Slowing the ageing process

Your chronological age and your biological age are not necessarily the same.

Some people age faster than their calendar years – others age more slowly. They look and act more youthfully. And there’s a scientific reason, which was explored at a recent conference I chaired in London.

Given the right nutrition and lifestyle, our bodies have amazing powers of self-healing and regeneration.

The natural process of wear and tear
Almost every cell and tissue in your body breaks down and is replaced on a regular basis. Bone is re-absorbed into the body and then renewed, cartilage in joints experiences wear and tear but is renewed, membranes of nerve and other cells are broken down and replaced. This natural process of wear and repair is going on all the time in your more than 60 trillion cells.

The first 20 years – growth in cells exceeds breakdown
In approximately the first 20 years of life, rates of tissue-building greatly outstrip the rate of tissue breakdown, and we grow physically in size. This is known as ‘anabolic dominance’.

Between 20 and 50 – balanced wear and repair
Then comes a period – typically the third and fourth decades of life – where the processes of breakdown and repair are more or less in balance. There is little apparent change, but under the surface tissues and organs are constantly renewing themselves.

Over 50 – wear starts to exceed repair
Finally there comes a period when wear exceeds repair – a condition known as ‘catabolic dominance’. Arteries begin to fur up, bones get weaker, cartilage thins, brain and other cells start to malfunction. Symptoms of degenerative disease appear and we begin to age – sometimes rapidly.

The expected pattern of ageing
The first illustration shows what we have come to expect as inevitable.

But it doesn’t have to be like that .

Catabolic factors come to dominate because, as we age, too many people become ever-more depleted in the nutrients needed for tissue repair, and also in the nutrients needed to slow tissue decay.

The potential pattern of ageing
Sub-optimal nutrition allows the forces of wear to exceed the forces of repair (leading directly to catabolic dominance).

By supporting your body’s own natural powers of self healing through optimum nutrition and a healthy lifestyle, you should extend the period where wear and tear are in balance.

That reduces the risk of disease, and you should stay healthy longer and age more slowly. This second illustration summarises the objective.

But how can this be achieved? First, cut the risk of degenerative disease; second, provide the body with optimum – not just adequate – nutrition.

FIRST, CUT THE RISK OF DEGENERATIVE DISEASE
The main threats to health are known. And nutrition can reduce the risk of them occurring. Statistically, the leading risks to health are the degenerative diseases such as heart disease/stroke, cancer, hypertension and dementia – all of which are made more likely if diabetes is present. The viral and contagious diseases like pneumonia and influenza are also a threat.

Cut the risk of these, and logically you can increase your chance of living a longer, healthier life.

Of course, genetic factors influence longevity and the likelihood of disease , but whatever your genetic inheritance, there is strong evidence that your risk can be cut through diet, nutrition and lifestyle.

The four main causes of degenerative disease
Although the main degenerative diseases seem very different, they share some surprisingly similar underlying causes. In fact, the latest research indicates that just four main factors underlie most health problems, and a good diet supplemented by the right nutrients at the right levels can help protect against each one.

Protection from a good diet
A ‘good diet’ can be defined as the so-called Mediterranean Diet, with olive oil as the principal fat, lots of fresh fruit and vegetables, whole grain bread and cereals, beans and lentils, nuts and seeds, moderate amounts of oily fish and eggs, up to two glasses of red wine a day and limited red meat. This diet is also a Low GL (Glycaemic Load) Diet.

[Note: GI (Glycaemic Index) refers to the rate at which the intake of a particular food raises blood sugar. GL(Glycaemic Load) is a better measure as it takes into consideration not just the GI of a food, but also the amount eaten in a complete meal. Thus a food may have a very high GI, like potato, but if you only eat a very small amount, that particular intake may have little effect on blood sugar levels.]

The four main causes of degenerative disease

Free radical damage
Free radicals are unstable elements in the body that can be produced through metabolic actions involving oxygen, and by stress and pollution.

Excess free radicals are damaging to body cells and are thought to be a prime cause of ageing. They can damage artery linings and therefore become a causative factor in heart disease, and they can damage DNA to become a factor in cancer. They are implicated in Alzheimer’s.

You can actually see free radical damage when oxygen in the air reacts with fat to oxidate it – turning it rancid. Or when the surface of an apple becomes oxidated and turns brown.

Anti -oxidants counter the effect of oxidation -free radical action. This is why vitamin E protects against rancidity in fats and vitamin C stops an apple going brown.

Dietary Defence
Antioxidants can help protect you against free radical damage.Powerful antioxidants include vitamin E, (preferably in the form of mixed tocopherols), beta carotene and vitamin C, flavonoids (in fruits and vegetables and green tea extract), lycopene (extracted from tomatoes), lutein, Co-Enzyme Q10, and antioxidant mineral co-factors like selenium, copper, manganese and zinc. NOTE
High homocysteine levels in the blood are also associated with heart disease risk.

The B group vitamins B12, folic acid and the nutrient betaine help lower homocysteine levels

Inflammation
Inflammation is involved in arthritis, in heart disease (where the lining of the arteries becomes inflamed), in some cancers (especially of the bowel and colon), in asthma, in diabetes, and in Alzheimer’s.

Dietary Defence
Anti-inflammatory nutrients include flavonoids from fruits and vegetables (some of the most potent being the curcuminoids from turmeric, the yellow spice in curry), Omega 3 oils, pre-biotics and pro-biotics, isoflavones (from soy).
[Low dose aspirin is also advised.]

Immune system failure
The immune system is critical in defending you against cancer and, if weakened, leaves you vulnerable to contagious threats like flu, colds and super-bugs. Stress and lack of sleep are contributory factors.

Dietary Defence
Nutrients that support the immune system include vitamin D, selenium, zinc, pre-biotic fibre, pro-biotics and, most powerful of all, 1-3, 1-6 beta glucans derived from baker’s yeast .

Excessive insulin stress
This is caused by a diet that is high in starchy foods and confectionery ie. a high GL (Glycaemic Load) Diet. A high GL Diet raises blood sugar levels and triggers the release of insulin. Over time, this constant triggering of insulin can lead to insulin resistance and excessive sugar levels in the blood.

This in turn can cause a variety of health problems in-cluding Type 2 diabetes. Diabetes raises the risk of heart disease, stroke, blindness, kidney failure and dementia.

Dietary Defence
A low GL diet is the answer – combined with nutrients that reduce stress on the insulin mechanism.Helpful nutrients include pre-biotic fibre, flavonoids, chromium, manganese, and cinnamon.

In summary, diets and nutritional supplements that lower the GL factor and include significant amounts of anti-oxidants, anti-inflammatory nutrients, and immuno-boosters, are healthy and protective . And are the dietary elements that slow ageing.

SECOND, YOU NEED MORE THAN A ‘BALANCED DIET’ FOR OPTIMUM NUTRITION
A balanced diet does not necessarily provide all the nutrients you need, in the amounts you need.
The Recommended Daily Allowances (RDAs) established for certain vitamins and minerals are generally calculated to prevent deficiency diseases – like scurvy and rickets. They were never designed to be optimum levels – to fully support anabolic cell regeneration.

Nevertheless, surveys of the average person’s diet show that we do not even achieve the RDA levels of many key nutrients – never mind optimum levels.

Inadequate diets and declining nutrient contents
Deficiencies occur partly because of inadequate diets and partly because the nutritional value of many foods has declined with changes in farming and seed breeding methods over the last 50 years or so.

Surveys show that most of us do have adequate intakes of some vitamins and minerals – eg vitamin A, niacin, vitamin B12, calcium, magnesium. However, the chart below shows that the status of some of the more important protective nutrients is poor.

Some average intakes below even RDA
Note especially that intakes of vitamin D and selenium, which are both important components of a healthy immune system, are well below the RDA. Note, too, that many nutritionists believe that the current RDAs for vitamin C, D and E need to be increased.

Many important nutrients have no RDA
And many protective nutrients – like lycopene (researched for its role in cancer risk reduction), the heart-healthy omega 3, eye-healthy lutein, and the antioxidant and anti-inflammatory flavonoids, have no current RDA established – although they are widely acknowledged to be important.

