1

Piti Palungwachira MD, PhD.

SCIENTIFIC REVIEW

OF THERAPIES THAT MAY EXTEND

LIFESPAN IN HUMANS

2

“Anti-Aging” Synonyms

Gerontology establishment rebrands as their own a

revolution in preventive healthcare that they cannot deny

“Longevity medicine”

“Successful aging”

“Healthy aging”

“Optimal aging”

“Age management”= “Anti-aging”

3

Definition of Anti-Aging Medicine

Anti-aging medicine is a medical specialty founded on the application of advanced scientific and medical technologies for the early detection, prevention, treatment, and reversal of age-related dysfunction, disorders, and diseases

It is a healthcare model promoting innovative science and research to prolong the healthy human lifespan

As such, anti-aging medicine is based on principles of sound and responsible medical care that are consistent with those applied in other preventive health specialties

The phrase "anti-aging" is, as such, a euphemism for the application of advanced biomedical technologies focused on the

early detection, prevention, and treatment of aging-related

disease.

4

Why do we age? Current theories of aging at the cellular and

molecular level generally revolve around two themes: aging is

programmed and aging is accidental. Programmed aging theories

are based on the idea that from conception to death, human

development is governed by a biological “clock”. This clock sets

the appropriate times for various changes to take place. The

changes in vision, loss of calcium in the bones, decreasing hearing

acuity, and lowered vital capacity of the lungs all are examples of

programmed aging. Accidental theories of aging rely on chance---

the notion that organisms get older by a series of random events.

An example is DNA damage from free radicals or just the wear

and tear of daily life.

5

The Neuroendocrine Theory of Aging: Hormones

Decline As We Age

PEAK: Teens thru Late 20s

LOW: Early 50s +

0

20

40

60

80

100

120

0 10 20 30 40 50 60 70 80

Age

% o

f M

axim

um

Secre

tio

n (P

eak a

t 100%

)

HGH

DHEA

Melatonin

Testosterone (men)

Estrogen (women)

6

Gerontology believes that aging is

natural process, and seeks to palliate

and comfort the aged with their

multitude of medical complaints due

to failing health.

7

The Anti-Aging physician proclaims

that aging is not inevitable. While no one can

stop time and the age of man, it is in reality a

progressive decline and diminution of

metabolic processes which lead to

dysfunction, disease, and ultimately death.

8

THE OLDER POPULATION IS INCREASING

THE OLDEST OLD

=(80 year or older) make up 12% of the population aged

60 year or older.

By 2050 it will be 19%

the number of centenarians (>100 years)

is projected to increase 15-fold, from approxi.

210,000 in 2002 to 3.2 million people.

World Population prospects. The 2000 Revision, vol I; Comprehensive Tables (United Nations publication. Sales No E

01 XIII 8) vol sex and age (United National publication. Sales No. E.01.XIII.9); United Nations, Demographic Yearbook

(Various issues). national statistics; United States Bureau of the Census. International Programs Center. International

Data Base. Estimates and Projections of the Economically Active Population.1950-2010. 4th ed; (Geneva. International

Labor Office. 1996); Social Security Programs Throughout the World-1999 (Washington D.C. united States Social

Security Administration

9

The Climbing Maximum Human Lifespan

“Healthy People 2010,” U.S. Department of Health and Human Services. Washington DC: January 2000; “Americans living longer, ” Reuters, Sept. 12, 2002; “Old age continues to push boundaries,” UPI Science News, May 21, 2002; "Broken limits to life expec tancy,” Science, May 10, 2002, 296 (5570), pp. 1029-1031.

48in 1900

100by 205080

in 2000

10

The Answers

from

Scientific

Research...

11

1. Lifestyle improvement

2. Lean body: 22-24 of BMI

3. Diet

4. Healthy blood &body parameters

5. Hormone replacement treatments

6. Vitamin, mineral and trace elements replacement

7. Healthy, comfortable home

8. Solid, Healthy psychology & spirituality

9. Female sex

What can make humans live longer?

12

1. Healthy lifestyle

=> Survival?

13

Exercise => improves the blood, making it

flow more easily & clot less readily

Inactivity Regular exercise

Plasma volume reverses all these

Hematocrit adverse changes

Plasma fibrinogen &

Blood viscosity helps prevent

Platelet aggregability stroke

fibrinolysis

Eichner ER. Exercise and arthritis. The hematology of inactivity. Rheum Dis Clin North Am. 1990 Nov; 16(4): 815-25. Section of Hematology, University of oklahoma health Scienes Center, Oklahoma city 73190.

14

Physical activity => Mortality

n=1,404 American

women (age=50-74 yrs; follow-

up = 16 yrs); 319

(23%) women

died after 16 yrs)

Figure: Women who were more active lived longer. This effect was not the

result of decreased cardiovascular disease as there was no association between

activity levels & cardiovascular morbidity or mortality.

Sherman SE, D’Agostino RB, Cobb JL, Kannel WB Physical activity and mortality in women in the Framing-ham Heart

Study. Am Heart J. 1994 Nov; 128(5):879-84, Velerans Affairs

WOMAN

Mortality for all causes

(Adjusted Odds)

1,6

0,8

0(CI=0.72-1.26)

Least physically

active Mildly active

1 0.950.63 0.67

Quite active -37 %

Most active -33%

(0.48-0.92)(0.46-0.86)

15

Tai Chi Chuan exercise program => BP & serum cholesterol

Figure: after 12-weeks of Tai Chi training (3x30-50/week), the treatment group

showed signif. Decrease in systolic & diastolic blood pressure & total cholesterol.

HDL cholesterol, & both trait anxiety & state anxiety

JC. The beneficial effects of Tai Chi Chuan on blood pressure and lipid profile and anxiety status in a randomized

controlled trial. J Altern Complement Med Taipei

WOMEN

Changeafter 12 weeks(compared toinitial value)

5

-15

-20

HDL

-8.8

Total

n=2groupsof 76

healthy subjects with

blood pressure at high-normal

or stage I hypertension

-10

-5

0

Systolic Diastolic

-15.6-15.2

4.7

Serum Cholesterol(mg/dl)

Blood Pressure(mm Hg)

16

Remaining Physically Able

Feeling Useful

Having Future Prospects

=> Longevity ?

17

Going to cinema, concerts, museums, art

exhibitions => Mortality

Figure: higher mortality risk for people who rarely visited the cinema, concerts,

n=10,609 subjects; follow-up = 14-15 yrs

Konlaan BB, Bygren LO, Johansson SE Visiting the cinema, concerts, museums or art exhibitions as determinant of survival:

a Swedesh 14-year cohort follow-up. Scand J Public Health. 2000 Sep;28(3):174-8. University of Umea, Sweden

Mortalityfor all causes

(Relative risk of Dying)

0,4

0

0,8

1,2

1,6

Risk of persons most often attending Rarely

visiting art exhibitions

1.14(1.01-1.31)

P<0.05

Rarely visiting

cinemas or concerts

Rarely visiting

museums +42%

1.42(1.25-1.6)

P<0.05 P<0.05

18

Not too long

Not too short

=> Longevity ?

7-8 h of Sleep

19

Sleep pattern of the average 70-yr-old

• Sleeps only 6 hrs a night

• May obtain 1 or 2 hrs more during daytime naps

• Number of sleep disruptions

• Incidence of chronic diseases => poorer sleep

• The 2 most common geriatric sleep disorders =

• Obstructive sleep apnoea syndrome

• Restless legs syndrome

Left untreated, sleep disorders may cause

=> Serious patient’s health & morbidity & mortality.

