Life Extension Magazine®

Issue: Jul 2010

You Are Eating More Calories Than You Think

A startling Mayo Clinic analysis confirms that millions of normal-weight people are ingesting more calories than their bodies can utilize, significantly jeopardizing their health and longevity. The good news is a unique class of plant extracts simulates some of the effects of reduced caloric intake at the genetic level. Find out how the latest of these advanced calorie restriction mimetics enhances the benefits of resveratrol.

By Julius Goepp, MD.

You Are Eating More Calories Than You Think

An estimated 30 million Americans over age 201,2 face lethal risks from excess caloric intake, but have no idea they are jeopardizing their health and longevity.

The reason why may surprise you: these individuals appear thin and healthy. Many adhere to a decent dietary and exercise regimen.1,2 But according to a comprehensive analysis conducted by heart researchers at the Mayo Clinic, they are still ingesting more calories than their bodies are able to utilize. The deadly consequences, published earlier this year, include:

  • Four-fold higher rates of metabolic syndrome in later life
  • Increased cardiovascular disease risk
  • Blood lipid abnormalities in men and women
  • Hypertension in men
  • Double the risk of cardiac death in women.1,2

This modern scourge of overconsumption happens to be an independent risk factor for virtually all age-related diseases—from cancer and atherosclerosis to arthritis and dementia.3-8

It is also the principal challenge confronting aging individuals who wish to reap the extraordinary benefits of caloric restriction or CR. Reducing the number of calories you consume while maintaining optimal nutritional status initiates a system-wide anti-aging cascade. By “switching on” genes that favor youthful physiological function, caloric restriction dramatically slows the pathological aging process.

Caloric Restriction: The Longevity Gene Activator

CR also improves biomarkers of health across the board, from cognitive function and cancer risk to glucose control and cardiac health.9-14 Yet most people cannot submit to a sufficiently restrictive dietary regimen to obtain the benefits.

The good news is that avant-garde researchers have brought to light a novel class of nutrients called calorie restriction mimetics. This handful of natural compounds has been shown to safely simulate some of the beneficial effects of calorie restriction without the need for stringent dietary measures.

Earlier this year, Life Extension® provided you with the first comprehensive review of five known CR mimetics, some that Foundation members have been taking for many years.

In this article, you will learn of the latest research on these cutting-edge compounds. You will also discover the sixth CR mimetic to emerge in the scientific literature. This little-known but potent flavonoid called fisetin is difficult to obtain in sufficient amounts through diet alone.15 The most recent scientific evidence indicates it affords particular protection to the aging brain—and enhances the action of resveratrol!16-20

Caloric Restriction: The Longevity Gene Activator

A wealth of scientific data spanning more than seven decades confirms caloric restriction’s unmatched power to boost longevity in nearly all forms of life, as much as 100% in some species.21,22

One of the primary means by which calorie restriction induces its profound anti-aging effects is through favorable gene expression. CR has been shown to activate a class of powerful signaling molecules known as silent information regulators (Sir), or sirtuins. These operate across multiple cellular pathways, regulating gene expression, aging, metabolism, DNA repair, and apoptosis (programmed cell death).23-25

Sirtuins are ubiquitous in nature; one or more sirtuins are present in most species, from bacteria to mammals.23 This may explain why calorie restriction so radically increases life span across the full range of living organisms.

In response to a reduction in caloric intake—sirtuins initiate a sequence of profoundly beneficial age-delaying processes. The sirtuin-mediated effects of calorie restriction have been successfully replicated in species ranging from yeast to higher primates.9,26 Sirtuins have been shown to:

  • Enhance protection against oxidative stress
  • Minimize protein damage by glucose (glycation)
  • Prevent accumulated DNA damage
  • Inhibit inflammation
  • Improve mitochondrial function
  • Promote the function of organelles (cellular sub-structures) responsible for maintaining structural and functional integrity 27-40

Through these and other mechanisms of action, caloric restriction improves virtually all biomarkers of health. In a landmark 20-year controlled study of CR in primates published last year, a moderately restricted diet produced a three-fold reduction in the risk of age-related disease. Cardiovascular disease and cancer incidence were less than half in the calorie restricted group, and none of the monkeys developed impaired glucose control or diabetes.9

Fisetin: A New Multimodal CR Mimetic

Fisetin: A New Multimodal CR Mimetic

Although present in strawberries, the flavonoid fisetin is a relatively rare nutrient found only in minute quantities in the plant kingdom. It has been shown to maintain levels of glutathione (the primary antioxidant internal to most cells in the body) in the presence of oxidative stress.17 Its exceptional capacity to ward off age-related cognitive decline through the modulation of multiple neuronal (nerve cell-related) pathways has drawn the most intense scientific interest.17 Fisetin also exerts multimodal effects common to known caloric restriction mimetics.

Among the many recent findings on fisetin, one in particular stands out: it may act to stabilize resveratrol by shielding it from metabolic breakdown in the liver.20 Scientists believe fisetin may thus increase the amount of resveratrol staying in the blood, enhancing its effects. This is important because one of resveratrol’s possible limitations is a relatively short half-life in the body.

