Life Extension Magazine®

Whole and opened pomegranate with the protective natural enzyme PON1

Fight Heart Disease by Activating a Protective Enzyme

An enzyme found in the body called PON1 provides natural protection against atherosclerosis and cardiovascular disease. Researchers have found that pomegranate extracts boost the multiple benefits of PON1, which increases HDL efficacy and supports healthy endothelial function.

Scientifically reviewed by: Dr. April Parks, MD, MS, in August 2023. Written by: Seth Richards.

Fight Heart Disease by Activating a Protective Enzyme

Despite billions being spent each year on coronary artery stents, bypass surgeries and statin drugs, heart disease remains the number one killer of Americans.1

While much of the initial research into pomegranate’s extensive health benefits focused on its juice, exciting findings reveal the multi-modal actions of pomegranate’s other components, including the juice, flower, leaves, and seed oil.2,3,5

How PON1 Can Save Your Life

In the past five years, researchers from around the world have discovered how the various constituents of the pomegranate all work together to offer protection from a spectrum of inflammatory conditions as varied as heart disease, arthritis, cancer, diabetes, oral health, and genito-urinary tract diseases.4,5

Increasingly, research is targeting the application of pomegranate extracts for their ability to reduce the risk of cardiovascular disease. Pomegranate extracts accomplish this effect through multiple pathways. One of the most intriguing pathways is pomegranate’s ability to raise blood levels of beneficial high-density lipoprotein (HDL) cholesterol, something few other therapeutic strategies can accomplish. Raising HDL cholesterol is a proven means to reduce your cardiovascular risk.3,4

We know that higher levels of HDL are associated with reduced risk for cardiovascular disease such as heart attack or stroke, but how does HDL actually produce these favorable effects on your body?

The answer lies with a group of medium-sized enzymes called the paraoxonases, which form a part of the HDL cholesterol particle.7 Paraoxonases exert powerful antioxidant effects not only on the fats contained in the HDL particle, but also on the dangerous low-density lipoprotein (LDL) cholesterol.2,8,9

Oxidized LDL is largely responsible for the creation of arterial plaques and the inflammatory response that ultimately blocks arteries and triggers deadly vascular events.10 Increasing levels of paraoxonase-containing HDL protects your tissues from deadly LDL oxidation.9

Enhancing PON1 (paraoxanase-1) activity in blood increases the antioxidant powers of beneficial HDL cholesterol, and increases the concentration of HDL in the blood.4 PON1 slows the maturation of the inflammatory cells (macrophages) that accumulate oxidized LDL to set up arterial plaque formation.11 Pomegranate extracts offer a potent means of increasing paraoxonase activity.12-14. Similarly, treatment with the main pomegranate polyphenol known as punicalagin, reduced triglyceride synthesis by as much as 40%.15

Let’s turn now to the practical impact of all this biochemistry on your body, to learn how pomegranate extracts can extend your life by preserving your cardiovascular health.

Pomegranate’s Powerful Cardioprotective Effects

Pomegranate’s Powerful Cardioprotective Effects

Increased oxidative stress is both a cause and a consequence of atherosclerosis. Conditions such as diabetes and obesity only serve to worsen the impact of oxidative stress on your body’s protective mechanisms.8,13 Boosting your body’s paraoxonase function and enhancing its HDL content with pomegranate extracts produces many important reductions in cardiovascular risks.16

One of the main causes that leads to atherosclerosis is development of an abnormal lipid profile. Typically, if your blood test shows a rise in LDL cholesterol and triglycerides and a drop in HDL levels, you are on the road to atherosclerosis. In one study, fifty-one patients with abnormal lipid profiles consumed 400 mg of pomegranate seed oil twice daily for four weeks.17 By the end of the trial, not only were their triglyceride levels lower by 62 mg/dL, but their HDL cholesterol levels had risen by more than 5 mg/dL; control patients’ beneficial HDL levels fell.

