Das ist ein Vortrag, den Dr. Clarence P. Davis im Jahre 2007 im Rahmen eines Anti-Aging Kongresses in Paris gehalten hat. Er beinhaltet theoretisches Basis- und Hintergrundswissen zu den verschiedenen Diaettypen, sowie einige praktische Beispiele aus dem aerztlichen Alltag. Der Vortrag ist auf Englisch und einem hohen Niveau. Er richtet sich ausschliesslich an professionelle Leser mit fundierten Vorkenntnissen.

2. The best dietetic principles to life extensionA review of the studies Dr. Clarence P. Davis Bergstrasse 8 CH-8702 Zollikon

3. Causes of Death in the US McGinnis JM, Foege WH. JAMA. 1993 Nov 10;270(18):2207-12

4. Causes of Death in the US Table 2. Actual Causes of Death in the United States in 1990 and 2000 Mokdad AH et al. JAMA. 2004 Mar 10;291(10):1238-45

5. Causes of Death in the US Table 1. Leading Causes of Death in the United States in 2000* Mokdad AH et al. JAMA. 2004 Mar 10;291(10):1238-45

7. Number of Surviving Rats Rats + ad libitum diet Rats + caloric diet 1400 -1499 1100-1199 21-399 days 500-599 700-799 900-999 1300-1399 Age (days) Rats + ad libitum diet + cancer (29 % = 72/250) Rats +  cal. diet + cancer (19 % = 48/250) A  calorie diet =>  mean & maximal life span & delays risk of cancer Ross MH, Bras G. J Nutr 1973 Jul;103(7):944-63

8. Sedentary rats (W = 271 g) + ad libitum diet 55 Rats (W = 170 g) +physical exercise Rats (W = 170 g) +low caloric diet 0 0 Rats were followed from age 40 days => At 50 days they received a series of DMBA injections => 18 weeks later: only rats fed an ad libitum diet & sedentary hadmammary tumors Physical exercise or  Calorie diet => delays &  risk of cancer in rats Number of Female Rats with mammary tumor Moore C, Tittle PW. Surgery. 1973 Mar;73(3):329-32

9. Dietary Restriction in Mice beginning at 1 Year of Age Body weights and survival of two different strains of mice fed on control and restricted diets. Each point in the survival curves represents one mouse. Weindruch R, Walford RL. Science. 1982 Mar 12;215(4538):1415-8

10. Periodically diet-restricted rats (food regimen: alternate day ad libitum Diet- Rats 9 days after t. i. unrestricted surviviving 80 10 days control rats (%) after t. i. 60 66.7% 9 days after tumor 50 % 10 days ttumor-bearing 40 inoculation after t. i. Fisher rats) 20 20.8 % 12.5 % 0 Short-term alternate day-dietary-restriction initiated 1 week before intraperitoneal inoculation of ascites tumor cells Short-term calorie restriction =>  longevity of tumor-bearing rats feeding followed by alternate day fasting) n = 3-4-month-old Siegel I, et al. Cancer Invest. 1988;6(6):677-80

11. Repeatedly Fasting mice Control (4 consecutive days, mice every 2 weeks) Mean Survival Time (weeks) + 34 % 80 60 64.0 weeks 40 47.9 weeks 20 0 Short-term repeated fasting mice survived sign.longer than full-fed mice in spite of the fasting group having a heavier body weight than controls. Short-term repeated fasting manipulation was also effective on the rolongation of life-span in autoimmune-prone mice Short-term calorie restriction =>  longevity of mice Sogawa H, et al. Mech Ageing Dev. 2000 May 18;115(1-2):61-71

12. Ad libitum-fed mice Chronic calorie Periodically calorie- restricted mice restricted mice Mammary tumor development In mouse species prone to MT (%) (matches calorie (3-week intervals of ad intake of weight- libitum food intake 80 cycled mice) followed by 3-week intervals of food restriction 77 % 60 40 44 % 20 3 % 0 n = 1/30 n = 15/33 n = 23/30 Periodic restriction of food intake by 3-weeks interval starting in adulthood (10 weeks of age) drastically reduces the incidence of mammary tumors & the mean weight of the tumor & delays its detection. Peridocal calorie-restriction => reduces mammary tumor development Cleary MP, et al. Cancer Epidemiol Biomarkers Prev. 2002;11(9):836-43