Antioxidant Protection

Fisetin’s antioxidant potency is comparable to quercetin.41 Alone among the polyphenols, fisetin induces genetic expression of a powerful cellular antioxidant system called quinone reductase or QR, which is vital in preventing oxidant-induced carcinogenesis.42 The antioxidant action of fisetin has been shown to significantly extend the life span of C. elegans—a benchmark indicator of CR mimesis (simulation).43,44 Its proven ability to inhibit oxidation of harmful LDL cholesterol also indicates fisetin’s potential in preventing cardiovascular disease.45,46

Glycation Blockade

Laboratory studies show that fisetin inhibits glycation (destructive binding of sugar molecules to functional proteins) in human hemoglobin, protecting red blood cells from long-term damage.47 It interacts beneficially with other human proteins and with DNA.48 These effects likely account for its specific ability to protect brain and nerve tissues. Studies show that advanced glycation end-products (AGEs) and their receptors are closely linked to conditions such as Alzheimer’s disease and other forms of cognitive decline.49-51

DNA Protection

Fisetin ranks very high among flavonoids at preventing DNA damage.52 Low doses of fisetin offer superior protection against DNA strand rupture induced by hydrogen peroxide, a potent free radical.53 These effects also place fisetin high on the list of potentially effective cancer-preventing agents.

Inflammation Control

Fisetin suppresses inflammatory cytokine production by diverse mechanisms.54 It downregulates the master inflammatory modulator NF-kB,55 which may reduce inflammatory responses, cancer-related cell proliferation, and metastatic alterations through a unique set of cellular mechanisms.56,57

Mitochondrial Support

Fisetin has been shown to protect mitochondria against repeated oxidative stress.17 Cells treated with fisetin are able to maintain mitochondrial-dependent levels of adenosine triphosphate or ATP—the body’s primary “energy currency”—in the presence of powerful mitochondrial toxins.17 In live animal studies, researchers found that fisetin could significantly improve behavioral outcomes when administered five minutes after the initiation of an embolic stroke.17 Strokes impose a huge metabolic burden on brain tissue, and destruction of mitochondria is one reason for the neurological deficits observed after such events. Fisetin was shown to reduce the amount and volume of brain damage following induction of stroke in animal models.17

What You Need to Know: Caloric Restriction
  • Scientists estimate that 30 million Americans face the lethal risks of excessive energy (calorie) intake, even though they appear thin and healthy.
  • The result is a four-fold increase in risk of developing metabolic syndrome, increased risk of cardiovascular disease, and more than double the risk of cardiac death in women.
  • These alarming findings reflect the difficulty of avoiding excess calories in affluent societies—and underscore the enormous challenge facing individuals wishing to obtain extraordinary benefits of caloric restriction.
  • Fortunately, avant-garde research has brought to light a handful of nutrients that can safely simulate the effects of caloric restriction.
  • Each operates in a multitargeted and complementary fashion to attain calorie restriction-like effects within cells.
  • They have been shown to limit oxidation, reduce glycation, restrict or even repair DNA damage, quell inflammation, support mitochondrial health, and enhance the function of the cellular sub-units called proteasomes and lysomes.
  • In addition to the five natural CR mimetics Life Extension reviewed earlier this year, a sixth has been identified called fisetin.
  • Fisetin has been shown to optimize levels of the endogenous antioxidant glutathione in cells, target factors implicated in brain aging, and may even enhance the action of resveratrol.

Protection of Vital Cellular Components

Fisetin consistently increases activity of a vital cellular waste excretion unit called the proteasome, to such an extent that it promotes nerve cell survival following withdrawal of otherwise vital growth factors.58 Proteasome activity is decreased in a variety of age-associated neurological disorders including Alzheimer’s and Parkinson’s diseases.17 Researchers in the laboratory of Dr. Pamela Maher of the Salk Institute for Biological Studies found that fisetin was able to modestly increase proteasome activity in primary cultures of brain cells, promoting their survival and preserving their optimal functioning.17

Maher and her colleagues found that fisetin promotes long-term potentiation of brain neurons, thereby enhancing memory in two pre-clinical models of aging.17,18

Compelling New Evidence for Established CR Mimetics

Resveratrol

Resveratrol, the most widely known of the CR mimetics, is a polyphenol found most abundantly in red wine grape skins, as well as in many other darkly colored fruits, accounting in part for their known health-promoting effects.59 Its ability to activate sirtuins has been thoroughly documented in the scientific literature.26,59-64

Compelling New Evidence for Established CR Mimetics

While a potent sirtuin activator and antioxidant in its own right, resveratrol also mobilizes a number of antioxidant processes internal to cells.59,65-69 These combined effects are responsible for resveratrol’s ability to prevent oxidative damage following heart attack or stroke, heading off many of its deadly consequences.70 Similarly, resveratrol’s antioxidant function is credited with prevention of the neuronal damage observed in Alzheimer’s and other neurodegenerative diseases.63,68,71,72

Resveratrol also inhibits advanced glycation end products (AGEs) that arise from lifelong exposure to glucose in blood—both effects and causes of type 2 diabetes. Resveratrol inhibits AGE-induced smooth muscle cell overgrowth in blood vessel walls.73 It protects laboratory animals from kidney damage in early-stage diabetes by switching on a protective enzyme system called adenosine monophosphate-activated serine/threonine kinase (AMPK).74

