Life Extension Blood Test Super Sale

Life Extension Magazine

Life Extension Magazine December 2012
Report  

Slash Chronic Disease Risk with LYCOPENE

By Alex Wilson
Slash Chronic Disease Risk with LYCOPENE  

You probably know that a steady intake of food-based antioxidants is important to protecting your DNA and lowering risk of diseases.1

What you may not realize is that one important plant antioxidant is commonly consumed—but poorly absorbed by the body!2,3

Lycopene is a carotenoid with a unique structure that drives its intense free-radical-trapping activity. Lycopene also operates by additional mechanisms to provide health-giving benefits in the form of cellular communication and cell cycling.

The problem is that the fiber content in lycopene-rich foods such as tomatoes interferes with lycopene absorption and bioavailability.2,3 Eating concentrated tomato-based foods like pasta sauce with olive oil provides far greater absorption. Supplementation with lycopene also boosts absorption into the bloodstream, especially when taken with the heaviest meal of the day.

In this article, you'll learn about controlled studies showing that increased lycopene levels result in broad cellular benefits and reduced incidences of cancer, diabetes, Alzheimer's, and cardiovascular disease! 1

What is Lycopene?

Lycopene is a member of the carotenoid family of plant pigment molecules. Carotenoids give vegetables and fruits their yellow, red, and orange colors; they are part of the plant's natural mechanism for processing and protecting themselves from the sun's energy.4,5 Carotenoids, and especially lycopene, are extremely powerful antioxidants.

By capturing reactive oxygen species, lycopene prevents damage to fats, proteins, and DNA strands that we now recognize to be the causes of aging and other chronic diseases, including cardiovascular and neurological diseases, diabetes, cancer, and even osteoporosis.4,5

In addition to its antioxidant characteristics, lycopene has at least four other important health-promoting mechanisms:5,6

  1. Lycopene facilitates cell-to-cell communication at sites called "gap junctions;" these junctions are essential for cells to know when to stop growing which is key for preventing cancer from developing.
  2. Lycopene stimulates the immune system to help destroy invading microorganisms and early cancer cells.
  3. Lycopene regulates endocrine (glandular) communication pathways.
  4. Lycopene regulates the cell reproductive cycle, preventing cancer development.

Humans are incapable of producing carotenoids, so we rely on our diet to obtain sufficient amounts.5 Tomatoes are our main dietary source of lycopene, but lycopene from fresh tomatoes is less bioavailable than that from processed tomato products.7,8

There's no question that boosting your lycopene intake has major protective effects. 9

Higher lycopene intake and higher blood lycopene levels are strongly associated with reduced risk for a variety of cancers, as well as cardiovascular diseases and the metabolic syndrome.

What You Need to Know

Reduce Risk of Chronic Disease with Lycopene
Reduce Risk of Chronic Disease with Lycopene 
  • Oxidant stress causes aging and other life span-shortening diseases.
  • Food-derived antioxidants are critical in combating the effects of aging.
  • Lycopene, a member of the carotenoid family of nutrients, has especially powerful antioxidant effects.
  • But lycopene, found in nature in tomatoes and other red fruits, is not well-absorbed in the intestinal tract from unprocessed foods.
  • Studies show that people who consume large quantities of processed tomato products like ketchup, pizza sauce, and tomato paste have lower rates of chronic illness.
  • But eating enough of those products to obtain sufficient lycopene can be challenging.
  • Lycopene supplementation has been shown to prevent or reduce the risk of chronic diseases such as cancer, cardiovascular disease, diabetes, and neurodegenerative disorders.
  • Lycopene belongs on your supplement "short list" if you want broad-spectrum antioxidant support.

Lycopene and Cancer Prevention

Cancer is the second leading killer of adult Americans, resulting in more than 527,000 deaths annually in the US.10 Because cancer is closely associated with a lifetime burden of oxidative stress, lycopene, with its strong antioxidant effects, is a subject of keen interest to oncologists and public health workers.11 As we've seen, lycopene has additional mechanisms that add to its cancer preventive powers.

