Life Extension Magazine April 2009
Life Extension Responds to Misleading Article Published in Journal of the American Medical Association
A problem facing researchers today is that by the time human clinical trials are designed, funded, and conducted over multi-year periods, the primary reason for doing the study often turns out to be obsolete.
Based on a number of favorable reports, the US government decided to spend over $114 million dollars to see if alpha toco-pherol and/or selenium supplements prevent prostate cancer.
Data collected after five years found no reduction in prostate cancer incidence in men taking these supplements.1
We have known for over 10 years that when alpha tocopherol is taken by itself, it displaces critically important gamma toco-pherol in our cells. An abundance of evidence points to the gamma tocopherol form of vitamin E as the most protective against prostate cancer.2-6
By supplementing aging men with only alpha tocopherol, scientists may have unwittingly increased these men’s prostate cancer risk by depriving prostate cells of critical gamma tocopherol. This is only a tiny part of the real story behind this flawed study.
The American Medical Association used this study to discredit vitamin E and selenium supplements. An editorial by the American Medical Association concludes by advising:
“… physicians should not recommend selenium or vitamin E— or any other antioxidant supplements—to their patients for preventing prostate cancer.”7
What follows are some succinct facts to rebut the AMA’s misleading assertions, along with more detailed discussions about what aging men need to do to reduce their risk of prostate cancer.
Alpha Tocopherol, Selenium, and Prostate Cancer: An Overview
A Journal of the American Medical Association (JAMA) report released on December 9, 2008 suggests that nutritional intervention (selenium and synthetic vitamin E) does not reduce prostate cancer risk.1
In January 2008, as part of our article “Merv Griffin’s Tragic Death from Prostate Cancer,”8 Life Extension predicted that this specific trial would fail. We also knew that this flawed study would be misused by the mainstream medical establishment to “prove” to the lay public that low-cost nutrients like vitamin E and selenium do not reduce prostate cancer risk and, by extra-polation, to impugn other low-cost, efficacious nutrients like vitamin D, fish oil, and soy as having no benefit.
In fact, Life Extension’s members were made aware of a fundamental fact eight years ago that all but guaranteed the failure of this attack against dietary supplements.
In the JAMA clinical trial, men supplemented with synthetic alpha tocopherol experienced significant gamma tocopherol depletion. Men supplemented with alpha tocopherol and alpha tocopherol plus selenium experienced a 45-49% depletion in gamma tocopherol levels by six months that was sustained during the course of this five-year trial.1
In March 2001, in an article titled “Avoiding Prostate Cancer,” Life Extension identified the phenomenon of gamma tocopherol depletion associated with excess alpha tocopherol.9
Furthermore, Life Extension identified the critical importance of gamma tocopherol supplementation in dramatically lowering the risk of developing prostate cancer—in fact, a study of 10,456 men showed that men who had the highest blood levels of gamma tocopherol were five times less likely to get prostate cancer.5
In addition, Life Extension reported in the landmark article “Eating Your Way to Prostate Cancer,”10 published in February 2007, about the importance of controlling dietary intake of arachidonic acid and the grave consequences of failing to mitigate up-regulation of the 5-lipoxygenase (5-LOX) enzyme caused by poor dietary choices.
The following article reviews what aging men really need to do to protect against today’s prostate cancer epidemic.
We know that free radical-induced damage to DNA genes can cause cancer, but oxidative stress may only be partly to blame for most prostate cancers.
While prostate cancer is not usually diagnosed until men reach older ages, it can be initiated 15-25 years prior to clinical manifestation. In fact, there is convincing evidence that the initiating DNA damage inflicted by estrogen to prostate cells can occur before a man is even born!11
Studies show that as early as the second and third trimester of life, exposure to elevated estrogens in the womb can initiate prostate cancer that may not manifest for 80 years.11-17 A man’s lifetime exposure to higher than normal estrogen may be a contributing factor to prostate cancer development. There is no evidence that antioxidants like alpha tocopherol vitamin E and selenium would protect against this kind of prostate cancer induced by prolonged excess estrogen exposure.
