Disclaimer: This post is not intended to be medical advice, seek the independant advice of a medical doctor before acting on any information. This post is for research pruposes only.
I wanted to start a discussion on the emerging epigenetic link between folate (possibly also other methyl-donors), methionine restriction (“MR”) and possible life-extending drugs like metformin.
Cabreiro F. et al. (2013) showed that metformin mediated life extension via altered methionine and folate metabolism. Further, Cabreiro F. et al. (2013) show that metformin induced MR and extended lifespan dependant on: E.coli strain, metformin sensitivity and glucose concentration. According to Cabreiro F. et al. (2013), metformin alters methionine metabolism in gut E. coli and this in turn influences host metabolism. Storeli G. et al. (2013) described metformin as a methionine restriction mimetic; the latter will be discussed again later. See:
- Storelli G. et al. (2013). Metformin, microbes, and aging. Cell Metab. 2013 Jun 4;17(6):809-11.
- Cabreiro F. et al. (2013). Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell. 2013 Mar 28;153(1):228-39.
This may seem somewhat farfetched since those studies were conducted worms; however human studies have also shown decreases in serum folate and increases in homocysteine. See:
- M. G. Wulffelé et al. (2003). Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial
- Stefano Palomba et al. (2012). Effects of Metformin With or Without Supplementation With Folate on Homocysteine Levels and Vascular Endothelium of Women With Polycystic Ovary Syndrome
So the question is: how important are folate levels to life-extending intervention? Nguyen TP and Clarke CF. (2012). conclude that pharmacological interventions that manipulate the gut microbiome (and thus folate) may be viable ways to extend lifespan .This suggests that folate may be important:
- Nguyen TP and Clarke CF. (2012). Folate status of gut microbiome affects Caenorhabditis elegans lifespan. BMC Biol.; 10:66.
The following study puts some of these findings into the context of human microbiome health:
- Eleftheria Maratos-Flier. (2013). Metabolic Disease Puts Up a Fight: Microbes, metabolism and medications. Nature Medicine19,1218–121
Taking a Closer look at Methionine Restriction:
A recent paper by Tang et al. (2015) shed light on the epigenetics behind methionine restriction and more specifically showed that when MR is initiated, "S-Adenosyl-L-methionine (SAM)" reserves are readily used up in the biosynthesize of creatine. This results in epigenetic modifications like reduced methylation and changes to gene transcription. Tang, X. et al. (2015) seem to show that these SAM reserves aren't used up when glycine or arginine are lacking; as these two substrates are required for creatine biosynthesis. See:
- Tang X, Keenan MM, Wu J, Lin C-A, Dubois L, Thompson JW, et al. (2015) Comprehensive Profiling of Amino Acid Response Uncovers Unique Methionine-Deprived Response Dependent on Intact Creatine Biosynthesis. PLoS Genet 11(4): e1005158. doi:10.1371/journal.pgen.1005158
DNA hypomethylation was likewise noted in this study:
- Johnson JE, Johnson FB (2014). Methionine Restriction Activates the Retrograde Response and Confers Both Stress Tolerance and Lifespan Extension to Yeast, Mouse and Human Cells. PLoS ONE 9(5): e97729. doi:10.1371/journal.pone.0097729
Methyl Donors and their Role in MR and MR Mimetics:
While we know that adequate intake of vitamin b12, folate and other methyl donors is essential for health, we may be wise to play closer attention to how much we are consuming. Since metformin may act as a methionine restriction mimetic by altering intestinal microbiome metabolism, it could either enhance regular MR significantly, or lead to dangerous elevations in homocysteine due to Vitamin b12 and folate deficiencies.
Some people attempting MR do this by following a low protein vegan diet. See:
- McCarty, MF. et al. (2009). The low-methionine content of vegan diets may make methionine restriction feasible as a life extension strategy. Med Hypotheses. 2009 Feb;72(2):125-8.
While it is hard to make generalisations, some evidence seems to show that vegans consume high amounts of folate, but very little b12:
- Gilsing AM et al. (2010). Serum concentrations of vitamin B12 and folate in British male omnivores, vegetarians and vegans: results from a cross-sectional analysis of the EPIC-Oxford cohort study. Eur J Clin Nutr. 2010 Sep;64(9):933-9.
- Obersby D. et al. (2013). Plasma total homocysteine status of vegetarians compared with omnivores: a systematic review and meta-analysis. Br J Nutr. 2013 Mar 14;109(5):785-94.
Therefore one might conclude that vitamin b12 supplements would be essential for vegans. However the correct dosage must be titrated high enough to ensure that homocysteine remains very low, while at the same time b12 levels are not ecessively high; as to cause hyper-methylation. If anyone has more info on this, your input here would be appreciated!
For vegans getting enough folate in their diet, additional supplementation would seem to be unnecessary and even potentially harmful. Sticking close to recommended nutritional requirements would seem to be advisable. If folate levels are essential to MR, then this issue deserves further studies.
In the case of omnivores, it seems even harder to make generalisations since diet can vary so much. The best advice for everyone would seem to be: track your dietary intake in accordance with recommended levels and ask your doctor for blood tests.
Nutritional Supplements that act as Methyl Sinks:
Generally we know that many beneficial substances can become harmful when they cause hyper-homocysteine levels. One example would pharmacological doses of niacin (nicotinic acid); but I’m unsure whether the same applies to other forms of b3:
- Basu, T. et al. (2002).Niacin (nicotinic acid) in non-physiological doses causes hyperhomocysteineaemia in Sprague–Dawley rats. British Journal of Nutrition. Volume 87, Issue 02. pp 115-119
People have reported that supplementing folate, b12 and b6 is necessary to guard against homocysteine increases while taking higher doses of niacin. It appears that interventions like pharmacological doses of niacin should be studied more carefully to ascertain what the safest dose of methyl donors would be. This could be highly individual due to dietary intake.
The takeaway:
Folate and possibly also b12 intake should be titrated under medical supervision in order to ensure that the dose is neither inadequate, nor excessive. Further research into the link between epigenetics and the human microbiome seems warranted. How important are folate and methioine/SAMe mediated DNA methylation changes to life extension interventions? Finally, is metformin a useful MR memetic, or are the risks of side-effects, b12/folate deficiency and high homocysteine too great? Note: only medical doctors are trained to provide valid advice on the last point!
Edited by Phoenicis, 29 July 2015 - 04:22 AM.