Prostate cancer is the disease that is best known as a target for prevention by lycopene.6,12,13 In addition to reducing oxidant stress in prostate tissue, lycopene also reduces inflammatory signaling, prevents DNA damage, modulates the expression of important endocrine growth factors, and enhances communication between cancer cells at "gap junctions," helping them stop growing out of control.6 Lycopene also slows the new blood vessel growth that prostate cancers need to support their development.14

Human studies of lycopene and prostate cancer are encouraging. Lycopene intake is correlated with lower prostate cancer development and with slower progression if it does develop. Lycopene supplementation also reduces cancer-related symptoms such as pain and urinary tract symptoms.15

In one well-publicized investigation, men with newly-diagnosed prostate tumors were supplemented with lycopene 15 mg twice daily for three weeks prior to surgical removal of diseased tissue.16 In supplemented patients, the tumors were found at surgery to be significantly smaller and less invasive than those in control patients. The tumors were also significantly more likely to be lower-grade in supplemented than in control patients. Levels of the tumor marker called prostate specific antigen (PSA) fell substantially in supplemented patients, while they rose by about the same rate in control patients.16 Other human studies have shown similar effects, including slowing the rate of PSA increase.17,18

Breast cancer is the leading cause of cancer death in women.19 It too may yield to lycopene's preventive effects. After treatment with lycopene, human breast cancer cells in culture showed genetic changes resulting in improved DNA repair, slowing of cell replication, and increased death by apoptosis.20 Both alone and in combination with melatonin, lycopene sharply reduces markers of oxidant stress in breast tissue, while enhancing the breast's natural antioxidant enzyme protection systems.19

Lycopene may help reduce the risk of cervical cancer as well; women with the highest lycopene concentrations in blood are 56% less likely to have persistent infection with human papillomavirus, the main cause of cervical malignancies.21

Lycopene is also showing promise in preventing lung cancer. Lung tissue has a very high exposure to oxygen, making it especially vulnerable to the oxidant stress that can lead to cancers. Lycopene reduces lung cells' oxidant-induced DNA damage in humans, and people with the highest dietary intakes of lycopene have a 28% lower risk of developing lung cancer.22,23

Colon cancer is the second most common cancer in adults. Like many other cancers, it is controlled in part by hormonal factors, including insulin-like growth factor-1, or IGF-1.24 Lycopene supplementation, 30 mg/day, in human subjects with a family or personal history of colon cancer, decreases IGF-1 concentrations while increasing levels of the IGF-1 binding protein, which has the effect of reducing IGF-1 availability to stimulate cancer cell growth.24,25

One important note: lycopene's antioxidant effects are so powerful that they have the potential to interfere with cancer chemo- and radiation therapy, both of which rely on producing free radicals within tumors to kill malignant cells.12 Experts warn that people who are undergoing either chemo- or radiation therapy for a known cancer should speak with their treating oncologist before increasing lycopene intake.12

Oxidation Ages You Before Your Time

Oxidation Ages You Before Your Time 

Your body is constantly under attack by highly reactive compounds called reactive oxygen species (ROS). ROS are generated as a result of your normal metabolic activity, as well as by unhealthy habits such as smoking, a high-fat diet, and excessive alcohol consumption. Even beneficial activities like exercise increase your exposure to oxidant stress.5

The result is damage to your body’s most fundamental and vulnerable components: the enzymes and other proteins that carry out vital chemical reactions and that structure your body, the lipids (fats) that form the bulk of your cell membranes, and the DNA that carries the blueprint for your body’s structure and function.5

Oxidation is not some subtle or theoretical risk: women at high risk for breast cancer excrete elevated levels of a marker of cell membrane oxidation, while prostate cancer patients have 20% more levels of those markers in their blood than matched controls.5

Oxidation of tumor suppressor proteins causes them to malfunction, allowing cancers to spring to life, while oxidized lipids in heart muscle and arteries promotes cardiovascular disease. And high levels of oxidized lipids, proteins, and DNA are found in otherwise healthy people as they age.5

The result of all this oxidation is a massive increase in your risk for chronic diseases, those preventable manifestations of aging that contribute to an untimely demise.5

For all of these reasons, then, you need to support your body’s struggling antioxidant defense system with a steady intake of powerful dietary antioxidants like lycopene.

Lycopene and Cardiovascular Disease

Cardiovascular diseases (heart attacks, stroke, congestive heart failure, and others) are the leading cause of death in Western societies; together they cause up to 1/3 of deaths around the globe.26,27 It has long been known that diet is strongly correlated with the risk of these diseases.