Resveratrol improves insulin sensitivity and regulates genetic expression of dangerous adipokines, cytokines produced by fat tissue, which are associated with development of diabetes and the consequences of the metabolic syndrome.75 In early 2010 it was discovered that resveratrol reduces body weight and fat content in obese animals through its effects on gene expression and enzyme activities.76

Pterostilbene

Pterostilbene is a polyphenol closely related to resveratrol, but with unique attributes, including potent cancer-preventing and lipid-lowering capabilities.77,78 It has powerful antioxidant capabilities, scavenging destructive free radicals and inhibiting oxidant-induced electrolyte loss from cells.79 Diabetic animals supplemented with pterostilbene demonstrate marked improvements in their damaged cellular antioxidant systems.80 Supplemented rats experience remarkable reversal of age-related cognitive deficits.81 Astonishingly, pterostilbene switches on genes governing the production of intracellular antioxidant enzymes such as superoxide dismutase (SOD).82

Pterostilbene has been shown to directly lower blood glucose, which may help prevent the formation of AGEs. Remarkably, pterostilbene’s ability to lower glucose was comparable to that of metformin, a pharmaceutical used in the management of diabetes.83

Pterostilbene

Pterostilbene displays potent cancer-preventing effects related to its ability to prevent or repair DNA damage, one of the first steps in cancer initiation. It inhibits development of pre-cancerous lesions in mouse models of breast cancer, similarly to resveratrol.79 And pterostilbene can prevent expression of genes that otherwise promote cancer metastasis; it has also been shown to inhibit metastatic malignant melanoma growth and extend host survival.84

Like its close relative resveratrol, pterostilbene is perhaps best known for its potent inflammation-quenching effects, which it achieves, as usual, by several complementary mechanisms. Pterostilbene inhibits the ubiquitous COX-2 enzyme responsible for producing inflammatory prostaglandins, which are also involved in creating the pain sensation.85 Pterostilbene also targets inflammatory cells called macrophages, reducing their ability to multiply; this has enormous application to atherosclerosis, which requires activated macrophages to initiate deadly inflammatory plaques.86,87

Grape Seed Extract

Grape seed extracts (GSE) favorably influence expression of genes involved in cellular aging, giving them a broad array of multitargeted benefits.88,89

GSE has been shown to enhance antioxidant status and decrease free radical-induced protein oxidation in aging rats’ brains.90 A 2009 study of type 2 diabetics at high risk of cardiovascular disease showed that GSE significantly improved markers of inflammation, oxidative stress, and blood sugar over a 4-week period.91

GSE’s remarkable cardiovascular health benefits also derive from their ability to fight advanced glycation end products (AGEs) in endothelial tissue.92,93

GSE effectively combats inflammatory responses throughout the body by modifying gene expression. One early study found beneficial alterations in expression of 13 proteins in brain tissue alone.88 GSE inhibited platelet inflammatory responses at doses easily attainable in humans, demonstrating an additional vascular protective effect.94 And GSE switched off the inflammatory “master molecule” NF-kB in mice exposed to UV radiation, helping to mitigate oxidant-induced inflammation.95

Quercetin

Grape Seed Extract

The polyphenol quercetin protects endothelial tissue against oxidative damage by preventing oxidation of LDL cholesterol, one of the chief offenders in the atherosclerosis cascade.96,97 It also reduces the new production of fats by liver cells.98 Quercetin’s antioxidant capacity prevents heart enlargement caused by blood pressure overload in laboratory animals.99 By a different mechanism, quercetin prevents migration and proliferation of vessel wall muscle cells in response to oxidative stress and activated platelets.100

Quercetin sharply reduces genetic expression of major inflammatory cytokines, suggesting its use for treatment of allergic and other inflammatory conditions.101,102 Inflammation plays a vital role in cancer development and cardiovascular disease as well, and quercetin’s anti-inflammatory effects lead to reduced invasiveness of certain breast cancers and reduced production of adhesion molecules in vascular endothelia.103,104

Black Tea

Consumption of black tea is widely known to improve circulating antioxidant status in humans.105,106 Black tea’s polyphenols and other constituents are particularly notable for their cardiovascular protective effects.107 These arise through a host of interlocking antioxidant-mediated mechanisms including reduced platelet aggregation, improved endothelial function, and reduced vascular inflammation.108-110

Components of black tea are powerful inhibitors of glycation and can prevent diabetic cataracts, further proving their calorie restriction mimetic credentials.111 Unlike most of the other nutrients we’ve discussed, the black tea polyphenols don’t directly reduce production of advanced glycation end products (AGEs); rather, they trap them as they are produced, reducing their concentrations in tissues.112,113

Activate Your Longevity Genes without Hunger

Scientists estimate that 30 million Americans face the lethal risks of excessive energy intake, even though they appear thin and healthy.

Quercetin

These alarming findings underscore the enormous challenge of avoiding excess energy intake and the obstacles of undertaking a caloric restriction regimen.

Fortunately, avant-garde research has brought to light a handful of nutrients that can safely simulate many of the effects of caloric restriction. Each operates in a multitargeted and complementary fashion. These nutrients have been shown to limit oxidation, reduce glycation, restrict or even repair DNA damage, quell inflammation, support mitochondrial health, and enhance the function of the cellular sub-units called proteasomes and lysosomes.

