therefore, and since we postulated that people at the lower ranges of B12 may show signs of abnormalities in their mfVEP recordings, we stratified the cohort for B12 levels above and below the mean (geometrical mean = 408 pmol/L). Albeit these B12 levels were considered normal, patients with lower levels of B12 showed a significant inverse association with mfVEP latency (estimate = −0.04; p = 0.023; Fig 2A) in a model correcting for age, sex at birth, CVRF, BMI, APOEε4 allele, HbA1C, and education. Thus, a measured total B12 below the mean, or below 408 pM, significantly associates with a delay in mfVEP latency, representing slower conductivity in the brain.
However, there might be an upper limit (unclear if causal or not or due to a high inactive B12 %):
Surprisingly, in a linear regression model correcting for age, sex, BMI, CVRF, education, APOEε4 status, HbA1C, and creatinine, there was a positive association between Tau concentration (z-score adjusting for the factors stated above) and B12 (β = 0.25, p = 0.005, ΔR2 = 0.052, Fig 4A), but not any of the other biomarkers (Table 3). To further investigate this association between Tau and B12, we investigated the correlation between B12 levels and blood B12 components adjusting for the factors mentioned above. While no association could be found between Holo-TC and any of the included biomarkers (Fig 4B), Tau and UCHL-1 increased with higher Holo-HC (β = 0.22 and 0.28, p = 0.015 and 0.022, respectively, Fig 4C,D). Both associations remained significant after bootstrapping (p = 0.012 and 0.042 for Tau and UCHL-1, respectively).
So until we have more data, the optimal serum B12 range seems to be 400–900 pmol/L? (so 550–1200 pg/mL?)
1 Like
AnUser
#125
MMA and HC can diagnose B12 deficiency despite normal B12 levels:
There are two enzymatic reactions that are dependent on vitamin B-12. Vitamin B-12 is required for methylmalonic acid (MMA) to be converted to succinyl-CoA, and in combination with folic acid, for homocysteine (HC) to be converted to methionine [9]. Therefore, MMA is clearly more specific to vitamin B-12 deficiency compared to HC. A deficiency of vitamin B-12 at the tissue level can lead to elevation of both MMA and HC [1] even when serum vitamin B-12 concentrations are within the reference values. Elevated MMA and HC levels together have been found to be 99.8% sensitive for diagnosing functional vitamin B-12 deficiency [10], which is defined as elevated MMA and HC levels despite normal vitamin B-12 levels in asymptomatic individuals [11–13]. Therefore, using serum vitamin B-12 testing alone may under-diagnose the deficiency of this vitamin.
MMA and HC have been identified as early markers of vitamin B-12 deficiency in different subjects such as general population [14], elderly [15–17], Asian Indians [18], infants [19], pregnant women [20], healthy women [21], type 2 diabetes [22], phenylketonuria [13] and renal insufficiency [12]
So I would test MMA + HC + Serum B12.
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My levels are 602 pg/mL, I also have not taken B12 very much lately despite being near-vegan
cl-user
#127
That paper is clearly competing with the Chinese ones to reach the lowest quality ever.
we compared a linear with a polynomial regression model. The polynomial model showed a better fit (R2 = 0.023) than the linear model (R 2 = 0.007), suggesting a non-linear association.
I mean seriously? Their models have an R-squared of 0.023 and 0.007, which basically means that there is no meaningful correlation between the model and the data, and they write a paper about it.
Their plots do show that and the funny (or sad) part is that they bravely plot the 95% confidence interval lines while it’s obvious that most of the data points are outside that interval. Look at that one for instance.
4 Likes
adssx
#129
Yes, that’s a problem, but I wouldn’t discard it entirely. UCSF team publishing in the Annals of Neurology, so I give them the benefit of the doubt. I see that paper as a signal (you might say it’s just noise, and you might be right!). Would the trend be more evident with a larger cohort? Only 231 healthy elderly volunteers here, but it’s unlikely we would get all these biomarkers in a large cohort.
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