People with low blood lycopene levels suffer from increased risk for atherosclerosis; including greater thickness and stiffness of their arteries.28 People with atherosclerosis visible on ultrasound in their carotid arteries (those leading to the brain) have lower blood levels of lycopene than do those with normal carotids.29

Conversely, those with the highest lycopene blood levels have a 45% lower risk of atherosclerosis.30 That group also has more flexible arteries than those in the lower lycopene group and a reduced risk of heart attack.31

Lycopene protects heart and blood vessel tissue by several mechanisms, including antioxidant function. Lycopene scavenges the powerful oxidant hypochlorous acid, which is associated with atherosclerosis.32 Lycopene also decreases fat and LDL cholesterol oxidation, steps that occur early in the chain of events that leads to atherosclerosis.33-35

Studies show that lycopene supplementation can decrease total cholesterol by 5.9% and LDL cholesterol by 12.9% (and by 50% in animal studies).36,37 Some of this effect may be due to lycopene's ability to inhibit cholesterol synthesis.31

Lycopene supplementation has powerful effects on the inflammation that is intimately involved with atherosclerosis.27 Lab and human studies demonstrate that lycopene decreases production of multiple pro-inflammatory mediators and markers of inflam-mation.38

One dramatic human study showed that 15 mg/day of lycopene orally improved endothelial function by 23%.39 At the same time the inflammatory marker, C-reactive protein (hs-CRP) fell dramatically, along with systolic blood pressure and important vascular adhesion molecules that trap platelets and immune cells to form inflammatory plaques. Some of that reduced inflammatory response is attributed to lycopene's ability to block fat oxidation in arterial lining cells.40,41

Intriguingly, neither diets high in tomatoes (10 ounces/day) nor diets containing 32-50 mg of lycopene from tomato-based foods have any detectable effects on inflammatory markers,42 though one study showed a modest 3.3% improvement in endothelial function after consumption of 2.3 ounces/day of tomato paste for 15 days.43

Even lycopene supplementation at moderate doses (10 mg/day) proved incapable of changing inflammatory markers or insulin resistance, another major cardiac risk factor.44 Studies showing a substantial impact of lycopene intervention, instead, used 15-30 mg/day of purified lycopene extracted from tomatoes.45

Higher Lycopene Intake Lowers Risk for Many Chronic Diseases

Higher Lycopene Intake Lowers Risk for Many Chronic Diseases 
Disease Lycopene Indicator Risk Reduction
Death from All Causes Moderate Blood Level 18%71
Overall Cancer Risk Highest Blood Level 45%72
Breast Cancer Highest Intake 74%73
Esophageal Cancer Highest Intake 30%74
Lung Cancer Highest Blood Level Highest Intake 54%75
29%76
Death from Lung Cancer Highest Blood Level 54%77
Death from Oral, Pharyngeal, Laryngeal Cancers Highest Blood Level 47%
(92% in Nonsmokers)78
Ovarian Cancer Highest Blood Level 91%79
Pancreatic Cancer Highest Intake 31%80
Prostate Cancer Highest Intake 82%81
Advanced Prostate Cancer Highest Blood Level 60%82
Cardiovascular Disease (Women) Tomato-based products, 10 or more servings/week 29%83
Cardiovascular Risk Factors (Women) Tomato-based products, 10 or moreservings/week High Total Cholesterol: 31% High LDL: 40% High Hemoglobin A1c: 66%84
Atherosclerosis Highest Blood Levels 55%30
Elevated Blood Sugar Highest Intake 43%50
Metabolic Syndrome Highest Intake 45%85
 

Lycopene and Diabetes

Diabetes, like other chronic age-related conditions, is powerfully driven by oxidation and inflammation. Not surprisingly, then, blood lycopene levels in diabetics are typically much lower than they are in healthy control patients, presumably the result of consumption of lycopene by reactive oxygen species.46

Diabetics may be able to protect themselves by increasing their lycopene intake; studies show that high consumption of tomato products can improve resistance to oxidation in people with type II diabetes.47 Diabetics with the highest blood lycopene levels also have greater glucose tolerance than do those with lower lycopene levels.48

Eating a lycopene-rich Mediterranean diet increases lycopene levels and can reduce levels of hemoglobin A1c, the blood marker of sustained blood sugar elevations, from 7.1 to 6.8%.49,50 (Tomatoes have other beneficial compounds such as chlorogenic acid that may have accounted for these marked reductions in hemoglobin A1c.)

The most common and life-threatening complication of diabetes is cardiovascular disease; like people in the general population, diabetics may be able to reduce their risk of cardiovascular complications by supplementing with lycopene.

