Life Extension Magazine®

A Novel Method to Protect Your Aging Arteries

An 86-year-old member who successfully reversed some serious medical conditions wrote me an interesting letter. He asked, since you helped correct my health problems and I am in good shape now…how will I die?

Scientifically reviewed by Dr. Gary Gonzalez, MD, in October 2024. Written by: William Faloon.

An 86-year-old member who successfully reversed some serious medical conditions wrote me an interesting letter. He asked, since you helped correct my health problems and I am in good shape now…how will I die?

This is a difficult question, but based on this member’s age and medical history, I predicted that he would most likely succumb to a vascular disease, be it a stroke or heart attack.

I told this member that if the nutrients he was taking worked for him the same way they did in the clinical trials, then it might be possible to restore healthy endothelial (inner arterial wall) function, and thus avoid these vascular catastrophes.

Recent findings show that certain plant extracts reverse clinical measurements of atherosclerosis. However, we still don’t know how long we can delay the endothelial dysfunction that causes so many aged humans to perish from blood vessel diseases.

Fortunately, nutritional scientists have uncovered a new way to counteract circulatory breakdown. We have thus scored another victory that provides an opportunity to postpone what mainstream doctors believe is an inevitable consequence of growing old.

I am pleased to report that this novel plant extract has been added to formulas that most Life Extension members already use on a daily basis.

One would think a scientific breakthrough that could drastically reduce the incidence of arterial disease would be recognized by physicians who treat vulnerable patients each day. After all, vascular disorders are by far the leading causes of disability and death in the Western world.

The harsh reality is that today’s medical practice is governed by economic, rather than scientific principles. Hurried doctors are bombarded with pharmaceutical promotions and seldom have the time to review the medical literature. The public is victimized by endless advertisements that make it appear that they can protect themselves against vascular disease if only they take the proper prescription drugs.

What has been sadly overlooked is a plethora of published scientific findings showing that the ingestion of certain foods and/or food extracts could slash the numbers of human beings who suffer and die from circulatory breakdown.1-4

Normal aging causes arterial damage

Even when conventional risk factors such as high cholesterol and blood pressure are kept within normal ranges, the aging process itself inflicts severe damage to our arteries.

The endothelium is the inner lining of our arteries. It comes in direct contact with toxic blood constituents such as oxidized LDL and triglycerides. The reason for today’s epidemic of atherosclerosis is the breakdown of endothelial function and structure. Most heart attacks and strokes are caused by atherosclerosis that restricts blood flow through our arteries.

Based on this wealth of scientific data, if aging humans are to gain long-term protection against vascular diseases, they must maintain healthy endothelial function (and structure).

Younger people can protect their endothelium by eating a healthy diet, exercising, taking dietary supplements, and using prescription drugs (if tests indicate drugs are needed). Despite these sensible interventions, harmful changes still occur in the endothelial lining of arteries, especially as humans mature past 70.

The encouraging news is that documented methods have been developed to help correct the underlying reason why arteries become occluded as people reach the later stages of their lives.

How most heart attacks and strokes occur

The two prime factors involved in occlusive arterial disease are abnormal platelet activation and endothelial dysfunction. When the endothelium is not functioning properly, our platelets (blood-clotting cells) become dangerously over-activated. This can cause a sudden arterial blood clot, or contribute to progression of atherosclerosis by stimulating inflammation.

A primary mechanism involved in endothelial dysfunction is the depletion of nitric oxide, often caused from the oxidation of LDL and other blood components. Nitric oxide is produced by endothelial cells. It regulates vascular elasticity, maintains cardiac contraction, prevents vessel injury, and helps protect against atherosclerosis.5-8

As humans age, endothelial function becomes altered. Due to a variety of insults, a depletion of nitric oxide occurs in the endothelium. One consequence of nitric oxide depletion is the inability of arteries to expand and contract with youthful elasticity. The continual stiffening and occlusion of aged arteries is the number one health risk that people in Western societies face.9-14 In order to maintain healthy arterial dilation, the endothelium has to manufacture enough nitric oxide. Impairment in nitric oxide release by the aging endothelium causes arterial dysfunction.15, 16

The band-aid therapies used by today’s mainstream cardiologists (aspirin, statin, and certain anti-hypertensive drugs) do have a beneficial effect on the endothelium, but they may only postpone a serious vascular event. If a person lives long enough, the chronic depletion of endothelial nitric oxide results in impairment of arterial function and progressive restriction of blood flow to vital parts of the body.

