Science & Research
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2012
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Nutrient 'Cocktail' Delays Aging and Extends Life Span

Life Extension Magazine®

Researcher preparing 30-nutrient cocktail for anti-aging study

Nutrient 'Cocktail' Delays Aging and Extends Life Span

In the quest to halt aging, an international team of researchers has formulated a 30-nutrient “cocktail” that acts along multiple pathways to inhibit five aging mechanisms. All of the nutrients used in the study are currently taken by health conscious humans, which is comforting considering the researchers documented increases in longevity and marked protection against pathological aging processes.

Scientifically reviewed by Dr. Gary Gonzalez, MD, in October 2024. Written by: Susan Machado.

Nutrient 'Cocktail'Delays Aging and Extends Life Span

An international coalition of researchers has proved in the laboratory that a comprehensive 'cocktail' of nutritional supplements significantly increased youthful life span.1

Since aging is a multifactorial process with overlapping causes, scientists formulated a 30-ingredient nutrient mixture with overlapping benefits designed to halt or slow the major causes of aging.

The nutrient mixture, developed by a team of life scientists led by Dr. C. David Rollo of McMaster University in Canada, targets five key mechanisms of aging.1-3 Researchers postulated that by slowing or reversing these five universal processes, they could slow or reverse the major factors of aging.

While this research was initially conducted on animals, every one of the 30 nutrients is already in human use as a supplement. All have established records of safety and effectiveness at promoting health and preventing specific disease processes. Many of the nutrients are already known to improve cognition, enhance mobility, slow aging, or extend life spans. Others have clear-cut beneficial effects on one or more of five key aging mechanisms, adding value to the combination as a whole.

The implications that this nutrient cocktail has on human longevity are profound.

Let's look now at these five fundamental causes of aging to understand the multiple ways that this nutrient mixture attacks them.

Targeting Five Key Mechanisms of Aging

Dr. Rollo's researchers recognized that, while aging is a complex phenomenon, most of its manifestations could be traced to a relatively small number of basic processes. Among these, there are five that account for most of the tissue, organ, and system dysfunction that produces chronic disease and untimely death. These five are well known to Life Extension® members: oxidative stress, inflammation, mitochondrial dysfunction, insulin resistance, and integrity of membranes.1-3

No single mechanism alone accounts for any one specific disease process. Instead, all five mechanisms interact with one another to produce both general aging and specific conditions that limit activity, cognitive function, and ultimately life span.

In developing a functional, multi-nutrient anti-aging formula, Dr. Rollo's group targeted the five key mechanisms of aging.

The scientists recognized that these specific mechanisms accounted for the vast majority of age-related, longevity-impairing conditions. In this way, the researchers cast a wide net to encompass as many disease states of aging as they could. Additionally, they chose laboratory mice to study the impact of the nutrients on aging because of the animals' short normal life span. This would help the researchers learn the most in the least amount of time. A mouse is considered 'old' by age 2 years, providing a convenient and realistic setting for the study of age-related conditions.3 A human study might have taken decades before they could draw meaningful conclusions.

Next, the researchers needed to establish markers of progressive aging. They wanted to know not only how long the animals lived, but also how well they functioned as they grew older. Most importantly, they needed measures that were equally applicable to both mice and to humans. Based on the work of others, Rollo's group decided that those criteria could be met by measuring how much the aging animals moved, and how their cognitive function changed with time.

Aging, Mobility, and Cognition

All animals, from worms to insects to humans, change in very similar fashions as they succumb to the five key mechanisms of aging. In particular, changes in mobility and cognition provide reliable ways to measure the impact of aging on an individual's function.

As they grow older, all animal species move about less and less each day, spending more and more time at rest or in sleep.3 Reduced mobility is an excellent marker of aging, because it is closely linked to overall metabolic rate, feeding, fat storage, brain neurotransmitter levels, mitochondrial function, and cardiovascular and skeletal muscle systems.3 And loss of mobility in humans is associated with muscle wasting, bone thinning, and other changes that increase the risk of other negative outcomes such as fractures, pneumonia, and skin infections.

Cognitive function also declines with age in all animal populations. Younger animals typically learn faster, requiring fewer repetitions to master a task. They can also bring up important memories faster and more accurately, allowing them to find food, escape threats, and protect other members of their species. Studies show that preserving cognitive function into older ages is associated with longer life spans.2,4

Thus, by choosing to examine the animals' mobility and cognitive function, in addition to their longevity, Dr. Rollo's research group was able to measure how their mice were aging in ways that are likely to be applicable to humans as well.

Let's see how the mice did.

Results from Animal Studies

After devising their 30-ingredient nutrient cocktail based on the five key mechanisms of aging, Dr. Rollo's group soaked the mixture into small pieces of bagel, which they then fed to the mice; control mice were fed only the bagel bits without the supplement.1-3

First, they determined the effect of the supplement on longevity. They used both normal mice and a special strain that demonstrates accelerated aging as a result of excessive sensitivity to all five aging mechanisms.1,5 Compared with control animals, the supplemented mice of the accelerated aging strain lived 28% longer.1 Supplemented normal mice survived 11% longer than their controls.1

Rollo's researchers then turned their attention to the animals' mobility as one measure of their general function with aging. They placed the mice in a system of transparent chambers, where they were given food, water, and an exercise wheel. Then they recorded the amount of time each animal spent moving about the enclosure over a 24-hour period.

Normal, unsupplemented mice showed a progressive decline in activity; by 24 months their mobility was roughly half that of younger normal animals. By 24 months of age, supplemented normal mice were moving roughly three hours more per day than were unsupplemented animals.3 No other treatment has ever been found that ameliorates declining mobility to this extent.3

Rollo's group also measured biochemical markers that might explain the differences in mobility between supplemented and unsupplemented animals. Supplemented older mice had:

Increased activity of the neurotransmitter dopamine; decreased dopamine levels are associated with loss of movement in aging humans and in those with Parkinson's disease.3
Increased measures of mitochondrial activity, suggesting that supplemented animals simply had more energy as they aged.3
Decreased levels of protein carbonyls, altered molecules that reflect the impact of glycation and oxidation on cells and tissues.3

Taken together, the results of this study provided compelling evidence that the multi-nutrient mixture could slow down and perhaps even stop many age-related changes that contribute to the dangerous loss of mobility so common in older individuals.