Consuming about 7 ounces of raw tomatoes daily for 8 weeks successfully lowered both systolic and diastolic blood pressure in diabetics.51 Part of that effect may arise from a reduction in activity of angiotensin converting enzyme (ACE), an effect produced by common antihypertensive drugs.52

In older diabetic women, 30 mg/day of lycopene reduced total and LDL cholesterol by 12 and 16% respectively, while also lowering a common marker of tissue oxidation that contributes to atherosclerosis.53

Other complications of diabetes are also less severe in those with higher lycopene levels. For example, diabetics with healthy eyes have higher levels of lycopene than do those with the blindness-inducing condition called diabetic retinopathy.54

Similarly, diabetic neuropathy, a painful and debilitating nerve condition that is among the hardest of pain syndromes to treat, is substantially ameliorated in animal studies of lycopene supplementation.55,56

Finally, cognitive decline associated with diabetes can be decreased with long-term lycopene supplementation.57

Of course, diabetics are not the only people who face neurological degeneration over time. In the next section we'll see how lycopene may improve brain health for everyone.

Lycopene and Your Brain

Lycopene and Your Brain 

Oxidative stress plays a major role in the neuro-degenerative diseases of aging.

Most of the carotenoid antioxidant nutrients, including lycopene, are reduced in one or more of those diseases such as Alzheimer's disease, vascular dementia, and Parkinson's disease with dementia.58 They were recently also shown to be depleted in mild cognitive impairment.59

These facts make lycopene an important dietary component for maintaining brain health.

Animal models of Alzheimer's, Parkinson's and Huntington's diseases have all confirmed lycopene's preventive potential.60-62 A lycopene-rich tomato powder supplement completely prevented destruction of essential dopamine-producing brain cells in a mouse model of Parkinson's disease.62 Raw tomato supplements had similar but considerably less impressive effects.63

Other studies have shown that lycopene improves brain resistance to oxidant stress in Parkinson's disease models, and it successfully prevented the neurobehavioral deficits associated with the disease.64

Huntington's disease is less common but by no means less tragic; it produces uncontrolled motor movements coupled with dementia, and is inevitably fatal.65 In animal models of Huntington's disease, lycopene reduced memory impairment while blocking the behavioral and biochemical abnormalities.66 The mechanism appears to be through inhibition of inflammatory nitric acid production, in addition to protective effects on brain mitochondria.67

Alzheimer's disease is practically the perfect example of brain destruction by oxidant stress. Lycopene may prevent Alzheimer's by inhibiting formation of oxidant-producing Abeta proteins.68 As a result, studies show decreased death rates of neurons, especially in the memory-processing hippocampus area of the brain.69

There's also growing evidence that lycopene can prevent the inflammatory response to an acute stroke, and can reduce the total size of the damaged brain area.70 Finally, lycopene has also recently been shown to be protective against environmental neurotoxins and excessive levels of certain elements such as manganese, again through its antioxidant effects.61

Summary

Our bodies are under continuous attack by oxidant stress, which produces inflammation and direct tissue damage. Ultimately, chronic inflammatory insult accelerates aging and other diseases that shorten life span.

Lycopene, a natural antioxidant derived from red fruits like tomatoes, has powerful antioxidant capabilities. It operates by additional mechanisms to provide health-giving benefits.

But lycopene in raw tomatoes is poorly bioavailable, and although it is more readily absorbed from processed tomato products (like tomato sauce), many people don't eat enough of these foods to obtain an adequate supply.

Studies show that lycopene supplementation holds promise for reducing the impact of aging and many other chronic conditions, through the interactions of its many target effects. Lycopene has been shown to reduce the risk of certain cancers, cardiovascular disease, and metabolic disorders such as diabetes, and neurodegenerative decline.

If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.

References

1. Kong KW, Khoo HE, Prasad KN, Ismail A, Tan CP, Rajab NF. Revealing the power of the natural red pigment lycopene. Molecules. 2010 Feb;15(2):959-87.

2. Riedl J, Linseisen J, Hoffmann J, Wolfram G. Some dietary fibers reduce the absorption of carotenoids in women. J Nutr. 1999 Dec;129(12):2170-6.

3. Hoffmann J, Linseisen J, Riedl J, Wolfram G. Dietary fiber reduces the antioxidative effect of a carotenoid and alpha-tocopherol mixture on LDL oxidation ex vivo in humans. Eur J Nutr. 1999 Dec;38(6):278-85.

4. Rao AV, Rao LG. Carotenoids and human health. Pharmacol Res. 2007 Mar;55(3):207-16.

5. Rao AV, Ray MR, Rao LG. Lycopene. Adv Food Nutr Res. 2006;51:99-164.

6. Wertz K. Lycopene effects contributing to prostate health. Nutr Cancer. 2009;61(6):775-83.

7. Agarwal A, Shen H, Agarwal S, Rao AV. Lycopene content of tomato products: its stability, bioavailability and in vivo antioxidant properties. J Med Food. 2001 Spring;4(1):9-15.