Barthlen GM. Sleep disorders. Obstructive sleep apnea syndrome, restless legs syndrome, andinsomnia in geriatric patients. Ge riatrics. 2002 Nov; 57(11); 34-9; quiz 40 Center for Sleep Medicine, Department of neurology, Weill Cornell Medical College, New York, NY,USA

20

Long sleep & daytime somnolence => Stroke

Figure: Persons who reported greater than 8 hours of sleep and/or daytime

somnolence are at risk for stroke. n= national cohort of 7,844 adults (First Natinal

Health & Nutrition Examination Survey Epidemiologic Follow-up Study hospital

Qureshi AL, Giles WH, Croft JB, Blivise DL Habitual sleep pattems and risk for stroke and coronary heart disease: a

10-year follow-up from NHANES I. Neurology. 1997 Apr, 48(4):904-11

Stroke incidence (Relative

Risk)

0,5

0

1

1,5

2

Persons sleeping 6-8 hrs

at night

Persons sleeping>

8hrs at night

+50%

1.5(1.1-2.0)

Persons + daytime

somnolence

+40%

Persons + daytime somnolence + sleeping

> 8hrs at night

+90%

1.4(1.1-1.8)1

1.9(1.2-3.1)

21

Monotonous work => coronary heart disease risk

1994 male & 832 female blue-collar

workers aged 20-60 yr

Monotonous work conditions

=>Repetitive work (in short-

cycle(<1’)

-women:

Mean systolic BP (p=0.003)

Diastolic (p = 0.01)BP,

Total cholesterol (p = 0.03)

Serum glucose (p = 0.05);

-men:

Systolic BP only (p = 0.002),

=> Varied work (vs work

underload):

In women: with

- total cholesterol (p = 0.05)

- HDL (p = 0.03)

* In men: mean systolic BP

(p=0.05)

Melarned S. Ben-Avi I. Luz J. Green MS Repetitive work work underload and coronary heart disease risk factors among

blue-collar workers-the CORDIS study Cardiovascular Occupational Risk Factors Determination in Israel. J Psychosom Res

1995 Jan 39(1) 19-29 Behavioral Medcine Unit. Occupational health and Rehabilitation

22

Feeling good

No Psychological

Distress

=> Survival ?

23

Stress => HbA1c, systolic & diastolic BP

Figure: Stress is detected at a higher frequency in patients with non-

insulin dependent diabetes mellitus than in healthy controls.

Okada S, Hamada H, Ishii K, ichiki K, Tanokuchi S, Ota Z Factors related to stress in patients with non- insulin-dependent

diabetes mellitus. J Int Med Res. 1995 Nov-Dec, 23(6):449-57. Okayama University.

Scoresor levels

10

0

20

30

40

Stress (anxiety)

43.6

50

Trait State Glycosylatedhemoglobin

Systolic

n=40 patients non-ins. Dep diabetes vs 40 controls

Blood

diastolic35.8 41.3 35.8 8.4% 7.3% 151.4 143.4

84 77

P<0.0001 P<0.0001P<0.0002 P<0.0017 P<0.0018

12 weeks of anxiolytic fludiazepam (0.25 mg, 3x daily) lowered stress score BP,

HbAc1, total cholesterol, triglycenrides, apolipoprotein BA1, & increased HDL

24

Negative Emotions => immune-related diseases

Negative emotions & stressful experiences

•intensify diseases + onset & course that are influenced by the

immune system

•Stimulate production of pro-inflammatory cytokines

•Contribute to prolonged infection & delayed wound healing

=> close personal relationships ( negative emotions) : positive

impact on immune & endocrine regulation.

Kiecolt-Glaser JK, McGuire L, Robles TF, Glaser R. Emotions. Morbidity, and mortality: new perspectives from

psychoneuroimmunology. Annu Rev Psychol. 2002.53:83-107. Department of Psychiatry The Ohio State University College

of Medicine. 1670 Upham Drive. Columbus. Ohio 43210 USA Kiecolt-Glaser_1@osu.edu

25

=> Survival ?

1. Avoid Smoking

26

Tobacco fumes

Contains approx. 350 toxic molecules

- formaldehyde

- nitrogen, ammonia

- phenols

- nitrogen & sulfate oxides

- carcinogens (benzopyrene)

- …

27

TOBACCO SMOKING: weakens the ovaries

• 2-hydroxylation (& thus inactivation) of estradiol (Michnovicz 1986)

• secretion of testosterone (Brigs 1973)

• osteoporosis (Daniell 1976)

• disturbs pregnancies: risk of placenta praevia (williams 1991), ectopic pregnancy

(Coste 1991), etc.

• disturbs postpartum: in breast milk (Kio 1991)

toxins:

-benzopyrene (Mattison 1987)

-nitrous oxide (Ginsburg 1991)

-nicotine (Rick 1997)

- …

28

TOBACCO SMOKING: weakens the ovaries

• the age of menopause:active smoker : 2,2 years earlier

(Everson 1986)

- >35 cigarettes a day : 2 years

- 25-34 cigarettes a day : 1 year & 8 month 1/2

- 15-24 cigarettes a day : 1 year & 5 months

- 1-14 cigarettes a day : 6 months (Willet 1983) passive

smoker : 1,1 year earlier (Everson 1986)

• urinary estrogens (esp.in luteal phase) in premenopausal

women (Mac Mahon 1982)

29

Cigarette smoking => urinary E2,E1 &

E3 in premenopausal women (<50 yrs)

Figure: Sign. Lower urinary estrogens in the luteal phase of the menstrual

cycle in current smokers among premenopausal women. The decline in

serum estrogens in the follicular phase is not sign. (mean:=

Macmahon B, Trickopoulos D. Cole P, Brown J. Cigarette smoking and urinary estrogens. N Engl J Med.

1982;307(17):1062-4

Urinary levels(% compared to

nonsmokers)

200

80

100

n=43

Normal

Non-smokers

n=22 n=39

4060

120

Estrone (E1) Previoussmokers

Smokers

Non-smokers

Estradiol (E2)Previoussmokers

Smokers

Non-smokers

Estrone (E3)

Previoussmokers

Smokers

n=106 premenopausal women (age: 24-49 yrs)

30

Cigarette smoking => serum E2 & E1 under

estradiol therapy in early postmenopausal women

Figure: Lower serum E2 & E1 under oral estradiol therapy were found in smoking

postmenop. Women, probably caused by increased hepatic metabolism A sign. inverse

correlation exists between the number of cigarettes smokers & changes in serum

estrogens.

Jensen JChristiensen C. Rodbro P . Clgarctle smoking.serum estrogens and bone lose during hormone replacement

therapy after. Menopause,N Emgl J Med 1985;313;973-5

SerumEstradiol

100

0

200

300

High dose

Low dose

n=23

(pmol/l)Non-

smokers

Smokers

Non-smokers

Non-smokers

n=136 postmenopausal women

SmokersSmokers -

50%

Medium dose

P<0.05

n=42 n=63

Low dose = 1 mg estradiol, medium

dose= 2 mg estradiol, high dose = 4 mg estradiol orally;

estradiol was taken 22 days 28;each

preparation was taken + 10 days of 1

mg/day of noethisterone from

day 13-55 (Trisequens mite

normal, forte)

31

Smoking => impotence, miscarriages,

& infertility

Report of the British Medical Association 2-2004:

Smoking causes :

120 000 impotent men in the United Kingdom (30 to 50 y)

1200 cases of malignant cervical cancer

3000 to 5000 miscarriages every year

40% reduction each month of chances to conceive

couples who smoke are less likely to respond to infertility

treatment.

