Folate pathway, drawbacks of high folate
plus updates on the website
Hi everyone,
Folic acid is ubiquitous in our food system - added to cereals, incorporated into bread and pasta, and fortified in rice. The addition of folic acid began in the mid-1990s in the US as a way to increase folate in the diet and prevent neural tube defects.[ref] (Anyone remember the March of Dimes walk-a-thons and fundraisers for spina bifida and neural tube defects?)
Research now shows that methylfolate may be a better form of folate for people with certain DHFR or MTHFR variants, and some online health gurus promote taking high doses of methylfolate. When you go to buy methylfolate, doses start at 400 mcg and go up to 15 mg, a huge range. You may wonder if more is better. The RDA is 400 mcg of dietary folate with an upper limit of 1mg.[ref] The larger doses of methylfolate exceed the recommended upper limit... While folate is a water-soluble vitamin, the recent study on niacin is a good reminder that more is not always better (nor benign).
I've written a full article on my Longevity Lifehacks substack about my concerns with higher doses of folate from a longevity standpoint. In the article, I explain the trade-offs between the benefits of folate and the risk of promoting cancer growth. I've learned a lot from reading through decades of research, and I hope you find it thought-provoking.
The folate cycle and story of folic acid is more than just MTHFR. To better explain it, I've created a downloadable folate pathway diagram (for members) and added two more short articles on genes in the folate cycle - FOLR1/2 and MTHFD1. There are more pathway diagrams in the works as well.
Finally, I wanted to mention that I've spent some time working on the flow of the site navigation to make it easier to find information. With over 400 articles containing genotype reports, I know that a lot gets missed because it is hard to find. This is an ongoing project, so you may see more changes next week. Please let me know if you find anything confusing.
Gratefully yours,
Debbie
FOLR1 and FOLR2: Transporting folate, folinic acid, and folic acid into cells
Key takeaways:
~ While the reduced folate carrier (SLC19A1) is the dominant folate receptor throughout the body, two other folate receptors enhance folate uptake in a few specific tissues.
~ The folate receptor alpha (FOLR1 gene) is important for the higher folate levels in the cerebrospinal fluid that provide the folate needed in the brain. FOLR2 is important in the immune response.
~ There are a couple of genetic variants and rare mutations that can affect the function of FOLR1 and FOLR2.
Read the rest of this article…
MTHFD1: Folate and Choline
The MTHFD1 gene encodes the methylenetetrahydrofolate dehydrogenase enzyme, which is an essential part of the folate cycle. It’s a trifunctional enzyme that catalyzes three sequential reactions in the folate cycle, which is essential for DNA synthesis, DNA repair, and DNA methylation.
What I've been reading:
1) Folic acid and methotrexate use and their association with COVID-19 diagnosis and mortality: a case–control analysis from the UK Biobank
This new study looked at medical data from over 380,000 people in the UK including Covid cases and prescription information. The results showed that people taking folic acid (as noted in their medical records) were at a 50% increased risk of Covid. The researchers "adjusted for age sex, ethnicity, Townsend deprivation index, body mass index, smoking status, presence of rheumatoid arthritis, sickle cell disease, use of anticonvulsants, statins and iron supplements." Theoretically, this could be because folate helps in the viral replication of SARS-CoV-2. However, I question whether a cofounder is how many people were on doctor-ordered folic acid due to heart issues and therefore not in optimal health.
2) Rare genetic variation in fibronectin 1 (FN1) protects against APOEε4 in Alzheimer’s disease
Researchers found that a variant in the fibronectin 1 gene is protective against Alzheimer's in people with APOE E4. The variant reduced Alzheimer's risk by about 70% in the study.
The FN1 variant from the study is not in 23andMe or AncestryDNA data. However, I'm going to look into this more and see if there is a tagging SNP. This is potentially a very exciting finding -- the fibronectin 1 gene is involved in the extracellular matrix at the blood-brain barrier, which is altered in APOE E4 carriers.
A new study on ME/CFS "revealed the significance of Th2-type cytokines and highlighted synergistic activities between mast cells and eosinophils, skewing Th1 toward Th2 immune responses in ME/CFS pathogenesis, particularly in cognitive impairment and sensorial intolerance. This suggests a potentially shared underlying mechanism with major ME/CFS comorbidities such as HSD, Mast cell activation syndrome, postural orthostatic tachycardia syndrome (POTS), and small fiber neuropathy."
While not specific to long Covid, this study may also be of interest there.