When diabetic patients with abnormal lipid profiles consumed 40 grams/day of concentrated pomegranate juice, their total and LDL cholesterol levels fell significantly, as did the ratios of those lipids to beneficial HDL cholesterol.18 Importantly, urinary markers of oxidative stress and inflammation also fell significantly in supplemented patients, but not in controls. Pomegranate seed oil, administered to patients with disturbed lipid profiles for four weeks, also significantly reduced blood triglyceride levels.17

Pomegranate extracts repair damage caused by oxidized LDL cholesterol, the main culprit in early atherosclerosis development. Oxidized LDL is highly inflammatory, and it decreases important cellular protective functions, leaving you open to blood vessel damage. For example, oxidized LDL reduces activity of protective endothelial nitric oxide synthetase (eNOS); treating cells with pomegranate juice before exposing them to oxidized LDL restores normal eNOS levels.19,20

Even people with pre-existing cardiovascular disease can benefit from supplementing with pomegranate extracts. A group of 45 patients with ischemic coronary heart disease (angina or history of heart attack) was given pomegranate juice (240 ml/day) or a placebo drink for three months.21 Subjects underwent a single-positron emission computed tomography (SPECT) scan that evaluated how well their hearts were being perfused with blood; they also performed exercise stress testing. The pomegranate-supplemented patients had a significant reduction of 0.8 points on a standardized 4-point ischemia score, while control patients saw an increase of 1.2 points.

What You Need To Know: Preserve Cardiovascular Health With Pomegranate
    Preserve Cardiovascular Health With Pomegranate
    • Cardiovascular disease remains the #1 killer of Americans, the result of lifelong exposure to oxidant stress, disordered lipid metabolism, and inflammation.
    • Your body has a natural protectant mechanism, the paraoxonases, that join with HDL cholesterol to help fight the dangerous lipid peroxidation that triggers atherosclerosis.
    • People with higher levels of serum para-oxonase 1 (PON-1) have fewer serious cardiovascular events.
    • You can boost your paraoxonase levels by supplementing with pomegranate extracts, which are more potent than juice alone at promoting cardiovascular health.
    • Pomegranate supplementation helps raise HDL and lower LDL cholesterol levels, while improving blood flow to heart muscle cells.
    • Pomegranate extracts also regulate blood sugar levels, reduce body fat mass, and prevent weight gain, thus indirectly lowering cardiovascular risk.
    • Pomegranate extracts relieve post-exercise muscle soreness and restore strength, while reducing the joint pain and limitations imposed by arthritis; together these effects promote regular exercise, still another means of reducing cardiovascular risk.
    • A whole-fruit pomegranate extract belongs in your repertoire of supplements aimed at promoting long life and strong cardio-vascular health.

When cardiac ischemia proceeds too far, heart muscle cells begin to die, causing a heart attack or myocardial infarction. Animal studies show that pre-treatment with pomegranate extracts can protect cardiac cells from death that arises from excessive adrenaline-like compounds and from damage by the potent oxidant-inducing chemotherapy drug doxorubicin.22,23 In both cases, pomegranate extracts prevented EKG abnormalities and elevation of serum markers of heart muscle injury.

Underlying heart disease and stroke is the dysfunction of your arteries’ lining layer, the endothelium. Endothelial cells are powerful regulators of blood flow, and in health they are a first line of defense against plaque formation. Under continuous assault, however, from oxidant stress and inflammation, endothelial cells begin to malfunction, losing their blood flow and pressure-regulating abilities; this change constitutes the earliest stage of atherosclerosis.24

It’s hardly surprising that PON1 activity, which reflects serum antioxidant activity, should be closely correlated with endothelial function. Studies show that as PON1 activity declines with age, endothelial function worsens, atherosclerosis increases, and the ability for the heart and brain to supply themselves with oxygen and nutrients deteriorates accordingly.24-27

Given the ability of pomegranate extracts to enhance PON1 enzyme activity in the body, one might expect that pomegranate would have favorable effects on endothelial function, thereby reducing your risk of atherosclerosis and its consequences. There’s strong evidence for just such cause and effect.28

Adolescents with metabolic syndrome represent a new and challenging group of people with obesity- and diabetes-induced endothelial dysfunction and a high risk for cardiovascular problems. A pair of studies in this population points to the potent effects of pomegranate extracts as protectors of the blood vessel lining.

Obese teens with metabolic syndrome were given pomegranate juice supplements daily for one month, and their blood levels of oxidants and inflammatory markers were followed. In addition, the overweight adolescents underwent testing of their endothelial function through measurement of their arteries’ ability to regulate blood flow. After just four hours, there was significant improvement in that measurement in the supplemented group.29 That improvement persisted after the full month of supplementation, as did significant reduction in serum markers of inflammation, another important predictor of long-term arterial function.30

These studies reveal how pomegranate extracts can improve vascular health and lower your risk for heart disease and stroke through their PON1-boosting effects.