Dr Vivienne Nathanson, the MBA's head of science and ethics

32

In pregnancy:

smoking can the risks of miscarriage

certain fetal malformations, such as cleft lip & palate

stillbirth & death of the new born

triple the chances of having a low birthweight baby

the quality of breast milk.

In infants and children passive smoking

can cause sudden infant death syndrome, respiratory infections,

& asthma.

Dr Vivienne Nathanson, the BMA’s head of science and ethics

33

Smokers => in coronary heart disease

mortalityCoronary heart

disease mortality rales for men (per 1000 person yrs)

Figure: Age-adjusted 23-year coronary heart disease mortality rales

increased with the number of cigarettes smoked per day

Rodriguez BL, sharp DS, et al. Fish imtake may limit the increase in risk of coronary heart disease morbidity and mortality

among heavy smokers Circulation 1996.

Current smokers > 30 cigarettes/day

…reduced by high fish intake in heavy

smokers

0

2

4

6

8

2.3 3.1

6.9

20-30 cigarettes/day

P<0.0001

<20cigarettes/day

34

=> Survival

2. Lean body

35

n=69 Chinese elderly (42 women & 25 men) aged >= 100 yrs

- 26% belonged to 3th generation of centenarians

- the average first marriage age was late

- the interval to first birth was long

- the centenarians tended to be light & thin in build

- most fed & toileted themselves

- 80.3% reported good or average health

- 21.7% had good eye sight,&

- 36.2% had good hearing

- 55.1% had their own teeth

(Xiao Z,Xu Q, Yuan Y, solving the mystery of the status & longevity of centenarians in Bama. Chin J Popul Sci. 1996;

8(4);385-94)

Centenarians

36

Being Lean

No overweight: BMI: 22-24

=> Survival ?

37

Or weight => Coronary heart disease

Mortality

Figure: Both body weight loss & weight gain are associated with sign, increased

mortality from all causes & from coronary heart disease but not from cancer.

Lee IM, Paflenbarger RS jr. Change in body weight and longevity. JAMA 1992 Oct 21,268(15):2045-9 Departm. Of

Epidemiology, Harvard university School of Public health., Boston Mass 02115

MEN

0

0,8

1,6

(CL=0.91-1.80)

n=11,703 men (mean age=58 yrs; follow-up=12 yrs

after 12-16 yrs follow-up for life style; 1,441 men died after 12 yrs, 459 from cancer,

345 from coronary heart disease

Mortalityfor allcauses

(RelativeRisk)

11.23

2.33 1.431.75

Men+ stableweight

(+/- 1 kg)

Men+ weight

GAIN1-5 KG

+6%

Men+weight

gain>5kg

+36%

Men+weight

loss1-5 kg

+26%

Men+weight

loss>5 kg

+57%

(CL=1.36-2.97) (CL=1.05-1.93) (CL=1.26-2.43)

2,4

38

=> Survival ?

3. Healthy diet

39

Calorie

intake

40

Average energy intake in 4 populations

0

500

1000

1500

2000

2500

France Okinawa Vilcabamba Abkhazia

Men

Women

41

Comparative incidence of

Chronic diseases (USA: base 100)

0102030405060708090

100

USA Okinawa

Mammary cancer

Prostate c.

Colon c.

Ovarian c.

Myocardial infarct

42

Calorie restriction => Neuroprotective

Patel NV, Finch CE. The glucocorticoid paradox of caloric restriction in slowing brain aging Neurobiol Aging 2002

Sep-Oct; 23(5):707-17. Department of Biological Sciences, Andrus Gerontology Center, University of Southern

California, 3715 McClintock Avenue, Los Angeles, CA

caloric restriction in rodents

extends life-span in rodents

many brain aging changes => neuroprotective:

serum glucose

free radical generation

alterations of the vasculature

age-related glial activation

expression of heat shock proteins

neurotrophic factors

resistance of neurons to toxins & injury

=>neuroprotective effects of calorie restriction outweigh > deleterious effects of

glucocorticoids

43

0

1

2

3

4

5

6

Physical exercise or Calorie diet delays

& risk of cancer in rats

Sedentary rats (W=271 g) + ad libitum diet

Number of Female Rats with mammary tumor

Rats (W=170 g) + low caloric diet

Rats (W=170 g) + physical exercise

0% 0%

55%

Figure: 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

Moore C, title PW. Muscle activity, body fat, and induced rat mammary Tumors. Surgery. 1973

44

Moderately Calorie Intake

No Excess Food Intake

=> Survival ?

45

24 middle-aged non-obese men: 8 controls,

16 In moderate (80%) energy restriction 10 weeks

Moderate (80%) energy restriction:

weight: -7.4 kg (+/- 2.6) (mainly fat loss)

diastolic & systolic blood pressure

HDL -cholesterol

Velthuis-te Wierik EJ, van den Berg H, Schaafsma G, Hendriks HF, Brouwer A. Energy restriction, a useful intervention to

retard human ageing? Results of a feasibility study.Eur J Clin Nutr. 1994 Feb; 48(2); 138-48.

TNO Toxicology and Nutrition Institute, Zeist, The Netherlands

Energy restriction (10 weeks) => weight (mainly fat)

BP

HDL cholesterol

46

Healthy

foods

47

Fruit & Vegetable Intake

=> Longevity ?

48

Fruit & vegetable intake => CANCER &

CARDIOVASCULAR MORTALITY

Figure: increasing vegetable & fruit intake up to that of the highest consuming group

could result in considerable improvements in health within the European Union (based on

WHO mortality data & recommendations of fruit & vegetables > 400 g/day)

Joffe M, Robertson A. the potential contribution of increased vegetable and fruit consumption to

health gain in the European Union Public Health Nutr. 2001 Aug, 4(4); 893-901 Depart Epidem

Public Health St Mary’s Campus, London in joffeZjc.ac.uk

Estimated Mortality Mean intake of fruits &

vegetables <275 g/day

Increased intake of fruit & vegetables>400 g/day (reduced risk)

(average risk)

00.2

1

0.40.60.8

Major cancers

-10%Cerebrovascular disease

-30%Coronary heart disease

-50%10.9

0.70.5

49

Eat fish

=> Survival ?

50

Fish consumers => serum lipid levels

Figure: The lipid profil in village inhabitants who consume great quantities of fish

from a lake, is better than the one found in inhabitants of an other village situated

inside the land and whose diet is vegetarian

0

50

100

Serum levels

(in % compared to level of

vegetarians)

Fish consumers

150

-14% -30% -37%

Vegetarians Total

CholesterolTriglycerides

Lipoprotein a

Pauletto P. Puato M, et al. Blood pressure and atherogenic lipoprotein profiles of fish-diet and vegetarian villagers in

Tanzania Lancet 1996; 348;781-88

51

Variation in

Healthy Foods

=> Longevity ?

52

<< Healthy diet>> =

•fruits, vegetables

•Whole grain breads, cereals

•Fish

•Low fat dairy products

=> sign. mortality

<< Unhealthy diet>> : Foods considered to promote disease =

•Red meats,

•Refined carbohydrates & sugars

•Foods w/ saturated or trans fats

Cardiovascular mortality part among women who reported consuming variety of healthy foods.

Sign. Cancer mortality in women who reported consuming less healthy food than in those who consumed few of these foods

Int J Epldemiol 2002 Aug;3(4);847-54 A prospective study of variety of healthy foods and mortality in women.Michels KB, Wolk A. Obstetrics & Gynecology Epidemiology Center, Brigham & Women’s hospital, HarvardMedical School, harvard Shool of Public Health, Boston, MA, USA. kmkels@rics.bwh.harvard.edu

0

20

40

60

80

100

120Regularity

healthy foods

53

What is the best diet?