8. van het Hof KH, de Boer BC, Tijburg LB, et al. Carotenoid bioavailability in humans from tomatoes processed in different ways determined from the carotenoid response in the triglyceride-rich lipoprotein fraction of plasma after a single consumption and in plasma after four days of consumption. J Nutr. 2000 May;130(5):1189-96.

9. Rao AV. Processed tomato products as a source of dietary lycopene: bioavailability and antioxidant properties. Can J Diet Pract Res. 2004 Winter;65(4):161-5.

10. Available at: http://www.cdc.gov/nchs/fastats/deaths.htm/. Accessed July 10, 2012.

11. Rao AV, Agarwal S. Bioavailability and in vivo antioxidant properties of lycopene from tomato products and their possible role in the prevention of cancer. Nutr Cancer. 1998;31(3):199-203.

12. Cassileth B. Lycopene. Oncology (Williston Park). 2010 Mar;24(3):296.

13. Lowe JF, Frazee LA. Update on prostate cancer chemoprevention. Pharmacotherapy. 2006 Mar;26(3):353-9.

14. Cervi D, Pak B, Venier NA, et al. Micronutrients attenuate progression of prostate cancer by elevating the endogenous inhibitor of angiogenesis, platelet factor-4. BMC Cancer. 2010;10:258.

15. Haseen F, Cantwell MM, O'Sullivan JM, Murray LJ. Is there a benefit from lycopene supplementation in men with prostate cancer? A systematic review. Prostate Cancer Prostatic Dis. 2009;12(4):325-32.

16. Kucuk O, Sarkar FH, Djuric Z, et al. Effects of lycopene supplementation in patients with localized prostate cancer. Exp Biol Med (Maywood). 2002 Nov;227(10):881-5.

17. Stacewicz-Sapuntzakis M, Bowen PE. Role of lycopene and tomato products in prostate health. Biochim Biophys Acta. 2005 May 30;1740(2):202-5. Epub 2005 Mar 13.

18. Barber NJ, Zhang X, Zhu G, et al. Lycopene inhibits DNA synthesis in primary prostate epithelial cells in vitro and its administration is associated with a reduced prostate-specific antigen velocity in a phase II clinical study. Prostate Cancer Prostatic Dis. 2006;9(4):407-13.

19. Moselhy SS, Al mslmani MA. Chemopreventive effect of lycopene alone or with melatonin against the genesis of oxidative stress and mammary tumors induced by 7,12 dimethyl(a)benzanthracene in sprague dawely female rats. Mol Cell Biochem. 2008 Dec;319(1-2):175-80.

20. Chalabi N, Delort L, Le Corre L, Satih S, Bignon YJ, Bernard-Gallon D. Gene signature of breast cancer cell lines treated with lycopene. Pharmacogenomics. 2006 Jul;7(5):663-72.

21. Sedjo RL, Roe DJ, Abrahamsen M, et al. Vitamin A, carotenoids, and risk of persistent oncogenic human papillomavirus infection. Cancer Epidemiol Biomarkers Prev. 2002 Sep;11(9):876-84.

22. Arab L, Steck-Scott S, Fleishauer AT. Lycopene and the lung. Exp Biol Med (Maywood). 2002 Nov;227(10):894-9.

23. Holick CN, Michaud DS, Stolzenberg-Solomon R, et al. Dietary carotenoids, serum beta-carotene, and retinol and risk of lung cancer in the alpha-tocopherol, beta-carotene cohort study. Am J Epidemiol. 2002 Sep 15;156(6):536-47.

24. Vrieling A, Voskuil DW, Bonfrer JM, et al. Lycopene supplementation elevates circulating insulin-like growth factor binding protein-1 and -2 concentrations in persons at greater risk of colorectal cancer. Am J Clin Nutr. 2007 Nov;86(5):1456-62.

25. Walfisch S, Walfisch Y, Kirilov E, et al. Tomato lycopene extract supplementation decreases insulin-like growth factor-I levels in colon cancer patients. Eur J Cancer Prev. 2007 Aug;16(4):298-303.

26. Mordente A, Guantario B, Meucci E, et al. Lycopene and cardiovascular diseases: an update. Curr Med Chem. 2011;18(8):1146-63.

27. Bohm V. Lycopene and heart health. Mol Nutr Food Res. 2012 Feb;56(2):296-303.

28. Riccioni G, D'Orazio N, Palumbo N, et al. Relationship between plasma antioxidant concentrations and carotid intima-media thickness: the Asymptomatic Carotid Atherosclerotic Disease In Manfredonia Study. Eur J Cardiovasc Prev Rehabil. 2009 Jun;16(3):351-7.

