Breaking Bad: Homocysteine and Aging
Share this post
The role of B vitamins in cardiovascular and neurological health
“If I’d known I was going to live this long, I’d have taken better care of myself.” – Eubie Blake, American composer, upon reaching the age of 100
By now it’s widely known that high blood cholesterol levels can be harmful to our health. Low-density lipoprotein (LDL)-cholesterol is also called “bad” cholesterol for its tendency to build up in the arteries, increasing the risk of heart disease and stroke. Lipoprotein (a) is another culprit. But there is another blood marker that poses health risks and is not often discussed: an amino acid known as homocysteine (Hcy).
Half of all people with atherosclerosis and/or heart attack have normal cholesterol levels, so checking markers like Hcy may help catch cardiovascular risk factors and address them before they occur.
Hcy is produced in the body from methionine, an essential amino acid found at high levels in animal proteins as well as some nuts and beans. Although many of us have had our cholesterol levels checked, we may never have had our Hcy levels tested. And yet studies conducted over the last 30 years have shown that elevated Hcy levels contribute to atherosclerosis (plaque build-up in the arteries), which increases the risk for heart attack and stroke.,, Two eye-opening studies have shown that half of all people with atherosclerosis and/or coronary artery disease (a major factor contributing to heart attacks) have normal cholesterol levels, so checking markers like Hcy may help catch cardiovascular risk factors and address them before they cause problems later on.,
Elevated Hcy levels are not only linked to heart disease, but also increase the risk of Alzheimer’s disease, colorectal cancer, congestive heart failure, deep vein thrombosis (blood clot),, depression, erectile dysfunction, kidney disease, non-alcoholic fatty liver disease,, and osteoporosis – in short, a laundry list of conditions associated with aging.
Smoking, lack of exercise, alcohol consumption, certain genetic variants, and many prescription drugs tend to increase Hcy levels.,, Elevated Hcy levels are also associated with impaired kidney function, hypothyroidism, the decline of hormones seen in menopause, type 2 diabetes, and autoimmune disease – issues that collectively impact much of the population.
Statistics show a cause and effect relationship between Hcy levels and cardiovascular disease: when Hcy levels are elevated by 5 micromole/L, the risk of heart disease increases by 32% and the risk of stroke increases by 59%.
According to the American Heart Association, normal blood Hcy concentrations range from 5-15 micromole/L, although others argue for an upper limit of 11-12 micromole/L.,, A high level of Hcy is known as hyperhomocysteinemia (HHcy). Note that there is a lower limit (5 micromole/L), because – like cholesterol – some Hcy is needed for normal functions.
Even in otherwise healthy individuals, Hcy levels rise with age by about 1 micromole/L per decade. Statistics show a cause and effect relationship between Hcy levels and cardiovascular disease: when Hcy levels are elevated by 5 micromole/L, the risk of heart disease increases by 32% and the risk of stroke increases by 59%.
To understand this relationship, let’s look at the ways HHcy accelerates aging.
How homocysteine accelerates aging
At high levels, Hcy damages the vascular and nervous systems, essentially speeding up the aging process., Scientists have identified several ways in which Hcy causes tissue damage:
- Hcy inhibits glutathione peroxidase, an enzyme that normally protects cells against oxidation. Elevated Hcy levels produce oxidative stress, inflammation, and cell death.,,,, Even mildly elevated Hcy causes cellular damage that is visible upon microscopic examination of the brain.,
- Hcy causes an increase in a modified amino acid called ADMA (asymmetric dimethylarginine), which inhibits nitric oxide (NO) production., Low levels of NO are associated with cardiovascular disease and stroke.,
- Excess Hcy is metabolized to toxic byproducts that damage the neurons that produce dopamine, a brain chemical that is closely associated with feelings of happiness. The effect of Hcy on dopamine may explain why there is an association between HHcy and depression. HHcy also worsens the symptoms of Parkinson’s disease, a condition linked to low dopamine levels.,
How B vitamins and other nutrients impact Homocysteine levels
About two-thirds of HHcy cases are attributable to B vitamin deficiency. When B vitamin levels are low, Hcy cannot be properly metabolized and thus builds up in the blood.
About two-thirds of HHcy cases are attributable to B vitamin deficiency. When B vitamin levels are low, Hcy cannot be properly metabolized and thus builds up in the blood.