Pomegranate extracts’ cardiovascular benefits don’t stop at early prevention of atherosclerosis. A steady thickening of vital arteries throughout the body is an indication of moderately advanced atherosclerosis. Measured by ultrasound, it is a useful measure of one’s risk for heart attack or stroke. A study of adults 45 to 74 years old with one or more major heart disease risk factors showed that consumption of pomegranate juice, 240 ml/day, for 18 months reduced progression of arterial wall thickening among patients with the highest degree of oxidative stress and the most severe disturbances in their lipid profiles.31

Thickened, plaque-ridden arteries are targets for a blood clot which is often the final event leading to a stroke or heart attack. When blood platelets stick together they form clots. Pomegranate juice, and especially whole pomegranate extract, reduce platelet “stickiness” through suppressing several different aggregation factors.32

Pomegranate Extracts Suppress Appetite, Slow Weight Gain
Pomegranate Extracts Suppress Appetite, Slow Weight Gain

Animal studies suggest that pomegranate extracts may have an important role in preventing diet-induced obesity.35 They suppress appetite in animals fed a high-fat diet and inhibit lipase, the pancreatic enzyme that helps break down fats for absorption.83 They also inhibit another enzyme, alpha-glucosidase, responsible for starch breakdown and absorption.84 This reduces after-meal glucose spikes, which are a known contributor to cardiovascular disease risk in both diabetic and non-diabetic people.84

Pomegranate Extracts Fight Diabetic Complications

Diabetes is another condition in which oxidant stress is a major factor as both a cause and a consequence.10 Compared with healthy people, diabetics have sharply lower levels of PON1, and frequently have resulting reductions in their HDL cholesterol levels; this is one cause for their high rate of cardio- vascular complications.10,13,33 In addition, diabetics are in a constant struggle against weight gain and inflammation, both of which further impair their ability to control blood sugar levels.

Pomegranate extracts offer multiple ways to battle the impact of diabetes. They increase the degree to which PON1 binds to HDL particles, enhancing their antioxidant function.13 In turn, this enhances pancreatic insulin release and reduces obesity-related insulin resistance.34,35

One means by which pomegranate extracts enhance insulin sensitivity is by suppressing secretion of resistin, the compound recently discovered to be the link between obesity and type 2 diabetes.36 Pomegranate extracts may become an essential part of the fight against obesity itself. Animals fed a high-fat diet and supplemented with pomegranate extracts show reduced total body and liver fat accumulation, along with significant reductions in body weight.35,37,38 These effects are also attributed to PPAR activation by pomegranate, as well as to other biochemical events.39 Human diabetics supplemented with pomegranate saw their weight levels plateau, rather than continuing to rise over time as did unsupplemented control patients.40

Since all of us develop some degree of insulin resistance with aging, it is worth noting a study that demonstrated improvements in age-related insulin resistance even in non-diabetic animals.41 That study also revealed a reduction in abdominal fat stores, a known cardiovascular risk factor. Just as in non-diabetic people, pomegranate extracts improve diabetics’ lipid profiles by lowering LDL and total cholesterol, while raising beneficial HDL levels.18,33 Pomegranate extracts reduce the sometimes massively elevated levels of serum oxidant markers in diabetics, increasing their cellular antioxidant systems, and markedly reducing uptake of oxidized LDL by macrophages.10 Together these effects can reduce the risk of a diabetes-related cardiovascular event.

Diabetics can realize other benefits from pomegranate supplementation as well. The extracts can prevent hypertension through reduced oxidative stress and inhibition of angiotensin-converting enzyme (ACE), which stimulates higher blood pressure.42,43 And, while learning and memory are impaired in diabetic animals, pomegranate supplementation restores cognitive performance on a maze test, an observation that has important bearing on human diabetics.44

Pomegranate Extracts Increase Your Freedom to Move

Pomegranate Extracts Increase Your Freedom to Move

Osteoarthritis and rheumatoid arthritis are two quite different conditions with a common presentation, namely joint pain, swelling, and reduction in movement. People with arthritis are substantially less likely to be able to exercise, which adds to the already elevated risk of heart attack and stroke in these populations.45-49 Fortunately, pomegranate extracts are a promising therapy for both conditions.

Osteoarthritis is the most common form of arthritis. It is caused by a steady degradation of the vital cartilage cushion that protects and lubricates joints. Animal studies now show that supplementation with pomegranate juice can prevent experimentally-induced osteoarthritis, reducing damage to cartilage.50 Other studies suggest that this effect is the result of inhibition by pomegranate polyphenols of the biochemical signaling pathways that trigger cartilage loss and inflammation.6,51

Rheumatoid arthritis carries with it an increased risk of atherosclerosis and cardiovascular diseases.48,49 People with rheumatoid arthritis have decreased levels of PON1 in their blood, limiting their ability to fight off dangerous lipid oxidation that promotes inflammation.47,52 Pomegranate’s PON1-restoring capabilities make it an appealing therapy in rheumatoid arthritis.