In addition to the five natural CR mimetics Life Extension reviewed earlier this year, a sixth has been identified called fisetin. It optimizes levels of the endogenous antioxidant glutathione in cells, targets factors implicated in brain aging, and may even enhance the action of resveratrol.

To read an in-depth scientific report that describes all of the documented benefits of calorie restriction mimetic nutrients, log on to www.LifeExtension.com/Calorie-Restriction

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. Romero-Corral A, Somers VK, Sierra-Johnson J, et al. Normal weight obesity: a risk factor for cardiometabolic dysregulation and cardiovascular mortality. Eur Heart J. 2010 Mar;31(6):737-46.

2. Winslow R.“The Scales Can Lie. Hidden Fat: New Study Argues Even Thin People Can Face Health Risks From Fat; It’s ‘Normal Weight Obesity’” Wall Street Journal. Heart Beat section. January 26, 2010.

3. Ardigo D, Valtuena S, Zavaroni I, Baroni MC, Delsignore R. Pulmonary complications in diabetes mellitus: the role of glycemic control. Curr Drug Targets Inflamm Allergy. 2004 Dec;3(4):455-8

4. Chang SC, Ziegler RG, Dunn B, et al. Association of energy intake and energy balance with postmenopausal breast cancer in the prostate, lung, colorectal, and ovarian cancer screening trial. Cancer Epidemiol Biomarkers Prev. 2006 Feb;15(2):334-41.

5. Fujita A, Hashimoto Y, Nakahara K, Tanaka T, Okuda T, Koda M. Effects of a low calorie vegan diet on disease activity and general conditions in patients with rheumatoid arthritis. Rinsho Byori. 1999 Jun;47(6):554-60.

6. Andersson SO, Wolk A, Bergström R, et al. Energy, nutrient intake and prostate cancer risk: a population-based case-control study in Sweden. Int J Cancer. 1996 Dec 11;68(6):716-22.

7. Pan SY, DesMeules M, Morrison H, Wen SW, et al. Obesity, high energy intake, lack of physical activity, and the risk of kidney cancer. Cancer Epidemiol Biomarkers Prev. 2006 Dec;15(12):2453-60.

8. Dahl A, Hassing LB, Fransson E, et al. Being overweight in midlife is associated with lower cognitive ability and steeper cognitive decline in late life. J Gerontol A Biol Sci Med Sci. 2010 Jan;65(1):57-62.

9. Colman RJ, Anderson RM, Johnson SC, et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science. 2009 Jul 10;325(5937):201-4.

10. Froy O, Miskin R. Effect of feeding regimens on circadian rhythms: implications for aging and longevity. Aging (Albany NY). 2010 Dec 11;2(1):7-27.

11. Lefevre M, Redman LM, Heilbronn LK, et al. Caloric restriction alone and with exercise improves CVD risk in healthy non-obese individuals. Atherosclerosis. 2009 Mar;203(1):206-13.

12. Witte AV, Fobker M, Gellner R, Knecht S, Flöel A. Caloric restriction improves memory in elderly humans. Proc Natl Acad Sci U S A. 2009 Jan 27;106(4):1255-60.

13. Wang ZQ, Floyd ZE, Qin J, et al. Modulation of skeletal muscle insulin signaling with chronic caloric restriction in cynomolgus monkeys. Diabetes. 2009 Jul;58(7):1488-98.

14. Ong KR, Sims AH, Harvie M, et al. Biomarkers of dietary energy restriction in women at increased risk of breast cancer. Cancer Prev Res (Phila Pa). 2009 Aug;2(8):720-31.

15. Kimira M, Arai Y, Shimoi K, Watanabe S. Japanese intake of flavonoids and isoflavonoids from foods. J Epidemiol. 1998 Aug;8(3):168-75.

16. Wood JG, Rogina B, Lavu S, et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature. 2004 Aug 5;430(7000):686-9.

17. Maher P. Modulation of multiple pathways involved in the maintenance of neuronal function during aging by fisetin. Genes Nutr. 2009 Sep 10.

18. Maher P, Akaishi T, Abe K. Flavonoid fisetin promotes ERK-dependent long-term potentiation and enhances memory. Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16568-73.

19. Maher P, Salgado KF, Zivin JA, Lapchak PA. A novel approach to screening for new neuroprotective compounds for the treatment of stroke. Brain Res. 2007 Oct 10;1173:117-25.

20. De Santi C, Pietrabissa A, Spisni R, Mosca F, Pacifici GM. Sulphation of resveratrol, a natural compound present in wine, and its inhibition by natural flavonoids. Xenobiotica. 2000 Sep;30(9):857-66.

21. McCay CM, Crowel MF. Prolonging the life span. The Scientific Monthly. 1934 Nov;39(5):405–14.

22. McCay CM, Crowell MF, Maynard LA. The effect of retarded growth upon the length of life span and upon the ultimate body size. Nutrition. 1935;5:155-71.

23. Greiss S, Gartner A. Sirtuin/Sir2 phylogeny, evolutionary considerations and structural conservation. Mol Cells. 2009 Nov;28(5):407-15.

