Doron Garfinkel, M.DDoron Garfinkel, M.D

NUTRITION AND LONGEVITY CONFERENCE, ,

Danone Institute Israel, March 26, 2001.Danone Institute Israel, March 26, 2001.

NUTRITION AND LONGEVITY CONFERENCE, ,

Danone Institute Israel, March 26, 2001.Danone Institute Israel, March 26, 2001.

MICRONUTRIENTS IN THE ELDERLY

Age-related deficiencies in microelementsAge-related deficiencies in microelements

MICRONUTRIENTS IN THE ELDERLY

Age-related deficiencies in microelementsAge-related deficiencies in microelements

HEALTH PROMOTION THE ROLE OF NUTRITIONHEALTH PROMOTION THE ROLE OF NUTRITION

18th.18th.18th.18th. 19 th.19 th.19 th.19 th.

B.CB.C..

IN PREVIOUS CENTURIES,IN PREVIOUS CENTURIES,

20 th.20 th.20 th.20 th.

DEFICIENCIES OF SPECIFIC NUTRITIONAL DEFICIENCIES OF SPECIFIC NUTRITIONAL

ELEMENTS WERE RESPONSIBLE FOR ELEMENTS WERE RESPONSIBLE FOR

SIGNIFICANT MORTALITY AND MORBIDITY SIGNIFICANT MORTALITY AND MORBIDITY

IN THE GENERAL POPULATIONIN THE GENERAL POPULATION

DEFICIENCIES OF SPECIFIC NUTRITIONAL DEFICIENCIES OF SPECIFIC NUTRITIONAL

ELEMENTS WERE RESPONSIBLE FOR ELEMENTS WERE RESPONSIBLE FOR

SIGNIFICANT MORTALITY AND MORBIDITY SIGNIFICANT MORTALITY AND MORBIDITY

IN THE GENERAL POPULATIONIN THE GENERAL POPULATION

DETECTING SPECIFIC NUTRITIONAL DEFICIENCIES

DETECTING SPECIFIC NUTRITIONAL DEFICIENCIES

20th. Century20th. Century20th. Century20th. Century

VITAMIN A NIGHT BLINDNESS VITAMIN A NIGHT BLINDNESS

NIACIN PELLAGRANIACIN PELLAGRA

THIAMINE BERI BERITHIAMINE BERI BERI

VITAMIN A NIGHT BLINDNESS VITAMIN A NIGHT BLINDNESS

NIACIN PELLAGRANIACIN PELLAGRA

THIAMINE BERI BERITHIAMINE BERI BERI

DEFICIENCY DEFICIENCY DISEASEDISEASEDEFICIENCY DEFICIENCY DISEASEDISEASE

HEALTH PROMOTION IN 20th. CENTURYHEALTH PROMOTION IN 20th. CENTURY

VITAMIN C SCURVYVITAMIN C SCURVY

VITAMIN D RICKETSVITAMIN D RICKETS

PYRIDOXINE, IRON, FOLIC ACIDPYRIDOXINE, IRON, FOLIC ACID ANEMIAS ANEMIAS

IODINE HYPOTHYROIDISMIODINE HYPOTHYROIDISM

FLUORIDE CARIESFLUORIDE CARIES

VITAMIN C SCURVYVITAMIN C SCURVY

VITAMIN D RICKETSVITAMIN D RICKETS

PYRIDOXINE, IRON, FOLIC ACIDPYRIDOXINE, IRON, FOLIC ACID ANEMIAS ANEMIAS

IODINE HYPOTHYROIDISMIODINE HYPOTHYROIDISM

FLUORIDE CARIESFLUORIDE CARIES

20th. Century20th. Century20th. Century20th. Century

ENRICHING WATER AND FOOD WITH ENRICHING WATER AND FOOD WITH ESSENTIAL NUTRITIONAL ELEMENTS ESSENTIAL NUTRITIONAL ELEMENTS

IN ORDER TO AVOID DISEASES CAUSED IN ORDER TO AVOID DISEASES CAUSED BY SPECIFIC NUTRIENT DEFICIENCYBY SPECIFIC NUTRIENT DEFICIENCY

ENRICHING WATER AND FOOD WITH ENRICHING WATER AND FOOD WITH ESSENTIAL NUTRITIONAL ELEMENTS ESSENTIAL NUTRITIONAL ELEMENTS

