~ Beyond Vitamins - A Closer Look at Life Extension Mix, Part 2 - Broccoli, Apigenin, Luteolin

Broccoli: A Wealth Of Phytochemicals

Broccoli may contain more healthy nutrients than any other plant. In 1992, scientists identified a broccoli compound called sulforaphane that helps mobilize the body’s natural cancer-fighting resources and may reduce the risk of developing cancer.(54-60)

Sulforaphane has been shown to block the formation of tumors initiated by chemical carcinogens. Moreover, sulforaphane has been demonstrated to induce cancer cell death via the apoptosis (natural cell death) process.(61,62) A large amount of data shows that sulforaphane and other broccoli compounds act as cancer chemopreventive agents by favorably modifying carcinogen metabolism via modulation of both Phase 1 and Phase 2 detoxification enzyme systems.(62-66) These results suggest that broccoli compounds fight against cancer by activating detoxifying enzyme systems and inducing cancer cell apoptosis.

Phase II detoxifying enzymes, such as glutathione S-transferase, play an important role in the detoxification of chemical carcinogens. Recent studies have demonstrated that sulforaphane not only induces beneficial glutathione S-transferases but also inhibits of some major P450 enzymes that block the detoxification of organic poisons.(64,67,68)

Studies show that high human gastrointestinal tissue levels of glutathione S-transferase protect against a wide range of cancers. One study showed that a sulforaphane analog increased glutathione-S-transferase activity in all organs studied including the small intestine, liver and stomach. This study showed sulforaphane to be more potent than indole-3-carbinol in boosting beneficial glutathione S-transferase.(68)

Inhibiting DNA-adduct formation is known to reduce incidence of mammary tumor incidence. Sulforaphane was shown in one study to inhibit chemical-induced DNA adduct formation by 68% to 80%, suggesting that this extract from broccoli may function as a breast cancer fighter.(64) On the basis of mechanisms of carcinogenic effects cigarette smoke, sulforaphane appears to be a component against lung cancer.

imageBroccoli contains a high percentage of D-glucarate compared to most plants studied. As mentioned earlier in this article, D-glucarate is critical in maintaining the important glucuronidation detoxification process.

Broccoli provides a cornucopia of carotenoids and other nutrients that provide a wide range of health benefits. The new Life Extension Mix contains a super-concentrated broccoli extract that is standardized to deliver precise amounts of sulforaphane and D-glucarate in each dose.

Apigenin: A Potent Flavonoid

Apigenin is a flavonoid found in parsley, artichoke, basil, celery and other plants. Over the last three years, a large number of published studies have demonstrated the anti-cancer properties of apigenin.

To study the effects of various plant constituents, an examination was made of 21 different flavonoids on the growth of human breast cancer cells. Apigenin was shown to the most effective anti-proliferative flavonoid tested.(69) A related study showed that flavonoids such as apigenin bind to estrogen receptor sites on cell membranes in order to stop over-proliferation of these cells in response to estrogen.(70)

A study assessed the antioxidant potencies of several dietary flavonoids compared with vitamin C. Pretreatment with all flavonoids and vitamin C produced dose-dependent reductions in oxidative DNA damage. When ranked in order of potency, only apigenin, rutin and quercetin were more effective than vitamin C in reducing DNA oxidative damage.(71)

Apigenin was tested to ascertain its effect on human leukemia cells. Apigenin was shown to induce apoptosis more effectively than quercetin and other flavonoids tested. The researchers attributed a unique mechanism of inducing apoptosis to the activity of apigenin.(72) Another study showed that apigenin and another flavonoid called luteolin strongly inhibited the growth of human leukemia cells and induced these cells to differentiate.(73) Topoisomerases are involved in many aspects of leukemic cell DNA metabolism such as replication and transcription reactions. In one study, quercetin or apigenin were shown to inhibit topoisomerase-catalyzed DNA irregularities.(74) In a study of various agents used to induce differentiation of human promyelocytic leukemia cells, apigenin and luteolin were among the flavonoids shown to cause these leukemia cells to mature into healthy moncytes and macrophages.(75)