13. Effects of CR Reduced body weight and fat Mixed effect model of body weight as a function of age in male and female rhesus monkeys on a control diet (CON) or caloric restriction (CR). This result is not surprising considering that generally a 30– 40% reduction in caloric intake is imposed. Mattison JA et al. Exp Gerontol. 2003 Jan-Feb;38(1-2):35-46

14. Effects of CR Reduced trunk fat CR reduces abdominal (trunk) fat. Each bar represents the mean amount of trunk fat determined by dual energy X-ray absorptiometry after 6 (females) or 11 (males) years on CR. The effect of CR on reducing trunk fat was significant for both genders p<0.05. Lane MA et al. 1999a. Toxicol. Sci. 52 (suppl), 41–48

15. Effects of CR Reduced body temperature Subcutaneous body temperature during CON feeding and 3 months at 30% CR for monkeys in a short-term study. Lane MA et al. 1996. Proc. Natl Acad. Sci. USA 93, 4159–4164

16. Effects of CR Reduced decrease of DHEAS CR slows the rate of decline in serum DHEAS. Each point represents the mean DHEAS level at a given age. Ages represent the average (± 0.3 year) age of young adult male rhesus monkeys for years 3–6 of the longitudinal study. The rate of change was significantly slower in CR monkeys P<0:005. Lane MA et al. 1997b J. Clin. Endocrinol. Metab. 82, 2093–2096

17. Effects of CR Reduced decrease of Melatonin An age-related decline of melatonin is not evident in the monkeys that are maintained on restriction for a 12- year period. In fact, melatonin levels in old CR monkeys are significantly greater than that observed in the age-matched controls. Roth GS et al. 2001 J. Clin. Endo. Metab. 86, 3292–3295

18. The Biosphere 2 Project Walford RL et al. Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11533-7

19. The Biosphere 2 Project: Effect of caloric Restriction on metabolic Parameters Mean systolic BP for males (M, four subjects) and females (F, four subjects) preclosure (period 0) and during the following 6 months. *, P < 0.05; **, P < 0.01. Walford RL et al. Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11533-7

20. The Biosphere 2 Project: Effect of caloric Restriction on metabolic Parameters Mean diastolic BP for males (M) and females (F) preclosure (period 0) and during the following 6 months. **, P < 0.01. Walford RL et al. Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11533-7

21. The Biosphere 2 Project: Effect of caloric Restriction on metabolic Parameters Mean fasting serum total cholesterol (●) and HDL cholesterol (▲) preclosure (period 0) and during the following 6 months *, Difference (P < 0.05) compared to period 0; **, P < 0.01. Walford RL et al. Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11533-7

22. CR in Humans Subjects in the BLSA are NOT CR. Genetic or environmental factors that contribute to the CR-like metabolic effects are unknown. Roth GS et al. Science. 2002 Aug 2;297(5582):811

25. CR enhances the induction of stress proteins in response to damage

28. Glycolytic inhibition

29. IGF-1 signaling pathway

30. Insulin sensitivity

31. PPARs (peroxisome proliferator activated receptors)

32. Sirtuins

33. Lipids

34. Body temperature

36. it does not significantly reduce long-term food intake

37. it activates stress response pathways observed in CR and provides protection against a variety of stressors

39. All inhibitors of the IGF-1 pathway (retinoids, soy isoflavones (e.g. genistein and daidzein), flavonoids (e.g. quercetin and kaempferol), somatostatin analogues (e.g. octreotide), and selective estrogen receptor modulators (e.g. tamoxifen))

40. Insulin sensitizers (e.g. metformin)

41. Resveratrol

42. agonists for peroxisome proliferator activated receptors (PPARs)

