Homocysteine Increases During Aging, But Can Be Reduced With Diet And Targeted Supplementation

[Alex K Chen]

Also it's not just MTHFR. Maybe hcy intervention works on those who have high hcy due to environmental not genetic reasons (like aging)

Ugh I looked at the meta studies and most say that b vitamins that decrease hcy don't decrease risk

One can try taurine and reducing methionine intake (god I'm veg but I still love veg protein, but this month I'm taking eggs out)

Meat increases hcy https://nutritionandmetabolism.biomedcentral.com/articles/10.1186/s12986-017-0233-z

Bc MTHFR affects way more than just hcy levels [horizontal pleiotropy]

 

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Individuals carrying the common MTHFR C677T mutation have decreased affinity for the essential cofactor FAD (riboflavin), exhibiting higher blood pressure values than controls, with a very high risk of diagnosed hypertension. McNulty et al. also found significant reductions in blood pressure in randomized control studies employing riboflavin (B2) averaging 6–13 mm Hg, independent of medication.³ In another randomized trial, it was demonstrated that as little as 1.6 mg/day of riboflavin decreased systolic blood pressure more effectively than hypertensive drugs alone.⁴ They noted that a 2 mm decrease in blood pressure reduces stroke risk by 10%.⁴ Other studies reveal consistent evidence that riboflavin administration represents an underutilized approach for the treatment of resistant hypertension and stroke prevention.^3,19

 

 

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is there horizontal pleiotropy between MTHFR variants and heart disease risk

 

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Research on the relationship between MTHFR gene variants, specifically the C677T polymorphism, and heart disease risk through mechanisms like horizontal pleiotropy offers nuanced insights. A meta-analysis of unpublished datasets involving over 48,000 cases of coronary heart disease (CHD) and nearly 68,000 controls found that the association between the MTHFR C677T polymorphism and CHD risk was minimal and not statistically significant. This analysis indicated that moderate lifelong elevation of homocysteine levels, which can be influenced by MTHFR variants, has little or no effect on CHD risk. The results suggest that previously observed associations between MTHFR gene variants and CHD in published studies might reflect publication bias or methodological issues rather than a causal relationship

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Furthermore, a Mendelian randomization study focusing on the genetic predictors of plasma homocysteine levels and their relationship with congestive heart failure or cardiomyopathy found no significant association. This study utilized data from large cohorts and applied various statistical methods to ensure the robustness of the findings. The results across different methods consistently showed no causal link between genetically predicted homocysteine levels and these heart conditions

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These findings collectively suggest that while the MTHFR gene variants may influence homocysteine levels, the impact of these variants, through mechanisms like horizontal pleiotropy, on the risk of heart disease, including CHD, congestive heart failure, or cardiomyopathy, is not supported by the current evidence. It's important to consider the broader genetic and environmental context when assessing risk factors for heart disease.

 

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folate on intracellular Hcy (might not decrease)

https://www.degruyter.com/document/doi/10.1515/cclm-2012-0694/html?lang=en

betaine might decrease intracellular Hcy, might take 4-6 grams for effect (the serving size is 500mg for my supplement)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3610948/

Hcy can be remethylated into methionine (thru folate/betaine) OR trans-sulfurated (thru B6) into cystathionine..

I know I once overdosed on both B12 and folate and it didnt decrease my Hcy.. But maybe excess folate inhibits Hcy catabolism?
 

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With a high dietary supply of methionine-rich animal proteins, an increase in tissue concentrations of SAM occurs, and 70% of homocysteine is catabolized by CBS through the transsulfuration pathway (Fig. 1, reaction 5). In contrast, under conditions of restricted protein supply, the remethylation pathway is favored by an acceleration of the MTHFR-dependent folate mobilization (Fig. 1, reaction 10). In this case, only 10% of the homocysteine pool is catabolized through the CBS transsulfuration pathway. Nevertheless, a long-term high methionine intake can lead to a saturation of the transsulfuration pathway. This saturation is associated with an inhibition of remethylation that leads to a cell homocysteine efflux. Studies have shown that methionine-enriched diets or acute methionine loads cause homocysteine to be exported from cells, leading to increased plasma homocysteine levels (Ueland and Refsum, 1989).

The intracellular pool of folates also is involved in the regulation of homocysteine metabolism by supplying 5-methylTHF. Indeed, 5-methylTHF is necessary for the cellular remethylation of homocysteine into methionine (Fig. 1, reaction 7). 5-methylTHF thus maintains optimum tissue levels of SAM when there is a restricted exogenous methyl group supply from methionine and choline. Moreover, under conditions of high folate intake, 5-methylTHF reduces the alternative transmethylation pathway by inhibiting glycine methyltransferase (Fig. 1, reaction 3). The resulting increase in tissue concentrations of SAM limits intracellular folate pool mobilization in the homocysteine remethylation route (Fig. 1, reaction 10). Conversely, a decrease in the bioavailability of 5-methylTHF generates a reduction of homocysteine remethylation (Fig. 1, reaction 7) and an acceleration of the alternative transmethylation (Fig. 1, reaction 3). Decreases in tissue concentrations of SAM, resulting from depletion of the folate stores, induce inhibition of the transsulfuration reactions

 

In which case I have to test again..

In the context of low B12, excess folate inhibits Hcy catabolism, but I had excess B12 last year when I had my Hcy of 8.5..

However, a vegan I contacted told me that he has to take A LOT (betaine, creatine, etc) just to get his Hcy down to 8...

Edited March 4 by InquilineKea

[Mike Lustgarten]

There are more potential methyl donors besides betaine, choline, creatine that could impact homocysteine, including proline and tryptophan betaines, and trigonelline

I'll cover this in-depth in a future video

[Alex K Chen]

How about beets?

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The betaine content of the beetroot grown in the field was between 3.0 and 4.8 mg/g fresh weight, approximately 20% higher than in plants from the greenhouse. There was great variation among the cultivars with respect to their contents of betalains and betaine.Feb 12, 2014

in 360g of canned beets, that's like roughly a gram of betaine/TMG

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well which methylation genes act on both homocysteine and epigenetic age?

Edited March 27 by InquilineKea