In studies against thyroid cancer cell lines, apigenin and luteolin were the most effective inhibitors found. Apigenin was shown to inhibit cancer cell signal transduction and induce apoptosis. The scientists concluded that apigenin may provide a new approach for the treatment of human anaplastic thyroid carcinoma for which no effective therapy is presently available.(76) Another study compared the effects genistein, apigenin, luteolin, chrysin and other flavonoids on human thyroid carcinoma cell lines. Among the flavonoids tested, apigenin and luteolin were shown to be the most potent inhibitors of these cancer cell lines. The scientists noted that because these thyroid cancer cells lacked an anti-estrogen receptor binding site and an estrogen receptor, that apigenin and luteolin are inhibiting these cancer cells via previously unknown mechanisms. The scientists concluded that apigenin and luteolin may represent a new class of therapeutic agents in the management of thyroid cancer.(77)

In a study on colorectal cancer cell lines, apigenin or quercitin were shown to interfere with epidermal growth factor cell stimulation. The researchers speculated that these flavonoids could be primary components in fruits and vegetables that reduce the risk colorectal cancer by inferring with the cancer cell growth signaling pathway.(78)

The epidermal growth factor signal transduction pathway is an essential component of both cancer cell growth and differentiation. Certain gelatinases are expressed in human cancers and are thought to play a critical role in tumor cell invasion and metastasis. Apigenin was shown to inhibit these gelatinases and interfere with the growth factor signaling pathways. The scientists concluded that compounds like apigenin may provide a novel means of controlling growth and invasive potential of certain tumors via these dual mechanisms.(79) In a related study, apigenin was shown to stop the degradation of tissue components by cultured human carcinoma cells, a mechanism by which cancer spreads to other parts of the body.(80)

The soy isoflavone genistein has been shown to be a potent inhibitor of cancer cell proliferation and in vitro angiogenesis. Moreover, the concentration of genistein in the urine of subjects consuming a plant-based diet is 30-fold higher than that in subjects consuming a traditional Western diet. Scientists have found in one study that apigenin and luteolin are more potent cancer inhibitors than genistein, and suggest that these plant components may contribute to the healthful effect of a plant-based diet on chronic diseases, including certain cancers. The scientists noted that the consumption of a plant-based diet may reduce the incidence and progression and growth of solid malignant tumors.(81)

Protein kinase C is over-expressed in many human tumors. One group of scientists has shown that apigenin blocks several points in the process of tumor promotion, including inhibiting kinases, reducing transcription factors and regulating cell cycle.(82) Another group of scientists showed that apigenin and other flavonoids inhibit prostate cancer cell growth by blocking tyrosine kinase activity.(83) Moreover, another study demonstrated that apigenin blocks mammary cell proliferation induced by several kinase-related pathways.(84)

The mutation and oxidation of estrogens is related to the development of certain cancers. The favorable influence of apigenin, genistein and other flavonoids on estrogen metabolism led researchers in one study to speculate that these plant extracts could be used against estrogen-related diseases.(85)

Another mechanism by which cells mutate into malignancies involves a process known as sulfation. One study showed that apigenin and ellagic acid were potent inhibitors of sulfation compared to quercetin.(86)

In a study on human promyelocytic leukemia cells, genistein, followed by apigenin and daidzein, were the most potent inhibitors of toxic free radical byproducts generated by these leukemia cells. Other flavonoids showed no effect. The scientists stated that the antioxidant effects of these flavonoids may contribute to their chemopreventive potentials against human cancers.(87)

Seven men and seven women participated in a randomized crossover trial to study the effect of intake of parsley, containing high levels of apigenin, on biomarkers for oxidative stress. This basic diet was supplemented with parsley providing 3.73-4.49 mg apigenin in one of the intervention weeks. The scientists observed increased activity of the natural antioxidants glutathione reductase and superoxide dismutase in red blood cells during intervention with parsley as compared to people taking the basic diet without added parsley.(88)

