APPLE POLYPHENOLS

AND

LONGEVITY

BY GEORGE RANDALL

In the last year alone, scientists from three different laboratories have published studies that demonstrate how polyphenol molecules derived from apples extend life span in various species by as much as 12%.1 These researchers are unraveling the various mechanisms of action that give apple polyphenols such promise as anti-aging nutrients. Initial ndings show that apple polyphenols modulate multiple signaling molecules to delay the onset of age-related disorders. They may also mimic the actions of calorie restriction, a known antiaging technique. One polyphenol, phloridzin, which is heavily concentrated in the skin of the apple, also potently suppresses several processes leading to glycation, another major contributor to aging. Scientists are discovering why an apple a day may help keep the doctor away. > >

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APPLE POLYPHENOLS AND LONGEVITY

Recent Longevity Research

In three different labs, scientists conducting initial investigations found that the use of apple polyphenols increased the life span of various species by 10 to 12%.1 While these studies are just the beginning of understanding how apple polyphenols contribute to longevity, they all found remarkably consistent results, despite being conducted in three very different species. The common yeast, S. cerevisiae, is often used in laboratory experiments as a model for understanding the biology of higher organisms because of the great similarity of basic life processes.2 When scientists added the unique apple polyphenol phloridzin to yeast cells in culture, they found that treated cultures lived an average of 2.3 generations longer than control cultures.2 A closer look revealed why. When yeast cultures were treated with apple polyphenols, it toughened the cells resistance to oxidative stress, both by inhibiting production of harmful reactive oxygen species and also by ramping up gene expression of vital natural cellular antioxidant systems.2 Furthermore, the yeast cultures increased expression of sirtuins, molecules known to trigger calorie restriction-like effects in multiple tissues, contributing to longevity. Another common model of aging and longevity is the tiny worm known as C. elegans, which reproduces rapidly and succumbs to many of the same basic destructive processes as do humans. Treatment with

apple polyphenols extended the life span of natural C. elegans by 12%.1 As with the previous experiment with apple polyphenols, activation of sirtuins calorie restriction-mimicking effects was evident. Finally, apple polyphenols have been shown to extend by 10% the life span of the fruit y, D. melanogaster, another commonly-used model of human biological processes and aging.3 Once again, the explanation lies in the activation of a suite of genes that produce natural antioxidant defense systems, and decrease of genes that contribute to death in older animals. Interestingly, in these more complex organisms, apple polyphenols also partially reversed early death and mobility impairment induced by a toxin.3 Loss of mobility is a common characteristic of aging shared across all animal species, and one which is attracting great scientic interest.4 The discovery of such similar results, from three independent laboratories using three different models of biological aging, means that the results are somewhat robust and may be applicable to all living things, humans included. But these encouraging studies only scratch the surface of how apple polyphenols function on multiple levels to delay the aging process and reduce lethal degenerative diseases. The laboratory investigations discussed above do shed light on why large epidemiological studies show that people who consume polyphenols in the highest quantities are protected against conditions such as cancer, cardiovascular disease, and other conditions that are generated by oxidant stress and

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APPLE POLYPHENOLS AND LONGEVITY

inammation.5-8 For example, those who consumed the largest amounts of avonoids (found in apples and other fruits) were shown in one study to have up to a 31% reduction in total mortality.9, 10 When intake of apples specically was examined, that study showed as much as a 43% reduction in death from heart attacks specically.9

