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


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Papers referenced in the video:
Bacteria Boost Mammalian Host NAD Metabolism by Engaging the Deamidated Biosynthesis Pathway: https://pubmed.ncbi.nlm.nih.gov/32130...
 
Comparison of the effects of nicotinic acid and nicotinamide degradation on plasma betaine and choline levels: https://pubmed.ncbi.nlm.nih.gov/27567...
 
Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study: https://pubmed.ncbi.nlm.nih.gov/7474221/
 
Total plasma homocysteine values among elderly subjects: findings from the Maracaibo Aging Study: https://pubmed.ncbi.nlm.nih.gov/16959...
 
Hyperhomocysteinemia as a Risk Factor and Potential Nutraceutical Target for Certain Pathologies: https://www.ncbi.nlm.nih.gov/pmc/arti...
 
Hyperhomocysteinemia and risk of incident cognitive outcomes: An updated dose-response meta-analysis of prospective cohort studies: https://pubmed.ncbi.nlm.nih.gov/30826...
 
Association between Homocysteine Levels and All-cause Mortality: A Dose-Response Meta-Analysis of Prospective Studies: https://www.nature.com/articles/s4159...
 
 
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Thanks, Mike. Interesting observation about protein. However, increased protein comes with its own caveats.

Have you tried creatine supplementation? I am not sure if you are a vegan. But if you are, take a look at this video by Greger.

Also, there are arguments that homocysteine levels are an effect, not a cause of CVD issues. See, for e.g. this video.

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Thanks Ron. Greger promotes veganism, so it makes sense that he believes creatine is the best option for lowering homocysteine, rather than other sources, including B12, which comes from animals. 

Homocysteine could be an effect, not a cause of CVD, but it's associated with or directly impacts the health of many organ systems, as I mentioned in the video. For me, I prefer to err on the side of caution for homocysteine.

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Thanks Mike for the video.    Well done.  Unfortunately,  the issue is  not at all simple.

As Ron pointed  pointed out,  " increased protein comes with its own caveats " ,  but there may also be downsides to taking  large, unnatural B12 dosages long term.    See the discussion here,  starting with my post ( B12/prostate cancer)  and continuing with posts by Ron Put (B12/all-cause mortality) and  Dean Pomerleau (p.2).

  Also see here:  

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Vitamin B12 supplementation continues to be a popular treatment even in patients without overt vitamin B12 deficiency [32]. Many reasons may contribute to this popularity of vitamin B12 supplementation, and in addition to expecting some specific—albeit weak—effects, vitamins are popular for use as placebo interventions in cases where no other treatment options are available [91].

Such liberal use of vitamin B12 supplementation, however, might encounter criticism in the light of recent observational studies linking vitamin B12 supplementation or serum levels with hip fractures [92], lung cancer [93,94], and all-cause mortality in the general population [95].

Evidence is contradictory.  And of course, association does not prove causation.

The study Ron cited:

Association of Plasma Concentration of Vitamin B12 With All-Cause Mortality in the General Population in the Netherlands (2020)

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... the association of all-cause mortality with high plasma concentrations of vitamin B12 could not be attributed to CVD. We demonstrated that adjustment for blood pressure, as well as lipid profile and type 2 diabetes, did not change the association. Furthermore, in sensitivity analyses conducted after exclusion of participants with history of CVD, the association remained. In addition, plasma concentration of vitamin B12 was not associated with risk of CVD mortality. Such results are in line with a 12-year follow-up study from 201929 that found that plasma concentrations of vitamin B12 were not associated with the incidence risk of atherosclerotic disease.

Considering the universal role of the 1-carbon pathway in mammals, the explanation of the described association seems to rely in the role of vitamin B12 in the homeostasis of nonproliferative tissues6 rather than proliferative tissues,1 such as the bone marrow and other hematopoietic tissues, as we demonstrated that this association was independent of cancer history.

To date, the underlying mechanism of the association of plasma concentration of vitamin B12 with mortality is incompletely understood, to our knowledge. The proposed mechanisms to explain the association are that high vitamin B12 plasma concentrations may represent a response to increased release of vitamin B12 from liver storage, decreased clearance, upregulation of haptocorrin and transcobalamin synthesis, or diminished affinity of vitamin B12 for transporter proteins.1,3 Those situations are often present as a consequence of liver damage or CKD, which could be represented by the baseline association of high plasma concentrations of vitamin B12 with elevated concentrations of hepatic enzymes. Nonetheless, a definite mechanism has not been described, to our knowledge.14,30

The results of this study could also be clinically interpreted in the context of oral vitamin supplementation. Concern about the excess intake of vitamins, particularly vitamin B12, has gained attention. A 2010 study by Løland et al31 reported that vitamin B supplementation had no beneficial effect on the progression of coronary artery disease, as had been hypothesized previously. Moreover, in a prospective study with 75 864 women,32 vitamin B12 supplementation was associated with an increased risk of hip fracture. In that sense, our results may also suggest that caution should be taken when considering vitamin B12 supplementation in the absence of vitamin B12 deficiency

On the other hand:

Relationship between serum B12 concentrations and mortality: experience in NHANES (2020)

