Breaking Bad: Homocysteine and Aging
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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
- 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.
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.
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Marina MacDonald, MS, PhD
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