A group of scientists studied the potential preventive effects of skin tumor promotion by apigenin. When topically applied, apigenin was shown to inhibit UV-induced skin tumorigenesis in mice. The scientists observed that apigenin facilitated several tumor suppressor factors including the important p53 binding activity.(89)

Grape skin and red wine contain resveratrol, which has been shown to inhibit platelet aggregation both in vivo and in vitro. One study showed that genistein, daidzein or apigenin produced inhibitory effects against an underlying cause of abnormal platelet aggregation similar to those seen with resveratrol.(90)

In order to better understand the mechanisms by which apigenin may prevent cancer, scientists looked at the effects this flavonoid would have on new blood vessel growth. Apigenin was shown to inhibit some factors involved in the process of tumor angiogenesis (new blood vessel growth that feeds rapidly dividing cells).(91)

Many types of cancer cells use cyclooxygenase-2 (COX-2) to propagate. COX-2 inhibiting drugs are being prescribed to cancer patients to slow the growth of existing tumors. One study showed that apigenin or genistein also suppresses formation of COX-2. The scientists conducting this study suggest that apigenin and related flavonoids may be important in the prevention of cancer and inflammation, partly via their COX-2 inhibiting properties.(92)

These studies as a whole provide a basis for cancer patients to consume a diet rich in certain fruits and vegetables as an adjunctive treatment for their disease. Apigenin is an antioxidant flavonoid with chemopreventive properties. It has been shown to arrest the growth of cancer cells, with concomitant inhibition of intracellular signaling cascades and decreased oncogene expression.

The Life Extension Foundation first introduced apigenin in 1985, but was unable to find a standardized plant extract that could consistently provide a specific number of milligrams per dose. Life Extension Mix contains a plant concentrate that provides 10 to 18 mg of apigenin and apigenin 7-glucoside per daily dose. Apigenin 7-glucoside is broken down into apigenin in the small intestine where it is absorbed.

Luteolin: Another Powerful Flavonoid

Luteolin is a flavonoid found in many of the same foods that contain apigenin. While luteolin produces effects similar to apigenin, it has its own unique beneficial properties as well.

When compared to other flavonoids, only luteolin and quercetin inhibited platelet activating factor and suppressed a type of inflammatory response induced by allergens. The scientists who conducted the study concluded that luteolin could be used to develop a novel type of anti-inflammatory, anti-allergic drugs.(93)

Like apigenin, luteolin inhibits the effects of epidermal growth factor and tyrosine kinase, and therefore may have potential as an anti-cancer and anti-metastasis agent.(94) When measured against 27 citrus flavonoids, luteolin had the most potent antiproliferative activities against several tumor and normal human cell lines.(95)

The soy flavonoid genistein is a specific inhibitor of tyrosine kinase and topoisomerase II. Genistein has been specifically shown to inhibit cancer during the phase G2 of the growth cycle. In contrast, luteolin and daidzein have been shown to arrest the cancer cell growth at the G1 phase of the cycle.(96) When compared to other flavonoids, luteolin more effectively inhibited proliferation of human leukemia (CEM-C1 and CEM-C7) cells.(97)

The cancer chemotherapy drug adriamycin causes heart and bone-marrow toxicity by depleting cells of glutathione peroxidase activity. One study showed adriamycin reduced glutathione peroxidase activity levels by 73% in heart cells, but this effect was reversed by a combination of luteolin and rutin. These two flavonoids also prevented increased lipid peroxidation in bone marrow cells in response to adriamycin.(98)

A study assessed the antioxidant potencies of several dietary flavonoids compared with vitamin C. Pretreatment with all flavonoids and vitamin C produced dose-dependent reductions in oxidative DNA damage. When ranked in order of potency, luteolin was more effective than vitamin C and seven other flavonoids in reducing DNA oxidative damage.(99)