Rollo's next study investigated the effects of the nutrient mixture on the cognitive decline that also threatens both quantity and quality of life as we age. Just as in the previous study, the researchers provided the nutrient mixture soaked onto bagel pieces, giving control animals plain bagels.2 Next, they tested the mice on a 'water maze' that required the animals to find and remember the location of a platform submerged just below the surface of a pool filled with water. This simple exercise, which tested the animals' learning skills as well as their memory, was repeated each day for five days.

As one might expect, on day 1 all of the mice had trouble finding the platform at first, taking an average of 81 seconds. By day 5, young mice had learned and remembered enough to find the platform 43% faster than on day 1. Older unsupplemented mice, however, showed no significant improvement in the time it took them to find the platform, indicating age-related impairments in learning and memory.

But with supplementation, old mice showed a level of learning almost identical to that of young mice; in fact on day 5 they took an average of 46% less time to find the platform than they did on day 1. In other words, supplemented old mice showed the same ability to learn and remember new tasks as did young animals (See figure 1).

As with their previous study, Rollo's researchers also sought biochemical and structural explanations for the observed improvements in the supplemented animals' behavior. They found that:

Brain mitochondrial activity fell steadily with age in the untreated mice, while supplemented animals showed a steady increase in this important measure of brain energy supply.2
Mice with higher brain mitochondrial activity proved to be significantly better learners than those with lower mitochondrial activity.2
Brain weights, which normally decrease with age, were higher in supplemented male mice by 7%, and in females by 11%, compared with brain weights of control animals.2

Together, Rollo's findings present a remarkable picture of our emerging ability to control not one, but five of the key pathways to an aging body and mind. In their papers, the researchers freely admit that they don't yet have precise knowledge of exactly how each nutrient is working in their experimental model.1-3,5 But they recognize the great importance of addressing multiple aging pathways each through multiple mechanisms.

And there is no paucity of evidence that each of the 30 nutrients in the mixture has powerful, and often multiple, effects on the aging process, as shown in the next section.

What You Need to Know: Delay Aging and Extend Life Span

Aging is a complex, multifactorial process, but five major mechanisms are now known to account entirely or in part for most human age-related diseases, and to contribute to the aging process itself.
Scientists from Canada and China have devised a 30-nutrient supplement mixture designed to attack all five mechanisms of aging by multiple pathways.
Tested in mice, the supplement mix extends life span by up to 28% while improving the aging animals' mobility and cognitive function.
All 30 nutrients are known to be safe and effective in human beings.
If this mixture, or one like it, has similar effectiveness in humans, one could expect an 80-year-old to add nearly 9 years of life, with youthful levels of activity and cognition.

Ingredients Synergize to Slow Aging, Enhance Cognition, Boost Mobility

Rollo's group of researchers chose nutrients with known abilities to attack five of the key mechanisms of aging. As shown in the Table of Ingredients, the majority of the ingredients have more than one mode of action on more than one of the major mechanisms of aging. This kind of multitargeted activity is a hallmark of nutritional supplements. The fact that the formula contains many multitargeted nutrients with overlapping mechanisms of action may underlie its dramatic effects. Such characteristics are typically lacking in prescription drugs, which generally target only one mechanism, and when they interact it is often in a negative, rather than a synergistic fashion.

The nutrient mixture's ingredients have individually been shown to have powerful disease-fighting, health-promoting effects. Those effects, like the ones demonstrated in Dr. Rollo's series of studies, promise not only to increase longevity, but also to promote healthy mobility and preserve youthful cognitive function. Here is a summary of the impact these effects have on real-life human aging:

Antioxidant nutrients protect brain cells, slow brain aging, and reduce memory impairment, while also lowering cardiovascular and metabolic disease risks, preventing cancer, and improving immune function.6-18

Ingredients with anti-inflammatory actions protect against neurodegenerative diseases, improve cardiovascular and endothelial function, prevent fatty liver disease, improve muscle function, and fight cancer.14,19-33

The mitochondrial-enhancing nutrients improve energy availability in many tissues, preventing fatty liver disease, promoting weight loss and preventing obesity, improving cardiovascular and skeletal muscle function, improving cognition, and protecting brain cells from Parkinson's disease.34-47

Nutrients that overcome insulin resistance further aid in normalizing energy utilization, enhancing cognitive function, preventing metabolic syndrome from emerging, improving glucose and insulin responses during exercise, while of course lowering acute and chronic blood glucose, reducing hemoglobin A1C levels, and delaying complications of diabetes.48-59

Finally, nutrients that preserve membrane integrity improve cell-to-cell signaling and protect cellular DNA, improving brain cell and muscle function, inducing cancer cell death, protecting against atherosclerosis and slowing progression of cardiovascular disease, enhancing muscle health, and protecting liver cells.34,60-72

As you can see, this is an exhaustive list of preventive actions, many of which overlap. That, of course, is one of the desirable features of this formulation: aging is a complex, multifactorial process with overlapping causes, so preventing it requires a multitargeted approach using overlapping mechanisms.