IN ORDER TO AVOID DISEASES CAUSED IN ORDER TO AVOID DISEASES CAUSED BY SPECIFIC NUTRIENT DEFICIENCYBY SPECIFIC NUTRIENT DEFICIENCY

THE GOAL: THE GOAL:

ACHIEVING THE ACHIEVING THE

RECOMMENDED DIETARY ALLOWANCE RECOMMENDED DIETARY ALLOWANCE

( R. D. A. )( R. D. A. )

THE GOAL: THE GOAL:

ACHIEVING THE ACHIEVING THE

RECOMMENDED DIETARY ALLOWANCE RECOMMENDED DIETARY ALLOWANCE

( R. D. A. )( R. D. A. )

HEALTH PROMOTION IN 20th. CENTURYHEALTH PROMOTION IN 20th. CENTURYSUCCESSFUL PREVENTION OF

SPECIFIC NUTRITIONAL DEFICIENCIESSUCCESSFUL PREVENTION OF

SPECIFIC NUTRITIONAL DEFICIENCIES

HEALTH PROMOTION - 21st CENTURY

A NEW ROLE FOR NUTRITION ???

HEALTH PROMOTION - 21st CENTURY

A NEW ROLE FOR NUTRITION ???

21 ST.21 ST.

CENTURYCENTURY

21 ST.21 ST.

CENTURYCENTURY

NUTRITIONAL INTERVENTIONS NUTRITIONAL INTERVENTIONS

MAY REPRESENT THE EASIEST,MAY REPRESENT THE EASIEST,

MOST SIMPLE AND MOST SIMPLE AND

COST - EFFECTIVE MEANS FOR :COST - EFFECTIVE MEANS FOR :

NUTRITIONAL INTERVENTIONS NUTRITIONAL INTERVENTIONS

MAY REPRESENT THE EASIEST,MAY REPRESENT THE EASIEST,

MOST SIMPLE AND MOST SIMPLE AND

COST - EFFECTIVE MEANS FOR :COST - EFFECTIVE MEANS FOR :INHIBITING AGE RELATED PROCESSES INHIBITING AGE RELATED PROCESSES

DECREASING MORTALITY & MORBIDITY DECREASING MORTALITY & MORBIDITY

FROM CHRONIC AGE-RELATED DISEASESFROM CHRONIC AGE-RELATED DISEASES

EXPANDING HEALTH FRONTIERS IN THE 21ST CENTURY

EXPANDING HEALTH FRONTIERS IN THE 21ST CENTURY

CAN WE PREVENT OR POSTPONECAN WE PREVENT OR POSTPONE

THE OMINOUS CONSEQUENSES OF THE OMINOUS CONSEQUENSES OF

AGE - RELATED DISEASES BY AGE - RELATED DISEASES BY

DIETARY MANIPULATION ?DIETARY MANIPULATION ?

CAN WE PREVENT OR POSTPONECAN WE PREVENT OR POSTPONE

THE OMINOUS CONSEQUENSES OF THE OMINOUS CONSEQUENSES OF

AGE - RELATED DISEASES BY AGE - RELATED DISEASES BY

DIETARY MANIPULATION ?DIETARY MANIPULATION ?SPECIFIC NUTRIENT SUPPLEMENTATION ?SPECIFIC NUTRIENT SUPPLEMENTATION ?EFFECTIVE DOSE ? EFFECTIVE DOSE ? TOXICITY ? THERAPEUTIC RANGE ? TOXICITY ? THERAPEUTIC RANGE ?

R. D. A. or HIGHER?? “MEGADOSES” ??? R. D. A. or HIGHER?? “MEGADOSES” ???MAGIC-BOOLET?

THERE ARE NO MAGIC BOOLETSBOOLETS !

ZINC , COPPER, MAGNESIUM, ZINC , COPPER, MAGNESIUM, CHROMIUM , SELENIUM, MOLYBDEN CHROMIUM , SELENIUM, MOLYBDEN

ALUMINUM ALUMINUM BORE, BROMINE

BORE, BROMINETIN

TIN FLUORIDE

FLUORIDE LITHIUM, NICKEL

LITHIUM, NICKEL

SILICON

SILICON

VANADIUM, RUBIDIUM, GERMANIUM

VANADIUM, RUBIDIUM, GERMANIUM

(Lead, Arsenic, Cadmium... )(Lead, Arsenic, Cadmium... )