29. Riccioni G, Scotti L, Di Ilio E, et al. Lycopene and preclinical carotid atherosclerosis. J Biol Regul Homeost Agents. 2011 Jul-Sep;25(3):435-41.

30. Klipstein-Grobusch K, Launer LJ, Geleijnse JM, Boeing H, Hofman A, Witteman JC. Serum carotenoids and atherosclerosis. The Rotterdam Study. Atherosclerosis. 2000 Jan;148(1):49-56.

31. Arab L, Steck S. Lycopene and cardiovascular disease. Am J Clin Nutr. 2000 Jun;71(6 Suppl):1691S-5S; discussion 96S-7S.

32. Pennathur S, Maitra D, Byun J, et al. Potent antioxidative activity of lycopene: A potential role in scavenging hypochlorous acid. Free Radic Biol Med. 2010 Jul 15;49(2):205-13.

33. Agarwal S, Rao AV. Tomato lycopene and low density lipoprotein oxidation: a human dietary intervention study. Lipids. 1998 Oct;33(10):981-4.

34. Maruyama C, Imamura K, Oshima S, et al. Effects of tomato juice consumption on plasma and lipoprotein carotenoid concentrations and the susceptibility of low density lipoprotein to oxidative modification. J Nutr Sci Vitaminol (Tokyo). 2001 Jun;47(3):213-21.

35. Visioli F, Riso P, Grande S, Galli C, Porrini M. Protective activity of tomato products on in vivo markers of lipid oxidation. Eur J Nutr. 2003 Aug;42(4):201-6.

36. Silaste ML, Alfthan G, Aro A, Kesaniemi YA, Horkko S. Tomato juice decreases LDL cholesterol levels and increases LDL resistance to oxidation. Br J Nutr. 2007 Dec;98(6):1251-8.

37. Lorenz M, Fechner M, Kalkowski J, et al. Effects of lycopene on the initial state of atherosclerosis in New Zealand White (NZW) rabbits. PLoS One. 2012;7(1):e30808.

38. Lee W, Ku SK, Bae JW, Bae JS. Inhibitory effects of lycopene on HMGB1-mediated pro-inflammatory responses in both cellular and animal models. Food Chem Toxicol. 2012 Jun;50(6):1826-33.

39. Kim JY, Paik JK, Kim OY, Park HW, Lee JH, Jang Y. Effects of lycopene supplementation on oxidative stress and markers of endothelial function in healthy men. Atherosclerosis. 2011 Mar;215(1):189-95.

40. Neyestani TR, Shariat-Zadeh N, Gharavi A, Kalayi A, Khalaji N. The opposite associations of lycopene and body fat mass with humoral immunity in type 2 diabetes mellitus: a possible role in atherogenesis. Iran J Allergy Asthma Immunol. 2007 Jun;6(2):79-87.

41. Neyestani TR, Shariatzadeh N, Gharavi A, Kalayi A, Khalaji N. Physiological dose of lycopene suppressed oxidative stress and enhanced serum levels of immunoglobulin M in patients with Type 2 diabetes mellitus: a possible role in the prevention of long-term complications. J Endocrinol Invest. 2007 Nov;30(10):833-8.

42. Blum A, Monir M, Khazim K, Peleg A, Blum N. Tomato-rich (Mediterranean) diet does not modify inflammatory markers. Clin Invest Med. 2007;30(2):E70-4.

43. Xaplanteris P, Vlachopoulos C, Pietri P, et al. Tomato paste supplementation improves endothelial dynamics and reduces plasma total oxidative status in healthy subjects. Nutr Res. 2012 May;32(5):390-4.

44. Thies F, Masson LF, Rudd A, et al. Effect of a tomato-rich diet on markers of cardiovascular disease risk in moderately overweight, disease-free, middle-aged adults: a randomized controlled trial. Am J Clin Nutr. 2012 May;95(5):1013-22.

45. Devaraj S, Mathur S, Basu A, et al. A dose-response study on the effects of purified lycopene supplementation on biomarkers of oxidative stress. J Am Coll Nutr. 2008 Apr;27(2):267-73.

46. Li ZZ, Lu XZ, Ma CC, Chen L. Serum lycopene levels in patients with diabetic retinopathy. Eur J Ophthalmol. 2010 Jul-Aug;20(4):719-23.

47. Upritchard JE, Sutherland WH, Mann JI. Effect of supplementation with tomato juice, vitamin E, and vitamin C on LDL oxidation and products of inflammatory activity in type 2 diabetes. Diabetes Care. 2000 Jun;23(6):733-8.