Figure 1: Improvements in Learning and Memory in Supplemented Older Mice

Table of Nutrient Cocktail Ingredients
Nutrient	Mechanisms of Aging Affected
Nutrient	Oxidant Stress	Inflammation	Mitochondrial Function	Insulin Resistance	Membrane Integrity
B Vitamins (Vitamins B1, B3 (niacin), B6, B12) and Folate	X124		X73	X125
Vitamin C	X74
Vitamin D		X75,76		X77,78
Acetyl-L-carnitine	X126		X45-47
Alpha-lipoic acid	X128,130	X127	X44,131	X128-130
Acetylsalicylic acid (aspirin)		X79
Beta-carotene				X80	X65
Bioflavonoids	X13	X81
Chromium picolinate				X49,82,83
Garlic	X132	X84		X85	X64,86
Ginger root extract	X14,87	X14,58	X133	X57,88,89	X134
Ginkgo Biloba	X90-92
Ginseng	X93	X59	X94-96	X94,95	X96
Green tea extract	X97	X21,98,99		X100,101
L-Glutathione	X102
Magnesium	X103,104			X105-107
Manganese	X108			X109,110
Melatonin	X7	X111,112
N-Acetyl cysteine	X113
Potassium	X114			X114
Rutin	X115	X116
Selenium	X117	X118	X135	X51,52	X70
Vitamin E	X74,119
Cod liver oil (omega-3)		X120			X121
Coenzyme Q10	X136	X137	X42
Flax seed oil		X122			X123
TABLE: A total of 30 nutrients provides comprehensive coverage of all five key aging mechanisms. Note that most nutrients have multiple functions, and that all five mechanisms are addressed by multiple nutrients.

Summary

The 30 Nutrients Used in This Health and Longevity Study

Vitamin B1
Vitamin B3 (niacin)
Vitamin B6
Vitamin B12
Folate
Vitamin C
Vitamin D
Acetyl-L-carnitine
Alpha-lipoic acid
Acetylsalicylic acid (aspirin)
Beta-carotene
Bioflavonoids
Chromium picolinate
Garlic
Ginger root extract

Ginkgo biloba
Ginseng
Green tea extract
L-Glutathione
Magnesium
Manganese
Melatonin
N-Acetyl cysteine
Potassium
Rutin
Selenium
Vitamin E
Cod liver oil (omega-3)
Coenzyme Q10
Flax seed oil

Growing scientific evidence connects most of the chronic diseases, and even longevity itself, with five key mechanisms of aging.

By devising a supplement formula comprised of multiple nutrients that attack these five mechanisms through multiple pathways, international researchers have significantly lengthened the life span of experimental animals. Just as importantly, the nutrient mixture markedly enhances animals' overall mobility and cognition, restoring function in those areas to youthful levels.

The marked benefits demonstrated in response to this 30-ingredient nutrient cocktail help explain why studies with single-agent compounds do not always produce meaningful longevity-enhancing results.

All of the individual nutrients in the mixture are known to be safe and effective in humans, though time will tell if the specific combination of all thirty will prove as effective in humans as it has in mice. The preponderance of the evidence, however, suggests it may live up to expectations.

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

References

1. Lemon JA, Boreham DR, Rollo CD. A complex dietary supplement extends longevity of mice. J Gerontol A Biol Sci Med Sci. 2005 Mar;60(3):275-9.

2. Aksenov V, Long J, Liu J, et al. A complex dietary supplement augments spatial learning, brain mass, and mitochondrial electron transport chain activity in aging mice. Age (Dordr). 2011 Nov 27.

3. Aksenov V, Long J, Lokuge S, Foster JA, Liu J, Rollo CD. Dietary amelioration of locomotor, neurotransmitter and mitochondrial aging. Exp Biol Med (Maywood). 2010 Jan;235(1):66-76.

4. Barzilai N, Atzmon G, Derby CA, Bauman JM, Lipton RB. A genotype of exceptional longevity is associated with preservation of cognitive function. Neurology. 2006 Dec 26;67(12):2170-5.

5. Lemon JA, Boreham DR, Rollo CD. A dietary supplement abolishes age-related cognitive decline in transgenic mice expressing elevated free radical processes. Exp Biol Med (Maywood). 2003 Jul;228(7):800-10.

6. Khan MM, Ahmad A, Ishrat T, et al. Rutin protects the neural damage induced by transient focal ischemia in rats. Brain Res. 2009 Oct 6;1292:123-35.

7. Dkhar P, Sharma R. Amelioration of age-dependent increase in protein carbonyls of cerebral hemispheres of mice by melatonin and ascorbic acid. Neurochem Int. 2011 Dec;59(7):996-1002.

8. Sanchez-Sanchez AM, Martin V, Garcia-Santos G, et al. Intracellular redox state as determinant for melatonin antiproliferative vs cytotoxic effects in cancer cells. Free Radic Res. 2011 Nov;45(11-12):1333-41.

9. Weinreb O, Mandel S, Amit T, Youdim MB. Neurological mechanisms of green tea polyphenols in Alzheimer's and Parkinson's diseases. J Nutr Biochem. 2004 Sep;15(9):506-16.

10. Mahady GB. Ginkgo biloba for the prevention and treatment of cardiovascular disease: a review of the literature. J Cardiovasc Nurs. 2002 Jul;16(4):21-32.

11. Ray T, Maity PC, Banerjee S, et al. Vitamin C prevents cigarette smoke induced atherosclerosis in guinea pig model. J Atheroscler Thromb. 2010 Aug 31;17(8):817-27.

12. Catalgol B, Ozer NK. Protective effects of vitamin E against hypercholesterolemia-induced age-related diseases. Genes Nutr. 2012 Jan;7(1):91-8.

13. Inami S, Takano M, Yamamoto M, et al. Tea catechin consumption reduces circulating oxidized low-density lipoprotein. Int Heart J. 2007 Nov;48(6):725-32.

14. Sahebkar A. Potential efficacy of ginger as a natural supplement for nonalcoholic fatty liver disease. World J Gastroenterol. 2011 Jan 14;17(2):271-2.

15. Olatunji LA, Soladoye AO. Effect of increased magnesium intake on plasma cholesterol, triglyceride and oxidative stress in alloxan-diabetic rats. Afr J Med Med Sci. 2007 Jun;36(2):155-61.