MICROELEMENTS MICROELEMENTS

TESTING “ANTI-AGING” CLAIMS TESTING “ANTI-AGING” CLAIMS

IN MOST CASES,IN MOST CASES, THERE ARE NO THERE ARE NO RELIABLE, CONTROLLED STUDIESRELIABLE, CONTROLLED STUDIES

THAT HAVE BEEN SUGGESTED TO THAT HAVE BEEN SUGGESTED TO INDUCE AN “ANTI - AGING” EFFECTINDUCE AN “ANTI - AGING” EFFECT

(OR AN INHIBITING EFFECT ON AGE-RELATED DISEASES)

THAT HAVE BEEN SUGGESTED TO THAT HAVE BEEN SUGGESTED TO INDUCE AN “ANTI - AGING” EFFECTINDUCE AN “ANTI - AGING” EFFECT

(OR AN INHIBITING EFFECT ON AGE-RELATED DISEASES)

REGARDING THE EFFICACY AND/OR REGARDING THE EFFICACY AND/OR SAFETY OF NUTRITIONAL ELEMENTSSAFETY OF NUTRITIONAL ELEMENTSREGARDING THE EFFICACY AND/OR REGARDING THE EFFICACY AND/OR SAFETY OF NUTRITIONAL ELEMENTSSAFETY OF NUTRITIONAL ELEMENTS

SEARCHING “ANTI-AGING” AGENTS

SEARCHING “ANTI-AGING” AGENTS

IN OUR ATTEMPT TO DISCOVER NUTRITIONALIN OUR ATTEMPT TO DISCOVER NUTRITIONAL

“ “INHIBITORS” OF AGE-RELATED DISEASES, INHIBITORS” OF AGE-RELATED DISEASES,

IT WOULD BE LOGICAL TO CONCENTRATE IT WOULD BE LOGICAL TO CONCENTRATE ON FACTORS KNOWN TO HAVE BOTH:ON FACTORS KNOWN TO HAVE BOTH:

IN OUR ATTEMPT TO DISCOVER NUTRITIONALIN OUR ATTEMPT TO DISCOVER NUTRITIONAL

“ “INHIBITORS” OF AGE-RELATED DISEASES, INHIBITORS” OF AGE-RELATED DISEASES,

IT WOULD BE LOGICAL TO CONCENTRATE IT WOULD BE LOGICAL TO CONCENTRATE ON FACTORS KNOWN TO HAVE BOTH:ON FACTORS KNOWN TO HAVE BOTH:

BENEFICIAL EFFECTS ON LIVING CELLSBENEFICIAL EFFECTS ON LIVING CELLS

DECREASED CONCENTRATIONS AND/OR DECREASED CONCENTRATIONS AND/OR

ACTIVITY IN ELDERLY PEOPLEACTIVITY IN ELDERLY PEOPLE

INHIBITION OF AGING PROCESSES ....INHIBITION OF AGING PROCESSES ....

YES, I SEE !YES, I SEE ! Z I N C !!Z I N C !!

why zinc ? why zinc ?

??

INHIBITION OF AGING PROCESSES INHIBITION OF AGING PROCESSES

WHICH STARTS AT WEANING AND WHICH STARTS AT WEANING AND

CONTINUES THROUGHOUT LIFE , CONTINUES THROUGHOUT LIFE , CAN SLOW DOWN CAN SLOW DOWN THE AGING PROCESS THE AGING PROCESS

UNDERFEEDING

INHIBITION OF AGING PROCESSES INHIBITION OF AGING PROCESSES

THE PRECISE MECHANISM BY WHICH

THE UNDERFEEDING REGIMENS

PROLONGS MAXIMAL LIFESPAN ,

REMAINS UNKNOWN

THE PRECISE MECHANISM BY WHICH

THE UNDERFEEDING REGIMENS

PROLONGS MAXIMAL LIFESPAN ,

REMAINS UNKNOWN

INHIBITION OF AGING PROCESSES INHIBITION OF AGING PROCESSES

““RESTRICTED DIETSRESTRICTED DIETS””

HAVE HIGHER CONCENTRATIONS OF HAVE HIGHER CONCENTRATIONS OF

ZINCZINC

AND THEIR ALTERED COMPOSITION AND THEIR ALTERED COMPOSITION

HAS A BENEFICIAL EFFECT ON HAS A BENEFICIAL EFFECT ON

ZINC BIOAVAILABILITYZINC BIOAVAILABILITY

* * ** * *

IS AGING INEVITABLE ?