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Vitamin B12-containing supplements

In total, 7877 participants reported the use of oral vitamin B12-containing supplements in any form. Users of these supplements more frequently had a diagnosis of hypertension (35.7 vs 28.8%), hyperlipidemia (35.6 vs 29.2%), CVD (34.1 vs 30.8%), and cancer (44.8 vs 29.9%, all p < 0.001). A higher intake of vitamin B12 by supplements coincides with higher serum B12 concentrations (Table 3). Nevertheless, all groups contain participants with markedly elevated serum B12 concentrations. Although the unadjusted Cox proportional hazards analysis suggested a difference in all-cause mortality between different supplemental B12 intakes (Fig. 4), none of the adjusted models showed increased mortality in relation to intake of vitamin B12-containing supplements.

 

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Our unadjusted data showed a U-shaped association between serum B12 concentrations and subsequent all-cause mortality after a median follow-up duration of 109 months in NHANES participants aged 18 and above. After adjusting for relevant confounders, including socioeconomic status, education, ethnicity, smoking, comorbidity, and laboratory parameters, low serum B12 was associated with a moderate increase in all-cause and cardiovascular mortality. Sensitivity analyses revealed that this effect was no longer significant when adjusted for the relevant biomarkers homocysteine and MMA, which indicate a tissue B12 deficiency.

High serum B12 concentrations > 700 pmol/l were associated with an increase in cardiovascular mortality only (HR 1.45, 95% CI 1.01–2.06, p = 0.042). Participants with a diagnosis of hypertension, dyslipidemia, CVD, and cancer more frequently used vitamin B12-containing supplements than those without these diagnoses. Congruently, we found no indication that a higher intake of vitamin B12-containing supplements was associated with adverse effects on mortality.

 

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...there is nothing in those reports that indicates causality in the direction of a priori raised serum B12 leading to increased mortality. While the findings in our study confirm the overall U-shaped association of serum B12 concentration with mortality, they lend no support to the suggestion that high serum B12 concentrations per se are harmful or detrimental.

 

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The association between elevated serum B12 and cardiovascular mortality, together with the absence of any association between high B12 supplement intake and mortality likely indicates “reverse causality.” The increased use of vitamin B12-containing supplements by people with a chronic (cardiovascular) condition supports this conclusion, as well as the growing body of literature that serum B12 concentrations increase in states of inflammation [33]. However, there are several other factors which by themselves may negatively influence long-term morbidity and mortality, and are associated with higher serum B12 concentrations, for instance, high consumption of red meat.

 

Edited by Sibiriak
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4 hours ago, Mike Lustgarten said:

Greger promotes veganism, so it makes sense that he believes creatine is the best option for lowering homocysteine, rather than other sources, including B12, which comes from animals. 

In fairness to Greger,  he suggests creatine as a consideration only for vegans that are already supplementing B12 and still have high homocysteine levels. 

Greger promotes B12 supplementation: " getting enough vitamin B12 is absolutely nonnegotiable for those centering their diets around plant-based foods" and supplementing is the "easiest way" to get enough.

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Thanks Sibiriak. In terms of homocysteine being an association vs a causative factor, the abundance of the literature is somewhat divided, and as I mentioned, I usually prefer to err on the side of caution. That said, I'm familiar with the B12 literature, and although that's somewhat divided, too, one of the measurements that are on my testing to-do list is to identify the minimum dose that keeps homocysteine as low as possible, while also minimizing excess B12-related risk.

Ah, gotcha on Greger's creatine position for those with high B12 and homocysteine, good point.

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  • 5 weeks later...
On 5/10/2021 at 12:47 AM, Ron Put said:

Btw,  a full text of the key study cited by Greger can be found here:

Effects of dietary supplementation with creatine on homocysteinemia and systemic microvascular endothelial function in individuals adhering to vegan diets

https://crearene.com/wp-content/uploads/2021/04/R-Bavel_et_al-2019-Fundamental__Clinical_Pharmacology.pdf

A few excerpts:

Quote

The main findings of this study are as follows:

i) In strict vegan subjects, CrS v[creatine supplemenation,  5 g/day for 3 weeks] significantly increased the body weight, body mass index, and creatinine levels;

ii) CrS significantly reduced the plasma homocysteine levels and increased folic acid levels only in the group of hyperhomocysteinemic subjects;

iii) CrS was able to increase the perfusion of capillaries in the basal state and after hyperemia, which is an effect that was verified in both the normal and hyperhomocysteinemic vegan subjects.

 

 

Quote

In this study, we hypothesized that the possible increase in the creatine kinase–phosphocreatine ratio (Cr/PCr ratio) induced by CrS in endothelial cells could activate AMPK and increase adenosine levels [31,32,35–37]. Thus, in our study, although the activation of AMPK still needs to be demonstrated, CrS may have activated the expression of vascular endothelial growth factor, independent of the release of nitric oxide, through changes in DNA methylation, thereby collaborating to increase capillary perfusion at rest, which is highly suggestive of the process of angiogenesis [38].