16. Son EW, Lee SR, Choi HS, et al. Effects of supplementation with higher levels of manganese and magnesium on immune function. Arch Pharm Res. 2007 Jun;30(6):743-9.

17. Hoffmann FW, Hashimoto AC, Shafer LA, Dow S, Berry MJ, Hoffmann PR. Dietary selenium modulates activation and differentiation of CD4+ T cells in mice through a mechanism involving cellular free thiols. J Nutr. 2010 Jun;140(6):1155-61.

18. Abete I, Goyenechea E, Zulet MA, Martinez JA. Obesity and metabolic syndrome: potential benefit from specific nutritional components. Nutr Metab Cardiovasc Dis. 2011 Sep;21 Suppl 2:B1-15.

19. Panchal SK, Poudyal H, Arumugam TV, Brown L. Rutin attenuates metabolic changes, nonalcoholic steatohepatitis, and cardiovascular remodeling in high-carbohydrate, high-fat diet-fed rats. J Nutr. 2011 Jun;141(6):1062-9.

20. Queen BL, Tollefsbol TO. Polyphenols and aging. Curr Aging Sci. 2010 Feb;3(1):34-42.

21. Ahn HY, Kim CH. Epigallocatechin-3-gallate Regulates inducible nitric oxide synthase expression in human umbilical vein endothelial cells. Lab Anim Res. 2011 Jun;27(2):85-90.

22. Babu PV, Liu D. Green tea catechins and cardiovascular health: an update. Curr Med Chem. 2008;15(18):1840-50.

23. Chiang KC, Yeh CN, Chen MF, Chen TC. Hepatocellular carcinoma and vitamin D: a review. J Gastroenterol Hepatol. 2011 Nov;26(11):1597-603.

24. Prasad K. Flaxseed and cardiovascular health. J Cardiovasc Pharmacol. 2009 Nov;54(5):369-77.

25. Moertl D, Hammer A, Steiner S, Hutuleac R, Vonbank K, Berger R. Dose-dependent effects of omega-3-polyunsaturated fatty acids on systolic left ventricular function, endothelial function, and markers of inflammation in chronic heart failure of nonischemic origin: a double-blind, placebo-controlled, 3-arm study. Am Heart J. 2011 May;161(5):915 e1-9.

26. Chen YH, Lin SJ, Chen YL, Liu PL, Chen JW. Anti-inflammatory effects of different drugs/agents with antioxidant property on endothelial expression of adhesion molecules. Cardiovasc Hematol Disord Drug Targets. 2006 Dec;6(4):279-304.

27. Janakiram NB, Rao CV. Role of lipoxins and resolvins as anti-inflammatory and proresolving mediators in colon cancer. Curr Mol Med. 2009 Jun;9(5):565-79.

28. Kannappan R, Gupta SC, Kim JH, Reuter S, Aggarwal BB. Neuroprotection by spice-derived nutraceuticals: you are what you eat! Mol Neurobiol. 2011 Oct;44(2):142-59.

29. Colin-Gonzalez AL, Ortiz-Plata A, Villeda-Hernandez J, et al. Aged garlic extract attenuates cerebral damage and cyclooxygenase-2 induction after ischemia and reperfusion in rats. Plant Foods Hum Nutr. 2011 Nov;66(4):348-54.

30. Williams MJ, Sutherland WH, McCormick MP, Yeoman DJ, de Jong SA. Aged garlic extract improves endothelial function in men with coronary artery disease. Phytother Res. 2005 Apr;19(4):314-9.

31. Singhal NK, Srivastava G, Agrawal S, Jain SK, Singh MP. Melatonin as a neuroprotective agent in the rodent models of Parkinson's disease: Is it all set to irrefutable clinical translation? Mol Neurobiol. 2011 Dec 24.

32. Olcese JM, Cao C, Mori T, et al. Protection against cognitive deficits and markers of neurodegeneration by long-term oral administration of melatonin in a transgenic model of Alzheimer disease. J Pineal Res. 2009 Aug;47(1):82-96.

33. Nair SM, Rahman RM, Clarkson AN, et al. Melatonin treatment following stroke induction modulates L-arginine metabolism. J Pineal Res. 2011 Oct;51(3):313-23.

34. Cabral de Oliveira AC, Perez AC, Prieto JG, Duarte ID, Alvarez AI. Protection of Panax ginseng in injured muscles after eccentric exercise. J Ethnopharmacol. 2005 Feb 28;97(2):211-4.

35. Li XT, Chen R, Jin LM, Chen HY. Regulation on energy metabolism and protection on mitochondria of Panax ginseng polysaccharide. Am J Chin Med. 2009;37(6):1139-52.

36. Zhao W, Zhang X, Wang W, Zhang L. Experimental study for the anti-fatigue effect of ginseng general ginsenosides P.E. in vivo. Wei Sheng Yan Jiu. 2009 Mar;38(2):184-7.

37. Wu Z, Luo JZ, Luo L. American ginseng modulates pancreatic beta cell activities. Chin Med. 2007 Oct 25;2:11.

38. Naidu MU, Kumar KV, Mohan IK, Sundaram C, Singh S. Protective effect of Gingko biloba extract against doxorubicin-induced cardiotoxicity in mice. Indian J Exp Biol. 2002 Aug;40(8):894-900.

39. Mozet C, Martin R, Welt K, Fitzl G. Cardioprotective effect of EGb 761 on myocardial ultrastructure of young and old rat heart and antioxidant status during acute hypoxia. Aging Clin Exp Res. 2009 Feb;21(1):14-21.

40. Muller WE, Chatterjee SS. Cognitive and other behavioral effects of EGb 761 in animal models. Pharmacopsychiatry. 2003 Jun;36 Suppl 1:S24-31.

