the best dietetic principles to life extension
TRANSCRIPT
The best dietetic principles to life extension
A review of the studies
Dr. Clarence P. DavisBergstrasse 8
CH-8702 Zollikon
McGinnis JM, Foege WH. JAMA. 1993 Nov 10;270(18):2207-12
Causes of Death in the US
Mokdad AH et al. JAMA. 2004 Mar 10;291(10):1238-45
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
Causes of Death in the US
Table 1. Leading Causes of Death in the United States in 2000*
Caloric Restriction
Early studies date back to 1914: Reducing food intake inhibits the occurrence of spontaneous tumors in rodents- Rous F. The influence of diet on transplant and spontaneous
tumors. J Exp Med. 1914 20:433-451 1915/1917: Restricted food intake leads to an increase
in fertility and longevity in female rats– Osborne TL, Mendel LB. The resumption of growth after long
continued failure to grow. J Biol Chem. 1915 23:439-454 – Osborne TL, Mendel LB. The effect or retardation of growth
upon the breeding period and duration of life in rats. Science. 1917:294-295
Many studies followed showing all a significant increase in longevity for a vast group of poikilothermic and homeothermic species
Ross MH, Bras G. J Nutr 1973 Jul;103(7):944-63
A calorie diet => mean & maximal life span & delays
risk of cancer
1100-11990
50
100
150
200
250
Rats + ad libitum diet + cancer (29 % = 72/250)
Rats +ad libitum diet
Number of Surviving Rats
Rats + caloric diet
Rats + cal. diet + cancer (19 % = 48/250)
Age (days)
21-399 days
500-599
700-799
900-999 1300-1399 1400
-1499
Moore C, Tittle PW. Surgery. 1973 Mar;73(3):329-32
Physical exercise or Calorie diet => delays
& risk of cancer in ratsNumber of Female Rats
with mammary
tumor
0
2
4
6
Sedentary rats (W = 271 g)+ ad libitum diet
Rats (W = 170 g) +low caloric diet
55Rats (W = 170 g) +physical exercise
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 had mammary tumors
Weindruch R, Walford RL. Science. 1982 Mar 12;215(4538):1415-8
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.
Siegel I, et al. Cancer Invest. 1988;6(6):677-80
Short-term calorie restriction
=> longevity of tumor-bearing rats
n = 3-4-month-old
feeding followed by alternate day fasting)
0
20
40
60
80Diet-
unrestricted control rats
Short-term alternate day-dietary-restriction initiated 1 week before intraperitoneal inoculation of ascites tumor cells
Rats surviviving
(%)
ttumor-bearing Fisher rats)
9 days after tumor
inoculation
Periodically diet-restricted rats (food regimen: alternate day ad libitum
66.7%
9 days after t. i.
10 days after t. i.
10 days after t. i.
50 %
20.8 %12.5 %
Sogawa H, et al. Mech Ageing Dev. 2000 May 18;115(1-2):61-71
Short-term calorie restriction
=> longevity of mice
0
20
40
60
80
Control mice Mean Survival
Time (weeks)
47.9 weeks
Repeatedly Fasting mice
(4 consecutive days, every 2 weeks)
64.0 weeks
+ 34 %
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
Cleary MP, et al. Cancer Epidemiol Biomarkers Prev. 2002;11(9):836-43
Peridocal calorie-restriction => reduces mammary tumor
development
0
20
40
60
80
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.
Ad libitum-fed miceMammary tumor
developmentIn mouse species prone to MT (%)
77 %
44 %
3 %
Chronic calorie restricted mice(matches calorie intake of weight-
cycled mice)
Periodically calorie- restricted mice
(3-week intervals of ad libitum food intake followed by 3-week
intervals of food restriction
n = 1/30n = 15/33n = 23/30
Mattison JA et al. Exp Gerontol. 2003 Jan-Feb;38(1-2):35-46
Effects of CRReduced 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.
Lane MA et al. 1999a. Toxicol. Sci. 52 (suppl), 41–48
Effects of CRReduced trunk fat
CR reduces abdominal (trunk) fat. Each bar represents the meanamount of trunk fat determined by dual energy X-rayabsorptiometry 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. 1996. Proc. Natl Acad. Sci. USA 93, 4159–4164
Effects of CRReduced 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. 1997b J. Clin. Endocrinol. Metab. 82, 2093–2096
Effects of CRReduced 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 monkeysP<0:005.
Roth GS et al. 2001 J. Clin. Endo. Metab. 86, 3292–3295
Effects of CRReduced 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.