Four different B vitamins are needed in sufficient amounts for normal Hcy metabolism: folate (vitamin B9), cobalamin (vitamin B12), pyridoxine (vitamin B6), and riboflavin (vitamin B2). Due to genetic polymorphisms, some people cannot methylate, or “turn on,” the folic acid and cyanocobalamin (B12) found in many cheaper, commercially-available supplements. For this reason, the methylated, or activated, forms of the nutrients – 5-MTHF and methylcobalamin, respectively – may more effectively reduce Hcy levels. Other nutrients that help modulate Hcy levels include the amino acid serine;, a nutrient known as betaine (aka trimethylglycine or TMG);,, zinc, an essential mineral;, omega 3 fatty acids; and the antioxidants N-acetylcysteine and glutathione,, which also help protect against oxidative stress.
Homocysteine and the cardiovascular system
Vitamin B12 deficiency in particular is quite common, especially in vegetarians or vegans and the elderly, but often is not diagnosed., B vitamin supplementation helps prevent clots from forming and can reduce the risk of stroke., Scientists believe that the diagnosis and treatment of vitamin B12 deficiency and supplementation with B vitamins to reduce Hcy may lower the risk of stroke by 30% – a very significant effect.,,,,
As mentioned above, HHcy may further cause injury to the vasculature and increase the risk of cardiovascular disease and stroke by means of increasing ADMA and inhibiting NO. The form of vitamin B12 known as methylcobalamin has been shown to lower both Hcy and ADMA., For this and other reasons, methylcobalamin is preferred over cyanocobalamin, another form of B12.
Homocysteine and brain function
Intervention trials in elderly with cognitive impairment show that Hcy-lowering treatment with B vitamins markedly slows the rate of whole and regional brain atrophy and also slows cognitive decline.
Low blood levels of B vitamins – and elevated Hcy – are risk factors for Alzheimer’s disease (AD)., Even moderately raised Hcy (>11 micromole/L, a level that is fairly common), can double the risk of dementia.
In volunteers aged 70 and older with mild cognitive impairment, daily supplementation with B vitamins (folic acid, vitamin B12 and vitamin B6) reduced the rate of brain atrophy by 53% over a two-year period. A 2018 report by an international panel of experts concludes: “Intervention trials in elderly with cognitive impairment show that Hcy-lowering treatment with B vitamins markedly slows the rate of whole and regional brain atrophy and also slows cognitive decline.” Moreover: “The public health significance of raised Hcy in the elderly should not be underestimated, since it is easy, inexpensive, and safe to treat with B vitamins.”
Although we can’t stop the aging process, we may be able to slow it down if we adopt a healthy lifestyle and address obvious risk factors like elevated Hcy and cholesterol. Food sources alone may not always provide enough nutrients to sustain optimal Hcy levels. Fortunately, supplemental B vitamins can help lower Hcy and support heart and brain health throughout life.
Click here to see References
 McCully KS. Homocysteine and the pathogenesis of atherosclerosis. Expert Rev Clin Pharmacol. 2015 Mar;8(2):211-9.
 Ganguly P, Alam SF. Role of homocysteine in the development of cardiovascular disease. Nutr J. 2015 Jan 10;14:6.
 Ji Y, et al. Vitamin B supplementation, homocysteine levels, and the risk of cerebrovascular disease: a meta-analysis. Neurology. 2013 Oct 8;81(15):1298-307.
 Fernández-Friera L, et al. Normal LDL-cholesterol levels are associated with subclinical atherosclerosis in the absence of risk factors. J Am Coll Cardiol. 2017 Dec 19;70(24):2979-91.
 Sachdeva A, et al. Lipid levels in patients hospitalized with coronary artery disease: an analysis of 136,905 hospitalizations in Get With The Guidelines. Am Heart J. 2009 Jan;157(1):111-7.
 Seshadri S, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med. 2002 Feb 14;346(7):476-83.
 Shiao SPK, et al. Meta-analysis of homocysteine-related factors on the risk of colorectal cancer. Oncotarget. 2018 May 22;9(39):25681-97.
 Vasan RS, et al. Plasma homocysteine and risk for congestive heart failure in adults without prior myocardial infarction. JAMA. 2003 Mar 12;289(10):1251-7.
 Ekim M, et al. Study on relationships among deep vein thrombosis, homocysteine & related B group vitamins. Pak J Med Sci. 2015 Mar-Apr;31(2):398-402.