Why Some Elderly People Need More Than a Statin Drug

Did you know that popular “statin” drugs used to reduce LDL and cholesterol often lose their ability to protect against vascular disease as people age?17-19 The reason is simple. Aging arteries are subjected to more destructive forces than blood vessels of young people.

Statins have shown beneficial effects to the endothelium in addition to reducing cholesterol and LDL. As we age, however, we must go beyond basic therapies (such as statin drugs) that may have protected us in younger years.

Prevention of the epidemic of stroke and heart disease in the elderly requires that we aggressively counteract the underlying causes of endothelial dysfunction.

Some people require the proper dose of statin drug to control excess cholesterol-LDL, but all aging humans need to take assertive actions to protect their precious endothelium against the functional and structural distortions that lead to arterial occlusion.

Measuring endothelial function in humans

The most accepted way to evaluate endothelial function is to measure the blood flow-induced dilation and contraction of the brachial artery. The brachial artery runs from the shoulder down to the elbow. The flow mediated dilation test uses a highly sensitive ultrasound to assess how blood is flowing through this artery.

A carefully controlled study was conducted on male smokers to evaluate the effects of ingesting chocolate on endothelial function and platelet activation. Based on the mechanisms by which cigarette smoking damages the endothelium, smokers serve as an ideal model to identify agents that will protect against age-related vascular disease.20

Half the group received cocoa-standardized dark chocolate while the other half received white chocolate. The cocoa used to make dark chocolate contains unique polyphenols that have demonstrated impressive results in human clinical trials. White chocolate is devoid of these polyphenols.20

The results of this study showed a significant improvement in flow mediated dilation in the dark chocolate group, but no change in the white chocolate group. Compared to baseline, flow mediated dilation improved by 37% in the dark chocolate group and this beneficial effect persisted for about eight hours.20

Dangerous platelet activation was reduced by 36% two hours after ingestion of the dark chocolate, but no effect was observed for the white chocolate group of men.20

This study documented that dark chocolate induced a rapid and significant improvement in endothelial and platelet function. As you may recall, it is the lethal combination of endothelial dysfunction and platelet over-activation that causes most heart attacks and strokes.20

The authors of this study noted that the unique polyphenols found in dark chocolate protect against the inactivation of nitric oxide, thus rapidly reversing a key measurement of endothelial dysfunction in humans.

A second human study using a standardized cocoa polyphenol beverage corroborated these findings. The results showed significant improvement in flow mediated dilation and blood markers of endothelial function. The doctors who conducted this second study stated:

“Therefore, ingested flavonoids may reverse endothelial dysfunction through enhancement of nitric oxide bioactivity.” 21

(Note: Two mechanisms by which polyphenols protect nitric oxide are to inhibit its oxidative conversion to the dangerous free radical peroxynitrite and to increase the enzymatic activity needed to produce nitric oxide, from L-arginine.)

Cocoa reduces insulin resistance and blood pressure in humans

Insulin resistance causes impairment of vascular nitric oxide and creates endothelial dysfunction that then contributes to hypertension. By increasing nitric oxide, one has the potential to improve endothelial function, decrease blood pressure, and slow down atherosclerotic processes.22

A 15-day study was done on hypertensive human volunteers to evaluate the effects of eating polyphenol-assayed dark chocolate or a white chocolate on various circulatory measurements. Hypertensive patients who ingested the dark chocolate showed an 11-point (mmHg) reduction in systolic blood pressure and a 6.2-point (mmHg) decrease in diastolic pressure. The participants consuming white chocolate showed no change in blood pressure.22