?

54

Japanese & Mediterranean peoples who eat in the

traditional manner

=>Highest life expectancy in the

world &

their longevity has much to do

with their diet.

=>2 diets seem very different, but

they have in common:

- a relative absence of

saturated fats & margarines

- An emphasis on fish,

vegetables & fruit.

55

Eating a mediterranean diet =>

myocardial infarct recurrence in patients

who have had a 1st infarct

Figure: Risk factors for myocardial infarct recurrence (non fatal+ fatal) in the

Lyon Diet heart Study after 27 months of follow-up (p=0.00014 to 0.0002).

De Longeril M. et al. Mediterranean diet. Traditional risk factors and the rate of cardiovascular complications after

myocardial infarction; final repot of the Lyon Diet Heart Study. Circulation 1999;99; 779-785

00.5

1

1.52

2.5

Mean risk

Blood pressure 10 mg Hgincrease

Cholesterol(Serum):[mmol]

increase = 38.7 mg/dl

+18 to +28%

Leukocytes(serum):

>9000-64 to -186%

Aspirin use

-8 to 1%

Mediterranean diet

-47 to-72%

Femalesex

-54 to-73%

rate of cardiovascular complications after

myocardial infarction

56

OKinawaJapan

= country + world’s longest living population

=> 8.97 centenarians 100,000 persons

Okinawa

= Japan’s island w/ highest life expectancy

=> 28.86 centenarians / 100,000 persons

=> 365 centenarians /population of 1.3 million

57

Features of the Japanese diet are:

Rice

Vegetables include bamboo shoots, eggplant, various

mushrooms, sweet potato, & Chinese cabbage.

Fruit is served at the end of a meal

Soy products (incl. Tofu) - + .40 x more>Western intake

2x more fish>meat Westerners, by contrast, have on average

47 x more meat >fish!

Many natural flavour additives in the form of herbs, spices

condiments such as ginger, lemon, sesame seed, mustard.

Variety of foods, esp. plant foods.

Fat content-esp. in saturated fat

( meat=a major factor in the low bowel cancer rate in Japan)

Dairy food intake

58

What are the special features of the Okinawa diet?

Northern Japan (mainland) Okinawa (Island)

Salt salt salt

Fish Dried fish w/ salt Fresh fish w/ salt Pork=a big element

Dish flavor Salt or soy sauce (contains 16% salt)

Thick soup made from dried bonito chips or water used in boiling pork

Salted pickles No salted pickles

A salt intake (soy sauce, for example, contains 16% salt).

=> implicated in the Japanese incidence of hypertension,

stroke & stomach cancer (commonest cause of death in Japan).

=>implicated in liver & nasopharyngeal cancer.

59

What are the special features of the Okinawa diet?

Northern Japan(mainland)

Okinawa(Island)

Pork Pork = a big element

Vegetables goya, a bitter tasting green vegetable => rich in vit. B, C & E, antioxidants; helps serum glucose & cholesterol among diabetics.

Tofu Tofu: highest tofu consumption in the country. Okinawan tofu is bigger & more solid than the mainland variety, is partic. rich in protein containing phytoestrogen.

Okinawan pork dishes => not a problem because the meat is boiled for

hours before it is eaten & the fat is drained off.

60

Water Intake

No Chlorine

=> Survival ?

61

Wilkens LR, Kadir MM., Kolonel LN, Nomura AM. Hankin JH, Risk factors for lower urinary tract cancer. The role of total fluid consumption, nitrites and nitrosamines, and selected foods. Cancer Epidemiol Biomarkers Prev 1996 Mar,5(3); 161-6 Epidemiology Program. Cancer Research Center of Hawaii, Honolulu, 96813. USA

water intake=> urinary tract

cancer

Figure: Total fluid intake, & tap water in particular ,showed a strong inverse

dose-reponse relationship to cancer risk among women. This association was

stronger in smokers than non smokers. In men no overall association, but

among smokers findings were suggestive of an effect similar to that found in

woman

Lowerurinarytract cancerrisk (Oddsratio)

N=66 females matched with 2 control groups

Lowest quartileof fluid intake

Highest quartile of fluid intake

1

0.3

0

0.2

0.4

0.6

0.8

1

62

0

0.5

1

1.5

2

2.5

water intake => coronary heart disease

Coronary heart disease risk (Odds ratio)

INTAKE OF FLUIDS OTHER THAN WATER

WATER INTAKE

Figure: All associations remained virtually unchanged in multivariate analysis

adjusting for age, smoking, hypertension, body mass index, education,& (in

women only) hormone replacement therapy

Chan J, Knutsen SF, Bix GG, Lee Jw, Fraser Ge Water, other fluids, & fatal coronary heart disease; the Adventist Health

Study. Am J Epidemiol 2002 May 1;155(9):827-33

<=2glasses/day

>=5MEN

Glasses/daywomen

MEN WOMEN

N=8-,280 males, n=12,017 females; Age = 38-100 yrs

63

0

0.2

0.4

0.6

0.8

1

water intake => rectal cancer in men

Rectal cancer risk (Odds risk)

WATER INTAKE

Figure: strong inverse dose-response relation between increased water int &

rectal cancer was found among men after adjustment for other risk fact Similar

but not significant trends were seen among women (p=0.29).

Morales KH, Ryan L, Kuo TL, Wu MM, Chen CJ. Risk of intestinal cancers from arsenic in drinking water. Environ Health

Perspect . 2000 Jul; 108(7):655--61

Lowest tertile

Highest tertile-92%1

0.08

(p=0.0005) (95% Cl, 0.02-0.35)

WATER INTAKE

64

0

0.2

0.4

0.6

0.8

1

Colon cancer risk (Odds risk)

WATER INTAKE

Figure: sign. Lower risk of colon cancer for men in the highest tertile of

active leisure-time physical activity: 5 x less risk than sedentary men.

Morales KH, Ryan L, Kuo TL, Wu MM, Chen CJ. Risk of intestinal cancers from arsenic in drinking water. Environ Health

Perspect . 2000 Jul; 108(7):655--61

Lowest tertile

Highest tertile-81%1

0.19

(p=0.03) (95% Cl, 0.05-0.77)

WATER INTAKE

water intake => colon cancer in men

65

New

research

Fluid

consumption

Signif. the risk of

/ urinary stone disease

/ cancers of the breast, colon, & urinary tract

/ childhood & adolescent obesity

/ mitral valve prolapse

/ salivary gland malfunction

/ overall health in the elderly.

Kleiner SM. Water: an essential but overlooked nutrient. J Am Diet Assoc 1999 Feb; 99(2):200-6

66

Cereal Intake

=> Survival ?

67

0

200

400

600

800

1000

Glucose-rich diet => shortens the life span of mice

Survival

(day)

Mlekusch W, Lamprecht M, ottl K, Tillian M, Reibnegger G. A. Glucose-rich diet shortens longevity of mice. Mech Ageing

Dev 1996 Nov 29;92(1):43-51

Average life span of the 70 mice Average life span of 7 oldest mice

Control diet Diet+20% glucose-10%

-6,4%

n=70 n=70 n=7 n=7P<0.05 P<0.05

68

Alcohol

=> Survival?

69

Beer & cancer

Probable Cause?

Demethyl – nitros - amine in many

beers (111 to 154-Spiegelholte)

Lederer J. Alimentation du cancer Ed. Nauwelaerts & Maloine; Bauvechain (B), Paris (Fr), 1986

70

0

10

20

30

40

50

Alcohol & tobacco => risk of

esophageal cancer

Esophageal cancer risk

Figure: high consumers of alcohol & tobacco have a 44 times increased risk of

esophageal cancer

Tuyns in Lederer J, Alimentation et protection du cancer Ed. Nauwelaerts & Maloine; Bauvechain (B),

paris (Fr).