 Aday AW, et al. Homocysteine is associated with future venous thromboembolism in two prospective cohorts of women. J Am Coll Cardiol. 2018 Mar 10;71(11 Supplement):A2106.
 Gu P, et al. Relationship between serum homocysteine levels and depressive symptoms: the Cooper Center Longitudinal Study. J Clin Psychiatry. 2012 May;73(5):691-5.
 Zhang Z, et al. Elevated serum homocysteine level as an independent risk factor for erectile dysfunction: a prospective pilot case-control study. Andrologia. 2017 Aug;49(6):e12684.
 Chen CH, et al. High homocysteine, low vitamin B-6, and increased oxidative stress are independently associated with the risk of chronic kidney disease. Nutrition. 2016 Feb;32(2):236-41.
 de Carvalho SC, et al. Plasmatic higher levels of homocysteine in non-alcoholic fatty liver disease (NAFLD). Nutr J. 2013 Apr 2;12:37.
 Sun MY, et al. Associations between methylenetetrahydrofolate reductase (MTHFR) polymorphisms and non-alcoholic fatty liver disease (NAFLD) risk: a meta-analysis. PLoS One. 2016 Apr 29;11(4):e0154337.
 Zhu Y, et al. Plasma homocysteine level is a risk factor for osteoporotic fractures in elderly patients. Clin Interv Aging. 2016 Aug 18;11:1117-21.
 Refsum H, et al. The Hordaland homocysteine study: a community-based study of homocysteine, its determinants, and associations with disease. J Nutr. 2006 Jun;136(6 Suppl):1731S-40S.
 Desouza C, et al. Drugs affecting homocysteine metabolism: impact on cardiovascular risk. Drugs. 2002;62(4):605-16.
 Frederiksen J, et al. Methylenetetrahydrofolate reductase polymorphism (C677T), hyperhomocysteinemia, and risk of ischemic cardiovascular disease and venous thromboembolism: prospective and case-control studies from the Copenhagen City Heart Study. Blood. 2004 Nov 15;104(10):3046-51.
 Morris MS, et al. Hyperhomocysteinemia and hypercholesterolemia associated with hypothyroidism in the third US National Health and Nutrition Examination Survey. Atherosclerosis. 2001 Mar;155(1):195-200.
 Hak AE, et al. Increased plasma homocysteine after menopause. Atherosclerosis. 2000 Mar;149(1):163-8.
 Ndrepepa G, et al. Circulating homocysteine levels in patients with type 2 diabetes mellitus. Nutr Metab Cardiovasc Dis. 2008 Jan;18(1):66-73.
 Lazzerini PE, et al. Hyperhomocysteinemia: a cardiovascular risk factor in autoimmune diseases? Lupus. 2007;16(11):852-62.
 Malinow MR, et al. Homocyst(e)ine, diet, and cardiovascular diseases: a statement for healthcare professionals from the Nutrition Committee, American Heart Association. Circulation. 1999 Jan 5-12;99(1):178-82.
 Maron BA, Loscalzo J. Should hyperhomocysteinemia be treated in patients with atherosclerotic disease? Curr Atheroscler Rep. 2007 Nov;9(5):375-83.
 Weiss N, et al. Endothelial dysfunction and atherothrombosis in mild hyperhomocysteinemia. Vasc Med. 2002 Aug;7(3):227-39.
 Smith AD, et al. Homocysteine and dementia: an international consensus statement. J Alzheimers Dis. 2018;62(2):561-70.
 McCully KS. Homocysteine, vitamins, and vascular disease prevention. Am J Clin Nutr. 2007 Nov;86(5):1563S-8S.
 Wald DS, et al. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ. 2002;325:1202-6.
 Djuric D, et al. Homocysteine and homocysteine-related compounds: an overview of the roles in the pathology of the cardiovascular and nervous systems. Can J Physiol Pharmacol. 2018 Aug 21:1-13.
 Weiss N, et al. Overexpression of cellular glutathione peroxidase rescues homocyst(e)ine-induced endothelial dysfunction. Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12503-8.
 Cavalca V, et al. Oxidative stress and homocysteine in coronary artery disease. Clin Chem. 2001 May 1;47(5):887-92.
 Tyagi N, et al. Mechanisms of homocysteine-induced oxidative stress. Am J Physiol Heart Circ Physiol. 2005 Dec;289(6):H2649-56.