24. Kang H, Jung JW, Kim MK, Chung JH. CK2 is the regulator of SIRT1 substrate-binding affinity, deacetylase activity and cellular response to DNA-damage. PLoS One. 2009 Aug 14;4(8):e6611.

25. Yamagata K, Kitabayashi I. Sirt1 physically interacts with Tip60 and negatively regulates Tip60-mediated acetylation of H2AX. Biochem Biophys Res Commun. 2009 Dec 25;390(4):1355-60.

26. Allard JS, Perez E, Zou S, de Cabo R. Dietary activators of Sirt1. Mol Cell Endocrinol. 2009 Feb 5;299(1):58-63.

27. Chen IY, Lypowy J, Pain J, et al. Histone H2A.z is essential for cardiac myocyte hypertrophy but opposed by silent information regulator 2alpha. J Biol Chem. 2006 Jul 14;281(28):19369-77.

28. Goto M. Inflammaging (inflammation + aging): A driving force for human aging based on an evolutionarily antagonistic pleiotropy theory? Biosci Trends. 2008 Dec;2(6):218-30.

29. Goligorsky MS, Chen J, Patschan S. Stress-induced premature senescence of endothelial cells: a perilous state between recovery and point of no return. Curr Opin Hematol. 2009 May;16(3):215-9.

30. He W, Wang Y, Zhang MZ, et al. Sirt1 activation protects the mouse renal medulla from oxidative injury. J Clin Invest. 2010 Apr;120(4):1056-68.

31. Kim HS, Patel K, Muldoon-Jacobs K, et al. SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell. 2010 Jan 19;17(1):41-52.

32. Kume S, Uzu T, Horiike K, et al. Calorie restriction enhances cell adaptation to hypoxia through Sirt1-dependent mitochondrial autophagy in mouse aged kidney. J Clin Invest. 2010 Apr;120(4):1043-55.

33. Shi T, Fan GQ, Xiao SD. SIRT3 reduces lipid accumulation via AMPK activation in human hepatic cells. J Dig Dis. 2010 Feb;11(1):55-62.

34. Yang Y, Cimen H, Han MJ, et al. NAD+-dependent deacetylase SIRT3 regulates mitochondrial protein synthesis by deacetylation of the ribosomal protein MRPL10. J Biol Chem. 2010 Mar 5;285(10):7417-29.

35. Yoshizaki T, Schenk S, Imamura T, et al. SIRT1 inhibits inflammatory pathways in macrophages and modulates insulin sensitivity. Am J Physiol Endocrinol Metab. 2010 Mar;298(3):E419-28.

36. Fontana L. Neuroendocrine factors in the regulation of inflammation: excessive adiposity and calorie restriction. Exp Gerontol. 2009 Jan-Feb;44(1-2):41-5.

37. Kassi E, Papavassiliou AG. Could glucose be a proaging factor? J Cell Mol Med. 2008 Aug;12(4):1194-8.

38. Vlassara H, Uribarri J, Ferrucci L, et al. Identifying advanced glycation end products as a major source of oxidants in aging: implications for the management and/or prevention of reduced renal function in elderly persons. Semin Nephrol. 2009 Nov;29(6):594-603.

39. Selsby JT, Judge AR, Yimlamai T, Leeuwenburgh C, Dodd SL. Life long calorie restriction increases heat shock proteins and proteasome activity in soleus muscles of Fisher 344 rats. Exp Gerontol. 2005 Jan-Feb;40(1-2):37-42.

40. Opalach K, Rangaraju S, Madorsky I, Leeuwenburgh C, Notterpek L. Lifelong calorie restriction alleviates age-related oxidative damage in peripheral nerves. Rejuvenation Res. 2010 Feb;13(1):65-74.

41. Firuzi O, Lacanna A, Petrucci R, Marrosu G, Saso L. Evaluation of the antioxidant activity of flavonoids by “ferric reducing antioxidant power” assay and cyclic voltammetry. Biochim Biophys Acta. 2005 Jan 18;1721(1-3):174-84.

42. Hou DX, Fukuda M, Johnson JA, Miyamori K, Ushikai M, Fujii M. Fisetin induces transcription of NADPH:quinone oxidoreductase gene through an antioxidant responsive element-involved activation. Int J Oncol. 2001 Jun;18(6):1175-9.

43. Kampkotter A, Gombitang Nkwonkam C, Zurawski RF, et al. Effects of the flavonoids kaempferol and fisetin on thermotolerance, oxidative stress and FoxO transcription factor DAF-16 in the model organism Caenorhabditis elegans. Arch Toxicol. 2007 Dec;81(12):849-58.

44. Cohen HY, Miller C, Bitterman KJ, et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science. 2004 Jul 16;305(5682):390-2.

45. Masternak MM, Bartke A. PPARs in calorie restricted and genetically long-lived mice. PPAR Res. 2007;2007:28436.

46. Luo GR, Le WD. Collective roles of molecular chaperones in protein degradation pathways associated with neurodegenerative diseases. Curr Pharm Biotechnol. 2010 Feb 1;11(2):180-7.

47. Sengupta B, Swenson J. Properties of normal and glycated human hemoglobin in presence and absence of antioxidant. Biochem Biophys Res Commun. 2005 Sep 2;334(3):954-9.