Alcohol consumption/dayNI risk

0-40 g/day

alcohol

41-80 g/day

≥81 g/day

0-9 g/dtobacco

10-19 g/d ≥ 20 g/d

≥ 20 g/dtobacco

71

Caffeine

=> Survival?

72

0.39

1.02

2.4

3.9

0

1

2

3

4

Increased risk of Parkinson’s disease in women who

take female hormone replacement & caffeine

Relative risk of Parkison’s disease

Figure: The risk of Parkinson’s disease in women who take female hormone

replacement therapy (HRT) increases with the intake of caffeine, but not in

women not taking female hormones

Ascherio A, Chen H, Schwarzschild MA, Zhang SM, Colditz GA, Spelzer FE. Caffeine, postmenopausal estrogen,

and risk of Parkinson’s disease. Neurology. 2003 Mar 11;60(5):790-5. Department of Nutrition Harvard School of

Public health.

Women not taking HRT (+variable caffeine intakes)

Low caffeine+HRT

Normal caffeine intake +HRT

High caffeine+HRT

Very high caffeine(>6 cups/d)+HRT

73

0

50

100

150

Caffeine drinking => mammary carcinoma incidence

mammary development in mice

Change in incidence of mammary carcinoma

(% more mice with breast cancer

Figure: 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.

Welsch CW, DeHoog JV, O’Connoor DH. Influence of caffeine consumption on carcinomatous and normal mammary gland

development in mice. Cancer res 1988 Apr 15;48(8):2078-82 Michigan State university-USA

Women not taking HRT (+variable caffeine intakes)

Caffeine 250 mg/l +-20 %

Caffeine 500 mg/l +40% Caffeine 250 mg/l

+13%

Caffeine 500 mg/l +117%

NS NSP<0.05 P<0.05

74

• Coffee consumption by pregnant women => fetal birth weight.

Fetal heart rate, respiration, & both maternal & fetal anemia are

increased with coffee consumption but coffee has not been show to be

teratogenic

• coffee intake => total cholesterol levels;

• boiled coffee cholesterol>filtered coffee

•>4 cups/day => acute myocardial infarct risk

• coffee consumption=> urinary bladder cancer risk

• coffee consumption appears to pose no particular threat in most

people if consumed in moderation.

• Naturally decaffeinated, filter-brewed coffee further diminishes its

potential harmful effects.

(Etherton GM, Kochar MS. Coffee. Facts and controversies. Arch Fam Med. 1993 Mar,2(3):317-

22. Medical College of Wisconsin, Milwaukee.)

75

Coffee => chronic airflow obstruction

Coffee consumption

=> ventilatory frequency in normal subjects and also

in the course of chronic air low obstruction

Coffee in large quantities by pregnant women=> risk

of neonatal apnoea in the newborn

(Martinet Y, Debry G.Effects of coffee on the respiratory system. Rev Mal Respir. 1992;9(6):587-92. Service de

Pneumologie, CHU de Nancy, Vandoeuvre-les-Nancy.

76

Caffeine => bioav. Testosterone, serum SHBG

(Ferrini RL, Barrett-Connor E. Caffeine intake and endogenous sex steroid levels in postmenopausal women. The Rancho

Bernardo Study. Am J Epidermiol.1996 Oct 1;144(7);642-4. General Preventive Medicine Residency Program, University of

California, San Diego/San Diego State University, USA.)

In postmenopausal women, caffeine intake

•Sign. Bioavailable testosterone, which persisted after

adjustment for age, waist/hip ratio, body mass index,

alcoholintake, cigarette smoking, & physical activity (r=-0.10,

p=0.02).

•Sign. Serum SHBG (adjusted r = 0.09, p = 0.03).

77

Avoid <<trans>> fatty acids

=> Survival?

78

1.51.67

0

0.5

1

1.5

2

foods rich in trans fatty acids (margarine, cakes, biscuits, &

white bread) => incidence of coronary heart disease in women

Relative risk of coronary heart disease

Figure: Women who consumed the greatest amount of foods rich in trans fatty acids

such as margarine, bakeries, bakeries, bisdcuits, cakes & white bread had a sign

increased risk of coronary heart disease. The association is more important in the highest

margarine consuming women during the first 10 yrs of follow-up (Nurses Health Study)

Willen WC, et al, intake of trans fatty acids and reisk of coronary heart diseaseamong women lancer

1995;341;8845:581-5

Lowest Quintile

Highest Quintile of foods rich in trans

fatty acids

+50

Highest Quintile of margarine intake

+67%

Trans fatty acids that are formed by partial

hydrogenation of w\vegetable oils to

produce margarine & other foods increase the

ratio LDL/HDL cholesterol in serum(1.12-2.00)

p=0.001

1.05-2.66p=0.002

79

4. Vitamin, trace element, fatty

acid,.. Supplements

=> Survival ?

80

0

0.2

0.4

0.6

0.8

1

Nutritional supplements => Mortality in men

Mortality in men (Relative

risk)

Control

Figure: French adults of the SUVIMAX cohort (Supplementation en Vitamins et

Minotaur Antioxidants) (women:35-60 yrs; men;45-60 yrs).

The SUVIMAX (France) study; role of antioxidants in prevention of cancer & cardiovascular disease

100 mg vit. C + 30 mg vit. E + 100 g beta-carotene/day

Mortality

-37%

Cancer (lungs, skin,..)

-30%

n (total) = > 15,000

81

Women consuming the most folic acid, vitamin B6 & multivitamins

=> coronary artery disease

Figure: Lower risk of coronary disease in women situated in the highest

quintile compared to the risk of women in the lowest quintile of folic acid (696

vs 158 g/d), vit.B6 (4,6 vs 1,1 mg/d) & multivitamin intake)

Ramon EB, Willell WC, et al. Folate and vitamin B6 from diet and supplements in relation to risk of

coronary heart disease among women. JAMA 1998;279:359-64

1

0.67

0.25

0.65 0.55

0.76

0

0.5

1

Relative risk of

coronary artery

disease

Lowest Quintile

+max. 1 glas of

alcohol/d-31%

In Folic acid

+>1glas of alcohol/d

-75%

In vit. B6-33%

In Folic acid & vit.B6

-45%

In multivitamins

-24%

n=80.082 women

(Nurse’s Health Study)

followed during 14 yrs

Highest Quintiles of Consumption

82

What Nutrients

can do

to mortality ...

83

Vit. A

84

1

0.510.42 0.37 0.32

0.060

0.2

0.4

0.6

0.8

1

Vit. A supplements => Mortality in children w/ pneumonia

Mortality(Odds risk)

PLACEBO

Figure: Vitamin A supplements, a low cost intervention, reduce mortality of

HIV-infected children.

(687 children (age:6 months-5yrs) w/ pneumonia, children who were severely malnourished or had clinical signs of

vitamin A deficiency were excluded; mean follow-up = 24.4 months)

VIT. A SUPPLEMENTS400,000 IU (or half that for infants)

(p=0.02)

Overall Mortality

-49%

Mortality of uninfected children

Mortality of HIV-infected

children-63%

Mortality form AIDS

Mortality from diarrhea

-95%

(p=0.04) (p=0.14) (p=0.05) (p=0.01)

85

Beta-carotene

& other

carotenoids ...

