William Faloon

The New York Times headline read:¹

"Kilmer McCully, 91, Dies, Pathologist Vindicated on Heart Disease Theory"

"His studies showed that a B vitamin deficiency could cause hardened arteries. It took the medical profession more than a decade to catch up."

Dr. McCully was a pathologist at Harvard Medical School who became famous, then infamous, and finally vindicated for his discovery that elevated homocysteine is a risk factor for cardiovascular diseases.¹

For relentlessly advocating for lower homocysteine levels, his colleagues banished him to the basement, burying his theory for many years.¹

Dr. Kilmer McCully

Not accepting Dr. McCully’s theory may have cost countless lives. Simple solutions can lower homocysteine and help reduce cardio- vascular risks. Still, most physicians today debate the value of homocysteine blood testing.

Kilmer McCully passed away on February 21, 2025, at the age of 91 from metastatic prostate cancer.¹

The irony of this is that both homocysteine and PSA (prostate specific antigen) can be tested in blood and offer a chance to take corrective actions before serious diseases manifest.

We published an article about the science supporting Dr. McCully’s homocysteine hypothesis in 1981 and suggested our readers initiate steps to lower this atherogenic compound if elevated.²

This editorial is a tribute to Dr. McCully’s pioneering research and describes strategies to reduce homocysteine, including a surprising method to optimize even stubbornly high homocysteine blood levels.

What is Homocysteine?

Homocysteine is an amino acid formed in the body from intake of another amino acid called methionine, which is high in certain meats and dairy products.³

High levels of homocysteine are associated with a range of diseases including Alzheimer’s,^4,5 migraines,⁶ hearing loss, ⁷ cerebrovascular,8 and cardiovascular diseases.^9,10

Data going back many decades indicated a value in testing homocysteine levels as part of a comprehensive cardiovascular risk assessment.

Yet despite published evidence, most doctors still ignore this marker—potentially leaving some of their patients vulnerable to preventable cardiovascular disorders, including ischemic stroke.

Multiple B vitamins play a role in breaking down homocysteine.^11-13 Deficiency in these vitamins can result in elevated homocysteine levels.¹⁴

Dr. McCully’s Discoveries

Homocystinuria (very high urine and plasma homocysteine levels) is a rare genetic disorder that results in early-age onset vascular disease.15 In a case-series study of homocystinuria, a nine-year-old girl died from a stroke just like her uncle did at the age of eight.¹

Hearing about this in the late 1960’s, McCully tracked down the autopsy reports from these children which revealed hardened arteries but no cholesterol or fat in the plaque buildup.¹

McCully ran experiments in rabbits which showed that injecting high doses of homocysteine led to moderate thickening in all their aortas. Upon further research he found that vitamins B6 and B12 helped lower homocysteine levels. When presenting his findings to the medical establishment, however, they were not motivated to take any action.¹

McCully’s theory on homocysteine was ignored until the 1990s when large-scale studies led by other researchers produced results that supported his theories.

The famous Framingham Heart Study found that hardening of the arteries connected to the brain was associated with elevated homocysteine levels.¹⁶

Another study by authors that included researchers from the Harvard School of Public Health found that men with the highest levels of homocysteine had a three-fold greater risk of suffering a heart attack than men with lower levels.¹⁷

Regarding McCully’s theory, an epidemiologist who helped lead the study that found men with high homocysteine levels faced triple the heart attack risk said:

"At the end of the day, he was right in the sense that homocysteine is a marker for higher risk for cardiovascular disease and he gets the credit for developing this theory and helping to provide the evidence for it."¹

Who is Most At Risk of High Homocysteine?