Walford RL et al. Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11533-7
The Biosphere 2 Project
The Biosphere 2 Project: Effect of caloric Restriction on metabolic ParametersMean 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
The Biosphere 2 Project: Effect of caloric Restriction on metabolic ParametersMean
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
The Biosphere 2 Project: Effect of caloric Restriction on metabolic ParametersMean fasting
serum total cholesterol (●) and HDLcholesterol (▲) preclosure (period 0) and during the following 6months *, 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
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
Hypotheses of CR and longevity Reduced caloric intake leads to a decrease of oxidative stress
- Caveat: The role of oxidative stress in aging has not yet been clearly demonstrated
Alteration of the glucose-insulin system- CR causes decrease in plasma glucose and insulin levels- Hyperglycemia and hyperinsulinemia have damaging effects similar to
those occurring in senescence Alteration of the GH-IGF-1 Axis
- CR decreases GH secretion and lowers plasma [IGF-1] Hormesis (=beneficial action resulting from the response of an
organism to a low-intensity-stressor)- CR causes a moderate increase in daily levels of plasma free
corticosterones- CR enhances the induction of stress proteins in response to damage- Single-gene mutations that extend the life of invertebrate species also
increase the ability of these organisms to cope with damaging agents
Feasibility of CR in Humans and Outlook Is CR relevant to human aging?
- Yes and no- A caloric restriction of 30-50% of total daily caloric intake is hardly
feasible for the general population (much less as a lifetime intervention…)
can mechanisms of CR relevant to human aging be identified?- Yes
- Glycolytic inhibition- IGF-1 signaling pathway- Insulin sensitivity- PPARs (peroxisome proliferator activated receptors)- Sirtuins- Lipids- Body temperature- DHEA and immunosenescence (and other hormonal actions)
can interventions be identified that operate through these mechanisms to mimic CR?- Yes
CRMs Criteria for a candidate to be used as a CRM
- It mimics the metabolic, hormonal, and physiological effects of CR- it does not significantly reduce long-term food intake- it activates stress response pathways observed in CR and provides
protection against a variety of stressors- It produces CR-like effects on longevity, reduction of age-related
disease and maintenance of function Some examples of promising candidates
- 2-deoxy-D-glucose (inhibition of the enzyme phosphohexose isomerase and thus reduction of glycolytic processing)
- 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))
- Insulin sensitizers (e.g. metformin)- Resveratrol- agonists for peroxisome proliferator activated receptors (PPARs)- Hypolipidemic drugs?
Possible life extending eating behavior
Avoid sugar– Insulin resistance
CVD cancer
Avoid caffeinated drinks– Cancer?
Eat vegetables/fruits– Lowers cancer rate
Drink alcohol in moderate dose– Preventive effects for CVD
Mlekusch W et al. Mech Ageing Dev 1996 Nov 29;92(1):43-51
Glucose diet => life span of mice
0
200
400
600
800
1000Survival
(days )
n = 70
Control diet 20 % glucose diet
-10 %
-6,4 %
Average life span of the 70 mice
Average life span of 7 oldest mice
n = 70p < 0.05 p < 0.05
n = 7 n = 7
Bidoli E et al. Ann Oncol. 2005 Jan;16(1):152-7
Starch intake => risk of Prostate cancer
0
0.5
1
1.5
large-scale Italian cohort study; 1294 cases
Starch
1.4
-20%
LOWEST quintile
Linolenicacid (3)
Linoleicacid (6)
0.7 0.8
-30 %
Prostate cancer (odds Ratio)
+40 %
p < 0.05 p< 0.05 p< 0.05
HIGHEST quintile of intake of
Adapded from: Jee SH et al. Yonsei Med J. 2005 Aug 31;46(4):449-55
Metabolic SyndromeHypertension Atherosclerosis Diabetes Dyslipidemia
Genetics Lifestyle EnvironmentObesity
Insulin resistance (IR)
Oxidative StressInflammation
ER Stress ROS
Risc Factor
Pathogenesis
FFA +TNF a +IL-6 +
Resistin +Adiponectin -
NADPH oxidase +Antioxidantenzymes -
Insulin +
IGF1Bioavailability +
Apoptosis –Cell proliferation +
CancerStroke CVD
SHBG -
SexHormones +
Gonadal and adrenalstimulation
Aromatase +
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
Caffeine drinking => mammary carcinoma
incidence
Welsch CW et al. Cancer Res 1988 Apr 15;48(8):2078-82
020406080
100120
Female BD2F1 mice DMBA-induced BC
+ 117 %
Change in incidence
of mammary carcinoma
(% more mice with
breast cancer) NS
Female C3H mice spontaneous BC
NSp < 0.05 p < 0.05
+ 40 %+ 13 %
Caffeine 500 mg/l
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 250 mg/l
+ 20 % Caffeine 250 mg/l
Caffeine 500 mg/l
Coffee => breast cancer risk: in lean women, in
obese women
Vatten et al. Br J Cancer. 1990 Aug;62(2):267-70
(Relative
Breast Cancer
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
0
0.5
1
1.5
2
2.5
Risk)1
2.1
0.5
Drinking ≥ 5 cups/day
Lean women(BMI ≤ 24)
Drinking < 2 cups of coffee/day
Heavier women(BMI ≥ 24)
1
Drinking < 2 cups of coffee/day
Drinking ≥ 5 cups/day
Coffee => risk of bladder cancer
Vena JE et al. Ann Epidemiol. 1993;3(6):586-91
Coffee consumption 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.