Animals supplemented with pomegranate extracts before induction of experimental rheumatoid arthritis have a delayed onset and lower incidence of the disease; their joints also show less severe inflammatory destruction.53 In a study of those with rheumatoid arthritis who took a pomegranate extract for 12 weeks, they showed a significant reduction in their disease activity, mainly the result of a reduction in the number of tender joints.54 These impressive results were accompanied by a significant increase in PON1 and reduction in markers of oxidation.

Additional Benefits of Pomegranate

Our growing understanding of the molecular mechanisms of action of pomegranate fruit, juice, and extracts is revealing a host of benefits in addition to those we’ve discussed. Here is a brief synopsis of some of what we are learning, and a hint of what the future will bring.

Pomegranate extracts are proving their usefulness in laboratory models of multiple forms of cancer. Thus far, cancers of the breast, lung, colon, liver, skin, and prostate have yielded in one way or another to pomegranate’s multi-targeted mechanisms of action.55-60 For example, pomegranate extracts slow cancer cell proliferation while increasing the rate at which cancer cells kill themselves through the programmed cell death process known as apoptosis.61-64 Pomegranate extracts also inhibit the rate of cancerous invasion and spread by metastasis, processes which are ultimately responsible for death in a majority of cancer patients.65,66 And, in certain sex hormone-dependent cancers such as those of the breast and prostate, pomegranate has shown its ability to inhibit both the enzymes that produce sex hormones, and the cellular receptors for those hormones on cancer cells.67-69 Finally, pomegranate extracts can sensitize breast cancer cells to the chemotherapy agent tamoxifen, potentially allowing the use of lower doses of the drug.70 Together, these capabilities may make these common and widely-feared cancers more tractable to treatment than does conventional therapy.

The most dramatic example of pomegranate’s cancer-fighting effects comes from a study of prostate cancer in humans. Men who had undergone surgery or radiation therapy for their cancers were followed to determine the rate of rise of the cancer-marking chemical called prostate-specific antigen, or PSA.71 The rate at which PSA levels double is a useful predictor of the rate of progression of the disease following treatment. At baseline, the rate of PSA doubling time was 15 months; with pomegranate supplementation that rate slowed dramatically to 54 months, a remarkable improvement.

Pomegranate has benefits related to oral health as well, specifically in controlling the dangerous dental plaque that leads to the gum disease gingivitis.72 Extracts of pomegranate kill the germs involved in plaque formation.73 Studies of pomegranate extracts used as oral rinses, or applied directly to diseased gums, show up to an 84% reduction in dental plaque organisms, a reduction in inflammatory markers in saliva, and dramatic improvements in the way the gum tissue attaches to teeth.72-76

Finally, there is a small but growing body of evidence that pomegranate extracts may be helpful in preventing or treating various disorders of the urinary and genital tracts. Animal studies suggest that the extracts enhance sperm production through their antioxidant effects.77,78 Others show protection against dangerous kidney stone development.79 And there’s encouraging evidence that the extracts can prevent prostatitis, an irritaing prostate condition that causes misery to many older men.80

Laboratory and a few human studies have now shown that pomegranate extracts kill the organism Trichomonas vaginalis, a common cause of vaginitis in reproductive-aged women.81,82 While not deadly, Trichomonas infections cause considerable annoyance and discomfort to millions of women, and conventional drug treatment is increasingly ineffective and fraught with side effects.


Many people are catching on to the substantial health benefits of the pomegranate. Unfortunately, those who are consuming only commercial pomegranate juice are missing out on many other beneficial parts of the plant, such as the leaves, flowers, and oil from the seeds. Each component of pomegranate works together synergistically to maximize its beneficial effects on your health. Pomegranate extracts increase production of the vital paraoxonase enzymes that give HDL cholesterol its good name, helping it to fight the oxidative and inflammatory damage that leads to atherosclerosis. By lowering LDL and raising HDL cholesterol, pomegranate extracts directly reduce cardiovascular disease risk. The extracts also improve insulin sensitivity and glucose control, making pomegranate a versatile nutrient to supplement with. While some people enjoy pomegranate juice, we caution that it naturally contains more fructose than desirable for most individuals. Standardized pomegranate extracts supply the beneficial polyphenols without the sugar.

If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.


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