Nutrient

Average daily intake
Note
1

% of RDA

Optimum Level

% of optimum level
Note
2

Vitamin C

58 mg

97%

500 mg

12%

Vitamin D

2.9 mcg

58%

10 mcg

29%

Vitamin E

9.3 mg

93%

100 mg

9%

Folic Acid

252 mcg

126%

450 mcg

56%

Selenium

35 mcg

47%

150 mcg

24%

Chromium

30 mcg

24%

125 mcg

24%

Iodine

180 mcg

90%

280 mcg

64%

Beta carotene

1.9 mg

No RDA

7 mg

27%

Lutein

1.5 mg

No RDA

6 mg

25%

Lycopene

2.5 mg

No RDA

5 mg

50%

Flavonoids

140 mg

No RDA

250 mg

56%

Isoflavones

5 mg

No RDA

40 mg

12.5%

Omega 3

150 mg

No RDA

600 mg

25%

Pre-biotics

2 – 3 g

No RDA

9 – 10 g

30%

Coenzyme Q10

10 mg

No RDA

30 – 60 mg

17 -33 %

Glucosamine

n/a

No RDA

500 mg

Fruit and vegetable portions

2.5

50%

7

36%

Sources: Note 1: Council for Responsible Nutrition and trade sources.
Note 2 : Published in my book Health Defence.

 

High dose single nutrients can be dangerous – combination is the key
Although the average diet contributes well below the optimum level that many leading researchers have defined, I do not believe in taking high doses of single nutrients, which can be dangerous. Food contains a range of nutrients that combine with each other and work synergistically. It is this combination and synergy which exert the positive effect on health.

In the same way, I believe that a nutritional supplement should combine a full range of the most protective nutrients if it is to have a real impact on health.

Prevention is better than cure
Finally, it is clear that prevention is (much) better than cure. Of course we all want to avoid illness, but the value of prevention is underlined by the fact that pharmaceutical drugs can have serious side effects. Indeed, Adverse Drug Reactions are now a significant cause of death.

The language of pharmaceutical drugs is that of warfare – their role is to fight, oppose, interrupt and kill. And they work well when their target is a simple, single-cause, invading infection – in the way that antibiotics kill bacteria. But today’s health threats are complicated, multiple-cause degenerative diseases. And I believe the best initial defence against this type of disease is to support the body’s own natural capacity to heal and regenerate.

Summary
GOOD DIET
+ NUTRITIONAL SUPPLEMENTS
+ EXERCISE
+ ADEQUATE SLEEP
+ REDUCED STRESS

= EXTENDED PERIOD OF HEALTHY LIFE

Food and nutrients, at the right levels and in the right combinations, together with regular exercise, adequate sleep and reduced stress, can extend the period during which wear and tear are in balance. And achieving that outcome should cut the risk of disease and slow the ageing process.


References
Drug Safety
Bates DW, Cullen DJ, Laird N, Petersen LA, Small SD, Servi D, Laffel G, Sweitzer BJ, Shea BF, Hallisey R, et al. Incidence of adverse drug events and potential adverse drug events. Implications for prevention. ADE Prevention Study Group. JAMA, 1995 Jul 5; 274 (1):29-34.Bates DW. Drugs and adverse drug reactions: how worried should we be?JAMA, Apr 15 1998; 279 (15): 1216-7.

Leape LL. National Patient Safety Foundation Press Release. Nationwide Poll on Patient Safety Oct 9, 1997 New York. http://www.npsf.org/html/pressrel/finalgen.html

Moore TJ, Psaty BM, Furberg CD. Time to act on drug safety. JAMA, May 20 1998; 279 (19):1571-3.

Nebeker JR, Hoffman JM, Weir CR, Bennett CL, Hurdle JF. High Rates of Adverse Drug Events in a Highly Computerized Hospital: Arch Intern Med 2005; 165:1111-1116.

Reuters ’03. Medication side effects strike 1-in-4. April 17, 2003

Cancer
Ahmad N, Feyes DK, Nieminen AL, Agarwal R, Mukhtar H. Green tea constituent epigallocatechin-3-gallate and induction of apoptosis and cell cycle arrest in human carcinoma cells. J Natl Cancer Inst, 1999; 1989(24):1881-6

Amir H, Karas M, Giat J, Danilenko M, Levy R, Yermiahu T, Levy J, and Sharoni Y. Lycopene and 1,25-dihydroxyvitamin D3 cooperate in the inhibition of cell cycle progression and induction of differentiation in HL-60 leukemic cells. Nutr Cancer 1999;33(1):105-12

Arbiser JL, Klauber N, Rohan R, van Leeuwen R, Huang M-T, Fisher C, Flynn E, ByersHR. Curcumin is an in vivo inhibitor of angiogenesis. Mol Med 1998; 4: 376-383.

Balogh G, de Boland AR, Boland R, Barja P. Effect of 1,25(OH)(2)-vitamin D(3) on the activation of natural killer cells: role of protein kinase C and extracellular calcium.Exp Mol Pathol 1999 Oct; 67(2):63-74

Batty GD, Shipley MJ, Jarrett RJ, Breeze E, Marmot MG, Smith GD. Obesity and overweight in relation to organ-specific cancer mortality in London (UK): findings from the original Whitehall study. Int J Obes Relat Metab Disord. 2005 Jun 28;

Bertram JS. Carotenoids and gene regulation. Nutr Rev. 1999; 57(6):182-191.

Bezkorovainy A. Biochem & Physiol of Bifidobacteria, CRC Press ’89: pp147-177

Bianchini F, Kaaks R, Vainio H. Overweight, obesity, and cancer risk. Lancet Oncol. 2002 Sep; 3(9):565-74.

Brooks JD, Paton VG and Vidanes G. Potent induction of Phase 2 enzymes in human prostate cells by sulforaphane.CancerEpidemiology, Biomarkers & Prevention, 2001; 10 : 949-954.

Burgaleta C, Territo MC, Quan CG, Goide DW. Glucan activated macrophages: functional characteristics and surface morphology. J Reticuloendothel Soc 1978; 23: 195-204.

Ciolino HP, Daschner PJ, Wang TTY, Yeh GC. Effect of curcumin on the aryl hydrocarbon receptor and cytochrome P450 1A1 in MCF-7 human breast carcinoma cells.Biochem Pharm 1998; 56 : 197-206.

Constantinou A, Huberman E. Genistein as an inducer of tumor cell differentiation: possible mechanisms of action. Proc Soc Exp Biol Med. 1995; 208:109-115.

Chute JP, et al. Outcome of patients with small-cell lung cancer during 20 years of clinical research at the US National Cancer Institute. Mayo Clin Proc 1997 Oct; 72(10):901-12.

Cummings JH, Bingham SA. Diet and the prevention of cancer. BMJ 1998; 317:1636-1640.

Czop JK, Valiante NM, Janusz MJ. Phagocytosis of particulate activators of the human alternative complement pathway through monocyte beta-glucan receptors. Prog Clin Biol Res 1989; 297: 287-296; Dept of Med, Harvard Med S, Boston, MA.

Deguchi Y, Morishita T, Mud, M. Comparative studies on synthesis of water- soluble vitamins among human species of bifidobacteria Aspic. Biol Chem 1985; 49:13-19.

Di Renzo L, Yefenof E, Klein E. The function of human NK [Killer T] cells is enhanced by B-Glucan, a ligand of CR3 (CD11b/CD18).  Eur J Immunol 1991; 21:1755-1758.

Fahey JW, Talalay P. Antioxidant functions of sulforaphane: a potent inducer of Phase II detoxication enzymes. Food Chem Toxicol 1999; 37(9-10):973-9.

Gamet-Payrastre L, Li P, Lumeau S, Cassar G, Dupont MA, Chevolleau S, Gase N, Tulliez J, Terçé F. Sulforaphane, A Naturally Occurring Isothiocyanate, Induces Cell Cycle Arrest and Apoptosis in HT29 Human Colon Cancer Cells.Cancer Research 2000; 60(5):1426-1433.