 Zhao J, et al. Study on the relationship between serum homocysteine levels and oxidative stress in patients with coronary heart disease. J Modern Lab Med. 2016 Jan 1;31(5):27-9.
 Tripathi M, et al. Hyperhomocysteinemia causes ER stress and impaired autophagy that is reversed by Vitamin B supplementation. Cell Death Dis. 2016 Dec 8;7(12):e2513.
 Zhang Z, et al. Homocysteine induces apoptosis of human umbilical vein endothelial cells via mitochondrial dysfunction and endoplasmic reticulum stress. Oxid Med Cell Longev. 2017;2017:5736506.
 de S Moreira D, et al. Chronic mild hyperhomocysteinemia alters inflammatory and oxidative/nitrative status and causes protein/DNA damage, as well as ultrastructural changes in cerebral cortex: is acetylsalicylic acid neuroprotective? Neurotox Res. 2018 Apr;33(3):580-92.
 De Silva TM, et al. Microvascular dysfunction and cognitive impairment. Cell Mol Neurobiol. 2016 Mar;36(2):241-58.
 Chen S, et al. Asymmetric dimethyarginine as marker and mediator in ischemic stroke. Int J Mol Sci. 2012 Nov 28;13(12):15983-6004.
 Obradovic M, et al. Link between homocysteine and cardiovascular diseases. Current Pharmacology Reports. 2018 Feb 1;4(1):1-9.
 Willeit P, et al. Asymmetric dimethylarginine and cardiovascular risk: systematic review and meta-analysis of 22 prospective studies. J Am Heart Assoc. 2015 May 28;4(6):e001833.
 Sverdlov AL, et al. Aging of the nitric oxide system: are we as old as our NO? J Am Heart Assoc. 2014 Aug 18;3(4).
 Bhatia P, Singh N. Homocysteine excess: delineating the possible mechanism of neurotoxicity and depression. Fundamental & Clinical Pharmacology. 2015 Dec;29(6):522-8.
 Belujon P, Grace AA. Dopamine system dysregulation in major depressive disorders. Int J Neuropsychopharmacol. 2017 Dec 1;20(12):1036-46.
 Bhattacharjee N, et al. Chronic exposure of homocysteine in mice contributes to dopamine loss by enhancing oxidative stress in nigrostriatum and produces behavioral phenotypes of Parkinson’s disease. Biochem Biophys Rep. 2016 Feb 26;6:47-53.
 Christine CW, et al. Vitamin B12 and homocysteine levels predict different outcomes in early Parkinson’s disease. Mov Disord. 2018 May;33(5):762-70.
 Selhub J. The many facets of hyperhomocysteinemia: studies from the Framingham cohorts. J Nutr. 2006 Jun;136(6 Suppl):1726S-30S.
 Wolters M, et al. Effect of multivitamin supplementation on the homocysteine and methylmalonic acid blood concentrations in women over the age of 60 years. Eur J Nutr. 2005 Mar;44(3):183-92.
 Sim WC, et al. Inhibition of homocysteine-induced endoplasmic reticulum stress and endothelial cell damage by l-serine and glycine. Toxicol In Vitro. 2016 Aug;34:138-45.
 van Guldener C, et al. Homocysteine metabolism in renal failure. Kidney Int Suppl. 2001 Feb;78:S234-7.
 Craig SA. Betaine in human nutrition. Am J Clin Nutr. 2004 Sep;80(3):539-49.
 Imbard A, et al. High homocysteine induces betaine depletion. Biosci Rep. 2015 Apr 28;35(4).
 Olthof MR, Verhoef P. Effects of betaine intake on plasma homocysteine concentrations and consequences for health. Curr Drug Metab. 2005 Feb;6(1):15-22.
 Pakfetrat M, et al. Effects of zinc supplement on plasma homocysteine level in end-stage renal disease patients: a double-blind randomized clinical trial. Biol Trace Elem Res. 2013 Jun;153(1-3):11-5.
 Heidarian E, et al. Effect of zinc supplementation on serum homocysteine in type 2 diabetic patients with microalbuminuria. Rev Diabet Stud. 2009 Spring;6(1):64-70.
 Dawson SL. A combination of omega-3 fatty acids, folic acid and B-group vitamins is superior at lowering homocysteine than omega-3 alone: a meta-analysis. Nutr Res. 2016 Jun;36(6):499-508.