86

1

1.51.58

1.321.73

0

0.5

1

1.5

2

Serum level of oxygenated carotenoids in diets => mortality

7.2 yr-Mortality

(Odds ratio)

Highest tertile

Figure: Serum level of individual carotenoids, particularly the oxygenated

species are inversely associated with all-cause mortality

Bucher HC, Hamster P. Schindler C, Meier G, N-3 polyunsaturated fatty acids in coronary heart disease a meta-

analysis of randomized controlled trials Am J Med. 2002 Mar;112(4);298-304 Institute fur Klinische Epidemiologie,

Basel, Switzerland

n = 638 independently living elderly subjects aged 65-85 years, follow-up period of 7.2 years

Beta-crypto-xanthin+52%

Lutein+56%

Zeaxanthin +32%

Sum B+L+Z(oxygenated carotenoids)

+73%

Lowest tertiles

87

Beta-carotene & Vit. C

88

1

0.6 0.7 0.69

0

0.5

1

food-related vit. C & beta-carotene => mortality

Lowest tertile of food vit. C & beta-carotene intake

(mean vit. C=66 mg/day & beta-carotene = 2.3 mg/day)

Figure: Results support the hypothesis that consumption of foods rich in vit.C

& beta-carotene reduces risk of death in middle-aged men.

Pandey DK, Shekelle R,Selwyn BJ, Tangney C, Stamler J. Dietary vitamin C and beta-carotene and risk of death

in middle-aged men. The Western Electric Study. Am J Epidemiol. 1995 Dec 15;142(12);1269-78. University of

Texas, USA.

Highest tertile of food vit. C & beta-carotene intake

n = 1,556 employed, middle-aged men (median follow-up of 21 yrs)

Mortality

(mean vit. C=138 mg/day & beta-carotene = 5.3 mg/day)Cancer

mortality-40%

Coronary disease

mortality-30%

All-cause mortality

-31%

(95% Cl=0.39-0.93)

(0.49-0.98) (0.55-0.32)

89

Vit. E ...

90

0

25

50

75

100

serum vit. E => Mortality from Heart disease

Mortality with ischemic heart

disease(%)

Patient with low serum

vit. E

Figure: Serum vit. E has a strong inverse association with mortality from ischemic heart

& was the only signif. Risk factor found in 12 populations with normal cholesterol. Only

serum cholesterol & blood pressure were moderately associated when all populations

were evaluated, but their correlation was inferior to that of serum vit. E

Grey KF, Puska P. et al. Inverse correlation between plasma vitamin E and mortality from ischemic heart disease in cross-

cultural epidmiology. Am J cline Nutr. 1991. 53(1); Suppl: 3265-3345

62% 79% 83% 87%

Patient with low serum vit. E &

hypercholesterolemia

Patient with low serum vit. E & A &

hypercholesterolemia

Patient with low serum vit. E & A &

hypercholesterolemia & arterial hypertension

16 large studies of European population

91

1.341.07

0.7640.552

0

0.5

1

1.5

Pharmacological doses of vitamin E => serum triglycerides & ratio

LDL/HDL cholesterol in elderly patients

Serum level

Figure: 4 months of daily big dosed vit. E reduces serum triglycerides & the

serum ratio of LDL/HDL cholesterol in patients with stable angina pectoris at

exercise in a double-blind study controlled by placebo

Paolisso G, Gambardella A, et al. Chromic intake of pharmacological doses of vitamin E night be useful in the therapy of

elderly patients with coronary heart disease. Am J clin Nutr. 1995, 61(4):848-52.

Before n=30 elderly patients mean

= 73.8 yrs)

Vit. E(900 mg/j)

-23% Before Vit. E(900 mg/j)

-38%

Serum Triglycerides (mmol/l) Atherogenic Ratio LDL/HDL cholesterol

P<0.05 P<0.03

92

0

50

100

150

Vit. E => oxidation of LDL cholesterol in serum

Change(%)

Figure: The resistance of LDL cholesterol to oxidation can be measured by the

time lag before oxidation & its level of oxidation. These parameters are

improved by 6 weeks of vitamin E.

Simons LA, et al. What dose of vitamin E is required to reduce the susceptibility of LDL to oxidation? Aus N Zeal J

Med. 1996; 26 (4): 496-503

P<0.001

Placebo

Time lag before LDL oxidation

Oxidation level of LDL cholesterol

P<0.001

Vit E at 500 IU/d

+26%

1000 IU/d

+24%

1500 IU/d

35%

Vit E at 500 IU/d

-14%

1000 IU/d

-19%

1500 IU/d

-25%

93

Vitamin E

Oxidized LDL

Atherogenic Ratio

LDL/HDL

Triglycerides

LDL (?)

Protects

atherosclerosis

HDL /total

HDL (?)

Tests:

Serum vit. E

Treatment:

Efficient Doses:

15-800 mg/day

94

Vit. A

+ E ...

95

0.020.018

0.017

0.011

0

0.005

0.01

0.015

0.02

Daily vit. E & C supplement => Major of

atherosclerosis progression in men

Annual increase of

intima media thickness of

common carotid artery

(mm)

placebo

Figure: Sign. Reduction in men of the atherosclerotic progression of intima media

thickness of common carotid arteries measured by ultrasound thanks to the daily intake

of a combination of vitamin E & C during the first year of intake.

The % of men experiencing an atherosclerotic progression dropped too (-74%,

IC=36-89%,p=0.003). No significant effect in women.

Vit. E 90 mg/dVit. C 250 mg/d Vit. E+C

-39%

n=520 men &

postmenopausal

women aged 45-

69 yrsNS NSP=0.008

96

Vit. C...

97

1

0.54 0.51

0

0.5

1

serum vit. C=> all-cause mortality

All-cause mortality

Lowest 20% (serum vit.C <17 mol/l)

Figure: Strong inverse trends for serum vit. C w/ all-cause & cardiovascular disease

mortality, only marginally reduced after adjustm. For confounders or in fully adjusted

models, there was no evidence for an influence of vit. E, beta-carotene or retinol on total

mortality.

Fletcher AF. Breeze E. Shetty PS. Antioxidant vitamins & mortality in older persons; findings from the nutrition add-

on study to the Medical Research Council Trial of Assessment & Management of Older Community People Am J Clin

Nutr. 2003;78(5):999-1010.

Highest 20% (serum vit. C >66 mol/l)

Global mortality

-46%

Mortality after exclusion of subjects

w/ cardiovascular disease or cancer at

baseline

-49%

n = 1214 participants aged 75-84 yrs (median follow-up of of 4.4 yrs).

(95% Cl=0.34-0.84)

(95% Cl=0.28-0.93)

98

0

3

6

9

12

2 g/day Vit. C => serum cholesterol & triglycerides in diabetic

patients

Serum level Glucose(mmol/l)

Figure: The intake of a high dose of 2 grams/day of vitamin C during 90 days in double

blind by non-insulin-dependent diabetics significantly improved the glycemic control

and serum lipids.

Eriksson J, Kohvakka A Magnesium and ascorbic acid supplementation in diabetes mellitus Ann Nutr Metab 1995;

39:4:217-23

n = 56 diabetics

HbA1c(%)

Cholesterol (mmol/l) Triglycerides

(mmol/l)

Before-10% -9%

-5%

-12%

99

Co Q10 ...

100

0

20

40

60

Elderly sick patients with serum coenzyme Q10 => mortality

Mortality at 6 months

(%)

Patents with low serum coQ10 <0.55 g/ml

Figure: Severe increase of mortality at 6 months in patients w/serum coenzyme

Q10 under one standard deviation of the mean of a population of patients over

age 50 (mean age =72 yrs)

Jameson. Statistical data support prediction for death within six months on low levels of coenzymeQ10 and

other entities, Clin Investig.1993; 71;S137-9

P<0.001

4%n=3/79

53%

A low CoQ10 level was found in patients with

chemotherapy cytostatic or on

cholesterol lowering agents, or suffering

from heart failure or severe myalgias

n=94

101

Coenzyme Q10

Oxidized LDL

Apolipoprotein a

Atherogenic Ratio

LDL/HDL (?)