Garland CF, Garland FC, Gorham ED, Lipkin M, Newmark H, Mohr SB, Holick MF. The Role of Vitamin D in Cancer Prevention. Am J Public Health. 2005 Dec 27

Gelderman KA, Tomlinson T, Ross GD, Gorter A. Complement function in mAB-mediated immunotherapy. Trends in Immunology 2004; 25:158-164.

Grasten SM, Juntunen KS, Poutanen KS, Gylling HK, Miettinen TA, Mykkanen HM. Rye bread improves bowel function and decreases the concentrations of some compounds that are putative colon cancer risk markers in middle-aged women and men. J Nutr. 2000 Sep; 130(9):2215-21.

Hahn-Obercyger M, Stark AH, Madar Z. Grapefruit and Oroblanco Enhance Hepatic Detoxification Enzymes in Rats: Possible Role in Protection against Chemical Carcinogenesis. J Agric Food Chem. 2005 Mar 9;53(5):1828-32.

Hanif R, Qiao L, Shiff SJ, Rigas B.Curcumin, a natural plant phenolic food additive, inhibits cell proliferation and induces cell cycle changes in colon adenocarcinoma cell lines by a prostaglandin-independent pathway.

J Lab Clin Med . 1997; 130: 576-584.

Hansen LA, Sigman CC, Andreola F, Ross SA, Kelloff GJ and De Luca LM .Retinoids in chemoprevention and differentiation therapy. Carcinogenesis. July 2004; 21(7): 1271-1279.

Heerdt BG, Houston MA, Augenlicht LH. Potentiation by specific short-chain fatty acids of differentiation and apo-ptosis in human colonic carcinoma cell lines. Cancer Res. 1994; 54: 3288-3293.

Herbert V, Genomics and Proteomics 2001: Controlling some of the DNAs, RNAs, and proteins which blueprint health, disease, and life span, by controlling their methylation & demethylation. Presented at FASEB 2001 Summer Research Conference, “Biological Methylation”, Saxton’s River, Vermont, July 21-26, 2001

Herbert V, Snowmass 2002: Epigenetics, Genomics, Proteomics; Silencing “Bad” And Activating “Good” DNA, mRNA Transcripts, And Their Proteins, By Selective Targeted Chromatin Methylation And Demethylation. Presented at 2002 FASEB Summer Research Conference on “Folic Acid, Vitamin B 12 and One Carbon Metabolism”, Snowmass Village, Colorado, Aug 3-8, 2002.

Heys SD, Walker LG, Smith I, et al. Enteral nutritional supplementation with key nutrients in patients with critical illness and cancer. A meta-analysis of randomized controlled clinical trials. Ann of Surg. 1999;229(4):467-477

Hidaka H, Eida T, Takizawa T, Tokunaga T, Castro Y. Effects of fructooligosacchandes on intestinal flora and human health. Bifidobacteria Microflora 1986; 5(1):37-50.

Hong F, Hansen RD, Yan J, Allendorf DJ, Baran JT, Ostroff GR, Ross GD. Beta-glucan Functions as an Adjuvant for Monoclonal Antibody Immunotherapy by Recruiting Tumoricidal Granulocytes as Killer Cells. Cancer Research 2003; 63: 9023-9031.

Hong F, Yan J, Baran JT, Allendorf DJ, Hansen RD, Ostroff GR, Xing PX, Ross GD: Mechanism by which Orally Administered beta-1,3-glucans Enhance the Tumoricidal Activity of Antitumour Monoclonal Antibodies in Murine Tumor Models. J Immunol ’04; 173:797-806.

Hung HC, Joshipura KJ, Jiang R, Hu FB, Hunter D, Smith-Warner SA, Colditz GA, Rosner B, Spiegelman D, Willett WC. Fruit and vegetable intake and risk of major chronic disease. J Natl Cancer Inst. 2004 Nov 3; 96(21):1577-84.

Hwang ES, Bowen PE. Cell cycle arrest and induction of apoptosis be lycopene in LNCaP Human Prostate Cancer Cells. J Med Food 2004: 7(3); 284-289.

Janusz M.J, Austen KF, Czop JK. Isolation of a Yeast Heptaglucoside that Inhibits Monocyte Phagocytosis  of Zymosan Particles.The Journal of Immunology. 1989; 142:959-965.

Kemen M, Senkal M, Homann HH, et al. E arly postoperative enteral nutrition with arginine, omega-3 fatty acids and ribonucleic acid-supplemented diet versus placebo in cancer patients: an immunologic evaluation of Impact ®.Crit Care Med. 1995; 23:652-659

Kim EH, Kim HS, Kim SU, Noh EJ, Lee JS, Choi KS.Sodium butyrate sensitizes human glioma cells to TRAIL-mediated apoptosis through inhibition of Cdc2 and the subsequent downregulation of survivin and XIAP. Oncogene. 2005 Jun 27;

Klein-Szanto AJP. Carcinogenic effects of chemotherapeutic compounds,Prog. In Clinical and BiologicalResearch 1992; 374:167-74.

Lam LKT, Zhang J, Hasegawa S, Schut HAJ. Inhibition of chemically induced carcinogenesis by citrus limonoids. In Huang MT, Osawa T, Ho CT and Rosen RT (eds) Food Phytochemicals for Cancer Prevention I. American Chemical Society, ACS symposium series, Washington, DC, 1994; 546, 209-219.

Li Y, Upadhyay S, Bhuiyan M, Sarkar FH. Induction of apoptosis in breast cancer cells MDA-MB-231 by genistein. Oncogene. 1999; 18, 3166-3172.

Lotzova E, Gutterman JU.  Effect of Glucan on Natural Killer (NK) Cells: Further Comparison Between NK Cell and Bone Marrow Effector Cell Activities.J Immunol. 1979; 123: 607-611.

Macho A, Lucena C, Sancho R, Daddario N, Minassi A et al. Non-pungent capsaicinoids from sweet pepper -Synthesis and evaluation of the chemopreventive and ant-inflammatory properties. European Journal of Nutrition 2003; 42:2-9.
McIntosh GH, Noakes M, Royle PJ, Foster PR.Whole-grain rye and wheat foods and markers of bowel health in overweight middle-aged men. Am J Clin Nutr. 2003 Apr; 77(4):967-74.

Meira DA, Pereira PC, Marcondes-Machado J, Mendes RP, Barraviera B, Pellegrino J J, Rezkallah-Iwasso MT, Peracoli MT, Castilho LM, Thomazini I, Da Silva CL, Foss NT, Curi PR. The Use of Glucan as Immunostimulant in the Treatment of Paracoccidioidomycosis. Am J. Trop Med Hyg 1996; 55(5), 496-503

Meyskens FL. Development of Bowman-Birk inhibitor for chemoprevention of oral head and neck cancer.

Ann NY Acad Sci. 2001 Dec; 952:116-23. Review.

Murray GI, Duncan ME, O’Neil P, Melvin WT, Fothergill JE. Matrix metalloproteinase-1 is associated with poor prognosis in colorectal cancer.Nat Med 1996; 2:461-2.

Nair PP, Turjman N, Kessie G, Calkins B, Goodman GT, Davidovitz H, Nimmagadda G. , Diet, nutrition intake, and metabolism in populations at high and low risk for colon cancer. Dietary cholesterol, beta-sitosterol, and stigmasterol.American Journal of Clinical Nutrition Oct. 1984; 40(4 Suppl):927-30.

Noakes M, et al. Am. J. Clin. Nutr. 64: 944-951 (1996)

Ornish D, Weidner G, Fair WR, Marlin R, Pettengill EB, Raisin CJ, Dunn-Emke S, Crutchfield L, Jacobs FN, Barnard RJ, Aronson WJ, McCormac P, McKnight DJ, Fein JD, Dnistian AM, Weinstein J, Ngo TH, Mandell NR, Carroll PR.: Intensive lifestyle changes may affect the progression of prostate cancer. J Urology 2005 Sep: 174(3):1065-9.

Pienta KJ. Epidemiology and etiology of prostate cancer. In: Raghaven D, et al., eds. Principles and practice ofgenitourinary oncology. Philadelphia: Lippincott-Raven, 1997.

Poulose SM, Harris ED, Patil BS.Citrus limonoids induce apoptosis in human neuroblastoma cells and have radical scavenging activity. J Nutr. 2005 Apr; 135(4):870-7.