In 1998, the United States and Canada made it mandatory to fortify foods like cereal, flour, and bread with folate primarily to reduce the risk of neural tube defects, but it has also helped bring homocysteine down to healthy levels in many people.^18,19

An interesting study compared the changes in stroke mortality during and after folate fortification in the U.S. and Canada to England and Wales (countries without folate fortification). From 1990 to 2002, all populations experienced a decline in stroke mortality. However, when the U.S. and Canada fortified their food with folate the stroke death decline accelerated faster compared to England and Wales.²⁰

Post fortification, between 1999-2002, the mean levels of homocysteine amongst Americans declined to around 8-9 µmol/L.^21,22 This was also the last time the average homocysteine level in the American population was evaluated that we could find.

We at Life Extension^® recommend keeping homocysteine levels below 12 µmol/L, with under 8 µmol/L as the optimal target.

For those whose homocysteine levels are now in safe ranges because of fortification and increased use of folate-containing supplements, there is little to be concerned about.

Certain individuals, however, remain challenged with stubbornly high homocysteine levels.

Homocysteine is generally higher in men than women, with age, and in association with certain diseases such as chronic kidney disease, heart failure, dementia, and diabetes. Those hospitalized with these conditions frequently present with elevated homocysteine blood levels.^23-25

Elevated homocysteine may also arise from mutations in genes that code for enzymes involved in the metabolism of methionine, including the MTHFR gene.²⁶

These MTHFR genetic variants leave more folate in a less bioactive state due to inefficient methylation. Since the fortification of the food supply with folate, only about 12% of those with the worst genetic variant of MTHFR have elevated homocysteine, compared to 33% pre-fortification.²⁷

The only way to know your homocysteine level is with blood testing, and if elevated it can easily be reduced to better support cardiovascular health.

A Norwegian study of about 5,000 adults (ages 65–67), found that compared to those below 9 µmol/L, individuals with levels between 9–11.9 µmol/L had a 30% higher risk of cardiovascular death and 40% higher risk of non-cardiovascular death. Those with levels between 12–14.9 µmol/L faced a 110% and 90% increased risk, respectively.²⁸

Why Some Researchers Question The Benefits of Reducing Homocysteine

The cause of plaque build-up in the arteries will vary from individual to individual.

Including homocysteine testing in cardiovascular risk assessment could save many lives and much grief. Some clinical trials fail to show a benefit from homo- cysteine reduction alone; we believe this is because they fail to consider all the other risk factors for cardio- vascular disease.

There are 20 or more independent risk factors for cardiovascular disease. Targeting one without the others will not accomplish ideal disease prevention.^30,31

High plasma levels of homocysteine may further exacerbate damage to the inner lining of the blood vessels, called the endothelium, when combined with high LDL, glucose, and hypertension.⁹

How To Reduce Elevated Homocysteine

High homocysteine levels can be easily reversed by increasing intake of certain B vitamins such as vitamins B6, B12 (methylcobalamin) and folate (5-methyl-tetrahydrofolate) and reducing intake of methionine.^32,33

One overlooked approach to lowering homo- cysteine further is with high doses (around 1,800 mg/day) of N-acetyl-cysteine (NAC), which may help detoxify homocysteine via another mechanism.

It is believed that NAC’s supplying of abundant cysteine into the bloodstream causes displacement of homocysteine from its binding to albumin in plasma, freeing it to then be cleared by the kidneys.³⁴

Summary

We at Life Extension^® have alerted the public about the potential dangers of excess homocysteine since 1981, echoing Dr. McCully’s work.

Unfortunately, most blood test panels that screen for cardiovascular disease still omit homocysteine when convincing evidence suggests that homocysteine testing and treatment may save lives.

As we honor Dr. McCully, let us not repeat the mistakes of the past. Let’s ensure that homocysteine is no longer overlooked in the prevention of cardiovascular diseases.

20 Daggers of Arterial Disease

This graphic shows 20 daggers aimed at an artery occluded with atherosclerotic plaque.

Any one of these "daggers" can initiate and propagate atherosclerotic vascular disease.

Most readers of this magazine are aware of the pathologies involved in arterial disease and follow comprehensive preventive measures.

For longer life,

William Faloon, Co-Founder, Life Extension®

References

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