Ascorbate supports folate?

Folate (vitamin B₉) is an essential carrier of 1-carbon (1C) units for DNA synthesis and methylation. More specifically, this involves reduced tetrahydrofolate (THF; H₄PteGlu) derivatives which are highly sensitive to oxidation; initially to dihydrofolate (DHF; H₂PteGlu), before eventually being destroyed by irreversible scission of the C₉–N₁₀ bond. It has long been known that the antioxidant ascorbic acid (vitamin C) can reduce DHF (to THF) and protect folate from degradation ¹. Further, in humans, dietary ascorbate and THF synergistically correlated RBC folate ², and ascorbate supplementation boosted the blood response to both natural 5-methyl-THF (over 8 hours) ³ and synthetic folic acid (after 45 days) ⁴, supporting physiological relevance.

Oxidative ageing: from proximate to ultimate causes

Oxidative stress seems really important in age-related decline and disease—but what causes it? Here I’ve tried to express a broadening perspective, by exploring its core, context and ultimate causes; and largely anchored in human studies where possible.

We all die—what matters is how. While human life expectancy has increased, non-communicable diseases are now the major cause of disability and death globally (WHO and OWID). These are mostly age-related diseases (e.g. CVD, cancer, COPD, dementia, etc.), which develop slowly over time, and coexist as multimorbidity (e.g. most people >65 in US/UK ^1,2); resulting in functional decline/frailty and socioeconomic burden (i.e. ↓ productivity, ↑ sick care). This situation is growing globally, as populations are ageing, and diseases occur earlier—so we may live longer but sicker ¹. Moreover, this invisible epidemic underlies susceptibility to (communicable) infectious diseases, such as COVID-19 ³, elevating chronic disease to acute threat.

Synthetic vs. organic B12 metabolism—is cyanocobalamin inferior?

Cyanocobalamin is a common synthetic form of vitamin B₁₂ used in supplements and fortified foods—how does it compare to natural forms?

Vitamin B₁₂ (cobalamin, Cbl) has the most complex structure of all vitamins, which consists of a central cobalt atom bound to a corrin ring, a displaceable lower (a) ligand (5,6-dimethylbenzimidazole, DMBI) and a variable upper (b) ligand (e.g. cyano-, methyl-, 5’-deoxyadenosyl-, etc.) ¹ (see).

Cbl was originally isolated as cyanocobalamin (CNCbl), which was later recognised as an artefact arising from extraction methods ². Further advances led to identification of natural forms in microbes, animals and humans ^2–5, where methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl) serve as vital coenzymes for methionine synthase (MS) and methylmalonyl-CoA mutase (MCM), respectively.

Supplement concerns—an appeal to nature

I’ve become increasingly concerned about the efficacy and safety of some typical nutritional supplements—here’s why.

Initially, my concern is a logical appeal to nature. Food contains a complex matrix of chemicals in the balance and structure of life, to which our physiology (e.g. digestion, metabolism and microbiome) is adapted. By comparison, supplements supply concentrated food ingredients, to an extreme of isolated chemicals in unnatural forms and mega doses. My concern is fed by some studies reporting on potentially negative effects and long-term health outcomes (see table); common themes are the use of synthetic/isolated nutrients and high doses (note their use also in ME/CFS studies ^1–5). Could these deviations from nature impair bioactivity or induce imbalances which limit efficacy and introduce risk? Some specific examples are discussed below.

Homocysteine on the brain: many paths to many problems

2019 – end edit and update.

Homocysteine might be important in many neurological disorders, especially cognitive decline. I’ve been reading about potential mechanisms—there are a lot! Here’s an attempt to arrange some things of interest as a mini-review.

Homocysteine is a sulfur-containing amino acid, derived from the metabolism of dietary methionine. Homocysteine exists in various forms ¹ and is metabolised via two main pathways: remethylation and transsulfuration. Homocysteine remethylation to methionine maintains levels of SAM, the major methyl-donor, required in over 50 methylation reactions to DNA/RNA, proteins, phospholipids and other metabolites ². Whereas homocysteine catabolism via the transsulfuration pathway yields many other important sulfur metabolites (e.g. cysteine/glutathione, H₂S and taurine). Both of these pathways depend upon B vitamin-derived substrates/cofactors and are regulated by various physiological processes.

Sulfur in CFS: signals in the noise?

Some findings presented at a recent CFS conference got me interested in sulfur again. What is the current picture? How does it fit with everything else? Here’s a mini-review of my reading.

Sulfur is the 7th most abundant element in the body ¹. Most has been presumed to come from dietary proteins, specifically the two sulfur-containing amino acids: methionine and cysteine. However, a substantial amount also comes from other organosulfur compounds in plants (e.g. allium and cruciferous veg) and inorganic sulphates (i.e. water and food) ².