Rougier P, Sahmoud T, Nitti D, Curran D, Doci R, De Waele B, Nakajima T, Rauschecker H, Labianca R, Pector JC, Marsoni S, Apolone G, Lasser P, Couvreur ML, Wils J.Adjuvant portal-vein infusion of fluorouracil and heparin in colorectal cancer: a randomised trial. European Organisation for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group, the Gruppo Interdisciplinare Valutazione Interventi in Oncologia, and the Japanese Foundation for Cancer Research. Lancet. 1998 Jun 6; 351(9117):1677-81.

Rowland IR. Toxicology of the colon: Role of the intestinal microflora. In Gibson GR and McFarlane GT, eds. Human Colonic Bacteria: Role in Nutrition, Physiology and Pathology. Boca Raton Fl: CRC Press 1995;155-174

Schilling J, Vranjes N, Joller H, et al. Clinical outcome and immunology of postoperative arginine, omega-3 fatty acids, and nucleotide-enriched enteral feeding: a randomized prospective comparison with standard enteral and low calorie/low fat i.v. solutions.Nutrition. 1996;12:423-429

Sharoni Y, Danilenko M, Walfisch S, Amir H, Nahum A, Ben-Dor A, Hirsch K, Khanin M, Steiner M, Agemy L, Zango G, and Levy J. Role of gene regulation in the anticancer activity of carotenoids. Pure Appl. Chem. 2002; 74(8): 1469-1477.

Silverberg E, Lubera JA. A review of the American Cancer Society: estimates of cancer cases and deaths. CACancer J Clin 1986; 36:9.

Soldatenkov a VA, Prasad S, Voloshin Y and Dritschilo A. Sodium butyrate induces apoptosis and accumulation of ubiquitinated proteins in human breast carcinoma cells. Cell Death & Differentiation 1998; 5:307-312

Stahl W, Nicolai S, Briviba K, et al. Biological activities of natural and synthetic carotenoids: induction of gap junctional communication and singlet oxygen quenching. Carcinogenesis. 1997; 18(1):89-92.

Susan M, Rao MNA. Induction of glutathione S-transferase activity by curcumin in mice. Arzneim.-Forsch. 1992; 42: 962-964.

Tian Q, Miller EG, Ahmad H, Tang L, Patil BS.Differential inhibition of human cancer cell proliferation by citrus limonoids. Nutr Cancer. 2001; 40(2):180-4.

Topping, D., et al J. Nutr. 127: 615-622 (1997)

10.Pierre F, Perrin P, Champ M, Bornet F, Meflah K and Menanteau J. Short-chain fructo-oligosaccharides reduce the incidence of colonic tumors and develop the GALT in Min mice.Cancer Res 1997 ; 57: 225-8

Vetvicka V, Terayama K, Mandeville R, Brousseau P, Kournikakis B, Ostroff G. Pilot Study: Orally Administered Yeast Beta1,3-glucan Prophylactically Protects Against Anthrax Infection and Cancer in Mice. J AmNutraceutical Assocn 2002; 5:1-5.

Wilson AC, Thompson HJ, Schedin PJ, et al. Effect of methylated forms of selenium on cell viability and the induction of DNA strand breakage. Biochem Pharmacol 1992; 43:1137-41.

Witschi H, Kennedy AR. Modulation of lung tumor development in mice with the soybean-derived Bowman-Birk protease inhibitor. Carcinogenesis 1989; 10: 2275-2277

World Cancer Research Fund / American Institute for Cancer Research. Food, Nutrition and the Prevention of Cancer: a global perspective. 1997 1759 R St. NW Washington, DC 20009. 178-FNS/F27 pgs 10, 14.

Yan J, Vetvicka V, Xia Y, Coxon A, Carroll MC, Mayadas TN, Ross GD: Beta-glucan; a ‘Specific’ Biologic Response Modifier that Uses Antibodies to target Tumors for Cytotoxic Recognition by Leukocyte Complement Receptor Type 3(CD11b/CD18).J Immunol ’99; 163:3045-3052.

Zucker S, Hymowitz M, Conner C, Zarrabi HM, Hurewitz AN, Matrisian L, et al. Measurement of matrix metalloproteinases and tissue inhibitors of metalloproteinases in blood and tissues. Clinical and experimental applications.Ann N Y Acad Sci 1999; 878:212-27

Cardiovascular health
Actis-Goretta L, Ottaviani JI, Keen CL, Fraga CG.Inhibition of angiotensin converting enzyme (ACE) activity by flavan-3-ols and procyanidins. FEBS Lett. 2003 Dec 18; 555(3):597-600.

Bakris GL, Bank AJ, Kass DA, Neutel JM, Preston RA, Oparil S. Advanced glycation end-product cross-link breakers: a novel approach to cardiovascular pathologies related to the aging process. Am J Hypertens. 2004 Dec; 17(12 Pt 2):23S-30S.

Bo-Duffield-Lillico AJ, Begg CB. Reflections on the landmark studies of ß-carotene supplementation.Journal of the National Cancer Institute. 96(23): 1729-1731.

Boger RH, Ron ES. L-Arginine improves vascular function by overcoming deleterious effects of ADMA, a novel cardiovascular risk factor. Altern Med Rev. 2005 Mar; 10(1):14-23.

Bonaa KH et al: NORVIK trial report presented at European Society of Cardiology Congress, Stockholm 5.9.05 http://www.nutraingredients.com/news/ng.asp?id=62304

Brand-Miller JC. Glycemic load and chronic disease. Nutr Rev. 2003 May; 61(5 Pt 2):S49-55. Review.

Brown AJ, Jessup W. Oxysterols and atherosclerosis . Atherosclerosis. 1999 Jan; 142(1):1-28. Review.

Chacko BK, Chandler RT, Mundhekar A, Khoo N, Pruitt HM, Kucik DF, Parks DA, Kevil CG, Barnes S, Patel RP. Revealing anti-inflammatory mechanisms of soy isoflavones by flow: modulation of leukocyte-endothelial cell interactions . Am J Physiol Heart Circ Physiol. 2005 Aug; 289(2):H908-15.

Chalupsky K, Cai H. Endothelial dihydrofolate reductase: critical for nitric oxide bioavailability and role in angiotensin II uncoupling of endothelial nitric oxide synthase. Proc Natl Acad Sci USA . 2005 Jun 21; 102(25):9056-61

Chen HW, Huang HC, Effect of curcumin on cell cycle progression and apoptosis in vascular smooth muscle cells.Br J Pharmacol 1998 Jul; 124(6):1029-40

Cordova AC, Jackson LS, Berke-Schlessel DW, Sumpio BE.The cardiovascular protective effect of red wine. J AmColl Surg. 2005 Mar; 200(3):428-39. Review.

de Lorgeril M, Salen P, Martin JL, Monjaud I, Delaye J, Mamelle N.Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction : final report of the Lyon Diet Heart Study.Circulation. 1999 Feb 16; 99(6):779-85.

de Vegt F, Dekker JM, Ruhe HG, Stehouwer CD, Nijpels G, Bouter LM, Heine RJ. Hyperglycaemia is associated with all-cause and cardiovascular mortality in the Hoorn population: the Hoorn Study. Diabetologia. 1999 Aug; 42(8):926-31.

Dickinson S, Brand-Miller J. Glycemic index, postprandial glycemia and cardiovascular disease. Curr OpinLipidol. 2005 Feb; 16(1):69-75. Review.

Duncan RE, El-Sohemy A, Archer MC. Statins and cancer development.Cancer Epidemiol Biomarkers Prev. 2005 Aug; 14(8):1897-8.

Esposito K, Marfella R, Ciotola M, Di Palo C, Giugliano F, Giugliano G, D’Armiento M, D’Andrea F, Giugliano D.Effect of a mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial.
JAMA. 2004 Sep 22; 292(12):1440-6

Fang JC, Kinlay S, Beltrame J, Hikiti H, Wainstein M, Behrendt D, Suh J, Frei B, Mudge GH, Selwyn AP, Ganz P. Effect of vitamins C and E on progression of transplant-associated arteriosclerosis: a randomised trial.Lancet. 2002 Mar 30; 359(9312):1108-13.