The researchers then looked at measurements of insulin sensitivity in these hypertensive patients. After 15 days of dark chocolate consumption, fasting insulin levels declined by 29%, along with a 6% reduction in fasting glucose. This sharp reduction in excess fasting insulin without an increase in glucose indicates that dark chocolate polyphenols quickly improved insulin sensitivity in these study subjects. No improvements were seen in the group consuming the white chocolate.22

Insulin resistance is defined as a decreased cell sensitivity and/or responsiveness to metabolic actions of insulin. The pancreas responds to insulin resistance by secreting more insulin in an attempt to compensate for the cell’s inability to efficiently utilize insulin.  Elevated fasting insulin is commonly seen in obese patients and those suffering from metabolic syndrome, type II diabetes, and vascular disease. A decrease in fasting insulin, as was seen in the group ingesting the cocoa polyphenols, indicates an improvement in systemic insulin sensitivity.

When the flow mediated dilation test was done to assess endothelial function, hypertensive subjects who ingested the dark chocolate saw an improvement to almost normal. Flow mediated dilation improvements were not seen in the white chocolate group.22

This 15-day study showed that dark chocolate decreased daytime and nighttime blood pressure, reduced insulin resistance, and improved endothelial function (as measured by enhanced arterial relaxation and blood flow).22

A second study corroborated these findings when evaluating the effects of dark chocolate on healthy people. The results showed a remarkable 45% reduction in insulin resistance and a reduction in systolic blood pressure within normal values. The researchers who conducted the second study concluded by stating:

“Dark, but not white, chocolate decreases blood pressure and improves insulin sensitivity in healthy persons.” 22

HEALTH BENEFITS OF COCOA POLYPHENOLS

Improve Blood Flow via Vasodilation

  • Lowers blood pressure
  • Lowers vascular cell adhesion molecule (VCAM)
  • Increases circulating Nitric Oxide

May Reduce Overall Mortality

  • 15-year Amsterdam study showed inverse relation between cocoa intake and cardiovascular death and all-cause mortality

Antioxidant

  • Third highest daily source of antioxidants in U.S. diet
  • Epicatechin inhibits plasma lipid oxidation because it can bind to LDL
  • Animal model using cocoa powder inhibited atherosclerosis, lowered TC, LDL and TG, raised HDL, and inhibited LDL oxidation

Reduce Platelet Aggregation

  • Modest effect on platelet aggregation when cocoa polyphenols were used in a powder form, but additive effects when combined with 81 mg aspirin

Improve Insulin Sensitivity

  • Decrease in fasting insulin seen in study subjects taking cocoa polyphenols

Cognitive Performance

  • Increased blood flow to gray matter

Toxic effects of overeating

Eating too many calories creates a dangerous state in which the bloodstream is overloaded with fat and/or sugars long after a meal is consumed. Since most people tend to overeat, they suffer from postprandial (after meal) endothelial disorders throughout most of the day.

When the blood is overloaded with fats/sugars for sustained periods, a condition known as “postprandial oxidative stress” ensues that damages the endothelium and is associated with a higher risk of atherosclerosis, obesity, and diabetes.

Scientists addressed the issue of “postprandial oxidative stress” and stated that one could mitigate the dangers by consuming polyphenols from wine, cocoa, or tea during the meal. According to these researchers, polyphenols “improve endothelial dysfunction and lower the susceptibility of LDL lipids to oxidation.” 23

These researchers attributed the benefits of polyphenols not solely to their antioxidant capacity, but also to their ability to modulate signaling molecules involved in maintaining endothelial function.23

These findings help explain why consuming a glass of red wine with a heavy meal protects against vascular disease. Since it is not practical for most people to consume red wine with every meal, consuming polyphenols from tea or chocolate during a meal would appear to be an optimal strategy to benefit from their endothelial-protecting properties.

Polyphenols in cocoa improve lipid levels

A consistent finding amongst human clinical trials is that ingestion of cocoa polyphenols modestly lowers dangerous LDL, and in some cases, significantly boosts beneficial HDL. One challenge in protecting against atherosclerosis in aging people is that their HDL levels often decline.24-27

People with high levels of HDL have low vascular disease rates. Several years ago, a major American drug company spent about $1 billion for a synthetic compound that boosted HDL. The side effect of this drug unfortunately was increased mortality and the human studies were halted. Ingestion of plant polyphenols, on the other hand, results in decreased risks of a wide range of degenerative diseases.