44. Avoid Sugar

45. Average life span of the 70 mice Average life span of 7 oldest mice -6,4 % 1000 Survival 20 % glucose diet Control diet 800 -10 % (days ) 600 400 200 0 n = 70 n = 70 n = 7 n = 7 p < 0.05 p < 0.05  Glucose diet =>  life span of mice Mlekusch W et al. Mech Ageing Dev 1996 Nov 29;92(1):43-51

46. HIGHEST quintile of intake of Prostate cancer (odds Ratio) Starch LOWEST 1.5 Linolenic acid (3) Linoleic acid (6) quintile +40 % 1 -20% large-scale Italian cohort study; 1294 cases -30 % 0.5 1.4 0.8 0.7 0 p < 0.05 p< 0.05 p< 0.05 Starch intake =>  risk of Prostate cancer Bidoli E et al. Ann Oncol. 2005 Jan;16(1):152-7

47. Cancer Stroke CVD Apoptosis – Cell proliferation + Hypertension Atherosclerosis Diabetes Dyslipidemia Metabolic Syndrome Gonadal and adrenal stimulation IGF1 Bioavailability + Sex Hormones + Pathogenesis Insulin + SHBG - Insulin resistance (IR) FFA + TNF a + IL-6 + Resistin + Adiponectin - NADPH oxidase + Antioxidant enzymes - Aromatase + Oxidative Stress Inflammation ER Stress ROS Risc Factor Genetics Lifestyle Environment Obesity Adapded from: Jee SH et al. Yonsei Med J. 2005 Aug 31;46(4):449-55

48. Relationship between fasting serum glucose and risk of cancer Hazard ratios for all cancer deaths by fasting serum glucose levels in Korean men according to body mass index, 1993-2002 Jee SH et al. JAMA 2005 Jan 12;293(2):194-202

49. Avoid Caffeinated Drinks

50. Female C3H mice spontaneous BC Change in Female BD2F1 mice incidence DMBA-induced BC Caffeine 500 mg/l of + 117 % mammary 120 carcinoma Caffeine 500 mg/l Caffeine 250 mg/l 100 80 + 40 % + 20 % Caffeine 250 mg/l 60 + 13 % (% more mice 40 with 20 breast cancer) 0 NS NS p < 0.05 p < 0.05 Increased incidence of DMBA carcinogen-induced mammary carcinoma’s in BD2F1 & C3H mice drinking caffeine in drinking water starting at 8 weeks of age to experiment termination. Mammary gland development was sign. increased in high caffeine BALB/c mice. Caffeine drinking =>  mammary carcinoma incidence Welsch CW et al. Cancer Res 1988 Apr 15;48(8):2078-82

51. Heavier women Lean women (BMI ≥ 24) (BMI ≤24) Drinking ≥ 5 cups/day 2.5 2 Drinking < 2 cups of coffee/day Drinking < 2 cups of coffee/day 2.1 1.5 Drinking ≥ 5 cups/day Risk) 1 1 1 0.5 0.5 0 Coffee consumption reduces the risk of breast cancer in lean women, but might increase it in relatively obese women. This interaction between coffee intake & BMI was statist. sign. n = 152 breast cancer cases among 14,593 Norwegian women ; mean follow-up = 12 yrs Coffee => breast cancer risk: in lean women, in obese women Breast Cancer (Relative Vatten et al. Br J Cancer. 1990 Aug;62(2):267-70

52. Heaviest smokers (highest quartile) Heaviest coffee drinkers (highest quartile) 2.7 2,5 2.1 2 (95% CI: Relative risk of bladder cancer Lowest quartile 1.8 to 4.0) 1,5 (95% CI: 1.3-3.2) 1 1 0,5 p < 0.05 p < 0.05 0 Coffee =>  risk of bladder cancer Coffeeconsumption was assoc. + increased risk for bladder cancer among the heaviest coffee drinkers after adjustment for cigarette smoking & other dietary risk factors. The effect was more pronounced among nonsmokers, esp. among those 65 yrs & older. These findings support the contention that coffee is a weak carcinogen. After adjustment for age, education, & dietary risk factors by multiple regression, risk of bladder cancer was found to increase with increasing pack-years of cigarette use. Vena JE et al. Ann Epidemiol. 1993;3(6):586-91