Franco OH, Bonneux L, de Laet C, Peeters A, Steyerberg EW, Mackenbach JP . The Polymeal: a more natural, safer, and probably tastier (than the Polypill) strategy to reduce cardiovascular disease by more than 75%. BMJ 2004; 329:1447-1450

Geelen A, Brouwer IA, Schouten EG, Maan AC, Katan MB, Zock PL.Effects of n-3 fatty acids from fish on premature ventricular complexes and heart rate in humans.Am J Clin Nutr. 2005 Feb; 81(2):416-20.

Golomb BA. Implications of statin adverse effects in the elderly.Expert Opin Drug Saf. 2005 May; 4(3):389-97.

Gori AM, Corsi AM, Fedi S, Gazzini A, Sofi F, Bartali B, Bandinelli S, Gensini GF, Abbate R, Ferrucci L.

A proinflammatory state is associated with hyperhomocysteinemia in the elderly . Am J Clin Nutr. 2005 Aug; 82(2):335-41.

Heart Protection Study Collaborative Group.MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002 Jul 6; 360(9326):23-33.

Hou DX, Yanagita T, Uto T, Masuzaki S, Fujii M.Anthocyanidins inhibit cyclooxygenase-2 expression in LPS-evoked macrophages: structure-activity relationship and molecular mechanisms involved.A Biochem Pharmacol. 2005 Aug 1; 70(3):417-25.

HOPE & HOPE-TOO trial investigators: Effects of Long-term Vitamin E Supplementation on Cardiovascular Events and Cancer. JAMAMarch 16, 2005; 293(11):1338-1347

Imai H, Werthessen NT, Subramanyam V, LeQuesne PW, Soloway AH, Kanisawa M.Angiotoxicity of oxygenated sterols and possible precursors. Science. 1980 Feb 8; 207(4431):651-3.

Keys A, Taylor HL, Blackburn H, Brozek J, Anderson JT, Simonson E. Mortality and coronary heart disease among men studied for 23 years . Arch Intern Med. 1971 Aug; 128(2):201-14.

Keys A, Menotti A, Karvonen MJ, Aravanis C, Blackburn H, Buzina R, Djordjevic BS, Dontas AS, Fidanza F, Keys MH. The diet and 15-year death rate in the seven countries study.American Journal of Epidemiology 1986; 124: 903-915.

Khaw KT, Wareham N, Luben R, Bingham S, Oakes S, Welch A, Day N. Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of European prospective investigation of cancer and nutrition (EPIC-Norfolk).BMJ. 2001 Jan 6; 322(7277):15-8.

Knoops KT, de Groot LC, Kromhout D, Perrin AE, Moreiras-Varela O, Menotti A, van Staveren WA.Mediterranea n diet, lifestyle factors, and 10-year mortality in elderly European men and women: the HALE project . JAMA. 2004 Sep 22; 292(12):1433-9.

Konovalova GG, Lisina MO, Tikhaze AK, et al. A complex of antioxidant vitamins effectively inhibits free-radical oxidation of LDL phospholipids in blood plasma and membrane structures of the liver and myocardium. Bulletin of Experimental Biology and Medicine, 2003; 2:143-146.

Kwon HM, Choi YJ, Jeong YJ, Kang SW, Kang IJ, Lim SS, Kang YH . Anti-inflammatory inhibition of endothelial cell adhesion molecule expression by flavone derivatives. J Agric Food Chem. 2005 Jun 29; 53(13):5150-7.

Liu M, Wallin R, Wallmon A, Saldeen T. Mixed tocopherols have a stronger inhibitory effect on lipid peroxidation than alpha-tocopherol alone.Journal of Cardiovascular Pharmacology, May 2002; 39 (5): 714-721.

Machha A, Mustafa MR.Chronic treatment with flavonoids prevents endothelial dysfunction in spontaneously hypertensive rat aorta. J Cardiovasc Pharmacol. 2005 Jul; 46(1):36-40.

Marchioli R, Barzi F, Bomba E, Chieffo C, Di Gregorio D, Di Mascio R, Franzosi MG, Geraci E, Levantesi G, Maggioni AP, Mantini L, Marfisi RM, Mastrogiuseppe G, Mininni N, Nicolosi GL, Santini M, Schweiger C, Tavazzi L, Tognoni G, Tucci C, Valagussa F; GISSI-Prevenzione Investigators.Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione. Circulation. 2002 Apr 23; 105(16):1897-903.

Med Lett Drugs Ther. 2004 Safety of aggressive statin therapy. Nov 22;46(1196):93-5.

Mozaffarian D, Geelen A, Brouwer IA, Geleijnse JM, Zock PL, Katan MB.Effect of Fish Oil on Heart Rate in Humans. A Meta-Analysis of Randomized Controlled Trials. Circulation. 2005 Sep 19

Oh H, Kang DG, Kwon JW, Kwon TO, Lee SY, Lee DB, Lee HS.Isolation of angiotensin converting enzyme (ACE) inhibitory flavonoids from Sedum sarmentosum.Biol Pharm Bull. 2004 Dec; 27(12):2035-7.

Park OJ, Kang NE, Chang MJ, Kim WK.Resistant starch supplementation influences blood lipid concentrations and glucose control in overweight subjects. J Nutr Sci Vitaminol (Tokyo). 2004 Apr; 50(2):93-9.

Peng SK, Hu B, Morin RJ.Angiotoxicity and atherogenicity of cholesterol oxides. J Clin Lab Anal. 1991; 5(2):144-52. (Review)

Pereira DI, Gibson GR.Effects of consumption of probiotics and prebiotics on serum lipid levels in humans.

Crit Rev Biochem Mol Biol. 2002; 37(4):259-81. Review.

Pfeiffer CM, Caudill SP, Gunter EW, Osterloh J, Sampson EJ. Biochemical indicators of B vitamin status in the US population after folic acid fortification: results from the National Health and Nutrition Examination Survey 1999-2000. Am J Clin Nutr. 2005 Aug;82(2):279-80.

Pignone M, Phillips C, Mulrow C. Use of lipid lowering drugs for primary prevention of coronary heart disease: meta-analysis of randomised trials. BMJ. 2000 Oct 21; 321(7267):983-6.

Pitsavos C, Panagiotakos DB, Tzima N, Chrysohoou C, Economou M, Zampelas A, Stefanadis C.Adherence to the Mediterranean diet is associated with total antioxidant capacity in healthy adults: the ATTICA study. Am J ClinNutr. 2005 Sep; 82(3):694-9.

Psaltopoulou T, Naska A, Orfanos P, Trichopoulos D, Mountokalakis T, Trichopoulou A. Olive oil, the Mediterranean diet, and arterial blood pressure: the Greek European Prospective Investigation into Cancer and Nutrition (EPIC) study . Am J Clin Nutr. 2004 Oct; 80(4):1012-8. Erratum in: Am J Clin Nutr. 2005 May; 81(5):1181.

Ramirez-Bosca A, Soler A, Carrion MA, Diaz-Alperi J, Bernd A, Quintanilla C, Quintanilla Almagro E, Miquel J. An hydroalcoholic extract of curcuma longa lowers the apo B/apo A ratio. Implications for atherogenesis prevention. Mech Ageing Dev. 2000 Oct 20; 119(1-2):41-7.

SACN (2004) Advice to FSA: on the benefits of oily fish and fish oil consumption from SACN (http://www.sacn.gov.uk)

Salmeron J, Manson JE, Stampfer MJ, Colditz GA, Wing AL, Willett WC. Dietary fiber, glycemic load, and risk of non-insulin-dependent diabetes mellitus in women. JAMA. 1997 Feb 12; 277(6):472-7.

Salmeron J, Ascherio A, Rimm EB, Colditz GA, Spiegelman D, Jenkins DJ, Stampfer MJ, Wing AL, Willett WC. Dietary fiber, glycemic load, and risk of NIDDM in men.Diabetes Care. 1997 Apr; 20(4):545-50.

Schroder H, Marrugat J, Vila J, Covas MI, Elosua R.Adherence to the traditional mediterranean diet is inversely associated with body mass index and obesity in a Spanish population.
J Nutr. 2004 Dec; 134(12):3355-61.