In a human study conducted this year, those receiving cocoa polyphenols showed an astounding 24% increase in HDL levels after twelve weeks compar-ed to only 5% in the placebo group. The cocoa polyphenol group also showed a reduced measurement of markers of oxidative stress in the body by 24%, while a measurement of LDL oxidation was lowered by 9%. The placebo group did not show improvement.28

A second human study showed that after only three weeks of consuming dark chocolate, test subjects showed an 11.4% increase in HDL levels. In the group receiving dark chocolate enriched with cocoa polyphenols, a 13.7% increase in artery-protecting HDL was observed. The white chocolate group did not show these beneficial increases in HDL, but all three groups did show a decrease of LDL oxidation by 11.9%.26

A decrease in LDL oxidation rates is a consistent finding in those who ingest cocoa polyphenols. It is the oxidation of LDL that enables this lipid to play such a significant role in the atherosclerosis process.

Very few compounds increase bene-ficial HDL. Up until now, the most effective way of boosting this artery-protecting lipid has been to use relatively high doses of niacin. The unpleasant “niacin flush” precludes most people from taking this vitamin in high enough doses. The favorable effect on HDL shown in recent studies indicates that it might be possible to tolerably increase endothelial-protecting HDL by ingesting dark chocolate and/or standardized cocoa polyphenol supplements.

Even “Normal” Blood Pressure Is Dangerously Too High

Hypertension is usually clinically defined when systolic blood pressure greater than 140 (mmHg) and diastolic pressure readings greater than 90 are found. Most doctors still consider 120/80 as normal and acceptable. A considerable amount of data reveals that keeping blood pressure below 120/80 will slash vascular disease risk. A reasonable blood pressure goal for most people in Western societies is about 115/75 mmHg.

For diabetics, achieving blood pressure levels of 115/75 mmHg or less may be particularly important to reduce the risk of progression of diabetic kidney disease to kidney failure. All aging humans benefit in the long run by maintaining a low normal blood pressure reading.

One study showed that just a slight lowering of blood pressure (from 129/78 to 124/76) led to significant reductions in arterial plaque growth, heart attack, death, and hospitalization.29

Doctors are often shocked when they learn this, having been accustomed to not diagnosing hypertension until readings of 140/90 and higher are found. To remind ourselves of what truly optimal blood pressure should be, we need only look at blood pressure levels in cultures that lack access to processed foods and engage in physical activity much of the day. People in these cultures, who rarely suffer from cardiovascular disease, have blood pressures of around 90/60 mmHg.30

A study published in the July 4, 2007, issue of the Journal of the American Medical Association (JAMA) looked at the effect of ingesting small quantities (30 mg a day) of standardized dark chocolate polyphenols compared to white chocolate.31

This 18-week study sought to ascertain if this low dose of chocolate polyphenols would reduce blood pressure and improve blood markers of endothelial dysfunction in people with untreated pre-hypertension. These individuals had blood pressure readings ranging from 130/85 to 139/89.31

The results showed that in the group receiving the dark chocolate polyphenols, hypertension prevalence declined by 20%, average blood pressure fell slightly, and blood markers of endothelial function showed sustained improvement. There were no changes in the white chocolate group.31

The magnitude of the blood pressure reductions was small (systolic declined by 2.9 and diastolic by 1.9 mmHg) in the group consuming the low doses (30 mg/day) of dark chocolate polyphenols. As the researchers pointed out, however, even these tiny reductions in blood pressure would result in lower incidences of stroke, heart attack, and all-cause mortality. More significant blood pressure reductions have been found in studies using 88 mg and greater of dark chocolate polyphenols.31

Suppressing inflammatory factors

Aging is characterized by a chronic inflammatory state that is an underlying cause of most degenerative disorders. One of the most dangerous inflammatory-inducers to the vascular system is the leukotrienes that are formed in response to excess levels of the lipooxygenase enzymes and arachidonic acid.32-40 Poor dietary choices such as over-consumption of omega-6 fats and red meat are why so many people suffer the consequences of excess leukotrienes.