THE INTRACELLULAR ZINC DEFICIENCY HYPOTHESIS OF AGING

IS AGING INEVITABLE ?

THE INTRACELLULAR ZINC DEFICIENCY HYPOTHESIS OF AGING

D. GARFINKEL ,

MEDICAL HYPOTHESES 19: 117 - 137 , 1986

D. GARFINKEL ,

MEDICAL HYPOTHESES 19: 117 - 137 , 1986

why zinc ? why zinc ?

??

ZINC METALLOENZYMES (PARTIAL LIST - OUT OF 200)

ZINC METALLOENZYMES (PARTIAL LIST - OUT OF 200)

ALCOHOL DEHYDROGENASEALDOLASEALKALINE PHOSPHATASEALKALINE PROTEASECARBONIC ANHYDRASECARBOXYPEPTIDASES A, B, CDIPEPTIDASEGLYCERALDEHYDE PHOSPHATE DEHYDROGENASELEUCINE AMINOPEPTIDASEPHOSPHOGLUCOMUTASEPHOSPHOLIPASE CPYRUVATE CARBOXYLASERETINAL REDUCTASE

ALCOHOL DEHYDROGENASEALDOLASEALKALINE PHOSPHATASEALKALINE PROTEASECARBONIC ANHYDRASECARBOXYPEPTIDASES A, B, CDIPEPTIDASEGLYCERALDEHYDE PHOSPHATE DEHYDROGENASELEUCINE AMINOPEPTIDASEPHOSPHOGLUCOMUTASEPHOSPHOLIPASE CPYRUVATE CARBOXYLASERETINAL REDUCTASE

ZINC METALLOENZYMESINFORMATION HANDLING ENZYMESZINC METALLOENZYMES

INFORMATION HANDLING ENZYMES

DNA POLYMERASERNA POLYMERASEREVERSE TRANSCRIPTASETdTTHYMIDINE KINASE

DNA POLYMERASERNA POLYMERASEREVERSE TRANSCRIPTASETdTTHYMIDINE KINASE

ZINC FINGERSZINC FINGERS TRANSCRIPTION FACTORS ACTIVATE GENES USING

SMALL PROJECTIONS KNOWN AS ZINC FINGERS THAT ARE PERFECTLY SUITED

TO DNA RECOGNITION . . .

TRANSCRIPTION FACTORS ACTIVATE GENES USING SMALL PROJECTIONS KNOWN AS ZINC FINGERS THAT ARE PERFECTLY SUITED

TO DNA RECOGNITION . . .

ZINC FINGERS PLAY A KEY PART IN REGULATING THE ACTIVITY OF GENES IN MANY SPECIES, FROM YEAST TO HUMANS...

ZINC FINGERS PLAY A KEY PART IN REGULATING THE ACTIVITY OF GENES IN MANY SPECIES, FROM YEAST TO HUMANS...

D. Rhodes & A. Klug Scientific American, February 1993, pp. 32-39 D. Rhodes & A. Klug Scientific American, February 1993, pp. 32-39

ZINC IS AN ESSENTIAL

FACTOR

ZINC IS AN ESSENTIAL

FACTOR FOR GROWTH, FOR GROWTH,

DEVELOPMENTDEVELOPMENT

AND NORMAL FUNCTIONAND NORMAL FUNCTION

OF EVERY LIVING CELLOF EVERY LIVING CELL

IS THERE AN AGE-RELATED ZINC DEFICIENCY ?

IS THERE AN AGE-RELATED ZINC DEFICIENCY ?

zinczinc

AT PRESENT, THERE IS NO SIMPLE AND RELIABLE INDEX OF ZINC STATUS

THERE IS SELDOM A CORRELATION BETWEEN ZINC CONCENTRATIONS IN HAIR OR TOENAILS, ERYTHROCYTES , PLASMA OR URINE

AT PRESENT, THERE IS NO SIMPLE AND RELIABLE INDEX OF ZINC STATUS

THERE IS SELDOM A CORRELATION BETWEEN ZINC CONCENTRATIONS IN HAIR OR TOENAILS, ERYTHROCYTES , PLASMA OR URINE

PROBLEMS INASSESSING ZINC STATUS

PROBLEMS INASSESSING ZINC STATUS

NONE OF THESE MEASUREMENTS PROVIDES NONE OF THESE MEASUREMENTS PROVIDES

A SENSITIVE INDICATION OF ZINC STATUSA SENSITIVE INDICATION OF ZINC STATUS

ASSESSING ZINC STATUSASSESSING ZINC STATUS

In Apparently Normal Children with Poor In Apparently Normal Children with Poor

Growth but No Evidence of Zinc Deficiency, Growth but No Evidence of Zinc Deficiency,

Zinc Supplementation Induced a Significant Zinc Supplementation Induced a Significant

Increase in Height with No Significant Change Increase in Height with No Significant Change

in Plasma Zinc Levels... in Plasma Zinc Levels...