48. Sengupta B, Banerjee A, Sengupta PK. Interactions of the plant flavonoid fisetin with macromolecular targets: insights from fluorescence spectroscopic studies. J Photochem Photobiol B. 2005 Aug 1;80(2):79-86.

49. S Roriz-Filno J, Sa-Roriz TM, Rosset I, et al. (Pre)diabetes, brain aging, and cognition. Biochim Biophys Acta. 2009 May;1792(5):432-43.

50. Maczurek A, Shanmugam K, Munch G. Inflammation and the redox-sensitive AGE-RAGE pathway as a therapeutic target in Alzheimer’s disease. Ann N Y Acad Sci. 2008 Apr;1126:147-51.

51. Wilson JS, Mruthinti S, Buccafusco JJ, et al. Anti-RAGE and Abeta immunoglobulin levels are related to dementia level and cognitive performance. J Gerontol A Biol Sci Med Sci. 2009 Feb;64(2):264-71.

52. Devasagayam TP, Subramanian M, Singh BB, Ramanathan R, Das NP. Protection of plasmid pBR322 DNA by flavonoids against single-stranded breaks induced by singlet molecular oxygen. J Photochem Photobiol B. 1995 Oct;30(2-3):97-103.

53. Watjen W, Michels G, Steffan B, et al. Low concentrations of flavonoids are protective in rat H4IIE cells whereas high concentrations cause DNA damage and apoptosis. J Nutr. 2005 Mar;135(3):525-31.

54. Higa S, Hirano T, Kotani M, et al. Fisetin, a flavonol, inhibits TH2-type cytokine production by activated human basophils. J Allergy Clin Immunol. 2003 Jun;111(6):1299-306.

55. Kaneko M, Koike H, Saito R, Kitamura Y, Okuma Y, Nomura Y. Loss of HRD1-mediated protein degradation causes amyloid precursor protein accumulation and amyloid-{beta} generation. J Neurosci. 2010 Mar 17;30(11):3924-32.

56. Sung B, Pandey MK, Aggarwal BB. Fisetin, an inhibitor of cyclin-dependent kinase 6, down-regulates nuclear factor-kappaB-regulated cell proliferation, antiapoptotic and metastatic gene products through the suppression of TAK-1 and receptor-interacting protein-regulated IkappaBalpha kinase activation. Mol Pharmacol. 2007 Jun;71(6):1703-14.

57. Chien CS, Shen KH, Huang JS, Ko SC, Shih YW. Antimetastatic potential of fisetin involves inactivation of the PI3K/Akt and JNK signaling pathways with downregulation of MMP-2/9 expressions in prostate cancer PC-3 cells. Mol Cell Biochem. 2010 Jan;333(1-2):169-80.

58. Maher P. The flavonoid fisetin promotes nerve cell survival from trophic factor withdrawal by enhancement of proteasome activity. Arch Biochem Biophys. 2008 Aug 15;476(2):139-44.

59. Orallo F. Trans-resveratrol: a magical elixir of eternal youth? Curr Med Chem. 2008;15(19):1887-98.

60. Alcain FJ, Villalba JM. Sirtuin activators. Expert Opin Ther Pat. 2009 Apr;19(4):403-14.

61. Zhang J. Resveratrol inhibits insulin responses in a SirT1-independent pathway. Biochem J. 2006 Aug 1;397(3):519-27.

62. Dasgupta B, Milbrandt J. Resveratrol stimulates AMP kinase activity in neurons. Proc Natl Acad Sci U S A. 2007 Apr 24;104(17):7217-22.

63. Karuppagounder SS, Pinto JT, Xu H, Chen HL, Beal MF, Gibson GE. Dietary supplementation with resveratrol reduces plaque pathology in a transgenic model of Alzheimer’s disease. Neurochem Int. 2009 Feb;54(2):111-8.

64. Sadruddin S, Arora R. Resveratrol: biologic and therapeutic implications. J Cardiometab Syndr. 2009 Spring;4(2):102-6.

65. Stivala LA, Savio M, Carafoli F, et al. Specific structural determinants are responsible for the antioxidant activity and the cell cycle effects of resveratrol. J Biol Chem. 2001 Jun 22;276(25):22586-94.

66. Ozgova S, Hermanek J, Gut I. Different antioxidant effects of polyphenols on lipid peroxidation and hydroxyl radicals in the NADPH-, Fe-ascorbate- and Fe-microsomal systems. Biochem Pharmacol. 2003 Oct 1;66(7):1127-37.

67. Subbaramaiah K, Chung WJ, Michaluart P, et al. Resveratrol inhibits cyclooxygenase-2 transcription and activity in phorbol ester-treated human mammary epithelial cells. J Biol Chem. 1998 Aug 21;273(34):21875-82.

68. Pallas M, Casadesus G, Smith MA, et al. Resveratrol and neurodegenerative diseases: activation of SIRT1 as the potential pathway towards neuroprotection. Curr Neurovasc Res. 2009 Feb;6(1):70-81.

69. Khan MM, Ahmad A, Ishrat T, et al. Resveratrol attenuates 6-hydroxydopamine-induced oxidative damage and dopamine depletion in rat model of Parkinson’s disease. Brain Res. 2010 Apr 30;1328:139-51.