48. Coyne T, Ibiebele TI, Baade PD, et al. Diabetes mellitus and serum carotenoids: findings of a population-based study in Queensland, Australia. Am J Clin Nutr. 2005 Sep;82(3):685-93.

49. Itsiopoulos C, Brazionis L, Kaimakamis M, et al. Can the Mediterranean diet lower HbA1c in type 2 diabetes? Results from a randomized cross-over study. Nutr Metab Cardiovasc Dis. 2011 Sep;21(9):740-7.

50. Suzuki K, Ito Y, Nakamura S, Ochiai J, Aoki K. Relationship between serum carotenoids and hyperglycemia: a population-based cross-sectional study. J Epidemiol. 2002 Sep;12(5):357-66.

51. Shidfar F, Froghifar N, Vafa M, et al. The effects of tomato consumption on serum glucose, apolipoprotein B, apolipoprotein A-I, homocysteine and blood pressure in type 2 diabetic patients. Int J Food Sci Nutr. 2011 May;62(3):289-94.

52. Ozmutlu S, Dede S, Ceylan E. The effect of lycopene treatment on ACE activity in rats with experimental diabetes. J Renin Angiotensin Aldosterone Syst. 2012 May 15.

53. Olfer'ev AM, Il'ina MV, Berzak NV, et al. Effect of lycopene on blood lipoproteids in women with type 2 diabetes mellitus in postmenopause. Vopr Pitan. 2004;73(1):19-23.

54. Brazionis L, Rowley K, Itsiopoulos C, O'Dea K. Plasma carotenoids and diabetic retinopathy. Br J Nutr. 2009 Jan;101(2):270-7.

55. Kuhad A, Sharma S, Chopra K. Lycopene attenuates thermal hyperalgesia in a diabetic mouse model of neuropathic pain. Eur J Pain. 2008 Jul;12(5):624-32.

56. Kuhad A, Chopra K. Lycopene ameliorates thermal hyperalgesia and cold allodynia in STZ-induced diabetic rat. Indian J Exp Biol. 2008 Feb;46(2):108-11.

57. Kuhad A, Sethi R, Chopra K. Lycopene attenuates diabetes-associated cognitive decline in rats. Life Sci. 2008 Jul 18;83(3-4):128-34.

58. Polidori MC, Mattioli P, Aldred S, et al. Plasma antioxidant status, immunoglobulin g oxidation and lipid peroxidation in demented patients: relevance to Alzheimer disease and vascular dementia. Dement Geriatr Cogn Disord. 2004;18(3-4):265-70.

59. Rinaldi P, Polidori MC, Metastasio A, et al. Plasma antioxidants are similarly depleted in mild cognitive impairment and in Alzheimer's disease. Neurobiol Aging. 2003 Nov;24(7):915-9.

60. Kumar P, Kalonia H, Kumar A. Lycopene modulates nitric oxide pathways against 3-nitropropionic acid-induced neurotoxicity. Life Sci. 2009 Nov 4;85(19-20):711-8. Epub 2009 Oct 12.

61. Lebda MA, El-Neweshy MS, El-Sayed YS. Neurohepatic toxicity of subacute manganese chloride exposure and potential chemoprotective effects of lycopene. Neurotoxicology. 2012 Jan;33(1):98-104. Epub 2011 Dec 16.

62. Suganuma H, Hirano T, Arimoto Y, Inakuma T. Effect of tomato intake on striatal monoamine level in a mouse model of experimental Parkinson's disease. J Nutr Sci Vitaminol (Tokyo). 2002 Jun;48(3):251-4.

63. di Matteo V, Pierucci M, Di Giovanni G, et al. Intake of tomato-enriched diet protects from 6-hydroxydopamine-induced degeneration of rat nigral dopaminergic neurons. J Neural Transm Suppl. 2009;(73):333-41.

64. Kaur H, Chauhan S, Sandhir R. Protective effect of lycopene on oxidative stress and cognitive decline in rotenone induced model of Parkinson's disease. Neurochem Res. 2011 Aug;36(8):1435-43. Epub 2011 Apr 12.

65. Available at: http://www.mayoclinic.com/health/huntingtons- disease/DS00401/DSECTION=complications. Accessed July 25, 2012.

66. Kumar P, Kumar A. Effect of lycopene and epigallocatechin-3-gallate against 3-nitropropionic acid induced cognitive dysfunction and glutathione depletion in rat: a novel nitric oxide mechanism. Food Chem Toxicol. 2009 Oct;47(10):2522-30. Epub 2009 Jul 17.