The polyphenols in chocolate have been shown to reduce lipooxygenase enzymes and their pro-inflammatory byproducts (such as leukotrienes) that are so toxic to the endothelium and normal cell proliferating processes.21, 41

Epidemiological studies show that increased intake of polyphenols is associated with a reduced risk of major cardiac events. The ability of cocoa polyphenols to support endothelial function by maintaining healthy nitric oxide levels is the primary protective mechanism. The secondary benefit of suppressing dangerous inflammatory factors is another mechanism by which cocoa polyphenols may reduce cardiovascular risks.

How many cocoa polyphenols do we need?

The amount of polyphenol-containing cocoa used to make dark chocolate bars varies widely, making it difficult to obtain a consistent polyphenol dose from commercial candy products. The major problem with typical chocolate candy bars, however, is that they contain hundreds of fat and sugar calories. Intentionally adding chocolate candy to a diet already too high in calories could create as many health problems as the cocoa polyphenols help prevent.

Remember, the studies documenting the remarkable benefits of chocolate-cocoa polyphenols were relatively short term, and often used polyphenol standardized products rather than commercial, sugar-laden chocolate bars.

The encouraging news is that there are now cocoa standardized polyphenol products that are free of sugar and excess fat. Low-cost cocoa polyphenol-standardized supplements are also available.

Since Life Extension members already consume a lot of plant polyphenols (from pomegranate, green tea, blueberry, etc.), their minimum recommended intake of chocolate-cocoa polyphenols is 30 mg a day. The optimal dose of chocolate-cocoa polyphenols may be 100-130 mg a day.

Tying it all together

Arteries are the blood vessels that bear the full force of each heartbeat. Laypeople often think of arteries as flexible tubes whose only function is to carry blood that flows continuously throughout the body. In reality, arteries are dynamic, functioning muscular structures that in good health expand and contract to facilitate circulation and maintain optimal blood pressure.

Endothelial cells line the arteries, veins, arterioles, and capillaries of the vascular system. Twenty-two years ago, the endothelium was seen as a relatively inert structure that played no active role in vascular function. Since then, research has shown that the endothelium is dynamic and participates in vital aspects of arterial structure and function.42

Over the past year, Life Extension has reported on two major breakthroughs related to protecting the endothelium against age-related deterioration. The first was the remarkable ability of pomegranate to reverse clinical measurements of systemic atherosclerosis (in both carotid and coronary arteries).

The second was the finding that an SOD-enhancing nutrient (GliSODin®) also reversed a measurement of systemic atherosclerosis (as measured by carotid ultrasound).

The problem is that atherosclerosis remains the number-one cause of death and disability in the United States. Since Life Extension members take extraordinary steps to protect against atherosclerosis (and other degenerative disorders), they often find themselves reaching the outer limits of what the healthy human life span is supposed to encompass.

A typical 50-year-old human with atherosclerotic risk factors can follow relatively simple steps (such as taking fish oil, low-dose aspirin, and a statin drug if needed) to postpone a major cardiovascular event. When that same person reaches their 70s, however, the multiple lifelong pathological processes involved in endothelial dysfunction too often manifest in the form of a vascular-related disorder.

As you have learned, the endothelial cells that line blood vessels are crucial to maintaining vascular integrity. Endothelial dysfunction is a critical factor in the initiation and progression of cardiovascular disease.

Based on compelling evidence that cocoa polyphenols confer unique protective and restorative benefits to the endothelium, members should make sure that cocoa polyphenols are included as part of their daily health-promoting program.

References

1. Szponar L, Respondek W. [The role of nutrition in the development of circulatory system diseases] Wiad Lek. 1994 Oct;47(19-20):771-8. Review. Polish.

2. Sinatra ST, DeMarco J. Free radicals, oxidative stress, oxidized low density lipoprotein (LDL), and the heart: antioxidants and other strategies to limit cardiovascular damage. Conn Med. 1995 Oct;59(10):579-88.