What You Need to Know

Phloridzin, A Unique Polyphenol

Apples, and especially their skins, contain many of the polyphenols found in other fruits, albeit in considerably higher concentrations.11 Apple skins also contain a polyphenol called phloridzin.12-14 Phloridzin is especially active against glycation, one of the most common, preventable, and reversible causes of aging. Phloridzin attacks glycation and its destructive effects at many different levels. For example, almost as soon as you consume a carbohydrate-containing meal that could cause a dangerous post-meal spike in blood sugar, phloridzin goes to work. Studies show that phloridzin inhibits glucose uptake by 52%.13,15 Phloridzin accomplishes this feat through two distinct mechanisms in the small intestine. First, it inhibits glucose uptake from the intestines interior into its lining cells.15 Subsequently, phloridzin blocks the active transport of glucose out of those intestinal lining cells into the bloodstream.13,15 The net effect is fewer glucose molecules leaving the intestine to contribute to blood sugar levels. Some sugar, of course, is inevitably absorbed, and is responsible for formation of the dangerous carbonyl molecules that react with proteins and DNA to form advanced glycation endproducts, or AGEs. Phloridzin prevents formation of those carbonyl compounds;16 it also traps any remaining carbonyls that are produced, preventing them from reacting with more vulnerable body molecules.14,16,17 Phloridzin also protects cells from the inside out. In type 2 diabetes, cells dont efciently take up glucose, producing dangerous blood sugar elevations that cause so much destruction. But inside certain cells, theres too little glucose, contributing to energy depletion and poor function. One consequence is cell membrane disruption that contributes to early cell death and ultimately organ dysfunction. Phloridzin protects those energy-depleted cells membranes and prevents their death, helping to preserve tissue and organ function.18 The sum of all these effects is prevention of several major causes of aging, including blood glucose elevations and lipid metabolism disturbances.13 The ultimate effect, now demonstrated in laboratory models of aging, is an extension of the life span.13-16,19

Apple Polyphenols
Aging results from accumulation of tissue damage from just a small handful of reversible causes. Oxidant stress, inammation, and glycation are among the most universal causes of aging. Polyphenols derived from apples have powerful effects on preventing and even reversing the effects of oxidation, inammation, and glycation. Apple skins contain a unique polyphenol, phloridzin, that has powerful, multi-targeted effects that mitigate damage caused by high blood sugar. These effects produce measurable results in preventing chronic, age-related conditions including cardiovascular disease, cancer, high blood sugar, and even serious infections.

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APPLE POLYPHENOLS AND LONGEVITY

Apple Polyphenols Unique Fat Management

Various types of fats not only add pounds to our body but can destroy our health by fostering degenerative diseases such cardiovascular disease, diabetes, and cancer. Getting control of how your body handles fat is an important step in reducing your risk of an early death. Apple polyphenols demonstrate remarkable capabilities of fat management, as shown by a wealth of human, animal, and laboratory studies in two distinct areas. The rst is in where and how your body stores its fat. Fat in your organs, and especially in the lining of your abdomen (known as visceral fat), is a major risk factor for cardiovascular disease, diabetes, and cancer, as part of the metabolic syndrome.20,21 Apple polyphenols have been shown to reduce visceral fat accumulations in human studies. In one study, 45 overweight or obese adults were given 600 mg/day of apple polyphenols, and their weight and body fat distribution were tracked for 12 weeks.21 In that time the control patients gained weight, while supplemented patients lost nearly a pound. Of greater importance, the apple polyphenolsupplemented patients lost about 2 square inches of visceral fat area as measured by CT scans, while control patients gained those same 2 square inches of visceral fat, and about 4 square inches of fat overall. A similarly-designed study using the same 600 mg/ day dose followed patients for 16 weeks.22 It demonstrated a 9.4 square-inch loss of visceral fat in supplemented patients, an impressive 8.9% of their baseline area.22 Meanwhile, placebo patients gained 3.3 square inches, or 3.3% of their baseline amount. Detailed animal studies demonstrate that loss of total and visceral fat can be at least in part attributed to improved fat utilization by energy-requiring tissues such as muscle, helping them to burn fat more effectively while increasing muscle strength.23, 24 The second important area of fat management has to do with how your body absorbs triglycerides and cholesterol from your diet, and in what form it transports those fats to your tissues. Animal studies show that apple polyphenols slow triglyceride absorption from the intestine by blocking pancreatic lipase, an enzyme specically required to break down triglyceride fats.25,26 Blocking pancreatic lipase causes some triglycerides to pass out of the body in the feces.27 Similar effects in humans could potentially lower total triglyceride levels.27 Apple polyphenols also block cholesterol absorption and interfere