Relative risk of bladder cancer
Heaviest coffee drinkers
(highest quartile)
Lowest quartile
Heaviest smokers
(highest quartile)
0
0,5
1
1,5
2
2,5
1
2.1
(95% CI:1.3-3.2)
p < 0.05
2.7
(95% CI:
1.8 to 4.0)
p < 0.05
Caffeine increases BPLaboratory 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
Coffee => serum cholesterol
Wie M et al. J Clin Epidemiol. 1995 Oct;48(10):1189-96
A dose-response was found among those who decreased regular coffee 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.
176
180
184
188
192
196
200
0 1 2 3 4 5 6 7 8 9 10cups/day
Serum Cholesterol (mg/dl)
n = 2109 healthy nonsmokers aged 25-65 yrs (mean follow-up = 16.7 months)
(p < 0.001)
Increase of 1 cup of coffee per day = increase of 2 mg/dl total cholesterol
citrus fruits & intake of vit. C, vit. B2 & linoleic acid => all- cause mortality in
very elderly people
Fortes C et al. Epidemiology. 2000 Jul;11(4):440-5
0
0.5
1
MO
RTA
LITY
5-year cohort study among n = 162 self-sufficient residents in a public home for elderly
1.0
CITRUS FRUITconsumption SUPPLEMENT intake
LOW
0.52(95% CI = 0.28 - 0.95)
HIGH (≥ 2 x/wk)
LOW(< 1 x/wk)
-50 %
HIGHVIT. C HIGH
VIT. B2
-60 %
HIGH LINOLEIC
ACID-48 %
Frequent consumption of citrus fruit, and high intake of vitamin C, riboflavin, & linoleic (6) acid are associated with longevity
Fruit & vegetable intake => mortality
Steffen LM et al. Am J Clin Nutr. 2003 Sep; 78(3): 383-90
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.)
0
0.20.40.60.8
11.2
Fruit & vegetable intake(2th) Lowest
quintile(5th) Highest
quintile
(3th) Averagequintile
(4th) Higher quintile
n = 15,792 (age 45-64 yrs) P for trend = 0.02
(1st) Lowest quintile
Relative risk of dying
(11-yr mortality)
0.78 (0.61-1.01)
0.87 (0.68-1.10)
0.94 (0.75-1.17)
1.08 (0.88-1.33)
1.0 - 22 % - 11 % - 6 %
Fruit & vegetable intake => risk of hypertension
Alonso A et al. Br J Nutr. 2004;92(2):311-9
In a Mediterranean population with an elevated fat consumption (37 % of diet), a high fruit & vegetable intake is inversely associated with BP levels
0
0.2
0.4
0.6
0.8
1
Upper quintiles
Relative risk (adjusted prevalence odds ratio) n = 4393
Fruit & vegetable
consumption
P = 0.001P = 0.10
0.58 (95 % CI: 0.36-0.91)
Fruit consumption
0.68 (95 % CI:
0.43- 1.09) 0.23 (95 % CI:
0.43- 1.09)
P = 0.01
Vegetable consumption1
Lowest quintile
Fruit & vegetable intake => cardiovascular and all cause
mortality
Bazzano LA et al. Am J Clin Nutr. 2002 Jul; 76(1): 93-9
An inverse association of fruit & vegetable intake with the risk of cardiovascular disease & all-cause mortality was observed in the general US population.