3. Martyka Z, Kotela I, Blady-Kotela A. [Clinical use of magnesium] Przegl Lek. 1996;53(3):155-8. Review. Polish.

4. Grzegorczyk K, Rutkowski M, Drozda R. [Vitamin C in treatment of certain cardiovascular diseases] Pol Merkur Lekarski. 2001 Feb;10(56):122-5.

5. Rubio AR, Morales-Segura MA. Nitric oxide, an iceberg in cardiovascular physiology: far beyond vessel tone control. Arch Med Res. 2004 Jan-Feb;35(1):1-11.

6. Shaw CA, Taylor EL, Megson IL, Rossi AG. Nitric oxide and the resolution of inflammation: implications for atherosclerosis. Mem Inst Oswaldo Cruz. 2005 Mar;100 Suppl 1:67-71.

7. Shaul PW. Endothelial nitric oxide synthase, caveolae and the development of atherosclerosis. J Physiol. 2003 Feb 15;547(Pt 1):21-33.

8. Takimoto E, Champion HC, Li M, Ren S, et al. Oxidant stress from nitric oxide synthase-3 uncoupling stimulates cardiac pathologic remodeling from chronic pressure load. J Clin Invest. 2005 May;115(5):1221-31.

9. Aikawa K, Saitoh S, Muto M, et al. Effects of antioxidants on coronary microvascular spasm induced by epicardial coronary artery endothelial injury in pigs. Coron Artery Dis. 2004 Feb;15(1):21-30.

10. Angdin M, Settergren G, Starkopf J, Zilmer M, Zilmer K, Vaage J. Protective effect of antioxidants on pulmonary endothelial function after cardiopulmonary bypass. J Cardiothorac Vasc Anesth. 2003 Jun;17(3):314-20.

11. Meydani M. Dietary antioxidants modulation of aging and immune-endothelial cell interaction. Mech Aging Dev. 1999 Nov;111(2-3):123-32.

12. Schubert SY, Neeman I, Resnick N. A novel mechanism for the inhibition of NF-kappaB activation in vascular endothelial cells by natural antioxidants. FASEB J. 2002 Dec;16(14):1931-3.

13. Schulz E, Anter E, Keaney JF Jr. Oxidative stress, antioxidants, and endothelial function. Curr Med Chem. 2004 May;11(9):1093-104.

14. Taddei S, Virdis A, Ghiadoni L, Salvetti G, Bernini G, Magagna A, Salvetti A. Age-related reduction of NO availability and oxidative stress in humans. Hypertension. 2001 Aug;38(2):274-9.

15. Rubio AR, Morales-Segura MA. Nitric oxide, an iceberg in cardiovascular physiology: far beyond vessel tone control. Arch Med Res. 2004 Jan-Feb;35(1):1-11.

16. Sugawara J, Komine H, Hayashi K, et al. Effect of systemic nitric oxide synthase inhibition on arterial stiffness in humans. Hypertens Res. 2007 May;30(5):411-5.

17. Mungall MM, Gaw A. Statin therapy in the elderly. Curr Opin Lipidol. 2004 Aug;15(4):453-7.

18. ten Dam VH, Box FM, de Craen AJ, et al; PROSPER Study Group. Lack of effect of pravastatin on cerebral blood flow or parenchymal volume loss in elderly at risk for vascular disease. Stroke. 2005 Aug;36(8):1633-6.

19. Weverling-Rijnsburger AW, Blauw GJ, Meinders AE. Effect of atorvastatin on impaired vascular function in healthy old men. J Clin Pharm Ther. 2004 Apr;29(2):157-64.

20. Hermann F, Spieker LE, Ruschitzka F, Sudano I, Hermann M, Binggeli C, Luscher TF, Riesen W, Noll G, Corti R. Dark chocolate improves endothelial and platelet function. Heart. 2006 Jan;92(1):119-20.

21. Sies H, Schewe T, Heiss C, et al. Cocoa polyphenols and inflammatory mediators. Am J Clin Nutr. 2005a Jan;81(1 Suppl):304S-312S.

22. Grassi D, Necozione S, Lippi C, et al. Cocoa reduces blood pressure and insulin resistance and improves endothelium-dependent vasodilation in hypertensives. Hypertension. 2005a Aug;46(2):398-405.