Triglycerides

Protects atherosclerosis

Can mortality

HDL

HDL /total

Tests:

Serum co Q10

Treatment : Efficient

Doses:100-400 mg/day

102

Zinc ...

103

10.73

0

0.5

1

Zinc supplements => excess all-

cause mortalityAll-cause mortality

Placebo

Figure: Sign. Reduced mortality in participants who were randomly assigned to

receive zinc supplements in Age-Related Eye Disease Study (AREDS)

Clemons TE, Kurinij N, Sperduto RD. Associations of mortality with ocular disorders and on intervention of high-

dose ontioxidants and zinc in the Age-Related Eye Disease Study. AREDS Report No.13. Arch Ophthalmol.2004

May;122(5);716-26

Zinc supplements

-27%

(95% Cl=0.61-0.89)

n=4753 AREDS participants (median follow-up of 6.5 year). 534 (11%) of 4753 AREDS participants died.

104

Chromium ...

105

0.941.14

2.11.68

0

0.5

1

1.5

2

2.5

Chromium treatment => serum HDL cholesterol & serum

triglycerides

Taux serique

Figure: Lap rise de 250 g par jour de chrome pendant 7 in 16 moist de

ameliora significativement le taux serique du HDL cholesterol et des trigly

cerides chez ceux parmi 67 patients atteints de maladie atherosclerotique etablie

P<0.02P<0.05

HDL cholesterol (mmol/l) Triglycerides (mmol/l)

Avant

Chrome

+12%

Chrome

-20%

placebo

106

Chromium (trivalent)

Total cholesterol (?)

LDL

Atherogenic Ratio

LDL/HDL

Triglycerides (?)

Apolipoprotein B

Protects atherosclerosis

HDL (?)

Apolipoprotein A1

HDL /total

Tests:

Serum chromium

Treatment : Efficient

Doses: 0.25-1 mg/day

107

Omega-3

Polyunsaturated

Fatty Acids ...

108

n-3 polyunsaturated fatty acids in diets => mortality

How? => coronary disease mortality by

1. Improves blood

1. blood cholesterol & triglycerides

2. blood viscosity

3. Inflammation

2. Ischemia/reperfusion induced cell damage

3. Ischemia & reperfusion arrhythmias provide

protection when compared w/ no fish intake

=> only a low dose of n-3 PUFA (20 mg/kg/day) is

necessary to afford protection

109

0

50

100

150

Intake of omega 3 fatty acids => improves serum lipids, serum fibrinogen

& blood pressureSerum level or

parameter (in % compared to initial level)

Figure: The intake of fish oil containing EPA (eicosapentaenoic acid)

(2,7g/day) during 6 months maximum equivalent to the quantity consumed by

eskimos improves many levels & parameters of the arterial status.

With omega 3 fatty acids

Hagland O. Wallim R.et al. Effects of a new find fish oil concentrate. ESKIMO. 3 on trighycerides cholesterol.

Fibrinogen and blood pressure.J intern Med 1990; 227(5):347-55

initial

Triglycerides

-64%

Total cholesterol

-8%

HDL cholesterol

+21%

Arachidonic acid

-20%Fibrinogen

-23%

Blood pressure

-9%

110

Treatment : Efficient Doses:

3-10 grams/day of fish oil

Tests:

fatty acid profile in serum

HDL (?; increase or no change)

HDL /total cholesterol (?; increase or no change)

HDL /total

Total cholesterol (sometimes?)

LDL (?: reduce, increase or no change)

Oxidized LDL (?: reduce, increase or no change)

triglycerides (<omega 3-6-9)

apolipoprotein B

protects atherosclerosis

Can mortality

Polyunsaturated fatty acids (esp. omega3)

111

1

0.6 0.61

0

0.5

1

food-related linoleic acid => coronary

artery disease

Coronary artery disease (Odds ratio)

Figure: A higher intake of linoleic acid was inversely related to the prevalence odds

ratio of coronary heart disease (CAD) Linolenic &linoleic acid had synergistic effects on

the prevalence odds ratio of CAD

Dietary linoleic acid intake

Lowest tertile

Djousse L, Ponkow JS, Ellison Rc, et al. Relation between dietary linolenic acid and coronary artery disease in the

National Heart, Lung, and Blood Institule Family Heart Study, Am J Clm Nutr 2001 Nov;74(5);612-9 Boston

University. USA

Middle tertile

-40%

High tertile

-39%

n=4584 participants with a mean age of 52.1 yrs in National Heart, Lung, & Blood institute Family Heart Study

112

Omega-6

Polyunsaturated

Fatty Acids …

113

0.52

0

0.5

1

citrus fruits & intake of vit. C, vit. B2 & linoleic

acid => all - cause mortality in very elderly people

MORTALITY

Figure: frequent consumption of citrus fruit, and high intake of vitamin C,

riboflavin, & linoleic acid are associated with longevity

5-year cohort study among n= 162 self-sufficient residents in a public home for elderly

Fortes C, Forastiere F, Farchi S, Rapiti E, Pastori G, Perucci CA Diet and overall survival in a cohart of very elderly

people. Epidemiology; 2000 Jul.11(4);440-5. Department of Epidermiology. Lazio Regional Health Authority; Rome.

Italy.

CITRUS FRUIT

LOW(<1x/wk)

HIGH(>or = 2x/wk)

-48%

LOWHIGHVIT.C

-50%

HIGHVIT.B2

HIGH LINOLEIC

ACID

-60%

SUPPLEMENT intake

114

Anti-oxidants

Glutathion , vit. C

=> Survival ?

115

Serum Glutathione => physical health

33 representative elderly (community-

based)

=> serum glutathione: sign.

• Levels of self-rated health

(p<0.01)

• Number of illnesses (p<0.05)

• Cholesterol (p<0.05)

• Body mass index

• Blood pressures

=>Glutathione, by itself, accounted

for 24% of the variance of an index of

morbidity.

Patients with

arthritis,

diabetes, or

heart disease

(assessed by

physicians) had

at least

marginally sign.

Serum

glutathione than

those who were

disease free

Julius M, Lang CA, Gleiterman L, Harburg E, Difranceisco W, Schork A Glutathione and morbidity in a community-

based sample of elderly. J Clin Epidemiol. 1994 Sep;47(9):1021-5 Department of Epidemiology, School of Public

Health, University of Michigan, Ann Arbor 48109,USA

116

Critical studies

Showing

Adverse effects

Of vitamin use

on mortality

117

0

0.5

1

1.5

2

Beta-carotene + vit. A => Mortality from lung cancer

Relative risk of lung cancer

Figure: Beta-carotene w/ vit. A at pharmacol. Doses increases ling cancer risk

in people w/ risk factors for lung cancer (smoking & /or occupational exposure

to asbestos). No effect on total cancer incidence, mortality or all-cause mortality

NS

(META-ANALYSIS: n = 109,394 subjects 4 studies: 2+ smokers, 1+workers exposed to asbestos & 2+health

professionals, 2+subjects w/ no known risk factors, follow-up 2-5 yrs).

ALONE

VIT. A, E or BETA-CAROTENE

PLACEBO

Subjects+risk factors for lung

cancerincidence

mortalityincidence

mortalityincidence

mortalityincidence

mortality

incidencemortality

Subjects+no risk factors

Subjects+risk factors Subjects+risk factors

ALONE or combi.