41. Fu X, Ji R, Dam J. Antifatigue effect of coenzyme Q10 in mice. J Med Food. 2010 Feb;13(1):211-5.

42. Dai YL, Luk TH, Yiu KH, et al. Reversal of mitochondrial dysfunction by coenzyme Q10 supplement improves endothelial function in patients with ischaemic left ventricular systolic dysfunction: a randomized controlled trial. Atherosclerosis. 2011 Jun;216(2):395-401.

43. Jia H, Liu Z, Li X, et al. Synergistic anti-Parkinsonism activity of high doses of B vitamins in a chronic cellular model. Neurobiol Aging. 2010 Apr;31(4):636-46.

44. Koh EH, Lee WJ, Lee SA, et al. Effects of alpha-lipoic Acid on body weight in obese subjects. Am J Med. 2011 Jan;124(1):85 e1-8.

45. Pesce V, Fracasso F, Cassano P, Lezza AM, Cantatore P, Gadaleta MN. Acetyl-L-carnitine supplementation to old rats partially reverts the age-related mitochondrial decay of soleus muscle by activating peroxisome proliferator-activated receptor gamma coactivator-1alpha-dependent mitochondrial biogenesis. Rejuvenation Res. 2010 Apr-Jun;13(2-3):148-51.

46. Zhang H, Jia H, Liu J, et al. Combined R-alpha-lipoic acid and acetyl-L-carnitine exerts efficient preventative effects in a cellular model of Parkinson's disease. J Cell Mol Med. 2010 Jan;14(1-2):215-25.

47. Xia LJ, Folkers K. Improved methodology to assay carnitine and levels of free and total carnitine in human plasma. Biochem Biophys Res Commun. 1991 May 15;176(3):1617-23.

48. Keszthelyi Z, Past T, Koltai K, Szabo L, Mozsik G. Chromium (III)-ion enhances the utilization of glucose in type-2 diabetes mellitus. Orv Hetil. 2003 Oct 19;144(42):2073-6.

49. Cefalu WT, Rood J, Pinsonat P, et al. Characterization of the metabolic and physiologic response to chromium supplementation in subjects with type 2 diabetes mellitus. Metabolism. 2010 May;59(5):755-62.

50. Krikorian R, Eliassen JC, Boespflug EL, Nash TA, Shidler MD. Improved cognitive-cerebral function in older adults with chromium supplementation. Nutr Neurosci. 2010 Jun;13(3):116-22.

51. Li YB, Han JY, Jiang W, Wang J. Selenium inhibits high glucose-induced cyclooxygenase-2 and P-selectin expression in vascular endothelial cells. Mol Biol Rep. 2011 Apr;38(4):2301-6.

52. Iizuka Y, Ueda Y, Yagi Y, Sakurai E. Significant improvement of insulin resistance of GK rats by treatment with sodium selenate. Biol Trace Elem Res. 2010 Dec;138(1-3):265-71.

53. Zulet MA, Puchau B, Hermsdorff HH, Navarro C, Martinez JA. Dietary selenium intake is negatively associated with serum sialic acid and metabolic syndrome features in healthy young adults. Nutr Res. 2009 Jan;29(1):41-8.

54. Guerrero-Romero F, Tamez-Perez HE, Gonzalez-Gonzalez G, et al. Oral magnesium supplementation improves insulin sensitivity in non-diabetic subjects with insulin resistance. A double-blind placebo-controlled randomized trial. Diabetes Metab. 2004 Jun;30(3):253-8.

55. Mooren FC, Kruger K, Volker K, Golf SW, Wadepuhl M, Kraus A. Oral magnesium supplementation reduces insulin resistance in non-diabetic subjects - a double-blind, placebo-controlled, randomized trial. Diabetes Obes Metab. 2011 Mar;13(3):281-4.

56. Teramoto T, Kawamori R, Miyazaki S, Teramukai S. Sodium intake in men and potassium intake in women determine the prevalence of metabolic syndrome in Japanese hypertensive patients: OMEGA Study. Hypertens Res. 2011 Aug;34(8):957-62.

57. Saraswat M, Suryanarayana P, Reddy PY, Patil MA, Balakrishna N, Reddy GB. Antiglycating potential of Zingiber officinalis and delay of diabetic cataract in rats. Mol Vis. 2010;16:1525-37.

58. Li XH, McGrath KC, Nammi S, Heather AK, Roufogalis BD. Attenuation of liver pro-inflammatory responses by zingiber officinale via inhibition of NF-kappa B activation in high-fat diet-fed rats. Basic Clin Pharmacol Toxicol. 2011 Sep 8.

59. Jung HL, Kwak HE, Kim SS, et al. Effects of Panax ginseng supplementation on muscle damage and inflammation after uphill treadmill running in humans. Am J Chin Med. 2011;39(3):441-50.

60. Lee HU, Bae EA, Han MJ, Kim NJ, Kim DH. Hepatoprotective effect of ginsenoside Rb1 and compound K on tert-butyl hydroperoxide-induced liver injury. Liver Int. 2005 Oct;25(5):1069-73.

61. Hsu CC, Ho MC, Lin LC, Su B, Hsu MC. American ginseng supplementation attenuates creatine kinase level induced by submaximal exercise in human beings. World J Gastroenterol. 2005 Sep 14;11(34):5327-31.

62. Radad K, Moldzio R, Rausch WD. Ginsenosides and their CNS targets. CNS Neurosci Ther. 2011 Dec;17(6):761-8.

63. Butt MS, Sultan MT, Iqbal J. Garlic: nature's protection against physiological threats. Crit Rev Food Sci Nutr. 2009 Jun;49(6):538-51.

64. Benavides GA, Squadrito GL, Mills RW, et al. Hydrogen sulfide mediates the vasoactivity of garlic. Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):17977-82.

65. Machefer G, Groussard C, Vincent S, et al. Multivitamin-mineral supplementation prevents lipid peroxidation during 'the Marathon des Sables.' J Am Coll Nutr. 2007 Apr;26(2):111-20.