23. Sies H, Stahl W, Sevanian A. Nutritional, dietary and postprandial oxidative stress. J Nutr. 2005b May;135(5):969-72.

24. Grassi D, Lippi C, Necozione S, et al. Short-term administration of dark chocolate is followed by a significant increase in insulin sensitivity and a decrease in blood pressure in healthy persons. Am J Clin Nutr. 2005b Mar;81(3):611-614.

25. Mennen LI, Sapinho D, de Bree A, et al. Consumption of foods rich in flavonoids is related to a decreased cardiovascular risk in apparently healthy French women. J Nutr. 2004;134:923–926.

26. Mursu J, Voutilainen S, Nurmi T, et al. Dark chocolate consumption increases HDL cholesterol concentration and chocolate fatty acids may inhibit lipid peroxidation in healthy humans. Free Radic Biol Med. 2004;37:1351–1359.

27. Fraga CG, Actis-Goretta L, Ottaviani JI, et al. Regular consumption of a flavanol-rich chocolate can improve oxidant stress in young soccer players. Clin Dev Immunol. 2005;12:11–17.

28. Baba S, Osakabe N, Kato Y, et al. Continuous intake of polyphenolic compounds containing cocoa powder reduces LDL oxidative susceptibility and has beneficial effects on plasma HDL-cholesterol concentrations in humans. Am J Clin Nutr. 2007 Mar;85(3):709-17.

29. Nissen SE, Tuzcu EM, Libby P, et al. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial. JAMA. 2004 Nov 10;292(18):2217-25.

30. Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one-million adults in 61 prospective studies. Lancet. 2002 Dec 14;360(9349):1903-13.

31. Taubert D, Roesen R, Lehmann C, et al. Effects of low habitual cocoa intake on blood pressure and bioactive nitric oxide: a randomized controlled trial. JAMA. 2007 Jul 4;298(1):49-60.

32. Bremmer MA, Beekman AT, Deeg DJ, et al. Inflammatory markers in late-life depression: Results from a population-based study. J Affect Disord. 2007 Aug 21; [Epub ahead of print].

33. Cauley JA, Danielson ME, Boudreau RM, et al.; for the Health ABC Study. Inflammatory markers and incident fracture risk in older men and women: the health aging and body composition study. J Bone Miner Res. 2007 Jul;22(7):1088-95.

34. Csiszar A, Toth J, Peti-Peterdi J, et al. The aging kidney: role of endothelial oxidative stress and inflammation. Acta Physiol Hung. 2007 Mar;94(1-2):107-15.

35. Ferencik M, Stvrtinova V, Hulin I, et al. Inflammation—a lifelong companion. Attempt at a non-analytical holistic view. Folia Microbiol (Praha). 2007;52(2):159-73.

36. Lau FC, Shukitt-Hale B, Joseph JA. Nutritional intervention in brain aging: reducing the effects of inflammation and oxidative stress. Subcell Biochem. 2007;42:299-318.

37. Levick SP, Loch DC, Taylor SM, et al. Arachidonic acid metabolism as a potential mediator of cardiac fibrosis associated with inflammation. J Immunol. 2007 Jan 15;178(2):641-6.

38. Leng SX, Xue QL, Tian J, et al. Inflammation and frailty in older women. J Am Geriatr Soc. 2007 Jun;55(6):864-71.

39. Matsuyama W, Mitsuyama H, Watanabe M, et al. Effects of omega-3 polyunsaturated fatty acids on inflammatory markers in COPD. Chest. 2005 Dec;128(6):3817-27.

40. Van Bodegom D, May L, Meij HJ, et al. Regulation of human life histories: the role of the inflammatory host response. Ann N Y Acad Sci. 2007 Apr;1100:84-97.

41. Schewe T, Sadik C, Klotz LO, et al. Polyphenols of cocoa: inhibition of mammalian 15-lipoxygenase. Biol Chem. 2001 Dec;382(12):1687-96.

42. Rubanyi GM. The role of endothelium in cardiovascular homeostasis and diseases. J Cardiovasc Pharmacol. 1993;22 Suppl 4:S1-14.