BETA-CAROTENE at pharmacol.

doses

BETA-CAROTENE + VIT.A BETA-CAROTENE

+ VIT.E

NS NS NS NS NS P<0.05 NS NSP<0.05

118

0.98

1.8

2.8

1.91.5

0

0.5

1

1.5

2

2.5

Vit. E+Vit. A => Mortality in women w/ coronary artery

disease

Relative risk (Hazard ratio)

Figure: In postmenopausal women with coronary disease, neither HRT nor

antioxidant vitamin supplements provide cardiovascular benefit. Instead, a potential

for harm was suggested with each treatment

(a randomized, double-blind trial of n=423 postmenopausal women with at least 1

15% to 75% coronary stenosis at baseline coronary angiography mean follow-up:

2.8 yrs)

MORTALITY Death, stroke or nonfatal myocardial infarct

PLACEBO

HRT

800 IU Vit. E + 1000 mg/d

Vit.C HRTVit.E + Vit. C

Effects of hormone replacement therapy and antioxidant women supplements an coronary atherosclerosis in post-

menopausal women: a randomized controlled trial.JAMA 2002 No. 20;288(19);243240 San Francisco Gen. Hospital

119

=> Survival ?

6. healthy, comfortable home

120

Having a good home

comfort

Being Sociable

=> Longevity?

121

Psychosocial & demographic determinants =>

longevity

Indicators of a long life :

• Autonomous housing facility

• Positive subjective health

• Engaged attitude towards life in old age

n=455 respondents in a 12-year longitudinal research

that started in 1974 on relocation of older people

Mertens F. Do the fittest survive? Psychosocial and demographic determinants of longevity from a 12-year

longitudinal study on relocation of the aged. Tijdschr Gerontol Geriatr. 1988 Sep; 19(4): 153-62. intervakgroep

Sociale Gerontologie KU

122

=> Survival ?

7. solid, healthy psychology &

spirituality

123

=> Survival ?

8. Being a female

124

The Three Rules of Anti-Aging Medicine

#1. Don't get sick

#2. Don’t get old

#3. Don't die

125

While these rules may seem facetious, consider

the following simple steps you can take to help

ensure a longer life span:

• Drive a big car (2,800 pounds or more). The survivability in a

potentially fatal accident between the largest and the smallest

automobiles can differ tenfold.

• Avoid stress and depression. They are major causes for premature

aging.

• Exercise at least 30 minutes daily. It is your number-one defense

against the infirmities of old age.

• Limit harmful fats such as saturated fats and trans fatty acide in your

diet. They are directly associated with an increased risk of both heart

disease and cancer

• Sleep seven to eight hours a night. Quality sleep is essential for

rejuvenation and repair. If you’re like the 20 million Americans who

suffer from insomnia or other sleeping problems---get help!

126

• Consume little or no alcohol. It is neurotoxic.

• Don’t smoke. Not only does it stain your teeth and smell bad, it

also kills more Americans than all foreign wars combined. With

every minute you smoke, a minute of your life is taken away.

• Try to keep your weight at, or even 5 percent below, ideal body

weight (IBW). Mortality increases significantly at 20 percent or

more above IBW and 10 percent or more below IBW. (To

determine our IBW, see chart on page 361.)

• Maintain optimum antioxidant vitamin blood levels.Animal

studies indicate a 20 percent increase in longevity with optimum

nutrient supplementation.

• Early detection is the key to a cure for both heart disease and

cancer---get blood tests and comprehensive anti-aging physical

exams yearly.

127

• If age fifty-five or older, consider hormone replacement therapy, if needed,

administered by a knowledgeable physician.

• Drink eight to ten 8-ounce glasses of purified or bottled water. As much as

70 percent of municipal water systems surveyed were polluted with

potentially toxic amounts of flourine and chlorine. According to recent

Environmental Protection Agency reports, these chemicals have been

associated with an increased risk of urinary tract cancers.

• Think young. Aging is as much a state of mind as it is a state of physiology.

Lie about your age (especially to yourself). Keep young-feeling friends around

to remind yourself what “youth” feels and thinks like.

• Do not accept “just getting old”. Fight tooth and nail to remain youthful and

vigorous. At least forty anti-aging drugs now exist, and hundreds more are

under development, for everything from bone loss and Alzheimer’s

treatments, to wrinkle reduction and gray hair. It is the whole point of this

book to help you in your fight for longevity. In the pages that follow, we will

offer insights into every part of our life---how you can live it longer, better,

and healthier.

128

129

1992

2002

Nanotechnology: Miniaturization of Drug Delivery Mechanisms

* Estimated dates of availability from “Take your medicine,” Wired, March 2003.

Figures from http://www.aradigm.com; http://www.mchips.com/tech.html; http://www.alza.com.

1972

Tiny silicon or polymeric

microchips – each the

size of a US dime –

contain thousands of

micro-reservoirs, each of

which can be filled with

any combination of

drugs[MicroCHIPS (Massachusetts USA)]

2007*2006*

Liquid insulin is

converted into

aerosol and delivered

automatically by

the device’s

electromechanical

detector [Aradigm (California USA)]

One-inch patch

of electrical

components

including a

battery that

zaps drugs into

the skin. [Alza (California

USA)]

2006

*

130

Rate of Gains in Knowledge

Similarly, scientific and

biomedical knowledge

has increased

exponentially and

continues to do so.

Moore’s Law (1965) posited that the

number of components on an

integrated circuit (IC) would double

every 12-24 months. But

technological knowledge has

surpassed that projection numerous

times over.

20

40

80

160

320

640

1280

500,000

1 million

2 million

4 million

8 million

16 million

32 million

64 million

128 million

256 million

90 91 92 9493 95 96 97 9998 00

10/90

11/92

3/941/97

1/98

10/99

4/00

386855,000

transistors

20 MHz

4861.4 Mn

transistors

33 MHz

Pentium3.2 Mn

transistors

100 MHz

Pentium

MMX4.5 Mn

transistors

200 MHz

Pentium

II7.5 Mn

transistors

333 MHz

Pentium

III28 Mn

transistors

733 MHz

Pentium

Xeon150 Mn

transistors

933 MHz

01 02

512 million

1024 millionItanium

325 Mn

transistors

800 MHz

1/01 TECHNOLOGY-ADJUSTED LIMIT

LIMIT PER MOORE’S LAW

INTEL PREDICTS1 BN TRANSISTOR PROCESSOR

BY 2007*

FUTURE OF COMPUTING WITHDNA, QUANTUM, & NANOTECH

2000 2003 2006 2010 2013 2016 2020 2023 2026

4x

8x

16x 32x 64x 128x 256x

2x

131

Contributing Factors to Extension of the Maximum Human

Lifespan

add 50-100

years

add 10-20 years

add 10-20 years

add 15-30 years

add 35-70 years

0 20 40 60 80 100 120

fasting and caloric

restriction

high-tech biomedicine

anti-aging drugs

exercise & lifestyle

combined all factors

Inte

rve

nti

on

Years Added

132

The Arrival at Practical Immortality

Practical

immortality --healthy human

lifespans of

150 years and

longer -- may

be achieved

if we employ

anti-aging

therapeutics

as the bridge

between

now and the

immediate future

NOWLifespans of

80 years

SOON[Maybe by 2029]

Lifespans of 120 years

FUTURE[c. 2050-2095]

Lifespans of 150-200 Years

• Stem cells

• DNA repair

• Telomerase

• Cloning

• Machine-based

Human

Enhancements

133©Dr Bob Goldman/A4M

134