53. Caffeine increases BP Laboratory studies over the last 20 yrs => consistently demonstrated => caffeine dose of 2 to 3 cups of brewed coffee =>  blood pressure (BP) at rest: + 7 to + 10 mm Hg when administered either to "caffeine-naive" individuals or to habitual coffee drinkers after overnight abstinence. =>  BP reach a max. 30 to 60 minutes after caffeine administration & persist for several hours. Lane JD et al. Psychosomatic Med 2002; 64:595-603

54. Serum Cholesterol 200 (mg/dl) Increase of 1 cup of coffee per day = increase of 2 mg/dl total cholesterol 196 192 (p < 0.001) 188 184 n = 2109 healthy nonsmokers aged 25-65 yrs (mean follow-up = 16.7 months) 180 176 0 1 2 3 4 5 6 7 8 9 10 cups/day Coffee =>  serum cholesterol A dose-response was found among those who decreased regularcoffee consumption, those who continued the same dose, & those who increased consumption. The same trend was observed among those who quit drinking regular coffee, those who never drank coffee, & those who started to coffee. Wie M et al. J Clin Epidemiol. 1995 Oct;48(10):1189-96

55. Eat Vegetables & Fruits

56. CITRUS FRUIT consumption SUPPLEMENT intake LOW HIGH LOW (< 1 x/wk) HIGH (≥ 2 x/wk) HIGH LINOLEIC ACID HIGH VIT. C 1 VIT. B2 1.0 -48 % -50 % -60 % MORTALITY 0.5 0.52 (95% CI = 0.28 - 0.95) 0 5-year cohort study among n = 162 self-sufficient residents in a public home for elderly  citrus fruits &  intake of vit. C, vit. B2 & linoleic acid =>  all- cause mortality in very elderly people Frequent consumption of citrus fruit, and high intake of vitamin C, riboflavin, & linoleic (6) acid are associated with longevity Fortes C et al. Epidemiology. 2000 Jul;11(4):440-5

57. 0.87 0.78 (0.68- (0.61- 1.10) 1.01)  Fruit & vegetable intake =>  mortality Relative risk Fruit & vegetable intake of dying (11-yr mortality) th th th (2 ) Lowest (3 ) Average (4 ) Higher th st (5 ) Highest (1 ) Lowest quintile quintile quintile quintile quintile 1.2 - 6 % - 11 % - 22 % 1 1.08 1.0 0.8 (0.88- 0.94 1.33) (0.75- 0.6 1.17) 0.4 0.2 0 n = 15,792 (age 45-64 yrs) P for trend = 0.02 Over an 11-y follow-up period, the relative hazards of death for quintiles 2-5 of fruit & vegetable intake were 1.08 (95% CI:0.88-1.33) , 0.94 (0.75-1.17) , 0.87 (0.68-1.10) , & 0.78 (0.61-1.01), resp. Neither fruit, nor vegetable fiber intake were associated with incident cardiovascular death (P =.98, =.95 resp.) Steffen LM et al. Am J Clin Nutr. 2003 Sep; 78(3): 383-90

58. Upper quintiles Lowest Relative risk (adjusted prevalence odds ratio) quintile Fruit consumption 1 Vegetable 1 consumption Fruit & vegetable consumption 0.8 n = 4393 0.6 0.68 0.58 (95 % CI: 0.4 (95 % CI: 0.23 0.43- 1.09) 0.36-0.91) (95 % CI: 0.2 0.43- 1.09) 0 P = 0.001 P = 0.10 P = 0.01 Fruit & vegetable intake =>  risk of hypertension In a Mediterranean population with an elevated fat consumption (37 % of diet),a high fruit & vegetable intake is inversely associated with BP levels Alonso A et al. Br J Nutr. 2004;92(2):311-9