with production of the lipoprotein carrier molecules (LDL and VLDL cholesterol) that are associated with cardiovascular risk.28,29 The effects of lowered intestinal fat absorption are lowered plasma levels of LDL, VLDL, and triglycerides (the bad fats) by as much as 70%.21,30,31Apple polyphenols also reduce the deposition of fats in organs and in the linings of arteries, where atherosclerosis gets started.30 Animals fed apple polyphenols had up to a 17% reduction in the size of atherosclerotic lesions found in their arteries.32 Apple polyphenols not only lower plasma total and LDL cholesterol, but animal studies show that they have the potential to raise HDL cholesterol levels, further protecting from atherosclerosis.31,33,34 A human study providing 1,500 mg/day of concentrated apple polyphenols demonstrated a modest rise in HDL cholesterol levels, with signicant drops in LDL cholesterol.31 One reason that HDL cholesterol is protective is that it is rich in natural antioxidant molecules known as paraoxonases. Apple polyphenols can increase paraoxonase activity by as much as 23%.35 That may explain why apple polyphenols inhibit dangerous lipid peroxidation, the inammation-generating step that initiates atherosclerosis.

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APPLE POLYPHENOLS AND LONGEVITY

Polyphenols and How They Work in Your Body

Finally, apple polyphenols lower cardiovascular risk by reducing the stickiness of platelets and vessel walls, helping blood slip more readily through arteries.36 That can prevent the formation of dangerous clots. One cautionary note: Several human studies have failed to show much benet from consumption of whole apples and even polyphenol-enriched apple juices. One study showed an elevation in triglyceride levels in men who ate whole apples daily for an extended period.37 The reasons arent entirely clear, but it is safe to say that the greatest benets have been shown with concentrated polyphenols derived from apple skins only. Polyphenols are large, complex molecules found almost exclusively in plant products. These molecules possess unique chemical characteristics that include the ability to powerfully scavenge reactive oxygen and nitrogen species, blocking oxidative damage that leads to inammation and the biological aging of tissue.77 But polyphenols are more than just free radical scavengers. Depending on the specic type and source, they also potently modulate gene expression.1,78 That means that polyphenols with unique characteristics can be chosen to address specic disease processes. Phloridzin, for example, a polyphenol found in apples, is specically targeted at glycation, the destructive modication of vital proteins by continuous exposure to glucose.17

Apple Polyphenols Prevent Colon Cancer by Multiple Mechanisms

Colorectal cancer is the second leading cause of cancer-related deaths in the United States and the third most common cancer in men and in women.38 Apple polyphenols reach the colon in large concentrations, and they show great promise in reducing the burden of this common disease.39 Indeed, large-scale epidemiological studies show that those who consume larger amounts of apple polyphenols can cut their colon cancer risk by nearly 50%.40 Apple polyphenols act by multiple mechanisms against multiple targets in the toxic environment of the colon. They reduce the substantial oxidant stress

under which colon cells must survive, and they scavenge oxygen free radicals, a potent means of reducing cellular and DNA damage.41-43 They also enhance production of natural antioxidant enzymes that colon cells use to protect themselves.44-47 Inammation typically follows oxidant damage, and is a key event in promoting colon cancer. Apple polyphenols inhibit enzyme systems known as cyclooxygenase and lipoxygenase, both of which produce

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APPLE POLYPHENOLS AND LONGEVITY

Apple Polyphenols Quench Allergic Reactions

Apple polyphenols demonstrate powerful immune modulatory characteristics, which produce convincing anti-allergy effects. Animal and basic laboratory studies show that the polyphenols block release of inammatory histamine from specialized cells in the skin and mucous membranes.79-81 They may also help to prevent development of food allergies.82 Human studies show reduction in symptoms from seasonal allergies such as runny nose and sneezing, when subjects supplement with concentrated apple polyphenols.83,84 And a study in children demonstrated a reduction in atopic dermatitis, an uncomfortable skin condition triggered by an allergic response.85

manifested by a reduction of up to 50% in so-called aberrant crypt foci, the pre-cancerous lesions often found on colonoscopy.48,62 And apple polyphenols reduce the numbers of actual pre-cancerous polyps by up to 42% and their growth rate by as much as 60% in animal models.63