Shannon J, Tewoderos S, Garzotto M, Beer TM, Derenick R, Palma A, Farris PE . Statins and prostate cancer risk: acase-control study. Am J Epidemiol. 2005 Aug 15; 162(4):318-25.

Soni KB, Kuttan R. Effect of oral curcumin administration on serum peroxides and cholesterol levels in human volunteers. Indian J Physiol Pharmacol. 1992 Oct; 36(4):273-5.

Srivastava KC, Bordia A, Verma SK. Curcumin, a major component of food spice turmeric ( Curcuma longa) inhibits aggregation and alters eicosanoid metabolism in human blood platelets. Prost Leuk Essen Fat Acids . 1995; 52:223-7

Stoll LL, McCormick ML, Denning GM, Weintraub NL.Antioxidant effects of statins.Timely Top Med CardiovascDis. 2005 Feb 4;9.

Vlachopoulos C, Aznaouridis K, Alexopoulos N, Economou E, Andreadou I, Stefanadis C.Effect of dark chocolate on arterial function in healthy individuals. Am J Hypertens. 2005 Jun; 18(6):785-91.

Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003; 326:1419

Wallerath T, Li H, Godtel-Ambrust U, Schwarz PM, Forstermann U.A blend of polyphenolic compounds explains the stimulatory effect of red wine on human endothelial NO synthase. Nitric Oxide. 2005 Mar; 12(2):97-104.

Whincup PH., Gilg JA, Donald AE, Katterhorn M, Oliver C, Cook DG, Deanfield JE: Arterial distensibility in adolescents: the influence of adiposity, the metabolic syndrome, and classic risk factors. Circulation. 2005 Sep 20; 112(12):1789-97.

Wu CH, Yen GCInhibitory effect of naturally occurring flavonoid s on the formation of advanced glycation endproducts.J Agric Food Chem. 2005 Apr 20; 53(8):3167-73.

Xu B, Ji Y, Yao K, Cao YX, Ferro A. Inhibition of human endothelial cell nitric oxide synthesis by advanced glycation endproducts but not glucose: relevance to diabetes. Clin Sci (Lond). 2005 Jul 15; [Epub]

Yokozawa T, Nakagawa T: Inhibitory effects of Luobuma tea and its components against glucose-mediated protein damage.Food Chem Toxicol. 2004 Jun; 42(6):975-81

Diabetes
A.D.A. American Diabetes Association. Type 2 diabetes in children and adolescents. Diabetes Care 2000;23:381-9.

Amos AF, McCarty DJ and Zimmet P The rising global burden of diabetes and its complications: estimates and projections to the year 2010.. 1997. Diabetic Medicine, 14(Suppl. 5): S1-S85

Anderson, R.A., N.A. Bryden, and M.M. Polansky, “Serum Chromium of Human Subjects: Effects of Chromium Supplementation and Glucose,”The AmericanJournal of Clinical Nutrition , 41: 571-7,1985.

Anderson RA, Cheng N, Bryden NA, Polansky MM, Cheng N, Chi J, Feng J Elevated Intakes of Supplemental Chromium Improve Glucose and Insulin Variables in Individuals With Type 2 Diabetes Diabetes November 1997 Volume 46, Number 11

Baly DL, Schneiderman JS, Garcia-Welsh AL. Effect of manganese deficiency on insulin binding, glucose transport and metabolism in rat adipocytes. J Nutr 1990;120:1075-9.

Boyle DIR, Morris AD and MacDonald TM A record linkage capture-recapture technique to create a diabetes disease register for epidemiological research..1998. http://www.dundee.ac.uk/memo/dougie.htm

Boyle JP, Honeycutt AA, Narayan KMV, Hoerger TJ, Geiss LS, Chen H, Thompson TJ.  Projection of diabetes burden through 2050.  Diabetes Care 2001;24:1936-40.

Comuzzie AG, Duggirala R: In Depth: Healthy Living: Diabetes Care & Prevention. San Antonio Business Journal, June 24 ’05. http://sanantonio.bizjournals.com/sanantonio/stories/2005/06/27/focus2.html

Cordain L, Eaton SB, Sebastian A, Mann N, Lindeberg S, Watkins BA, O’Keefe JH and Brand-Miller J. Origins and evolution of the Western diet: health implications for the 21st century American Journal of Clinical Nutrition, Vol. 81, No. 2, 341-354, February 2005

Currie CJ, Kraus D, Morgan CL, Gill L, Stott NC, Peters JR. 1997 NHS acute sector expenditure for diabetes: the present, future, and excess in-patient cost of care. Diabetic Medicine, 14: 686-692

Diabetes Control and Complications Trial, 1996 [No authors listed] The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the diabetes control and complications trial. Diabetes. 1995 Aug;44(8):968-83.

Davis CM, Vincent JB. Chromium oligopeptide activates insulin receptor tyrosine kinase activity. Biochemistry. 1997 Apr 15;36(15):4382-5.

Diabetes UK 2005: http://www.diabetes.org.uk/news/aug03/global.htm

Engelgau MM, Geiss LS, Saaddine JB, Boyle JP, Benjamin SM, Gregg EW, Tierney EF, Rios-Burrows N, Mokdad AH, Ford ES, Imperatore G, Narayan KM: The evolving diabetes burden in the United States. Ann Intern Med 140:945-950, 2004

Fagot-Campagna A. Emergence of type 2 diabetes mellitus in children: the epidemiological evidence. J Pediatr Endocrinol Metabol 2000;13 Suppl 6:1395-402. Review

Ford ES, Giles WH, Mokdad AH: Increasing prevalence of the metabolic syndrome among U.S. adults. Diabetes Care 27: 2444-2449, 2004

Gatling W, Houston AC and Hill RD The prevalence of diabetes mellitus in a typical English community.. 1985. Journal of the Royal College of Physicians of London, 19(4): 248-250

Gilman MW, Cupples LA, Gagnon D, Posner BM, Ellison RC, Castelli WP, Wolf PA. Protective effect of fruits and vegetables on development of stroke in men. JAMA. 1995;273:1113-1117.

Harris MI, Flegal KM, Cowie CC, Eberhardt MS, Goldstein DE, Little RR, Wiedmeyer HM, Byrd-Holt DD: Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults. Diabetes Care 21:518-524, 1998

Ho L, Qin W, Pompl PN, Xiang Z, Wang J, Zhao Z, Peng Y, Cambareri G, Rocher A, Mobbs CV, Hof PR, Pasinetti GM.Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer’s disease. FASEB J. 2004 May;18(7):902-4.

Hypponen E, Laara E, Reunanen A, Jarvelin MR, Virtanen SM. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet. 2001;358(9292):1500-1503

Jandeleit-Dahm KA, Lassila M, Allen TJ. Advanced glycation end products in diabetes-associated atherosclerosis and renal disease: interventional studies. Ann N Y Acad Sci. 2005 Jun;1043:759-66.

Jee SH, Ohrr H, Sull JW, Yun JE, Ji M, Samet JM.Fasting serum glucose level and cancer risk in Korean men and women. JAMA. 2005 Jan 12;293(2):194-202

Key TJ, Thorogood M, Appleby PN, Burr ML. Dietary habits and mortality in 11000 vegetarians and health conscious people: results of a 17 year follow up. BMJ. 1996;313:775-779.

Klein S, Sheard NF, Pi-Sunyer X, Daly A, Wylie-Rosett J, Kulkarni K, Clark NG: Weight management through lifestyle modification for the prevention and management of type 2 diabetes: rationale and strategies: a statement of the American Diabetes Association, the North American Association for the Study of Obesity, and the American Society for Clinical Nutrition. Diabetes Care 27: 2067-2073, 2004

Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM; Diabetes Prevention Program Research Group.Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346:393-403, 2002

Leaf A. Dietary prevention of coronary disease. The Lyon Heart Study. Circulation 1999; 99: 733-5.