Please don’t feel helpless about this, as it requires more than mere initiation for cancer to fully develop. Dietary and other lifestyle factors have an enormous impact on whether men will develop prostate cancer, even if they are genetically predisposed.
The Cause of All Cancers
Cancer can be defined in one sentence as follows:
“Cancer is the accumulation of mutations in genes that regulate cellular proliferation.”18
All cancers are caused by gene mutations. Every time a cell divides, there are slight mutations to one’s genes. Oxidative stress accelerates gene mutation, but is by no means the primary factor. While selenium and vitamin E reduce some types of oxidative stress, the aged men in the study published by the American Medical Association1 had already sustained considerable genetic mutations that are not reversible by taking antioxidants.
Fortunately, there are nutrients that have been shown to favorably reverse the gene alterations involved in cancer initiation and progression. The most promising is vitamin D, which has been shown to cut prostate cancer risks in half.19 Serum levels of vitamin D were not assessed in the study used to bash vitamin E-selenium, so it was not possible to know which men had protective levels of vitamin D and those who had insufficient or even deficient levels. If men in the placebo group had even slightly higher vitamin D status, they would have been less likely to contract prostate cancer.
Failure to test for vitamin D status is not the fault of the researchers conducting this study. When the study was designed, it was not known that vitamin D conferred such a strong protective effect against prostate and other cancers.
The fundamental issue here is that we cannot expect to suppress the fires of oxidative stress (with nutrients like alpha tocopherol-selenium) and then see seven decades of genetic damage magically reverse itself.
Eating Your Way to Prostate Cancer
Cancer cells lurk in the prostate glands of most aging men, yet only one in six men are ever diagnosed with prostate cancer. If one looks at what is required for a single cancer cell to develop into a detectable tumor, it becomes obvious that natural barriers exist to protect people against full-blown cancer.
Unfortunately, the dietary choices of most men living in the modern Western world circumvent the body’s natural protective barriers. The end result is that most men unwittingly provide biological fuel for existing prostate cancer cells to propagate and metastasize.
Fortunately, an understanding of the biological roles of diet and specific nutrients can enable aging men to achieve a considerable amount of control over whether isolated cancer cells in their prostate gland will ever show up as a clinically diagnosed disease.
The impact of the food we ingest on cell growth and death is so pronounced that it can be identical to the effects displayed by anticancer drugs. As it relates to the study showing that alpha tocopherol-selenium did not prevent prostate cancer, if the study participants’ diet was not taken into consideration, then the findings would be so severely skewed as to have no meaning. Read on to see what we mean.
Omega-3 Fatty Acids: The First Line of Defense
Diets high in omega-6 fats and saturated fats are associated with greater prostate cancer risk, whereas increased intake of omega-3 fats from fish has been shown to reduce risk. Based on consistent epidemio-logical findings across a wide range of human populations, scientists have sought to understand why eating the wrong kinds of fat (saturated and omega-6 fats) provokes a stimulatory effect on prostate cancer.20,21
To ascertain what happens after we eat bad fats, all one has to do is look at the metabolic breakdown pathways that these fats follow in the body, as shown in the chart on the next page (Figure 1 to the right). For example, let us assume that for dinner, you eat a steak (a source of saturated fat) and a salad, along with a typical salad dressing of soybean and/or safflower oils (sources of omega-6 fats).