Apple Polyphenols Lower Blood Glucose, Prevent Glycation Damage

Even very small blood sugar elevations, especially those immediately following a meal, are now known to be a major cause of tissue damage, even in those who are not diabetic.64 Glucose, though a vital fuel for life, has substantial toxic effects on your bodys proteins over the long haul, producing damaging advanced glycation endproducts (AGEs). Once again, apple polyphenols can help. Apple polyphenols, especially the unique molecule phloridzin, prevent uptake of glucose from the intestinal tract.15, 65 They do this by inhibiting certain specic glucose transport molecules in the intestinal lining.15,65-68 Animal studies demonstrate signicant reductions in overall blood sugar levels.13,64,69 One such study also showed that apple polyphenols completely abolished the after-meal surge of blood sugar levels thats known to be so dangerous.70

inammatory cytokines.41,43,48-51 Apple polyphenols also enhance the rate at which your normal colonic bacteria produce the anti-inammatory molecule butyrate from dangerous long-chain fats.27,52,53 Butyrate is natural protective element against colon cancer and inammatory bowel disease.54,55 Many colon cancers are triggered by ingestion of carcinogens in the diet; apple polyphenols promote expression and activity of a range of vital detoxication enzyme systems.45,56 Those systems are essential in preventing carcinogenic chemicals from further damaging cells. Oxidation, inammation, and toxins all ultimately produce damage to DNA, which is a rst step in formation of cancerous cells. Apple polyphenols show powerful protection of colon cells DNA.46,57 Even once a cancer has formed, animal studies have shown that apple polyphenols can slow or stop its growth through several mechanisms. They block the chemical receptors for a molecule called epidermal growth factor, needed by tumor cells to continue their development.58 Apple polyphenols have also been shown to reactivate tumor suppressor genes that have been switched off in cancerous cells, restoring their ability to regulate their growth safely.59 And they induce the cellular suicide mechanism called apoptosis, which is also often switched off in tumor tissues.60,61 The end result of all these actions is to reduce the out-of-control growth typical of cancerous tissue.42 In the lining of the colon, where tumors begin, this is

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APPLE POLYPHENOLS AND LONGEVITY

Apple polyphenols also act to block the formation of advanced glycation endproducts, protecting cells from their damaging effects and from the inammation that can follow.19,75 Furthermore, apple polyphenols scavenge dangerous dicarbonyl molecules that promote glycation and accelerate aging.3,14 Most Life Extension members take nutrients like carnosine, benfotiamine, and pyridoxal-5-phosphate to inhibit deadly glycation reactions, but as already described in this article, apple polyphenols have unique benecial properties that extend beyond their anti-glycation effects.

ability to promote inammation.75 These effects have the potential to prevent recurrence of the bacterial infection and its results after conventional medical treatment. Of greatest interest is the recent discovery that apple polyphenols can protect animals infected with the deadly H1N1 inuenza virus, a potential cause of death among elderly people. Stressed animals with the u died much sooner than did control animals, but those treated with apple polyphenols survived at much higher rates and lived longer.76

Summary Apple Polyphenols Boost Immunity, Fight Infection

Infections are all too often the cause of an untimely death in older people, even in todays world of antibiotics. Apple polyphenols are powerful natural antimicrobial agents, and are showing great promise in arresting some of the most threatening infections. Apple polyphenols bind to toxins produced by the bacterium Staph aureus, inactivating them and preventing their deleterious effects.71 Those effects include deadly conditions such as toxic shock syndrome and massive food poisoning, which is common.72 The polyphenols are also active against other common bacterial infections such as Pseudomonas and Bacillus species, and against so-called atypical tuberculosis infections.73, 74 The bacterium Helicobacter pylori is the cause of gastritis and stomach ulcers. Apple polyphenols inhibit not only the organisms growth, but also its ability to bind to stomach lining cells, and its Apples, and especially their skins, are among the fruits richest in the specialized molecules called polyphenols. Apple polyphenols, found in high quantities in the apples skin, exert powerful antioxidant, antiinammatory, and anti-glycation effects. Together, these effects combine to protect your body from many of the reversible consequences of aging. Compelling evidence exists for apple polyphenols ability to prevent, and even reverse changes that produce cardiovascular disease, cancer, elevated blood sugar, and even serious infections. Since health conscious people today obtain a wide range of polyphenols (such as green tea and pomegranate extracts), a daily dose of 300 mg to 600 mg of apple polyphenols may be all that is needed to obtain desired benets.
If you have any questions on the scientic content of this article, please call a Life Extension Health Advisor at 1-866-864-3027.

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APPLE POLYPHENOLS AND LONGEVITY

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