Lusignan S, Sismanidis C, Carey IM, DeWilde S, Richards N and Cook DG. Trends in the prevalence and management of diagnosed type 2 diabetes 1994-2001 in England and Wales. BMC Fam Pract. 2005; 6: 13-23

Mokdad AH, Ford ES, Bowman BA, Nelson DE, Engelgau MM, Vinicor F, Marks JS: Diabetes trends in the U.S.: 1990-1998. Diabetes Care 23:1278-1283, 2000

Must A, Spadano J, Coakley EH, Field AE, Colditz G, Dietz WH: The disease burden associated with overweight and obesity. JAMA 282:1523-1529, 1999

Neil HA, Gatling W, Mather HM, Thompson AV, Thorogood M, Fowler GH, Hill RD, Mann JI. The Oxford Community Diabetes Study: evidence for an increase in the prevalence of known diabetes in Great Britain .. 1987. Diabetic Medicine, 4: 539-543

O’Dea K . Marked improvement in carbohydrate and lipid metabolism in diabetic Australian aborigines after temporary reversion to traditional lifestyle. Diabetes. 1984 Jun;33(6):596-603.

Onkamo P, Vaananen S, Karnoven M, Tuomilehto J. Worldwide increase in incidence of type 1 diabetes: the analysis of the data on published incidence trends. Diabetologia 1999:42:1395-403

Ostlund Jr RE, McGill JB, Herskowitz I, Kipnis DM, Santiago JV, Sherman WR: d-chiro-Inositol metabolism in diabetes mellitus.Proc Natl Acad Sci 90:9988-9992, 1993

Pan XR, Li GW, Hu YH, Wang JX, Yang WY, An ZX, Hu ZX, Lin J, Xiao JZ, Cao HB, Liu PA, Jiang XG, Jiang YY, Wang JP, Zheng H, Zhang H, Bennett PH, Howard BV: Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance: the Da Qing IGT and Diabetes Study. Diabetes Care 20: 537-544, 1997

Rimm EB, Ascherio A, Giovannucci E, Spiegelman D, Stampfer MJ, Willett WC. Vegetable, fruit and cereal fiber intake and risk of coronary heart disease among men. JAMA. 1996;275:447-451.

Robinson K, Arheart K, Refsum H, Brattström T, Boers G, Ueland P, Rubba P, Palma-Reis R, Meleady R, Daly L, Witteman J, Graham I. Low circulating folate and vitamin B 6 concentrations: risk factors for stroke, peripheral vascular disease, and coronary heart disease.Circulation. 1998;97:437-443.

Romero G, Luttrell L, Rogol A, Zeller K, Hewlett E, Larner J: Phosphatidylinositol-Glycan Anchors of Membrane Proteins: Potential Precursors of Insulin Mediators. Science 240:509-511, 1988

Sever PS, Dhalof B, Poulter NR, et al. ASCOT investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomized controlled trial. Lancet 2003;361:1149-1158.

Sigal RJ, Kenny GP, Wasserman DH, Castaneda-Sceppa C: Physical activity/exercise and type 2 diabetes. Diabetes Care 27: 2518-2539, 2004

Shepherd J, Blauw GJ, Murphy MB, et al. PROSPER study group. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomized controlled trial. Lancet 2002;360:1623-1630.

Simmons D, Williams DRR and Powell MJ The Coventry Diabetes Study: prevalence of diabetes and impaired glucose tolerance in Europids and Asians.. 1991. Quarterly Journal of Medicine, New Series, 81(296): 1021-1030

Sullivan PW, Morrato EH, Ghushchyan V, Wyatt HR, Hill JO. Obesity, inactivity, and the prevalence of diabetes and diabetes-related cardiovascular comorbidities in the U.S., 2000-2002. Diabetes Care. 2005 Jul;28(7):1599-603.

Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas M, Salminen V, Uusitupa M, The Finnish Diabetes Prevention Study Group: Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 344:1343-1350, 2001

Verhaar MC, Wever RM, Kastelein JJ, van Dam T, Koomans A, Rabelink TJ. 5-Methyltetrahydrofolate, the active form of folic acid, restores endothelial function in familial hypercholesterolemia. Circulation. 1998;97:237-241

Williamson DF, Vinicor F, Bowman BA; Centers For Disease Control And Prevention Primary Prevention Working Group. Primary prevention of type 2 diabetes mellitus by lifestyle intervention: implications for health policy. Ann Intern Med 140:951-957, 2004

Zhao L, Teter B, Morihara T, Lim GP, Ambegaokar SS, Ubeda OJ, Frautschy SA, Cole GM.Insu lin-degrading enzyme as a downstream target of insulin receptor signaling cascade: implications for Alzheimer’s disease intervention . J Neurosci. 2004 Dec 8;24(49):11120-6

Alzheimer’s and dementia
Ames BN.D elaying the mitochondrial decay of aging. Ann N Y Acad Sci. 2004 Jun;1019:406-11. Review.

Areosa SA, McShane R, Sherriff F. Memantine for dementia. Cochrane Database Syst Rev 2004(4);CD003154.pub2.

Baum L, Ng A. Curcumin interaction with copper and iron suggests one possible mechanism of action in Alzheimer’s disease animal models. J Alzheimer’s Dis 2004;6:367-77.

Baxter NJ, Lilley TH, Haslam E, Williamson MP. Multiple interactions between polyphenols and a salivary proline-rich protein repeat result in complexation and precipitation. Biochemistry. 1997 May 6;36(18):5566-77.

Behall KM, Scholfield DJ, Hallfrisch J. Effect of beta-glucan level in oat fiber extracts on blood lipids in men and women. J Am Coll Nutr 1997;16:46-51.

Bell S, Goldman VM, Bistrian BR, et al. Effect of beta-glucan from oats and yeast on serum lipids. Crit Rev Food Sci Nutr 1999;39:189-202 [review].

Bilikiewicz A and Gaus W. Colostrinin (a naturally occurring, proline-rich, polypeptide mixture) in the treatment of Alzheimer’s disease. Journal of Alzheimer’s Disease 6:17-26, ’04

Borenstein A, Dai Q, Wu Y, Jackson JC, Larson EB et al: Consumption of Fruit and Vegetable Juices Predicts a Reduced Risk of Alzheimer’s Disease: The Kame Project. Alzheimer’s Association 1 st Conference on Prevention of Dementia, Washington June ’05: abstract 05-A-103-ALZ-PC; Presentation P-161, Poster P-161.

Bosanquet N, May J, Johnson N, “Alzheimer’s Disease in the United Kingdom – Burden of Disease and Future Care”. Health Policy Review Paper No. 12, Health Policy Unit, Imperial College School of Medicine, 1998

Braaten JT, Wood PJ, Scott FW, et al. Oat beta-glucan reduces blood cholesterol concentration in hypercholesterolemic subjects. Eur J Clin Nutr 1994;48:465-74.

Bush AI, Pettingell WH, Multhaup G, et al. Rapid induction of Alzheimer A8 amyloid formation by zinc. Science 1994;265:1464-65.

Chandra V, Pandav R, Dodge HH, Johnston JM, Belle SH, DeKosky ST, Ganguli M . Incidence of Alzheimer’s disease in a rural community in India: the Indo-US study. Neurology. 2001 Sep 25;57(6):985-9.

Cherny RA, Legg JT, McLean CA, Fairlie DP, Huang X, Atwood CS, Beyreuther K, Tanzi RE, Masters CL, Bush AI. Aqueous dissolution of Alzheimer’s disease Abeta amyloid deposits by biometal depletion. J Biol Chem. 1999 Aug 13;274(33):23223-8.

Cole G.M.; Yang F.; Lim G.P.; Cummings J.L.; Masterman D.L.; Frautschy S.A.

A Rationale for Curcuminoids for the Prevention or Treatment of Alzheimer’s Disease . Current Medicinal Chemistry – Immunology, Endocrine & Metabolic Agents, March 2003, vol. 3, no. 1, pp. 15-25(11)

Cutler RG, Kelly J, Storie K, Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer’s disease. Proc Natl Acad Sci USA, 2004;101:2070-2075)

Gasparini L, Gouras GK, Wang R, Gross RS, Beal MF, Greengard P, Xu H.Stimulation of beta-amyloid precursor protein trafficking by insuli n reduces intraneuronal beta-amyloid and requires mitogen-activated protein kinase signaling. J Neurosci. 2001 Apr 15;21(8):2561-70.

