Genomics 2: Fixing Homocysteine

March 14, 2021

Genomics 2: Figuring out how to Repair Homocysteine

This is no joke! Homocysteine is a huge risk for developing Alzheimer's and cognitive decline. A rise from 7 to 12 means some 40% incremental risk as shown by a landmark paper in the New England Journal of Medicine that followed the aging population in the famous Framingham Study. The average American male is at 12, making the lowering of homocysteine to 7 a top priority.  And a lot of people have that risk.  

It should be easy, right? Traditional Internal Medicine shows the homocysteine cycle to be all about sufficient vitamins B12 and methyl folate. Take those two and you should be all fixed. Those are the two vitamins that provide methyl groups (a single carbon atom with 3 hydrogens on it) for your body to "methylate" which is a critical step in manufacturing neurotransmitters, digesting used-up compounds, and many more functions. You need methylation. Only problem, it didn't work. Many folks get halfway there, but not all the way. Double the dose of methyl-folate and B12, and still no progress. What to do?

This is where the frontier of medicine shows up. Genomics is the emerging science of observing your genes and seeing what SNPs, (single nucleotide polymorphisms) you have.   A SNP is a gene with one amino acid changed that alters the functional efficiency of the gene. The methylation family of genes, known as MTHFR has been bandied about as the key. These are the proteins that convert homocysteine back into methionine, the amino acid that is the actual donor or methyl groups. You can measure your genes and see if you have a SNP in one or two of them. The response to those deficits is to take much more B12 and folate, or B6. And that is what hasn't worked.  You might say this has been "push" therapy for homocysteine.  Time to try "pull".  

This is where the field of "Metabolomics" comes along. In measuring all the actual compounds that are present in your blood, which reflect how active the total balance of your genetic profile is, we have learned all sorts of new insights. And the summary on homocysteine is eye-opening. The simplest understanding is as follows. Homocysteine is not the problem. It's demand for (that's the "pull") methyl groups, probably in your muscles, and membranes that is the real driver. Homocysteine is the gas gauge, not the gasoline. Goodenowe, the genius behind discovering plasmalogens, found that.

The real problem with high homocysteine is that it is an indicator that your methyltransferase system is shut down. The feedback loop of homocysteine does that. A low homocysteine means your methyltransferase system is open for business. High means it's closed.  It's backing up because of too much demand, too much "pull".  And if it's closed, B12 and folate won't fix it. You can understand how to fix homocysteine if you examine it from the point of "methylation demand". There are two enzyme systems that produce homocysteine: the ones that make creatine for your muscles, and phosphatidylcholine for your nerve membranes make 75% of your homocysteine.

It is that step before homocysteine that matters. Methylation demand produces a homocysteine precursor called SAH (S-adenyl homocysteine). SAH is the potent feedback loop that turns off methylation when demand is high and too many methyl groups are being used up. Get that? It's methylation demand that drives up homocysteine. That means methylation is turned off. Off. Off. Can't fix it with more B12 and folate. It's turned off. You have to lower demand! How so?

In a slight of organic chemistry magic, you can take the two compounds whose production drives demand, creatine, and phosphatidylcholine. Provide those from outside and you reduce methylation demand. If you reduce demand, you make less SAH. Less SAH, less homocysteine. Finally, if you take NAC (N-acetyl cysteine), you force the homocysteine you do make down to glutathione, using up homocysteine via cysteine, and again, preserving methionine. The reserve sources of choline are the fats in your nervous system membranes: your sphingomyelin. Your plasmalogens will start stealing choline from your nerve cells if you turn off methylation with high SAH. As you steal sphingomyelin, you make ceramides that you can measure. And your brain deteriorates. Does this sound like gobble-di-gook to you? Well, me too. So, let's make it simpler. Get me to the bottom line.

The puzzle was solved by Metabolomics, the study of what's in your blood. It has been metabolomics that tells us exactly how fast some enzymes work and how much of any given compound they produce. That has been the genius of Goodenowe and his plasmalogen test. He has studied the contents of peoples' blood and determined the balance of what's healthy and what results in harm and reduced down to understandable and actionable events. Look at your genes and see where your enzyme difficulties are. Look at your blood and see what the genes you inherited are actually doing, and I can show you how to lower your homocysteine to normal.

www.What will Work for me. Homocysteine is oddly one of the pinnacle markers for risk of cognitive decline. Lowering it should be one of all of our key "wellness" actions. It is easily as important as A1c. Mine has stubbornly been above 10, down from 15 but still 9-10. I did the IntellxxDNA test and found I have a SNP in the choline pathway called PEMT that lowers my production of choline. I create high methylation demand with that SNP. Ah! I get it now. I need more choline and creatine, in addition to the B12 and folate, I faithfully take every day. Every single person I've seen an IntellxxDNA test on has revealed one "secret" or another. The PEMT SNP that I'm short of, well, it's actually present in 45% of us. So, I'm not so special as I thought.....or we are all in a leaky boat together. The good news is, with knowledge we can fix it before we are in too much trouble.

References: NEJM, Acta Biochem Pol.,

Pop Quiz

1. Are you completely confused by this?                                       Answer: Yes!! Sorry....let me make it simpler.

2. Just get this right. What is Genomics?                                         Answer: The study of the variability of your genes from normal. Each of us has several hundred SNPs that have some clinical implications. By chance, most of them are not so bad because you only had one from one of your parents. But if you get the same SNP from both parents, you may have problems. PEMT is considerably softened by taking B12 in much higher doses. That may be why some folks just get better with B12 shots.

3. What is Metabolomics?                                                          Answer: An examination of what your genes actually make and do. How fast and how efficiently they work.

4. What is the real driver of high homocysteine?                                           Answer: Methylation demand. You aren't getting enough creatine in your muscles, so you are trying to make more creatine, producing more SAH. Or your nerves don't have enough phosphatidylcholine, so you are trying to make more of that, creating more demand.

5. How can you lower that demand?                                               Answer: Creatine is a cheap supplement. Phosphatidylcholine is also pretty inexpensive. NAC is safe and effective. Simple food items, if you need them, when targeted effectively, work. Then, take the standard B12 and folate. And you get fixed. Read the paper.