Several studies show that luteolin reduces excess estrogen formation(100) by suppressing the aromatase enzyme(101,102) and blocks the binding of estrogens to breast cell receptor sites. One study showed that administration of estrone for 11 days stimulated mammary cell proliferation and caused a nine-fold increase in the cells in G1 phase and a 48-fold increase in the cells in S phase. When luteolin was concurrently administered, estrone was blocked from binding to type II receptor sites on mammary cells. Luteolin significantly reversed the effects of estrone treatment on both proliferation and differentiation in these animals. Changes in proliferation and cell cycle kinetics have been shown to lead to genetic instability, ultimately resulting in cell transformation that can lead to cancer.(103)

Since estradiol stimulation in the rat uterus is highly correlated with cellular hypertrophy and hyperplasia, scientists assessed the effects of various flavonoids on estradiol stimulation of uterine growth in the immature rat. Luteolin or quercetin blocked estradiol stimulation in the immature rat uterus and this correlated with an inhibition of uterine growth. These studies suggest bioflavonoids may be involved in cell growth regulation.(104)

The incidences of fibrosarcoma is 100% in mice injected with a specific chemical carcinogen. When luteolin is supplemented in the diet of these mice, fibrosarcoma rates decline by 40%. The scientists stated that mode of action may be through their influence on the initiation and promotion phases of the carcinogenic process coupled with enhancement of the detoxification process.(105) When a group of plant extracts were evaluated to ascertain if they could maintain normal cell regulation, luteolin demonstrated the highest anti-proliferative activity.(106)

Flavonoids are known to protect against radiation-induced free radical damage. In a comparison study, luteolin was found to be the most effective extract in reducing radiation damage to cells. The scientists who conducted the study stated that these plant flavonoids show antioxidative potency in vitro, work as antioxidants in vivo, and their radioprotective effects may be attributed to their scavenging potency towards free radicals.(107)

How important are flavonoids in protecting against cancer? A human epidemiological study showed a 56% reduction in stomach cancer in those consuming the highest levels of flavonoids compared to the lowest. The results of this study show that the well-established protective effect of fruit and vegetables could, in part, be due to the presence of flavonoids.(108)

Life Extension Mix has the most concentrated flavonoid complex ever put into a multi-nutrient supplement and now includes a standardized ratio of luteolin.

Enhancing Glucose Metabolism

Cells require glucose for energy production. Glucose that is not absorbed by cells is eventually converted into body fat. Aging cells lose their ability to utilize insulin for the purpose of absorbing glucose. This insulin-resistance is a direct cause of type II diabetes, obesity, atherosclerosis and a host of aging-related diseases.

Some of the underlying mechanisms required by cell membranes for youthful glucose metabolism have been identified and Life Extension Mix has many nutrients to help reduce age-related insulin resistance.

An enzyme called glucokinase has a central regulatory role in glucose metabolism. Efficient glucokinase activity is required for normal glucose-stimulated insulin secretion, hepatic glucose uptake, and the appropriate suppression of hepatic glucose output and gluconeogenesis by elevated plasma glucose. Recent studies have shown that increased hepatic gluconeogenesis is the predominant contributor to high fasting blood sugar — the hallmark of type II diabetes.(109,110)

In high doses, biotin enhances beneficial glucokinase activity. Administration of high-dose biotin has improved glycemic control in several diabetic animals models, and a recent Japanese clinical study concludes that biotin can substantially lower fasting glucose in type II diabetics, without side-effects.(111-122)

Biotin is a B-complex vitamin that provides health benefits ranging from the control of blood sugar levels to the improved appearance of hair and nails. In order to improve glucose utilization in aging people, Life Extension Mix contains 3000 mcg of biotin in each daily dose. This is almost four times as much biotin as was contained earlier formulas. (The recommended dose of biotin for type II diabetics is 8000 to 9000 mcg a day.)

