Favorably Modulates Gene ExpressionNovember 2009
By Julius Goepp, MD
When we consume fewer calories, one proven benefit is favorable changes in the expression of our genes. Favorable changes occur when “youth genes” that promote cellular vitality are “turned on,” while “senescence genes” that rob cellular functionality are “turned off.” Resveratrol has become popular because like calorie restriction, it favorably alters gene expression in ways that have been shown to protect against age-related disease. Several years ago, researchers discovered significant health benefits in response to pomegranate ingestion. New studies show that one way pomegranate protects against cancer, atherosclerosis, type 2 diabetes, and other disorders is by inducing beneficial alterations in gene expression.
This article discusses the many mechanisms that enable pomegranate to combat degenerative disease, including its newly discovered ability to modulate gene expression.
A Multi-Pronged Approach to Preventing Atherosclerosis
Atherosclerosis (hardening of the arteries) is a leading killer of older adults. Pomegranate extracts work at every step in the deadly atherosclerosis cascade to prevent or reverse the damage, thereby extending life.1,2
Pomegranate juice contains powerful antioxidant polyphenols called ellagitannins and ellagic acid.3,4 Early animal and human studies established that pomegranate juice consumption reduces oxidative stress, low-density lipoprotein (LDL) aggregation and oxidation, and platelet clumping associated with atherosclerosis.5-8 It also inhibits a serum enzyme called angiotensin-converting enzyme (ACE) that can produce high blood pressure, helping to lower systolic blood pressure in humans.9
Another vascular-protective mechanism of pomegranate extracts is inhibition of the inflammatory actions of NF-kappaB in vascular endothelial (vessel lining) cells.10 Israeli researchers found that pomegranate wine powerfully inhibited NF-kappaB that had been activated by blood flow disruptions—a step in development of the inflammatory atherosclerotic plaque.11 Cholesterol-lowering statin drugs have also been found to down regulate inflammatory NF-kappaB. However, these medications have side effects that many people find intolerable.12,13
Pomegranate researchers later found that they could reduce carotid artery wall thickness (a major risk factor for stroke) with three years of pomegranate juice supplementation.14 Excitingly, they discovered that this effect was accompanied by lower blood pressure and reduced LDL oxidation, vividly demonstrating pomegranate’s multi-pronged approach to stroke prevention.
Pomegranate juice exerts powerful control over atherosclerosis-related genes.15 For example, disrupted blood flow (shear stress) in arteries increases expression of oxidation-sensitive genes causing endothelial damage. Pomegranate juice concentrate reduced activation of those dangerous genes in cultured human coronary artery cells exposed to shear stress and blocked progression of atherosclerosis in mice with elevated cholesterol.16,17 Pomegranate juice also markedly increases the stability and activity of the vital paraoxonase-1 (PON-1) complex in humans.18 PON-1 is a component of high-density lipoprotein (HDL) that prevents lipid oxidation.19
Its extraordinary ability to support vascular health extends even further. The vital protective cytokine called prostacyclin prevents platelet clumping and clot formation. When human aortic endothelial cells were exposed to pomegranate juice, their prostacyclin production increased by 61%, a benefit that would be expected to significantly reduce arterial clotting risk (a major cause of heart attack and stroke).20,21 And pomegranate flower extracts radically improved heart muscle metabolism of excess lipids in diabetic rats.22 Human studies confirm this benefit—concentrated pomegranate juice consumption significantly lowered total cholesterol and LDL levels—markers of cardiovascular risk.23
Nearly one-third of all cancer deaths in the United States could be prevented through appropriate dietary modification.24 Pomegranate’s broad-spectrum antioxidant and anti-inflammatory powers, plus its proven safety record, make it a natural for cancer prevention.25 Compelling evidence details how pomegranate juice and extracts prevent a variety of common cancers.
Prostate cancer is a devastating malignancy, accounting for about 25% of all the newly diagnosed cancers in American men. Although it is highly survivable when detected early, the American Cancer Society estimates that prostate cancer was responsible for more than 29,000 deaths in 2008.26-28 Pomegranate and its extracts are potent suppressors of prostate cancer at virtually every phase of its development.25 Pomegranate extracts powerfully suppressed proliferation, growth, invasion, and blood vessel formation of human prostate cancer cells in culture and when implanted in experimental animals.29-32 Pomegranate juice also helps stimulate the programmed “cellular suicide” called apoptosis that often stops incipient cancer cells from developing into full-blown tumors.33,34 Dramatic synergistic effects were discovered by Israeli researchers, who found that extracts from various parts of the whole fruit acted in concert to block prostate cancer invasion in the laboratory.35 And pomegranate juice blocks activity of carcinogen-activator enzymes called cytochrome P450 in the liver.36
A landmark human clinical trial was published by urologists at the University of California in 2006.37 This study was conducted in a challenging population, showing the true power of pomegranate. The researchers studied men who had already undergone surgery or radiation treatment, but nevertheless had rising levels of prostate-specific antigen (PSA), the serum marker of tumor growth or reoccurrence. Men drank 8 oz of pomegranate juice daily, and the researchers measured the time it took for their PSA levels to double. The longer the doubling time, the more slowly the disease was progressing and the better the quantity and quality of life.
The mean PSA doubling time increased dramatically and significantly with pomegranate supplementation, rising from 15 months before the study, to 54 months post-treatment. In other words, before supplementation these men’s PSA was doubling in less than a year and a half, while it took four and a half years to double after supplementation! Lab studies on the men’s serum showed that it could drastically cut proliferation of prostate cells in culture while radically increasing the cells’ rate of death by apoptosis.
Later studies demonstrated that, by modulating gene expression, pomegranate polyphenols down-regulated production of androgens (male hormones) and the androgen receptors that many prostate cancers need to survive and grow.38 In fact, scientists have found that pomegranate is effective at inhibiting both androgen-dependent (often early) and androgen-independent (often more advanced) cancers of the prostate.39