It is noteworthy that the capillary densities in all of the groups of the present study appeared to be significantly higher than those observed in omnivores of the same age-group in another study conducted by our group [17], suggesting that vegans have a higher degree of tissue perfusion than omnivorous subjects.

Even if CrS did not alter the microvascular vasodilation induced by ACh or reactive hyperemia, there was a significant reduction in the area on the ACh curve after CrS in the normohomocysteinemic vegan subjects, which could be associated with an increasing trend of the homocysteine level. This profile was not observed in previously hyperhomocysteinemic vegan subjects. In this sense, increases of 1 lmol/L of homocysteine, as suggested by Jahandir et al., are sufficient to impair the endothelium-dependent vasodilation response [15].

 

Quote

As we had expected, CrS induced a significant increase in body mass and creatinine plasma levels that may be related to the intracellular augmentation of osmolarity due to cellular water retention and creatine metabolic degradation, respectively [44,45].

Although neither placebo nor CrS was able to alter the vitamin B-12 levels in normo- or hyperhomocysteinemic vegan subjects, these levels were marginally but significantly lower among the hyperhomocysteinemic vegan subjects.

 

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Limitations to this study must be considered. The  study did not evaluate the food intake of the volunteers for food containing creatine, folate, and vitamin B-12.  Nevertheless, volunteers who supplemented their diet with creatine or vitamin B-12 were not included in the study.

 

For those who haven't seen the video:  Greger suggests that vegans who still have high homocysteine levels  (> 10 μmol/L) even wtih B12 supplementation (eg. 2000 mcg cyanocobalamin/ wk consider taking 1 g/day high-purity creatine as an empirical experiment.

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9 hours ago, Sibiriak said:

For those who haven't seen the video:  Greger suggests that vegans who still have high homocysteine levels  (> 10 μmol/L) even wtih B12 supplementation (eg. 2000 mcg cyanocobalamin/ wk consider taking 1 g/day high-purity creatine as an empirical experiment.

My homocysteine has dropped from 16 or so, to between 8 and 9 μmol/L since I started supplementing with B-12. I've recently upped my 1000 B-12 dosage from 2 or 3, to 5 times a week.

I'll see what my blood panel is in a month or so.

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  • 1 month later...

As I said, I hate videos.

This paper was not previously posted:

Relationship between serum B12 concentrations and mortality: experience in NHANES.
Wolffenbuttel BHR, Heiner-Fokkema MR, Green R, Gans ROB.
BMC Med. 2020 Oct 9;18(1):307. doi: 10.1186/s12916-020-01771-y.
PMID: 33032595 Free PMC article.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545540/pdf/12916_2020_Article_1771.pdf
Abstract
Background: There is conflicting evidence in the literature on the association between (elevated) serum B12 concentrations and subsequent disease or mortality. We evaluated in the NHANES general population the association of serum B12 concentrations as well as vitamin B12 supplement intake with all-cause, cardiovascular, and cancer-related mortality, while taking into account demographic and lifestyle factors and significant other diseases which are known to be associated with poorer outcome.
Methods: The main outcomes of our study were all-cause mortality, cardiovascular mortality, and cancer-related mortality. Mortality status and cause of death were determined by NHANES-linked National Death Index public access files through December 31, 2015. The association of serum B12 concentrations and vitamin B12 supplement intake with mortality was assessed with Cox proportional hazard (PH) models, with adjustment for a number of relevant demographic and lifestyle factors and comorbidity.
Results: The final study population of 24,262 participants had a mean age of 48 (SD 19) years; 50.1% were males. The median follow-up duration was 109 months (range 1-201 months). On the census day of December 31, 2015, 3023 participants were determined as deceased (12.5%). The fully adjusted Cox PH model indicated that low serum B12 concentrations < 140 pmol/l were associated with a small increase in all-cause (hazard ratio, HR 1.39, 95% CI 1.08-1.78, p = 0.011) and cardiovascular (HR 1.64, 95% CI 1.08-2.47, p = 0.020) mortality. Similarly, high serum B12 concentrations > 700 pmol/l were associated with an increase in cardiovascular mortality only (HR 1.45, 95% CI 1.01-2.06, p = 0.042). Participants with a diagnosis of hypertension, dyslipidemia, CVD, and cancer more frequently used vitamin B12-containing supplements than those without these diagnoses. We could not demonstrate an association between vitamin B12 supplement intake and mortality, when adjusted for comorbidity.
Conclusions: In the general population of NHANES, low serum B12 concentrations were associated with a moderate increase in all-cause mortality. There was a small but significant increase in cardiovascular mortality in the groups with low or high serum B12. High intake of vitamin B12 in the form of supplements was not associated with any adverse effect on mortality and therefore can be regarded as safe.
Keywords: Epidemiology; Mortality; NHANES; Prognosis; Supplement; Vitamin B12.

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I had been wondering about B-12 as my numbers increased from low-mid 300s on no supplementation, to mid-600s with supplementation of about 4-5000 B-12 per week.

My homocysteine was high before I started supplementing, about 16-17, with supplementation it's hovering around 10.

I am reducing the B-12 to about 2000 per week and will see how the panel looks in a couple of months.

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