Chromium supplementation by type II diabetes has been shown to improve peripheral insulin sensitivity—a parameter that is unlikely to be directly influenced by biotin. Thus, the joint administration of high doses of biotin and chromium is likely to combat insulin resistance, improve beta-cell function, enhance glucose uptake by both liver and skeletal muscle, and inhibit excessive hepatic glucose production. Conceivably, this safe, convenient, nutritional regimen will constitute a definitive therapy for many type II diabetics, and may likewise be useful in the management of gestational diabetes. Biotin should also aid glycemic control in type I patients.

In a recent study, chromium picolinate was given in 600 mcg daily doses to corticosteroid patients who had developed glucose intolerance. Chromium supplementation resulted in fasting glucose levels declining from greater than 250 mg/dl to less than 150 mg/dl. Supplementation with chromium also enabled doctors to reduce the dose of anti-diabetic drugs by 50%. This study demonstrated that steroid-induced diabetes can be reversed by chromium supplementation. This is one of several new studies showing that chromium has a favorable effect on glucose metabolism.(152) Chromium improves insulin binding, insulin receptor number, insulin internalization, beta cell sensitivity and insulin receptor enzymes with overall increases in insulin sensitivity.(109,112,115,120)

Both the picolinate and polynicotinate forms of chromium can be found in Life Extension Mix. For type II diabetics seeking to use chromium to lower sugar levels, an additional 400 mcg a day of chromium is suggested.

Protecting Against Mitochondrial Aging

Massive free radical damage occurs in the cells’ energy power plants (the mitochondria), which can overwhelm the cells’ antioxidant defense systems.

Mitochondrial damage due to aging is a serious health problem in elderly people, whose energy levels decline precipitously even when they remain disease-free. N-acetyl-cysteine (NAC) has been shown to stimulate glutathione production for the purpose of providing protection against free radicals that are continuously being generated in mitochondria.122 In addition to protecting against mitochondrial free radical damage, NAC has been shown to reduce the effect of intracellular hydrogen peroxide by 93%.(123) Supplemental NAC can reduce the frequency and duration of infectious diseases.(124) NAC is used as a mucous dissolving agent in chronic bronchitis,(125-128) an antidote for liver damage induced by acetaminophen (the pain reliever),(129-131) and an inhibitor of hemorrhagic inflammation of the urinary bladder caused by tumor suppressing drugs.

Free radical damage is both a causative and contributing factor in the development of degenerative disease. Scientists are now concentrating on specific free radicals, the different part of the cell that these free radicals attack, and the types of antioxidants that are needed to provide intra- and inter-cellular protection against oxidative stress. Life Extension Mix provides antioxidants, such as NAC and taurine, to protect against differing types of free radicals both inside and outside of cells.(132,148)

Facilitating Youthful Methylation

Enzymatic and genetic activity throughout the body depends on the continuous re-methylation of DNA. The age-related breakdown of youthful methylation metabolism predisposes the body to a wide range of degenerative diseases. Maintaining healthy methylation patterns protects against DNA mutations that damage cells and can cause cancer.

Vitamin B12 works synergistically with folic acid and TMG to enhance DNA methylation and reduce toxic homocysteine in the blood. Scientific studies confirm that orally administered vitamin B-12 supplements are effectively absorbed by more than 99% of humans without gastric related diseases.(149) Vitamin B12 plays a critical role in many enzymatic processes required to maintain good health. Elderly people can suffer from severe neurological impairment if they are deficient in vitamin B12.(150-151)

Life Extension Mix contains high doses of folic acid and three different types of vitamin B12 along with a small amount of trimethylglycine (TMG).

Keep the Blood Flowing

As people grow older, their blood platelets become “sticky” and develop the propensity to clot inside blood vessels. While conventional doctors accept this as a normal consequence of aging, the scientific facts are that the risks of stroke and heart attack could be reduced dramatically by adhering to a program that inhibits abnormal platelet aggregation. Life Extension Mix contains a variety of nutrients that inhibit platelet aggregation.