59. FRUIT & VEGETABLE INTAKE ≥ 3x/day Relative risk of disease or death Ischemic heart disease mortality Cardiovascular disease disease mortality All cause mortality 1 <1x/day Stroke incidence Stroke mortality 0.8 0.6 - 27% - 24% - 27% - 15% - 42% 0.4 0.2 0.85 0.73 0.73 0.58 0.76 0 n = 9608 adults aged 25-74 yr (average 19-yr follow-up) P = 0.02 Fruit & vegetable intake => cardiovascular and all cause mortality An inverse association of fruit & vegetable intake with therisk of cardiovascular disease & all-cause mortality was observed in the general US population. Bazzano LA et al. Am J Clin Nutr. 2002 Jul; 76(1): 93-9

60. Liver Overall cancer mortality Stomach & cancer lung cancer (Almost) daily (Almost) daily green- Mean (Amost) daily FRUIT intake yellow VEGETABLE Risk FRUIT intake intake - 8 % - 12 % - 20% 1 - 25% 0.8 0.6 0.75 1.0 0.92 0.8 0.88 95%CI 0.4 0.94- = 0.80 0.60- 0.65- 0.2 1,01) -0,96) 0,95) 0.98) 0 P < 0.05 P < 0.05 P < 0.05 P < 0.05 38 540 men & women who were atomic-bomb survivors in Hiroshima & Nagasaki, Japan, were followed-up for cancer deaths until March 1998, during which time 3136 cancer deaths were identified. Fruit & vegetable intake => cancer mortality Relative risk of dying from cancer Daily consumption of fruit & vegetables reduces the mortality from total cancer, &specifically cancers of stomach, liver, & lung. Not statist. sign. associations were found w/ oesophageal cancer, but none w/ breast & colorectal cancer. Sauvaget C et al. Br J Cancer. 2003; 88(5): 689-94

62. dependent on -carotene & lutein + zeaxanthin (RR = 0.5 => 0.80)(Freudenheim 1994)

63. still some unexplained protectionattributable to total intake of vegetables

65. sterols(Jellinck 1991, Michnovicz 1991, Bradlow 1991) :  oxidation of E2 in liver ( catecholestrogen production) =>  secretion of 2-hydroxy-E1, -E3

66. lignans(phytoestrogens like enterolactone + other dephenols; Adlercreutz 1991):  aromatase competitively w/ testosterone + androstenedione in peripheral & cancer cells =>  estrogens (Adlercreutz 1993); have 1/75 - 1/360 potency of estrogens phytoestrogens

68. Coffee + Alcohol + smoking =>  risk of pancreatic cancer Smoking + Alcohol + Coffee Pancreatic 30 Alcohol Cancer + Coffee 26.3 20 (Relative Risk) 13.9 10 1 0 p = 0.02 p = 0.13 n = 29 cases + pancreatic cancer & 29 controls The combination of 2 to 3 risk factors increases considerably therisk of pancreatic cancer. Considered independently, only alcohol & coffee consumption were found to be sign. assoc. + pancreas cancer Pfeffer F et al. Rev Invest Clin. 1989 Jul-Sep;41(3):205-8

69. Alcohol =>  risk of breast cancer Follow-up: daily alcohol of 24 g continues Daily initial alcohol consumption of 24 g (2 drinks) Non drinkers 1,7 (95% CI, 1.4-2.2) 1,4 (95% CI, 1.0-1.8) Risk of breast cancer in daily alcohol drinkers & non-drinkers Longnecker MP et al. JAMA. 1988 Aug 5;260(5):652-6

70.  ALCOHOL consumption => predisposes to BREAST CANCER?

71. Alcoholusers >96 Prostate 22-96 grams cancer <22 grams grams risk 4 +210% alcohol (Rel. Risk) +160 % 3 per week 3.1 2 large-scale Nonusers 2.6 +10 % Iowa Cohort 1 study; 1.1 110 (?) cases 0 NS p< 0.05 p< 0.05 Increased risk of prostate cancer in alcohol consumers Alcohol =>  risk of Prostate cancer Putnam SD et al. Ann Epidemiol. 2000 Aug;10(6):361-9

72. Mediterranean diet => mortality Alonso A, Martinez-Gonzalez MA. JAMA. 2005 Feb 9;293(6):674

73. Thank you for your attention