As can be seen in the (Figure 1 to the right) flow chart, saturated and omega-6 fats convert to arachidonic acid in the body. The meat itself contains arachidonic acid. One way that the body rids itself of excess arachidonic acid is provoking a dangerous metabolizing pathway through 5-lipoxygenase (5-LOX). New studies show conclusively that 5-LOX products directly stimulate prostate cancer cell proliferation via several well-defined mechanisms.22-28 Arachidonic acid is metabolized by 5-LOX to 5-hydroxyeicosatetraeonic acid (5-HETE), a potent survival factor that prostate cancer cells use to escape destruction.24,29,30
(Figure 1 to the right) clearly demonstrates how consuming a diet of foods rich in arachidonic acid directly provokes the production of dangerous 5-LOX products, which can promote the progression of prostate cancer. In addition to 5-HETE, 5-LOX also metabolizes arachidonic acid to leukotriene B4, a potent proinflammatory agent that causes destructive reactions throughout the body and inflicts severe damage to the arterial wall.31-37
One reason that fish oil supplements have become so popular is that their beneficial EPA/DHA fatty acids can help reduce the production of arachidonic acid-derived eicosanoids in the body.38-43 As shown in (Figure 1 above), if arachidonic acid levels are reduced, there would be a corresponding suppression of the 5-LOX products 5-HETE and leukotriene B4.
Once one understands the lethal 5-LOX cascades, it is easy to see why people who excessively consume foods rich in arachidonic acid, and those who do not reduce the production of excessive arachidonic acid metabolites, are setting themselves up for prostate cancer and a host of inflammatory diseases (including atherosclerosis).
Men in the AMA-published study who took alpha tocopherol-selenium supplements, but consumed foods high in arachidonic acid and not enough omega-3s were more likely to develop prostate cancer. The researchers who designed this study might not have known to correct for this confounding factor when the study was designed.
5-LOX Is Over-Expressed in Prostate Cancer
Based on studies showing that consumption of foods rich in arachidonic acid is greatest in regions with high incidences of prostate cancer,22,23,27,44 scientists sought to determine how much of the 5-LOX enzyme is present in malignant versus benign prostate tissues.45
Using biopsy samples taken from living human patients, the researchers found that 5-LOX mRNA levels were an astounding six-fold greater in malignant prostate tissues compared with benign tissues. This study also found that levels of 5-HETE were 2.2-fold greater in malignant versus benign prostate tissues.45 The scientists concluded this study by stating that selective inhibitors of 5-LOX may be useful in the prevention or treatment of patients with prostate cancer.
5-LOX Promotes Tumor Growth Factors
As the evidence mounts that ingesting “bad fats” increases prostate cancer risk, scientists are evaluating the effects of 5-LOX on various growth factors involved in the progression, angiogenesis, and metastasis of cancer cells.
One study found that 5-LOX activity is required to stimulate prostate cancer cell growth by epidermal growth factor (EGF) and other cancer cell proliferating factors produced in the body. When 5-LOX levels were reduced, the cancer cell stimulatory effect of EGF and other growth factors was diminished.22
In a mouse study, an increase in 5-LOX resulted in a corresponding increase in vascular endothelial growth factor (VEGF), a key growth factor that tumor cells use to stimulate new blood vessel formation (angiogenesis) into the tumor. 5-Lipoxygenase inhibitors were shown to reduce tumor angiogenesis along with a host of other growth factors.46 In both androgen-dependent and androgen-independent human prostate cancer cell lines, the inhibition of 5-LOX has consistently been shown to induce rapid and massive apoptosis (cancer cell destruction).23,44, 47,48
Nutrients That Suppress 5-LOX
Health-conscious people already take nutrients like fish oil that help to lower 5-LOX activity in the body.49,50 Studies show that lycopene and saw palmetto extract also help to suppress 5-LOX.51,52 The suppression of 5-LOX by these nutrients may partially account for their favorable effects on the prostate gland.
As humans age, however, chronic inflammatory processes can cause the over-expression of 5-LOX in the body. For maturing males, the result of excess 5-LOX may be the epidemic of prostate cancer observed after the age of 60.
Based on the cumulative knowledge that 5-LOX products can promote the invasion and metastasis of prostate cancer cells, it would appear advantageous to take aggressive steps to suppress this lethal enzyme. The good news is that a natural 5-LOX inhibitor is included in a popular formula used to maintain healthy prostate function.