67. Sandhir R, Mehrotra A, Kamboj SS. Lycopene prevents 3-nitropropionic acid-induced mitochondrial oxidative stress and dysfunctions in nervous system. Neurochem Int. 2010 Nov;57(5):579-87. Epub 2010 Jul 17.

68. Obulesu M, Dowlathabad MR, Bramhachari PV. Carotenoids and Alzheimer's disease: an insight into therapeutic role of retinoids in animal models. Neurochem Int. 2011 Oct;59(5):535-41. Epub 2011 Jun 7.

69. Qu M, Zhou Z, Chen C, et al. Lycopene protects against trimethyltin-induced neurotoxicity in primary cultured rat hippocampal neurons by inhibiting the mitochondrial apoptotic pathway. Neurochem Int. 2011 Dec;59(8):1095-103. Epub 2011 Oct 19.

70. Wei Y, Shen XN, Mai JY, Shen H, Wang RZ, Wu M. The effects of lycopene on reactive oxygen species and anoxic damage in ischemia reperfusion injury in rats. Zhonghua Yu Fang Yi Xue Za Zhi. 2010 Jan;44(1):34-8.

71. Shardell MD, Alley DE, Hicks GE, et al. Low-serum carotenoid concentrations and carotenoid interactions predict mortality in US adults: the Third National Health and Nutrition Examination Survey. Nutr Res. 2011 Mar;31(3):178-89.

72. Karppi J, Kurl S, Nurmi T, Rissanen TH, Pukkala E, Nyyssonen K. Serum lycopene and the risk of cancer: the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) study. Ann Epidemiol. 2009 Jul;19(7):512-8.

73. Huang JP, Zhang M, Holman CD, Xie X. Dietary carotenoids and risk of breast cancer in Chinese women. Asia Pac J Clin Nutr. 2007;16 Suppl 1:437-42.

74. De Stefani E, Ronco AL, Boffetta P, et al. Nutrient intake and risk of squamous cell carcinoma of the esophagus: a case-control study in Uruguay. Nutr Cancer. 2006;56(2):149-57.

75. Ito Y, Wakai K, Suzuki K, et al. Serum carotenoids and mortality from lung cancer: a case-control study nested in the Japan Collaborative Cohort (JACC) study. Cancer Sci. 2003 Jan;94(1):57-63.

76. Gallicchio L, Boyd K, Matanoski G, et al. Carotenoids and the risk of developing lung cancer: a systematic review. Am J Clin Nutr. 2008 Aug;88(2):372-83.

77. Ito Y, Wakai K, Suzuki K, et al. Lung cancer mortality and serum levels of carotenoids, retinol, tocopherols, and folic acid in men and women: a case-control study nested in the JACC Study. J Epidemiol. 2005 Jun;15 Suppl 2:S140-9.

78. Mayne ST, Cartmel B, Lin H, Zheng T, Goodwin WJ, Jr. Low plasma lycopene concentration is associated with increased mortality in a cohort of patients with prior oral, pharynx or larynx cancers. J Am Coll Nutr. 2004 Feb;23(1):34-42.

79. Jeong NH, Song ES, Lee JM, et al. Plasma carotenoids, retinol and tocopherol levels and the risk of ovarian cancer. Acta Obstet Gynecol Scand. 2009;88(4):457-62.

80. Nkondjock A, Ghadirian P, Johnson KC, Krewski D. Dietary intake of lycopene is associated with reduced pancreatic cancer risk. J Nutr. 2005 Mar;135(3):592-7.

81. Jian L, Lee AH, Binns CW. Tea and lycopene protect against prostate cancer. Asia Pac J Clin Nutr. 2007;16 Suppl 1:453-7.

82. Key TJ, Appleby PN, Allen NE, et al. Plasma carotenoids, retinol, and tocopherols and the risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition study. Am J Clin Nutr. 2007 Sep;86(3):672-81.

83. Sesso HD, Liu S, Gaziano JM, Buring JE. Dietary lycopene, tomato-based food products and cardiovascular disease in women. J Nutr. 2003 Jul;133(7):2336-41.

84. Sesso HD, Wang L, Ridker PM, Buring JE. Tomato-based food products are related to clinically modest improvements in selected coronary biomarkers in women. J Nutr. 2012 Feb;142(2):326-33.

85. Sluijs I, Beulens JW, Grobbee DE, van der Schouw YT. Dietary carotenoid intake is associated with lower prevalence of metabolic syndrome in middle-aged and elderly men. J Nutr. 2009 May;139(5):987-92.