66. Su KP. Biological mechanism of antidepressant effect of omega-3 fatty acids: how does fish oil act as a ‘mind-body interface'? Neurosignals. 2009;17(2):144-52.

67. Chiu CC, Su KP, Cheng TC, et al. The effects of omega-3 fatty acids monotherapy in Alzheimer's disease and mild cognitive impairment: a preliminary randomized double-blind placebo-controlled study. Prog Neuropsychopharmacol Biol Psychiatry. 2008 Aug 1;32(6):1538-44.

68. Fiaccavento R, Carotenuto F, Vecchini A, et al. An omega-3 fatty acid-enriched diet prevents skeletal muscle lesions in a hamster model of dystrophy. Am J Pathol. 2010 Nov;177(5):2176-84.

69. Corsetto PA, Montorfano G, Zava S, et al. Effects of n-3 PUFAs on breast cancer cells through their incorporation in plasma membrane. Lipids Health Dis. 2011;10:73.

70. Micke O, Schomburg L, Buentzel J, Kisters K, Muecke R. Selenium in oncology: from chemistry to clinics. Molecules. 2009;14(10):3975-88.

71. Steinbrenner H, Bilgic E, Alili L, Sies H, Brenneisen P. Selenoprotein P protects endothelial cells from oxidative damage by stimulation of glutathione peroxidase expression and activity. Free Radic Res. 2006 Sep;40(9):936-43.

72. Soriano-Garcia M. Organoselenium compounds as potential therapeutic and chemopreventive agents: a review. Curr Med Chem. 2004 Jun;11(12):1657-69.

73. Ames BN. Delaying the mitochondrial decay of aging. Ann N Y Acad Sci. 2004 Jun;1019:406-11.

74. Kayan M, Naziroglu M, Celik O, Yalman K, Koylu H. Vitamin C and E combination modulates oxidative stress induced by X-ray in blood of smoker and nonsmoker radiology technicians. Cell Biochem Funct. 2009 Oct;27(7):424-9.

75. Choi B, Lee ES, Sohn S. Vitamin D3 ameliorates herpes simplex virus-induced Behcet's disease-like inflammation in a mouse model through down-regulation of Toll-like receptors. Clin Exp Rheumatol. 2011 Jul-Aug;29(4 Suppl 67):S13-9.

76. Adorini L, Penna G. Dendritic cell tolerogenicity: a key mechanism in immunomodulation by vitamin D receptor agonists. Hum Immunol. 2009 May;70(5):345-52.

77. Mitri J, Dawson-Hughes B, Hu FB, Pittas AG. Effects of vitamin D and calcium supplementation on pancreatic beta cell function, insulin sensitivity, and glycemia in adults at high risk of diabetes: the Calcium and Vitamin D for Diabetes Mellitus (CaDDM) randomized controlled trial. Am J Clin Nutr. 2011 Aug;94(2): 486-94.

78. Teegarden D, Donkin SS. Vitamin D: emerging new roles in insulin sensitivity. Nutr Res Rev. 2009 Jun;22(1):82-92.

79. Jung KJ, Kim JY, Zou Y, Kim YJ, Yu BP, Chung HY. Effect of short-term, low dose aspirin supplementation on the activation of pro-inflammatory NF-kappaB in aged rats. Mech Ageing Dev. 2006 Mar;127(3):223-30.

80. Kameji H, Mochizuki K, Miyoshi N, Goda T. beta-Carotene accumulation in 3T3-L1 adipocytes inhibits the elevation of reactive oxygen species and the suppression of genes related to insulin sensitivity induced by tumor necrosis factor-alpha. Nutrition. 2010 Nov-Dec;26(11-12):1151-6.

81. Salminen A, Kauppinen A, Kaarniranta K. Phytochemicals suppress nuclear factor-kappaB signaling: impact on health span and the aging process. Curr Opin Clin Nutr Metab Care. 2012 Jan;15(1):23-8.

82. Wang YQ, Dong Y, Yao MH. Chromium picolinate inhibits resistin secretion in insulin-resistant 3T3-L1 adipocytes via activation of amp-activated protein kinase. Clin Exp Pharmacol Physiol. 2009 Aug;36(8):843-9.

83. Wang YQ, Yao MH. Effects of chromium picolinate on glucose uptake in insulin-resistant 3T3-L1 adipocytes involve activation of p38 MAPK. J Nutr Biochem. 2009 Dec;20(12):982-91.

84. Vazquez-Prieto MA, Rodriguez Lanzi C, Lembo C, Galmarini CR, Miatello RM. Garlic and onion attenuates vascular inflammation and oxidative stress in fructose-fed rats. J Nutr Metab. 2011;2011:475216.

85. Liu CT, Hse H, Lii CK, Chen PS, Sheen LY. Effects of garlic oil and diallyl trisulfide on glycemic control in diabetic rats. Eur J Pharmacol. 2005 Jun 1;516(2):165-73.

86. Nahdi A, Hammami I, Kouidhi W, et al. Protective effects of crude garlic by reducing iron-mediated oxidative stress, proliferation and autophagy in rats. J Mol Histol. 2010 Oct;41(4-5):233-45.

87. Jagetia G, Baliga M, Venkatesh P. Ginger (Zingiber officinale Rosc.), a dietary supplement, protects mice against radiation-induced lethality: mechanism of action. Cancer Biother Radiopharm. 2004 Aug;19(4):422-35.

88. Rani MP, Padmakumari KP, Sankarikutty B, Cherian OL, Nisha VM, Raghu KG. Inhibitory potential of ginger extracts against enzymes linked to type 2 diabetes, inflammation and induced oxidative stress. Int J Food Sci Nutr. 2011 Mar;62(2):106-10.