 Hildebrandt W, et al. Oral N-acetylcysteine reduces plasma homocysteine concentrations regardless of lipid or smoking status. Am J Clin Nutr. 2015 Nov;102(5):1014-24.
 Ovrebø KK, Svardal A. The effect of glutathione modulation on the concentration of homocysteine in plasma of rats. Pharmacol Toxicol. 2000 Sep;87(3):103-7.
 Richie JP Jr, et al. Randomized controlled trial of oral glutathione supplementation on body stores of glutathione. Eur J Nutr. 2015 Mar;54(2):251-63.
 Morris MS, et al. Elevated serum methylmalonic acid concentrations are common among elderly Americans. J Nutr. 2002 Sep;132(9):2799-803.
 Green R, et al. Vitamin B12 deficiency. Nat Rev Dis Primers. 2017 Jun 29;3:17040.
 Wang X, et al. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet. 2007 Jun 2;369(9576):1876-82.
 Spence JD. Recent advances in preventing stroke recurrence. F1000Res. 2017 Jun 28;6:1017.
 Ji Y, et al. Prognostic significance of homocysteine levels in acute ischemic stroke: a prospective cohort study. Curr Neurovasc Res. 2015 Nov 1;12(4):334-40.
 Saposnik G, et al. Homocysteine-lowering therapy and stroke risk, severity, and disability: additional findings from the HOPE 2 trial. Stroke. 2009 Apr;40(4):1365-72.
 Koyama K, et al. Randomized controlled trial of the effect of short-term coadministration of methylcobalamin and folate on serum ADMA concentration in patients receiving long-term hemodialysis. Am J Kidney Dis. 2010 Jun;55(6):1069-78.
 Smith AD, 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 Sep 8;5(9):e12244.
Share this post
Marina MacDonald, MS, PhD
What is Bowel Tolerance?
A guide to dosing vitamin C, magnesium, and other nutrients We often talk about taking vitamin C and magnesium to “bowel tolerance” – but what does that mean? Dosing a supplement to bowel tolerance means taking the highest dose of that supplement possible without causing loose, watery stools (diarrhea). If you’re taking vitamin C…
Sturdy Joints and Glowing Skin
Hydrolyzed collagen and hyaluronic acid for joint and skin health Collagen: the protein that holds us together. Collagen is the most abundant protein in the body, important for the integrity and health of our skin, hair, bones, tendons, ligaments, and cartilage. It isn’t merely a metaphor to say collagen holds us together; 75 to…
Fat-Soluble Vitamins, Immunity, Vaccinations, and Respiratory Health (Video)
How vitamins A, D, and E help keep us safe all year long In this video, Dr. Erica Zelfand explains the important impact of fat-soluble nutrients on immune function. After explaining the difference between fat-soluble and water-soluble vitamins, Dr. Zelfand explores the details of how vitamins A and D and different forms of vitamin…
The Multivitamin Debate
What does science say about multivitamin and mineral supplementation? Dietary supplement use is common in the United States, with more than half of the population using such products.,,, Similarly, a majority of health professionals, including physicians and dieticians, use dietary supplements themselves and recommend them to patients.,, Among supplement users, multivitamin and mineral supplements…
Erectile Dysfunction and B Vitamins
Could a simple intervention like B vitamins improve ED? Multiple human studies suggest they might By far, the most common concern that comes up in discussions of male sexual health is erectile dysfunction. A large, multinational survey, published in 2004, found that erectile dysfunction (commonly referred to simply as ED) affects approximately 16% of…
Melatonin, the Antioxidant Recycler
Beyond sleep, melatonin protects against free radicals Melatonin’s age-old history in supporting aerobic life Melatonin is perhaps best known for its effects in regulating circadian rhythms and supporting sleep, but these are newer features of the hormone, evolutionarily-speaking. It’s theorized that melatonin’s original purpose – and primary function to this day – was as…
Subscribe for Updates
- Botanicals (57)
- GI Health (53)
- Healthy Aging (122)
- Immune Support (41)
- In The News (42)
- Kids Health (21)
- Stress and Relaxation (50)
- Video (9)
- Vitamins & Minerals (52)
Latest Issue of FOCUS Newsletter Available Now!
About Nutrition In Focus
Subscribe for Updates
Contents of this website are for the purpose of information and education only,
and not a guide to diagnosis or treatment of a particular disorder or its symptoms.
Copyright©2018-2021 Allergy Research Group®. All Rights Reserved.