In addition to potentially suppressing prostate cancer, the successful inhibition of 5-LOX should also slow the progression of atherosclerosis.53
5-LOXIN®: Nature’s 5-LOX Inhibitor
Specific extracts from the Boswellia plant selectively inhibit 5-lipoxygenase (5-LOX).54,55 This is not surprising when one considers that various boswellia extracts have been used for centuries in India as anti-inflammatory agents.56
In several well-controlled human studies, boswellia has been shown to be effective in alleviating various chronic inflammatory disorders.57-61 Scientists have discovered that the specific constituent in boswellia responsible for suppressing 5-LOX is AKBA (3-O-acetyl-11-keto-B-boswellic acid). Boswellia-derived AKBA binds directly to 5-LOX and inhibits its activity.55 Other boswellic acids only partially and incompletely inhibit 5-LOX.55,62
Methods to extract high concentrations of AKBA from boswellia have been intensively investigated due to AKBA’s potential in treating chronic inflammatory disorders. Even in standardized boswellia extracts, however, biologically active AKBA makes up only 2-5% of the final product.
Several years ago, researchers discovered how to obtain an economically viable boswellia extract standardized to contain a greater than 30% concentration of AKBA. This 30% AKBA extraction discovery was patented and given the trademark name “5-LOXIN®.” When tested against the best commercial boswellia compounds, 5-LOXIN® exhibited better inhibitory action against 5-LOX.63,64
5-LOXIN® Decreases Inflammation, Invasive Potential, Tumor Cell Adhesiveness, and Angiogenesis
A rat study was conducted to evaluate the efficacy of 5-LOXIN® compared with the popular anti-inflammatory drug ibuprofen. 5-LOXIN® reduced inflammation by 27% compared with 35% for ibuprofen.63 Another rat study compared 5-LOXIN® with the anti-inflammatory steroid drug prednisolone. 5-LOXIN® reduced inflammation by 55%, which was similar to the reduction by prednisolone used in this study.64 The significance of these findings is that prednisolone and ibuprofen can be toxic when used chronically, whereas natural 5-LOXIN® is free from side effects.
Ibuprofen has demonstrated anticancer effects, most probably due to its inhibition of COX-2, another enzyme that cancer cells use to facilitate their growth and survival. As you have just learned, 5-LOXIN® functions to block the 5-LOX enzyme. Since the effects of 5-LOXIN® and ibuprofen may be either additive or synergistic, a clinical trial of a combination of these agents is warranted.
Tumor necrosis factor-alpha (TNF-alpha) is a dangerous proinflammatory cytokine that often increases in aging people. In a gene-chip study, 5-LOXIN® blocked the expression of many genes that are sensitive to the pathological effects of TNF-alpha.63,64
From the standpoint of keeping prostate cancer cells in check, 5-LOXIN® was shown to prevent the TNF-alpha-induced expression of a protein-degrading enzyme called matrix metalloproteinase (MMP).64 Cancer cells use the MMP enzyme to tear apart natural barriers in the body that would normally encase them.115 Prostate cancer cells are notorious for inducing the production of this enzyme that causes containment structures within the prostate gland to vanish, thus enabling the mutated (cancerous) prostate cells to break through healthy prostate tissue and eventually metastasize.
Prostate cancer cells use adhesion molecules (known as VCAM-1 and ICAM-1) to facilitate their spread throughout the body. 5-LOXIN® was shown to prevent the up-regulation of these adhesion molecules, which are directly involved in inflam-matory processes.64 Chronic inflammation is tightly linked to the induction of aberrant angiogenesis used by cancer cells to facilitate the growth of new blood vessels (angiogenesis) into tumors.
In the JAMA study used to discredit alpha tocopherol-selenium, the use of aspirin or ibuprofen by the placebo group may have reduced the prostate cancer risk more than what could be expected in those receiving alpha tocopherol and selenium.