89. Heimes K, Feistel B, Verspohl EJ. Impact of the 5-HT3 receptor channel system for insulin secretion and interaction of ginger extracts. Eur J Pharmacol. 2009 Dec 10;624(1-3):58-65.

90. Chan PC, Xia Q, Fu PP. Ginkgo biloba leave extract: biological, medicinal, and toxicological effects. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2007 Jul-Sep;25(3):211-44.

91. Boveris AD, Galleano M, Puntarulo S. In vivo supplementation with Ginkgo biloba protects membranes against lipid peroxidation. Phytother Res. 2007 Aug;21(8):735-40.

92. Yao P, Liu LG, Jia WB, et al. Effect of flavonoids of ginkgo biloba on anti-oxidizing system of mice after acute alcohol administration. Wei Sheng Yan Jiu. 2005 May;34(3):303-6.

93. Kim HG, Yoo SR, Park HJ, et al. Antioxidant effects of Panax ginseng C.A. Meyer in healthy subjects: a randomized, placebo-controlled clinical trial. Food Chem Toxicol. 2011 Sep;49(9):2229-35.

94. Luo JZ, Luo L. Ginseng on hyperglycemia: effects and mechanisms. Evid Based Complement Alternat Med. 2009 Dec;6(4):423-7.

95. Luo JZ, Luo L. American ginseng stimulates insulin production and prevents apoptosis through regulation of uncoupling protein-2 in cultured beta cells. Evid Based Complement Alternat Med. 2006 Sep;3(3):365-72.

96. Voces J, Cabral de Oliveira AC, Prieto JG, et al. Ginseng administration protects skeletal muscle from oxidative stress induced by acute exercise in rats. Braz J Med Biol Res. 2004 Dec;37(12):1863-71.

97. Liu H, Guo Z, Xu L, Hsu S. Protective effect of green tea polyphenols on tributyltin-induced oxidative damage detected by in vivo and in vitro models. Environ Toxicol. 2008 Feb;23(1):77-83.

98. Tsai PY, Ka SM, Chang JM, et al. Epigallocatechin-3-gallate prevents lupus nephritis development in mice via enhancing the Nrf2 antioxidant pathway and inhibiting NLRP3 inflammasome activation. Free Radic Biol Med. 2011 Aug 1;51(3):744-54.

99. Ellis LZ, Liu W, Luo Y, et al. Green tea polyphenol epigallocatechin-3-gallate suppresses melanoma growth by inhibiting inflammasome and IL-1beta secretion. Biochem Biophys Res Commun. 2011 Oct 28;414(3):551-6.

100. Serisier S, Leray V, Poudroux W, Magot T, Ouguerram K, Nguyen P. Effects of green tea on insulin sensitivity, lipid profile and expression of PPARalpha and PPARgamma and their target genes in obese dogs. Br J Nutr. 2008 Jun;99(6):1208-16.

101. Cao H, Hininger-Favier I, Kelly MA, et al. Green tea polyphenol extract regulates the expression of genes involved in glucose uptake and insulin signaling in rats fed a high fructose diet. J Agric Food Chem. 2007 Jul 25;55(15):6372-8.

102. Loguercio C, D'Argenio G, Delle Cave M, et al. Glutathione supplementation improves oxidative damage in experimental colitis. Dig Liver Dis. 2003 Sep;35(9):635-41.

103. Bede O, Nagy D, Suranyi A, Horvath I, Szlavik M, Gyurkovits K. Effects of magnesium supplementation on the glutathione redox system in atopic asthmatic children. Inflamm Res. 2008 Jun;57(6):279-86.

104. Hans CP, Chaudhary DP, Bansal DD. Effect of magnesium supplementation on oxidative stress in alloxanic diabetic rats. Magnes Res. 2003 Mar;16(1):13-9.

105. Guerrero-Romero F, Rodriguez-Moran M. Magnesium improves the beta-cell function to compensate variation of insulin sensitivity: double-blind, randomized clinical trial. Eur J Clin Invest. 2011 Apr;41(4):405-10.

106. Barbagallo M, Dominguez LJ. Magnesium metabolism in type 2 diabetes mellitus, metabolic syndrome and insulin resistance. Arch Biochem Biophys. 2007 Feb 1;458(1):40-7.

107. Takaya J, Higashino H, Kobayashi Y. Intracellular magnesium and insulin resistance. Magnes Res. 2004 Jun;17(2):126-36.

108. Tu HK, Pan KF, Zhang Y, et al. Manganese superoxide dismutase polymorphism and risk of gastric lesions, and its effects on chemoprevention in a Chinese population. Cancer Epidemiol Biomarkers Prev. 2010 Apr;19(4):1089-97.

109. Manolopoulos KN, Klotz LO, Korsten P, Bornstein SR, Barthel A. Linking Alzheimer's disease to insulin resistance: the FoxO response to oxidative stress. Mol Psychiatry. 2010 Nov;15(11): 1046-52.

110. Houstis N, Rosen ED, Lander ES. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature. 2006 Apr 13;440(7086):944-8.

111. Ochoa JJ, Diaz-Castro J, Kajarabille N, et al. Melatonin supplementation ameliorates oxidative stress and inflammatory signaling induced by strenuous exercise in adult human males. J Pineal Res. 2011 Nov;51(4):373-80.

112. Perreau VM, Bondy SC, Cotman CW, Sharman KG, Sharman EH. Melatonin treatment in old mice enables a more youthful response to LPS in the brain. J Neuroimmunol. 2007 Jan;182 (1-2):22-31.

113. Santra A, Chowdhury A, Ghatak S, Biswas A, Dhali GK. Arsenic induces apoptosis in mouse liver is mitochondria dependent and is abrogated by N-acetylcysteine. Toxicol Appl Pharmacol. 2007 Apr 15;220(2):146-55.

114. Ando K, Matsui H, Fujita M, Fujita T. Protective effect of dietary potassium against cardiovascular damage in salt-sensitive hypertension: possible role of its antioxidant action. Curr Vasc Pharmacol. 2010 Jan;8(1):59-63.

