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

[Mike Lustgarten]

 

 

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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[Ron Put]

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.

[Mike Lustgarten]

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.

[Sibiriak]

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:  

Quote

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)

Quote

... 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)

Quote

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.

 

Quote

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.

 

Quote

...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.

 

Quote

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 May 10, 2021 by Sibiriak

[Sibiriak]

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.

Edited May 10, 2021 by Sibiriak

[Mike Lustgarten]

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.

[Sibiriak]

On 5/10/2021 at 12:47 AM, Ron Put said:

take a look at this video by Greger.

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.

 

Quote

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.

Edited June 9, 2021 by Sibiriak

[Ron Put]

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.

[Mike Lustgarten]

Homocysteine Update, What's Optimal For Vitamin B12?

 

https://www.youtube.com/watch?v=MOCQa1epzlg

[AlPater]

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.

[Ron Put]

Interesting B-12 study, Al. Thanks.

And thanks for the video, Mike. 

[Mike Lustgarten]

That study is in the video Al, and thanks Ron!

[Ron Put]

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.

[Mike Lustgarten]

Will Glycine Supplementation Reduce Homocysteine? 
 

 

[InquilineKea]

At my level of B12, I have a hazard ratio of 3x that of normal. My folate levels are also too high. I'm also ovo-vegetarian. Wtf [this was all temporary, the levels went down after i stopped mega-supplementing].

Also my homocysteine is now 9.2... Higher.

https://archive.ph/t11Yz

I did take creatine a lot over the past month (but lapsed in the week prior to the test). Clearly, more B12 is not for me. What then?

Edited January 14 by InquilineKea

[Ron Put]

In addition to 500 mcg daily B-12, I've been using glycine to keep my homocysteine in check and so far it appears to work better than just B-12. BTW, for me at least it doesn't seem like increasing B-12 affects homocysteine beyond certain level.

[InquilineKea]

I've been intermittently taking some glycine over the past month, maybe I should go more aggressively b/c it has side benefits

There's betaine/TMG, but glycine is more motivating

OF ALL PEOPLE, bryan johnson did not measure his homocysteine

Edited February 14, 2023 by InquilineKea

[mccoy]

On 2/14/2023 at 7:47 PM, InquilineKea said:

There's betaine/TMG, but glycine is more motivating

Why? AFAIK, TMG is one of the favourite choices to try and abate homocysteine levels. Plus Choline, plus folates and B12, Chris Masterjohn has spoken extensively about it. What has been retained in my memory though is that TMG alone may be sufficient. Good also for MTHFR gene polymorphisms.

[Ron Put]

13 hours ago, mccoy said:

TMG is one of the favourite choices to try and abate homocysteine levels.

Hi, mccoy. If I recall correctly, TMG may bump up LDL-C and TGs, while glycine may have the opposite effect.

[mccoy]

15 minutes ago, Ron Put said:

Hi, mccoy. If I recall correctly, TMG may bump up LDL-C and TGs, while glycine may have the opposite effect.

Ron, I may have missed that, but, from what you report, it's lucky that there is one thing (glycine) which doesn't bump up your cholesterol! 

 

[Ron Put]

8 minutes ago, mccoy said:

Ron, I may have missed that, but, from what you report, it's lucky that there is one thing (glycine) which doesn't bump up your cholesterol! 

 

Just did a very quick search, so only rats and general info came up:

Glycine:

Internet Scientific Publications (ispub.com)

TMG:

Betaine Information | Mount Sinai - New York

 

[mccoy]

Ron, I listened to so many things that my brain cannot retain all of'em. What I remember about glycine are Masterjohn's recommendations that we don't take too much since it's devoid of EAAs. No sweat, since it's abundant in animal broth. I consulted wikipedia, which is interesting, I didn't know glycine is also an inhibitory neurotransmitter

 

Quote

Physiological function[edit]

The principal function of glycine is it acts as a precursor to proteins. Most proteins incorporate only small quantities of glycine, a notable exception being collagen, which contains about 35% glycine due to its periodically repeated role in the formation of collagen's helix structure in conjunction with hydroxyproline.^[27][31] In the genetic code, glycine is coded by all codons starting with GG, namely GGU, GGC, GGA and GGG.

As a biosynthetic intermediate[edit]

In higher eukaryotes, δ-aminolevulinic acid, the key precursor to porphyrins, is biosynthesized from glycine and succinyl-CoA by the enzyme ALA synthase. Glycine provides the central C₂N subunit of all purines.^[27]

As a neurotransmitter[edit]

Glycine is an inhibitory neurotransmitter in the central nervous system, especially in the spinal cord, brainstem, and retina. When glycine receptors are activated, chloride enters the neuron via ionotropic receptors, causing an inhibitory postsynaptic potential (IPSP). Strychnine is a strong antagonist at ionotropic glycine receptors, whereas bicuculline is a weak one. Glycine is a required co-agonist along with glutamate for NMDA receptors. In contrast to the inhibitory role of glycine in the spinal cord, this behaviour is facilitated at the (NMDA) glutamatergic receptors which are excitatory.^[32] The LD₅₀ of glycine is 7930 mg/kg in rats (oral),^[33] and it usually causes death by hyperexcitability.

 

Edited February 17, 2023 by mccoy

[InquilineKea]

https://en.wikipedia.org/wiki/S-Adenosyl-L-homocysteine

is more dangerous

harder to measure, but look up genova diagnostics youtube (they have THREE VIDEOS)

Edited August 13, 2023 by InquilineKea

[InquilineKea]

Lustgarten says nicotinic acid *and* niacinamide *both* increase homocysteine

Tbf, increasing NAD doesn't really decrease aging rate...

 

Edited August 30, 2023 by InquilineKea

[InquilineKea]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10625852/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2651913/

Free reduced form of hcy.... Is most damaging

MR of MTHFR shows increased hcy increases risk, but b vitamins don't decrease the risk in those with elevated hcy....

Ugh gpt draw a IV diagram of ALL confounders like how b vitamins themselves might have their own casual shortcut (bottom arrow) to affecting heart disease risk - a collider.

MR assumes gene environment equivalence which is not the case.

Also MTHFR variant itself might have its own direct link to outcome - it doesn't just come through hcy levels

B vitamin intervention has arrows BOTH to the intermediate variable and outcome

 

----

Homocysteine (Hcy) can exist in several forms in the blood, including the free form and the protein-bound form. The "free reduced form" of homocysteine refers to homocysteine that is not bound to other proteins and is in its reduced state, meaning it has not been oxidized. This contrasts with the oxidized forms, such as homocystine (a dimer of homocysteine) or mixed disulfides with other thiols, particularly with cysteine.In human plasma, the majority of homocysteine is found bound to plasma proteins, primarily albumin. Only a small fraction is present in the free form, and of this free fraction, an even smaller portion exists in the reduced form. The free reduced form of homocysteine is considered the biologically active form, capable of participating directly in metabolic pathways, such as the methionine cycle and the synthesis of cysteine in the transsulfuration pathway.Elevated levels of total homocysteine (which includes all forms) have been associated with an increased risk of cardiovascular diseases, among other health issues. Measurement of homocysteine levels typically involves assessing the total plasma homocysteine, which includes both the free and protein-bound forms, rather than specifically measuring the free reduced form.

Edited March 3 by InquilineKea