What is Homocysteine and how does it impact healthspan?

Key Takeaways:

• Elevated levels of homocysteine have been linked with an increased risk of developing numerous health conditions.
• Age, genetics, diet, supplements, and prescription medications can all impact homocysteine levels.
• Supplementing with three key B vitamins, B6, B9, and B12, can help maintain healthy homocysteine levels to support optimal functioning as we age.

Related Product:

• Matter: Contains the Oxford-developed B vitamin complex clinically proven to slow brain atrophy associated with mild memory concerns in the VITACOG study. Matter is doctor-recommended to combat brain aging and support long-term brain health.*

Much has been written about homocysteine and its role in human health. Research studies have linked elevated homocysteine levels with numerous conditions related to heart, vascular, and brain health. It is imperative to understand what homocysteine is and what it does in our body so that we can better understand how to mitigate health conditions as we age.

The human body utilizes 20 amino acids to build every protein structure. Proteins are the basic molecules made by the human body to form virtually every structure in the body—from the collagen components of the skin to the hemoglobin in your red blood cells. Amino acids are the building blocks to form these structures. While homocysteine is technically an amino acid, it is not one used by humans in the formation of proteins and is created in the body during the breakdown and synthesis of other amino acids (methionine and cysteine). People have elevated levels of homocysteine when there are problems related to the process of breaking down and synthesizing these amino acids.

Elevated homocysteine levels have been found to be associated with an increased rate of biological aging in a recent study (Fig. 1) [1].  This risk is related to how elevated homocysteine levels affect normal processes within the body. Abnormally high levels of homocysteine have the following effects: hyperactivation of N-methyl-D-aspartate (NMDA) receptors in neurons which causes an influx of too much calcium into the cell, increased apoptosis (the process where your body signals for cells to self-destruct), increased accumulation of reactive oxygen species (ROS) which increases oxidative stress in blood vessels, and platelet dysfunction. Together, these effects explain the correlation of elevated homocysteine levels and conditions related to heart, vascular, and brain health.

Figure 1. 2-year change in rate of aging, measured by Index, and baseline homocysteine (tHcy) levels for placebo and B-vitamin treatment groups. Participants with clinically defined hyperhomocysteinemia (tHcy ≥15 μmol/L) are shown. Image adapted from Holmes HE, et al., Aging Cell. 2024.

As we age, homocysteine levels tend to increase naturally. Typically, homocysteine levels remain constant throughout the first four decades of life. These levels start to steadily increase thereafter and the rate of increase accelerates after the age of 70. The average level of homocysteine in people over 85 is double that of those under 40 [2,3].

Several different factors influence homocysteine levels in the body. As mentioned above, aging tends to result in an increase in homocysteine levels. As homocysteine is an intermediary amino acid formed when converting methionine to cysteine, processes that affect that conversion can result in an increase in homocysteine. This process is impacted by three key B vitamins: B6 (pyridoxine), B9 (folate), and B12 (cobalamin). Having healthy levels of these vitamins helps to ensure that homocysteine is effectively broken down in the body.

Figure 2. Levels of plasma homocysteine are regulated by the availability of vitamin B12, folate (vitamin B9), and vitamin B6. All of these B vitamins are cofactors or substrates for enzymes involved in homocysteine metabolism. 

In the U.S., 30% of people carry a copy of a gene that codes for a specific protein that has a reduced capacity to assist in the regulation of homocysteine levels. The gene codes for something called methylene tetrahydrofolate reductase (MTHFR). This version of the gene (T mutation) does not work as efficiently as the normal one. Ten percent of people carry two copies of the T mutation of the MTHFR gene and thus have increased levels of homocysteine at baseline. The T mutation has been linked with various health conditions such as cardiovascular diseases, pre-eclampsia, miscarriages, depression, cancer, and Alzheimer's disease, to name a few. This population likely needs to pay particularly close attention to how elevated homocysteine levels impact their healthspan.

Lastly, certain medical conditions and prescription medications can impact homocysteine levels, thus possibly increasing the risk of the aforementioned conditions. Homocysteine is eliminated from your body through two main pathways. It is either converted to cysteine or methionine, or it is cleared from your blood by your kidneys and excreted with the urine. People with chronic kidney disease are at increased risk of having elevated homocysteine levels. Additional medical conditions that can lead to increased homocysteine levels include vitamin deficiencies, gastrointestinal diseases that lead to poor vitamin absorption, diabetes, liver diseases, inflammatory diseases, and cancer. 

Specific medications are known to affect the function and availability of the three key B vitamins involved with homocysteine regulation. Since these B vitamins are less available to help process homocysteine, blood levels of homocysteine increase. Examples of these medications include antiepileptic medications, oral contraceptives, proton pump inhibitors, metformin, and diuretics.

Considering the role that elevated levels of homocysteine plays in a people’s health, maintaining healthy concentrations of the amino acid has been a focus of research and clinical development. Researchers at the University of Oxford (in their VITACOG study) found that supplementing with a B vitamin complex containing B6, B9, and B12, in a specific formulation can significantly reduce brain atrophy and homocysteine levels in individuals with high levels of homocysteine [4]. From this insight, Matter was developed. 

Matter contains the same B vitamin formulation used in the VITACOG study along with an advanced omega-3 formulation that augments the effect of the vitamins. This B vitamin complex has been clinically proven to regulate homocysteine levels. Optimizing homocysteine levels is an important part of maintaining wellness over time.

Homocysteine levels can be measured through a simple, routine blood draw. Genetic analyses can also determine whether a person carries the T-mutation within the MTHFR gene. It’s important to discuss your individual health goals with your healthcare provider who can decide if further diagnostics are right for you. In the meantime, ongoing scientific work suggests that optimized levels of B vitamins and healthy regulation of homocysteine can help support healthy aging and wellness.

References

1)  Holmes HE, Valentin RE, Jernerén F, et al. Elevated homocysteine is associated with increased rates of epigenetic aging in a population with mild cognitive impairment. Aging Cell. 2024;23(10):e14255. doi:10.1111/acel.14255

2) Garcia A, Zanibbi K. Homocysteine and cognitive function in elderly people. CMAJ. 2004;171(8):897-904. doi:10.1503/cmaj.1031586

3) Jacques PF, Bostom AG, Wilson PW, Rich S, Rosenberg IH, Selhub J. Determinants of plasma total homocysteine concentration in the Framingham Offspring cohort. Am J Clin Nutr. 2001;73(3):613-621. doi:10.1093/ajcn/73.3.613

4) Smith AD, Smith SM, de Jager CA, et al. Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial. PLoS One. 2010;5(9):e12244. Published 2010 Sep 8. doi:10.1371/journal.pone.0012244

*Based on a 2022 blinded and randomized survey of 151 internal medicine and preventative medicine doctors fielded by a leading healthcare professional sample provider. Each physician was required to have a medical degree (MD), be practicing medicine, and was provided small monetary compensation via the sample provider to participate in the survey.