0
0.2
0.4
0.6
0.8
1
FRUIT & VEGETABLE INTAKE ≥ 3x/dayRelative risk of disease or death
P = 0.02
0.85
<1x/day
n = 9608 adults aged 25-74 yr
Strokeincidence
- 27%
Ischemic heart
disease mortality
- 24%
Strokemortality
- 42%
0.730.73 0.58 0.76
(average 19-yr follow-up)
Cardiovascular disease disease
mortality
- 27%
All cause mortality
- 15%
Fruit & vegetable intake => cancer mortality
Sauvaget C et al. Br J Cancer. 2003; 88(5): 689-94
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.
Relative risk of dying
from cancer
0
0.2
0.4
0.6
0.8
1
(Almost) dailyFRUIT intake
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.
P < 0.05
95%CI= 0.80-0,96)
0.751.0 0.920.88
Overall cancer mortality Stomach &
lung cancerLiver
cancer(Almost) daily green-yellow VEGETABLE
intake
MeanRisk
0.8
0.94-1,01)
0.60-0,95)
0.65-0.98)
- 12 %- 25% - 20%
- 8 %
P < 0.05 P < 0.05 P < 0.05
(Amost) dailyFRUIT intake
Anti cancer action of vegetables VEGETABLE intake has a STRONG PROTECTIVE EFFECT :
- independent of vitamins C, E, folic acid & fiber (Freudenheim 1996)- dependent on -carotene & lutein + zeaxanthin (RR = 0.5 => 0.80)
(Freudenheim 1994)- still some unexplained protection attributable to total intake of
vegetables- possible synergetic effect of vit. E & beta-carotene (Krinsky 1993)
other substances may be protective:- indoles in cabbage, broccoli (Michnovicz 1991, Tivari 1994) :
chemoprevention- sterols (Jellinck 1991, Michnovicz 1991, Bradlow 1991) : oxidation
of E2 in liver ( catecholestrogen production) => secretion of 2-hydroxy-E1, -E3
- 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
- isoflavonoids (phytoestrogens) : some of these substances can E-metabolism (Adlercreutz 1993)
Coffee + Alcohol + smoking => risk of pancreatic cancer
Pfeffer F et al. Rev Invest Clin. 1989 Jul-Sep;41(3):205-8
The combination of 2 to 3 risk factors increases considerably the risk of pancreatic cancer.Considered independently, only alcohol & coffee consumption were found to be sign. assoc. + pancreas cancer
0
10
20
30Pancreatic
Cancer
(Relative Risk)
1
n = 29 cases + pancreatic cancer & 29 controls
p = 0.02
26.3
13.9
p = 0.13
Smoking+ Alcohol+ Coffee
Alcohol+ Coffee
Alcohol => risk of breast cancer
Longnecker MP et al. JAMA. 1988 Aug 5;260(5):652-6
Risk of breast cancer in daily alcohol drinkers & non-drinkers
0
0.5
1
1.5
2
Non drinkers
Daily initial alcohol
consumption of 24 g (2 drinks)
Follow-up: daily alcohol
of 24 g continues
1,4(95% CI, 1.0-1.8)
1,7(95%
CI, 1.4-2.2)
ALCOHOL consumption => predisposes to BREAST CANCER?
Alcohol => breast cancer : Several evidences
ALCOHOL PROMOTES BC
No Effect
ALCOHOL PROTECTS vs BC
ALCOHOL => BC risk :
Longnecker 1988: if 2 drinks a day (= 24 g alcohol/d) => + 40% BC risk
Swanson 1997 : 14 glasses or more of beer, wine or other alcoholic drinks/week => BC risk
WINE intake protects against BC :Note : several prospective studies (Copenhagen heart study, Harvard Nurses Health study) & retrospective studies (American Health Institute, J. American Cancer Institute 1995) show a risk of BC when moderate wine is consumed (1 glass/day, & not more !): of -7 to -22 % of BC risk
Alcohol => risk of Prostate cancer
Putnam SD et al. Ann Epidemiol. 2000 Aug;10(6):361-9
Increased risk of prostate cancer in alcohol consumers
0
1
2
3
4
large-scale Iowa Cohort
study; 110 (?) cases
<22 grams alcohol
per week
1.1
+210%
Nonusers
22-96 grams
Alcoholusers>96
grams
2.63.1
+160 %
Prostate cancer
risk (Rel. Risk)
+10 %
NS p< 0.05 p< 0.05
Mediterranean diet => mortality
Alonso A, Martinez-Gonzalez MA. JAMA. 2005 Feb 9;293(6):674
Thank you for your attention