70. Raval AP, Dave KR, Perez-Pinzon MA. Resveratrol mimics ischemic preconditioning in the brain. J Cereb Blood Flow Metab. 2006 Sep;26(9):1141-7.

71. Anekonda TS. Resveratrol--a boon for treating Alzheimer’s disease? Brain Res Rev. 2006 Sep;52(2):316-26.

72. Anekonda TS, Reddy PH. Neuronal protection by sirtuins in Alzheimer’s disease. J Neurochem. 2006 Jan;96(2):305-13.

73. Mizutani K, Ikeda K, Yamori Y. Resveratrol inhibits AGEs-induced proliferation and collagen synthesis activity in vascular smooth muscle cells from stroke-prone spontaneously hypertensive rats. Biochem Biophys Res Commun. 2000 Jul 21;274(1):61-7.

74. Ding DF, You N, Wu XM, et al. resveratrol attenuates renal hypertrophy in early-stage diabetes by activating AMPK. Am J Nephrol. 2010 Mar 20;31(4):363-74.

75. Kang L, Heng W, Yuan A, Baolin L, Fang H. Resveratrol modulates adipokine expression and improves insulin sensitivity in adipocytes: Relative to inhibition of inflammatory responses. Biochimie. 2010 Feb 25.

76. Szkudelska K, Szkudelski T. Resveratrol, obesity and diabetes. Eur J Pharmacol. 2010 Mar 19.

77. Rimando AM, Kalt W, Magee JB, Dewey J, Ballington JR. Resveratrol, pterostilbene, and piceatannol in vaccinium berries. J Agric Food Chem. 2004 Jul 28;52(15):4713-9.

78. Rimando AM, Nagmani R, Feller DR, Yokoyama W. Pterostilbene, a new agonist for the peroxisome proliferator-activated receptor alpha-isoform, lowers plasma lipoproteins and cholesterol in hypercholesterolemic hamsters. J Agric Food Chem. 2005 May 4;53(9):3403-7.

79. Rimando AM, Cuendet M, Desmarchelier C, Mehta RG, Pezzuto JM, Duke SO. Cancer chemopreventive and antioxidant activities of pterostilbene, a naturally occurring analogue of resveratrol. J Agric Food Chem. 2002 Jun 5;50(12):3453-7.

80. Amarnath Satheesh M, Pari L. The antioxidant role of pterostilbene in streptozotocin-nicotinamide-induced type 2 diabetes mellitus in Wistar rats. J Pharm Pharmacol. 2006 Nov;58(11):1483-90.

81. Joseph JA, Fisher DR, Cheng V, Rimando AM, Shukitt-Hale B. Cellular and behavioral effects of stilbene resveratrol analogues: implications for reducing the deleterious effects of aging. J Agric Food Chem. 2008 Nov 26;56(22):10544-51.

82. Priego S, Feddi F, Ferrer P, et al. Natural polyphenols facilitate elimination of HT-29 colorectal cancer xenografts by chemoradiotherapy: a Bcl-2- and superoxide dismutase 2-dependent mechanism. Mol Cancer Ther. 2008 Oct;7(10):3330-42.

83. Manickam M, Ramanathan M, Jahromi MA, Chansouria JP, Ray AB. Antihyperglycemic activity of phenolics from Pterocarpus marsupium. J Nat Prod. 1997 Jun;60(6):609-10.

84. Ferrer P, Asensi M, Segarra R, et al. Association between pterostilbene and quercetin inhibits metastatic activity of B16 melanoma. Neoplasia. 2005 Jan;7(1):37-47.

85. Hougee S, Faber J, Sanders A, et al. Selective COX-2 inhibition by a Pterocarpus marsupium extract characterized by pterostilbene, and its activity in healthy human volunteers. Planta Med. 2005 May;71(5):387-92.

86. Billack B, Radkar V, Adiabouah C. In vitro evaluation of the cytotoxic and anti-proliferative properties of resveratrol and several of its analogs. Cell Mol Biol Lett. 2008;13(4):553-69.

87. Boyle JJ. Macrophage activation in atherosclerosis: pathogenesis and pharmacology of plaque rupture. Curr Vasc Pharmacol. 2005 Jan;3(1):63-8.

88. Deshane J, Chaves L, Sarikonda KV, et al. Proteomics analysis of rat brain protein modulations by grape seed extract. J Agric Food Chem. 2004 Dec 29;52(26):7872-83.

89. Salas A, Subirada F, Perez-Enciso M, et al. Plant polyphenol intake alters gene expression in canine leukocytes. J Nutrigenet Nutrigenomics. 2009;2(1):43-52.

90. Balu M, Sangeetha P, Murali G, Panneerselvam C. Age-related oxidative protein damages in central nervous system of rats: modulatory role of grape seed extract. Int J Dev Neurosci. 2005 Oct;23(6):501-7.

91. Kar P, Laight D, Rooprai HK, Shaw KM, Cummings M. Effects of grape seed extract in Type 2 diabetic subjects at high cardiovascular risk: a double blind randomized placebo controlled trial examining metabolic markers, vascular tone, inflammation, oxidative stress and insulin sensitivity. Diabet Med. 2009 May;26(5):526-31.