Hagen TM, Liu J, Lykkesfeldt J, Wehr CM, Ingersoll RT, Vinarsky V, Bartholomew JC, Ames BN. Feeding acetyl-L-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):1870-5. Erratum in: Proc Natl Acad Sci U S A 2002 May 14;99(10):7184.

Hassing LB, Johansson B, Nilsson SE, Berg S, Pedersen NL, Gatz M, McClearn G.Diabetes mellitus is a risk factor for vascular dementia, but not for Alzheimer’s disease: a population-based study of the oldest old. Int Psychogeriatr. 2002 Sep;14(3):239-48.

Hensley K, Carney JM, Mattson MP, Aksenova M, Harris M, Wu JF, Floyd RA, Butterfield DA . A model for beta-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease. Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3270-4.

Hong J, Bose M, Ju J, Ryu J-H, Chen X, Sang S, Lee M-J, and Yang CS. Modulation of arachidonic acid metabolism by curcumin and related -diketone derivatives: effects on cytosolic phospholipase A 2, cyclooxygenases, and 5-lipoxygenase Carcinogenesis, Vol. 20, No. 3, 445-451, March 1999

Jarvis WD, Grant S. The role of ceramide in the cellular response to cytotoxic agents. Curr Opin Oncol 1998; 10(6):552-9.

Jeon SY, Bae K, Seong YH, Song KS.Green tea catechins as a BACE1 (beta-secretase) inhibitor. Bioorg Med Chem Lett. 2003 Nov 17;13(22):3905-8.

Joseph, J.A., Shukitt-Hale B., Denisova, N.A. Bielinksi D., Martin, A., McEwen, J.J., and Bickford, P.C. “Reversals of Age- Related Declines in Neuronal Signal Transduction, Cognitive, and Motor Behavioral Deficits with Blueberry, Spinach, or Strawberry Dietary Supplementation.” Journal of Neuroscience, September 15, 1999, Vol. 19, No. 18, pp. 8114-812

MP, “Folic Acid Deficiency and Homocysteine Impair DNA Repair in Hippocampal Neurons and Sensitize Amyloid Toxicity in Experimental Models of Alzheimer’s Disease,” Journal of Neuroscience 2002, 22:5,

Lim GP, Chu T, Yang F, Beech W, Frautschy SA, Cole GM. The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J Neurosci 2001;21:8370-7.

Lim GP, Calon F, Morihara T, Yang F, Teter B, Ubeda O, Salem N, Frautschy SA, and Cole GM : A Diet Enriched with the Omega-3 Fatty Acid Docosahexaenoic Acid Reduces Amyloid Burden in an Aged Alzheimer Mouse Model J. Neurosci., Mar 2005; 25: 3032 – 3040

Liu J, Atamna H, Kuratsune H, Ames BN.Delaying brain mitochondrial decay and aging with mitochondrial antioxidants and metabolites. Ann N Y Acad Sci. 2002 Apr;959:133-66. Review.

Liu J, Head E, Gharib AM, Yuan W, Ingersoll RT, Hagen TM, Cotman CW, Ames BN.Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: partial reversal by feeding acetyl-L-carnitine and/or R-alpha -lipoic acid. Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):2356-61. Erratum in: Proc Natl Acad Sci U S A 2002 May 14;99(10):7184-5.

Lovell MA, Ehmann WD, Butler SM, et al. Elevated thiobarbituric acid-reactive substances and antioxidant enzyme activity in the brain in Alzheimer’s disease. Neurology. 1995;45:1594-1601.

Mecocci P, MacGarvey U, Beal MF. Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease. Ann Neurol. 1994;36:747-751.

Morris MC, Evans DA, Bienias JL, Tangney CC, Bennett DA, Wilson RS, Aggarwal N, Schneider J.Consumption of fish and n-3 fatty acids and risk o f incident Alzheimer disease. Archives Neurology 60:940-946 (2003)

Nicolosi R, Bell SJ, Bistrian BR, et al. Plasma lipid changes after supplementation with beta-glucan fiber from yeast. Am J Clin Nutr 1999;70:208-12.

Ono K, Hasegawa K, Naiki H, Yamada M. Curcumin has potent anti-amyloidogenic effects for Alzheimer’s beta-amyloid fibrils in vitro. J Neurosci Res. 2004 Mar 15;75(6):742-50

Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Ferris S, Galasko D, Jin S, Kaye J, Levey A, Pfeiffer E, Sano M, van Dyck CH, Thal LJ; Alzheimer’s Disease Cooperative Study Group.Vitamin E and donepezil for th e treatment of mild cognitive impairment. N Engl J Med. 2005 Jun 9;352(23):2379-88.

Rockwood K, Kirkland S, Hogan DB et al. Use of lipid-lowering agents; indication bias, and the risk of dementia in community-dwelling elderly people. Arch Neurol 2002;59:223-227.

Rogers J. Inflammation as a pathogenic mechanism in Alzheimer’s disease. Arzneimittelforschung/Drug Res. 1995;45:439-442.

Saunders RD, Luttman CA, Keith PT, et al. Beta-amyloid protein potentiates H2O2-induced neuron degeneration in vitro. Soc Neurosci Abstracts. 1991;17:1447.

Schroeter H, Williams RJ, Matin R, Iversen L, Rice-Evans CA.Phenolic antioxidants attenuate neuronal cell death following uptake of oxidized low-density lipoprotein. Free Radic Biol Med. 2000 Dec 15;29(12):1222-33.

Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D’Agostino RB, Wilson PW, Wolf PA. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med. 2002 Feb 14;346(7):476-83.

Shiiki T, Ohtsuki S, Kurihara A, Naganuma H, Nishimura K, Tachikawa M, Hosoya K, and Terasaki T. Brain Insulin Impairs Amyloid-{beta}(1-40) Clearance from the Brain J. Neurosci., October 27, 2004; 24(43): 9632 – 9637.

Skrecky D: Blueberry supplementation enhances signalling and prevents behavioural deficits in an Alzheimer disease model. Nutr Neurosci. 2003 Jun;6(3):153-62

Sparks DL; Sabbagh MN; Connor DJ; Lopez J; Launer LJ; Browne P; Wasser D; Johnson-Traver S; Lochhead J; Ziolwolski C. Atorvastatin for the Treatment of Mild to Moderate Alzheimer Disease. Arch Neurol. 2005;62:753-757.

Sreejayan N, Rao MNA. Nitric oxide scavenging by curcuminoids. J Pharm Pharmacol 1997;49:105-7.

Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu J, Wands JR, de la Monte SM. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease—is this type 3 diabetes? J Alzheimer’s Disease 7, 63-80, 2005

Subbarao KV, Richardson JS, Ang LC. Autopsy samples of Alzheimer’s cortex show increased peroxidation in vitro. J Neurochem. 1990;55:342-345.

Uusitupa MI, Ruuskanen E, Makinen E, et al. A controlled study on the effect of beta-glucan-rich oat bran on serum lipids in hypercholesterolemic subjects: relation to apolipoprotein E phenotype. J Am Coll Nutr 1992;11:651-9.

Watson G.S, Craft S. The Role of Insulin Resistance in the Pathogenesis of Alzheimer’s Disease: Implications for Treatment CNS Drugs, 2003, vol. 17, no. 1, pp. 27-45(19)

Whitmer RA, Sidney S, Selby J, Johnston SC, Yaffe K. Midlife cardiovascular risk factors and risk of dementia in later life. Neurology. 2005; 64: 277-281.

Wolozin B, Kellman W, Ruosseau P et al. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Arch Neurol 2000;57:1439-1443.

Yang F, Lim GP, Begum AN, Ubeda OJ, Simmons MR, Ambegaokar SS, Chen PP, Kayed R, Glabe CG, Frautschy SA, Cole GM. Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem. 2005 Feb 18;280(7):5892-901.

Zablocka A, Janusz M, Macala J, Lisowski J. A proline-rich polypeptide complex and its nonapeptide fragment inhibit nitric oxide production induced in mice. Regul Pept. 2005 Feb 15;125(1-3):35-9

Zandi P et al: Reduced Risk of Alzheimer Disease in Users of Antioxidant Vitamin Supplements (Arch Neurol 2004; 61:82-88)