Enhanced imaging techniques have confirmed that aging people suffer a significant circulatory deficits to the brain and other parts of the body. These deficits often manifest in the microcapillaries in the eyes and skin in addition to the brain. The maintenance of a youthful vascular system is mandatory for healthy neurological and cardiovascular function. Many factors affect the body’s vascular system, and the scientific community has made it clear that a lot more than cholesterol control is required to maintain youthful arterial elasticity and blood flow to all the cells of the body. Life Extension Mix contains an abundance of nutrients that have been shown to help maintain vascular perfusion throughout the body.

The leading cause of disability and death in the Western world is thrombosis (the formation of an abnormal blood clot inside a blood vessel, blocking the flow of blood). Most heart attacks and strokes are caused by thrombotic events. Many of the nutrients in Life Extension Mix have proven anti-thrombotic properties. Ginger is consumed worldwide as a spice and flavoring agent. Ginger extract possesses antioxidative and anti-inflammatory properties.(133,138) It may also be one of the most effective nutrients in thrombosis. In two studies, powdered ginger produced a significant reduction in platelet aggregation.(134,135) Other findings suggest that ginger could be an effective and inexpensive anti-emetic (preventing nausea and vomiting) for patients on cancer chemotherapy.(136) There is evidence that ginger protects against skin tumor-promotion. In a mouse study, the topical application of ginger extract protected against the genesis and spread of skin tumors.(137,138) A pharmaceutical ginger extract is included in Life Extension Mix to provide additional protection against thrombosis, inflammation and other pathological conditions. Life Extension Mix also provides flavonoids found in bilberry, grape seed and grape skin. One of the most potent natural free radical scavenger may be the proanthocyanidins found in grape seed and skin. Proanthocyanidins and other extracts from the grape have been shown to inhibit abnormal blood clotting, promote the formation of collagen in the skin, and protect against cancer.(139-141) Grape and pine bark supplements have become popular because of the many health benefits the natural flavonoids in these plants provide.

Dr. Linus Pauling’s last great work was to show that specific components in the blood called apolipoproteins are involved in atherosclerosis and aortic valve stenosis. Dr. Pauling showed that vitamin C and lysine can protect against apolipoprotein-induced vascular disease. Life Extension Mix contains the amount of lysine found in most lysine supplements. Those with valvular stenosis or atherosclerosis may want to take additional lysine.

Magnesium deficiency is a prime culprit in the epidemic of arterial disease that plagues the Western world. Foundation members have obtained high doses of magnesium ever since Life Extension Mix was introduced. Studies show that different forms of magnesium provide beneficial effects at the cellular level in addition to vascular protection. Life Extension Mix contains an advanced magnesium complex to provide magnesium to different parts of the cell.

Modulating Immune Function

The immune system has been extensively studied over the last 20 years, and scientists have shown how specific nutrients can enhance components of immune function decimated by normal aging. Life Extension Mix contains a wide variety of nutrients that have been shown to improve immune function compromised by HIV, chemotherapy and aging.

Age-related autoimmunity can create a state of chronic inflammation throughout the body. New studies relate subclinical chronic inflammatory disease to the development of senility, atherosclerosis, aortic valve stenosis, some cancers and a host of other known inflammatory diseases such as arthritis and colitis. Despite their known toxicities, non-steroidal anti-inflammatory drugs (NSAIDS) have been shown to reduce the risks of Alzheimer’s disease and several types of cancer. Life Extension Mix contains nutrients that can be taken to safely alleviate chronic inflammatory disease at the cellular level.

Nutrient deficiencies have been implicated as a causative factor in almost every disease that occurs as a consequence of aging. Zinc and selenium supplements, for instance, when given to elderly populations, significantly reduce the incidences of infectious disease.(142) One of the most important nutrients is selenium. While too much selenium can be toxic, it appears that most people take too little supplemental selenium out of concern over toxicity. Optimal supplemental selenium intake for healthy people ranges from 200 mcg to 600 mcg a day. Life Extension Mix contains two different types of selenium and zinc from two different forms of zinc to ensure maximum absorption.

Continued . . .

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