92. Adisakwattana S, Jiphimai P, Prutanopajai P, Chanathong B, Sapwarobol S, Ariyapitipan T. Evaluation of alpha-glucosidase, alpha-amylase and protein glycation inhibitory activities of edible plants. Int J Food Sci Nutr. 2010 Jan 29.

93. Farrar JL, Hartle DK, Hargrove JL, Greenspan P. Inhibition of protein glycation by skins and seeds of the muscadine grape. Biofactors. 2007;30(3):193-200.

94. Vitseva O, Varghese S, Chakrabarti S, Folts JD, Freedman JE. Grape seed and skin extracts inhibit platelet function and release of reactive oxygen intermediates. J Cardiovasc Pharmacol. 2005 Oct;46(4):445-51.

95. Cheah KY, Howarth GS, Yazbeck R, et al. Grape seed extract protects IEC-6 cells from chemotherapy-induced cytotoxicity and improves parameters of small intestinal mucositis in rats with experimentally-induced mucositis. Cancer Biol Ther. 2009 Feb;8(4):382-90.

96. Reiterer G, Toborek M, Hennig B. Quercetin protects against linoleic acid-induced porcine endothelial cell dysfunction. J Nutr. 2004 Apr;134(4):771-5.

97. Cirico TL, Omaye ST. Additive or synergetic effects of phenolic compounds on human low density lipoprotein oxidation. Food Chem Toxicol. 2006 Apr;44(4):510-6.

98. Gnoni GV, Paglialonga G, Siculella L. Quercetin inhibits fatty acid and triacylglycerol synthesis in rat-liver cells. Eur J Clin Invest. 2009 Sep;39(9):761-8.

99. Han JJ, Hao J, Kim CH, Hong JS, Ahn HY, Lee YS. Quercetin prevents cardiac hypertrophy induced by pressure overload in rats. J Vet Med Sci. 2009 Jun;71(6):737-43.

100. Ishizawa K, Izawa-Ishizawa Y, Ohnishi S, et al. Quercetin glucuronide inhibits cell migration and proliferation by platelet-derived growth factor in vascular smooth muscle cells.J Pharmacol Sci. 2009 Feb;109(2):257-64.

101. Min YD, Choi CH, Bark H, et al. Quercetin inhibits expression of inflammatory cytokines through attenuation of NF-kappaB and p38 MAPK in HMC-1 human mast cell line. Inflamm Res. 2007 May;56(5):210-5.

102. Ruiz PA, Braune A, Holzlwimmer G, Quintanilla-Fend L, Haller D. Quercetin inhibits TNF-induced NF-kappaB transcription factor recruitment to proinflammatory gene promoters in murine intestinal epithelial cells. J Nutr. 2007 May;137(5):1208-15.

103. Lin CW, Hou WC, Shen SC, et al. Quercetin inhibition of tumor invasion via suppressing PKC delta/ERK/AP-1-dependent matrix metalloproteinase-9 activation in breast carcinoma cells. Carcinogenesis. 2008 Sep;29(9):1807-15.

104. Ying B, Yang T, Song X, et al. Quercetin inhibits IL-1 beta-induced ICAM-1 expression in pulmonary epithelial cell line A549 through the MAPK pathways. Mol Biol Rep. 2009 Sep;36(7):1825-32.

105. Langley-Evans SC. Consumption of black tea elicits an increase in plasma antioxidant potential in humans. Int J Food Sci Nutr. 2000 Sep;51(5):309-15.

106. Duffy SJ, Keaney JF, Jr., Holbrook M, et al. Short- and long-term black tea consumption reverses endothelial dysfunction in patients with coronary artery disease. Circulation. 2001 Jul 10;104(2):151-6.

107. Stangl V, Lorenz M, Stangl K. The role of tea and tea flavonoids in cardiovascular health. Mol Nutr Food Res. 2006 Feb;50(2):218-28.

108. Hodgson JM, Puddey IB, Burke V, Watts GF, Beilin LJ. Regular ingestion of black tea improves brachial artery vasodilator function. Clin Sci (Lond). 2002 Feb;102(2):195-201.

109. Widlansky ME, Duffy SJ, Hamburg NM, et al. Effects of black tea consumption on plasma catechins and markers of oxidative stress and inflammation in patients with coronary artery disease. Free Radic Biol Med. 2005 Feb 15;38(4):499-506.

110. Steptoe A, Gibson EL, Vuononvirta R, et al. The effects of chronic tea intake on platelet activation and inflammation: a double-blind placebo controlled trial. Atherosclerosis. 2007 Aug;193(2):277-82.

111. Vinson JA, Zhang J. Black and green teas equally inhibit diabetic cataracts in a streptozotocin-induced rat model of diabetes. J Agric Food Chem. 2005 May 4;53(9):3710-3.

112. Lo CY, Li S, Tan D, Pan MH, Sang S, Ho CT. Trapping reactions of reactive carbonyl species with tea polyphenols in simulated physiological conditions. Mol Nutr Food Res. 2006 Dec;50(12):1118-28.

113. Tan D, Wang Y, Lo CY, Ho CT. Methylglyoxal: its presence and potential scavengers. Asia Pac J Clin Nutr. 2008;17 Suppl 1:261-4.