Life Extension Magazine March 2010
How Aging Humans Can Slow and Reverse Atherosclerosis
By Richard Hathaway
Scientists long ago documented the ability of HDL (high-density lipoprotein) to remove cholesterol affixed to arterial walls and transport it to the liver for safe disposal.
This is why it is so important to maintain HDL levels above 50 mg/dL of blood and follow steps Life Extension® has outlined to ensure optimal reverse cholesterol transport of lipids away from the arterial wall.
HDL does more than just cleanse arterial walls of plaque. It also protects LDL against oxidation, while inhibiting chronic inflammation, vascular adhesion molecules, and platelet activation—factors that can all lead to atherosclerosis.
For HDL to perform its vital functions, an enzyme called paraoxonase-1 (PON-1) is attached to its surface.
As humans age, PON-1 levels markedly decline, thereby reducing the ability of HDL to protect against heart attack and stroke. This phenomenon helps explain the onset of accelerated atherosclerosis; where within a period of only a few years, an aging person’s healthy arteries rapidly occlude with plaque.
The age-related reduction in PON-1 may also explain studies showing that statin drugs lose their benefit in certain aging populations, since the effects of statins are no longer sufficient to protect against the multiple factors involved in the development of atherosclerosis in the elderly.1-3
Lipid peroxidation is a free radical reaction that severely damages cell membranes and is implicated in a host of degenerative diseases. PON-1 blocks destructive lipid peroxidation reactions,4-7 making it a crucial enzyme for aging humans to maintain.
PON-1 is anchored to the surface of HDL and is emerging as a formidable defense against atherosclerosis, diabetes, stroke, arthritis, and certain forms of cancer.
Pharmaceutical companies would pay a king’s ransom for a drug that elevates PON-1 levels in the body. Fortunately, scientists have discovered low-cost natural methods to elevate PON-1 and unleash its full antioxidant and anti-inflammatory power.
This article uncovers research substantiating the anti-aging effects of PON-1—and how nutrients that most Life Extension members already take boost PON-1 activity for maximum benefit.
Reduce Your Cardiac Risk Factors
Atherosclerosis is a leading cause of death in the Western world.8 A growing body of clinical evidence suggests that PON-1 (paraoxonase-1) may very well serve as one of the body’s primary defenses against it.
PON-1 is an enzyme produced in the liver and released into the blood, where it attaches exclusively to the HDL molecule.9 As an enzymatic engine that supports HDL’s beneficial action, PON-1 has been shown to inhibit the accumulation of lipoperoxides in LDL cholesterol—the process that results in oxidized LDL’s accumulation on arterial walls, leading to deadly hardening of the arteries.5,6,10
losesits ability to prevent LDL oxidation over time—and there is evidence that an age-related drop in serum PON-1 levels may be part of the reason.11 By preserving HDL’s integrity, activity, and efficacy, PON-1 helps HDL protect arterial health.
PON-1 selectively breaks down oxidized fats, acting as a “cleanup” system to prevent oxidized molecules from triggering inflammatory cells in the blood5,6,12 (one of the mechanisms of action behind HDL’s heart-protective benefit).13 Increases in PON-1 activity after red wine consumption provided some of the first clues to why red wine, and specifically its active component, resveratrol, are protective against cardiovascular diseases.14-16
In mice genetically engineered to lack the PON-1 gene, scientists have found a dramatic increase in oxidative stress on macrophages, immune cells that can become laden with oxidized lipids and contribute to a pro-atherogenic cascade of inflammation in vessel walls.4
Similarly, humans with low PON-1 levels are at substantially increased risk for cardiovascular events compared with those who have normal levels.17 Healthy humans endowed with the most active genetic expression of PON-1 also display enhanced protective responses to natural antioxidants.10,18 New methods of measuring PON-1 activity in the blood show that it is correlated to coronary artery disease risk, regardless of lipid profiles or lipid-lowering therapy.19
PON-1 is more closely related to cardiovascular risk in individuals already at high risk for atherosclerosis. People with chronic kidney disease on hemodialysis, for example, have 30% less PON-1 activity than normal, which produces a startling 127% decrease in their HDL’s antioxidant function.20 PON-1 levels, in fact, are an accurate predictor of cardiovascular mortality in kidney hemodialysis patients. Lower than average PON-1 levels were not only predictive of cardiovascular mortality, but also of all-cause mortality.7
In addition to its ability to protect HDL against oxidation, PON-1 has also been shown to hydrolyze (break apart) homocysteine thiolactones,21 which are responsible for damage to blood vessels. So PON-1 on its own is a blood vessel protector.
Evidence from animal research on PON-1 uniformly shows that PON-1 is protective against atherosclerosis. However, it has not been possible to definitively determine if decreased PON-1 activity is the cause of cardiovascular events, or a reflection of the events themselves.6 Prospective studies are needed to make this determination. Until now, there has been only one such study, and it clearly showed that low PON-1 in the blood was an independent risk factor for coronary events in men with pre-existing coronary artery disease.22
However, the increasingly persuasive substantiation of the relationship between PON-1 and a broad spectrum of cardiac risk factors has prompted researchers to deem this enzyme “a player in cardiovascular medicine”23 and “an important target for future pharmacological agents aimed at decreasing cardiovascular risk.”9
A Potent Weapon Against Diseases of Aging
With the boom in scientific interest in PON-1 over the past two decades,23 the documented range of its disease-fighting modes of operation in the body continues to broaden. As leading researcher Janice E. Chambers of Mississippi State University puts it, PON-1 has emerged as a “multitasking protein.”24
A growing roster of chronic, age-related conditions has been associated with dangerously low PON-1 levels. They also happen to be associated with significantly elevated levels of lipid peroxidation. This in turn increases the amount of PON-1 the aging body needs to compensate for the onslaught of oxidative damage to healthy cells.
To take one example, researchers have recently discovered that overweight individuals and those suffering from metabolic syndrome display a demonstrable decrease in PON-1 activity, rendering them still more vulnerable to cardiovascular disease.25,26
PON-1 plays a number of essential roles in preventing diabetes and its consequences, particularly in managing the postprandial (after-meal) spikes in blood sugar that produce deadly advanced glycation end products (AGEs). When blood sugar levels rise, liver production of PON-1 increases as well, possibly to compensate for the oxidative stress induced by glucose.27
This appears to be the reason why PON-1 levels increase following a meal in non-diabetic people, preventing oxidation levels in healthy tissue from rising.28 But in diabetics and people with impaired glucose tolerance (pre-diabetics), oxidation products rise rapidly after eating. Diabetics actually have a significant decrease in postprandial PON-1 concentrations, further boosting their risk for cardiovascular disease.28
Helicobacter pylori—a bacterium closely associated with ulcers and cancer of the stomach—also suffer from elevated oxidative stress, lower PON-1 levels, and increased risk of atherosclerosis.29 People with high homocysteine may have dysfunctional HDL molecules characterized by reduced PON-1 activity, which appears to account in part for their higher cardiovascular risk.30
Even those with seemingly unrelated diseases of aging—including osteoarthritis and age-related macular degeneration (AMD)—exhibit diminished PON-1 activity.31,32 High LDL and low HDL cholesterol levels commonly occur in individuals with AMD, further increasing susceptibility to lipid peroxidation and cardiovascular disease.