115. Ghiasi M, Heravi MM. Quantum mechanical study of antioxidative ability and antioxidative mechanism of rutin (vitamin P) in solution. Carbohydr Res. 2011 May 1;346(6):739-44.

116. Arjumand W, Seth A, Sultana S. Rutin attenuates cisplatin induced renal inflammation and apoptosis by reducing NFkappaB, TNF-alpha and caspase-3 expression in wistar rats. Food Chem Toxicol. 2011 Sep;49(9):2013-21.

117. Brozmanova J, Manikova D, Vlckova V, Chovanec M. Selenium: a double-edged sword for defense and offence in cancer. Arch Toxicol. 2010 Dec;84(12):919-38.

118. Clarke C, Baghdadi H, Howie AF, Mason JI, Walker SW, Beckett GJ. Selenium supplementation attenuates procollagen-1 and interleukin-8 production in fat-loaded human C3A hepatoblastoma cells treated with TGFbeta1. Biochim Biophys Acta. 2010 Jun;1800(6):611-8.

119. Vina J, Lloret A, Giraldo E, Badia MC, Alonso MD. Antioxidant pathways in Alzheimer's disease: possibilities of intervention. Curr Pharm Des. 2011 Dec;17(35):3861-4.

120. McDaniel JC, Ahijevych K, Belury M. Effect of n-3 oral supplements on the n-6/n-3 ratio in young adults. West J Nurs Res. 2010 Feb;32(1):64-80.

121. Mabile L, Piolot A, Boulet L, et al. Moderate intake of n-3 fatty acids is associated with stable erythrocyte resistance to oxidative stress in hypertriglyceridemic subjects. Am J Clin Nutr. 2001 Oct;74(4):449-56.

122. Barcelo-Coblijn G, Murphy EJ, Othman R, Moghadasian MH, Kashour T, Friel JK. Flaxseed oil and fish-oil capsule consumption alters human red blood cell n-3 fatty acid composition: a multiple-dosing trial comparing 2 sources of n-3 fatty acid. Am J Clin Nutr. 2008 Sep;88(3):801-9.

123. Mourvaki E, Cardinali R, Dal Bosco A, Corazzi L, Castellini C. Effects of flaxseed dietary supplementation on sperm quality and on lipid composition of sperm subfractions and prostatic granules in rabbit. Theriogenology. 2010 Mar 15;73(5):629-37.

124. Bîcu M, Moţa M, Panduru NM, Grăunţeanu C, Moţa E. Oxidative stress in diabetic kidney disease. Rom J Intern Med. 2010;48(4):307-12.

125. Gammon CS, von Hurst PR, Coad J, Kruger R, Stonehouse W. Vegetarianism, vitamin B12 status, and insulin resistance in a group of predominantly overweight/obese South Asian women. Nutrition. 2012 Jan;28(1):20-4.

126. Annadurai T, Vigneshwari S, Thirukumaran R, Thomas PA, Geraldine P. Acetyl-L-carnitine prevents carbon tetrachloride-induced oxidative stress in various tissues of Wistar rats. J Physiol Biochem. 2011 Dec;67(4):519-30.

127. Maczurek A, Hager K, Kenklies M, et al. Lipoic acid as an anti-inflammatory and neuroprotective treatment for Alzheimer's disease. Adv Drug Deliv Rev. 2008 Oct-Nov;60(13-14):1463-70.

128. Ansar H, Mazloom Z, Kazemi F, Hejazi N. Effect of alpha-lipoic acid on blood glucose, insulin resistance and glutathione peroxidase of type 2 diabetic patients. Saudi Med J. 2011 Jun;32(6):584-8.

129. Kamenova P. Improvement of insulin sensitivity in patients with type 2 diabetes mellitus after oral administration of alpha-lipoic acid. Hormones (Athens). 2006 Oct-Dec;5(4):251-8.

130. Evans JL, Goldfine ID. Alpha-lipoic acid: a multifunctional antioxidant that improves insulin sensitivity in patients with type 2 diabetes. Diabetes Technol Ther. 2000 Autumn;2(3):401-13.

131. Palacios HH, Yendluri BB, Parvathaneni K, et al. Mitochondrion-specific antioxidants as drug treatments for Alzheimer disease. CNS Neurol Disord Drug Targets. 2011 Mar;10(2):149-62.

132. Vazquez-Prieto MA, Rodriguez Lanzi C, Lembo C, Galmarini CR, Miatello RM. Garlic and onion attenuates vascular inflammation and oxidative stress in fructose-fed rats. J Nutr Metab. 2011;2011:475216.

133. Ramudu SK, Korivi M, Kesireddy N, et al. Nephro-protective effects of a ginger extract on cytosolic and mitochondrial enzymes against streptozotocin (STZ)-induced diabetic complications in rats. Chin J Physiol. 2011 Apr 30;54(2):79-86.

134. Chung WY, Yow CM, Benzie IF. Assessment of membrane protection by traditional Chinese medicines using a flow cytometric technique: preliminary findings. Redox Rep. 2003;8(1):31-3.

135. Taskin E, Dursun N. The protection of selenium on adriamycin-induced mitochondrial damage in rat. Biol Trace Elem Res. 2012 Jan 12. Epub ahead of print.

136. Lee BJ, Huang YC, Chen SJ, Lin PT. Coenzyme Q10 supplementation reduces oxidative stress and increases antioxidant enzyme activity in patients with coronary artery disease. Nutrition. 2012 Mar;28(3):250-5.

137. Schmelzer C, Kubo H, Mori M, et al. Supplementation with the reduced form of Coenzyme Q10 decelerates phenotypic characteristics of senescence and induces a peroxisome proliferator-activated receptor-alpha gene expression signature in SAMP1 mice. Mol Nutr Food Res. 2010 Jun;54(6):805-15.