Walravens PA et al. Am J Clin Nutr 1983; 38:195-201

Suggesting an Undetected Zinc Deficiency

in Those “Normal” Children...

IS A THERAPEUTIC TRIAL IS A THERAPEUTIC TRIAL OF ZINC ADMINISTRATIONOF ZINC ADMINISTRATION

Brit. Med. J. 1981 (Editorial)

ASSESSING ZINC STATUSASSESSING ZINC STATUS

THE CORNERSTONE OF THE DEFINITION

AND DETECTION OF ZINC DEFICIENCY

THE CORNERSTONE OF THE DEFINITION

AND DETECTION OF ZINC DEFICIENCY

IF WE ALL DEVELOP AN AGE - RELATED ZINC DEFICIENCY BUT ITS DETECTION IS IMPOSSIBLE

IF WE ALL DEVELOP AN AGE - RELATED ZINC DEFICIENCY BUT ITS DETECTION IS IMPOSSIBLE

TESTING THE HYPOTHESISTESTING THE HYPOTHESIS

WE CAN PERFORM THERAPEUTIC TRIALS

TO ASSESS EFECTS OF ZINC SUPPLEMENTATION ON MEASURABLE

AGE - RELATED PROCESSES

THE SUBJECTS THE SUBJECTS

HEALTHY MALES AND FEMALES AGED 40 - 65 , WHO PARTICIPATE IN A LONGITUDINAL STUDY OF AT LEAST 5 YEARS

HEALTHY MALES AND FEMALES AGED 40 - 65 , WHO PARTICIPATE IN A LONGITUDINAL STUDY OF AT LEAST 5 YEARS

(STARTED 1989AT THE WOLFSON MEDICAL CENTER)

THE COMPOUND THE COMPOUND

ZINC SULFATE 300 mg (68 mg ELEMENTAL ZINC)

A PLACEBO IDENTICAL IN APPEARANCE

ZINC SULFATE 300 mg (68 mg ELEMENTAL ZINC)

A PLACEBO IDENTICAL IN APPEARANCE

EFFECTS OF PROLONGED EFFECTS OF PROLONGED ZINC SUPPLEMENTATIONZINC SUPPLEMENTATION

EFFECTS OF PROLONGED EFFECTS OF PROLONGED ZINC SUPPLEMENTATIONZINC SUPPLEMENTATION

ON THEON THE

AGE - RELATED DECLINE AGE - RELATED DECLINE

OF THE IMMUNE SYSTEMOF THE IMMUNE SYSTEM

IMMUNITY AND ZINC IMMUNITY AND ZINC

ZINC DEFICIENCY IS ASSOCIATED WITH IMPAIRED T-CELL FUNCTION

ZINC ADMINISTRATION IMPROVES CELL - MEDIATED IMMUNITY IN THE ELDERLY

ZINC DEFICIENCY IS ASSOCIATED WITH IMPAIRED T-CELL FUNCTION

ZINC ADMINISTRATION IMPROVES CELL - MEDIATED IMMUNITY IN THE ELDERLY

IMMUNOLOGICAL STUDY METHODS IMMUNOLOGICAL STUDY METHODS

GLUTATHION REDUCTASE, GLUTATHION GLUTATHION REDUCTASE, GLUTATHION PEROXYDASE, CATALASE AND SUPER PEROXYDASE, CATALASE AND SUPER OXIDE DISMUTASE (SOD) - IN RBC.OXIDE DISMUTASE (SOD) - IN RBC.

LABORATORY TESTS :

MAGNESIUM, CERULOPLASMIN, COPPER, MAGNESIUM, CERULOPLASMIN, COPPER, BETA CAROTEN & VITAMIN E - IN SERUMBETA CAROTEN & VITAMIN E - IN SERUM

ZINC in PLASMA, RBC & MONONUCLEARSZINC in PLASMA, RBC & MONONUCLEARS

MAGNESIUM, CERULOPLASMIN, COPPER, MAGNESIUM, CERULOPLASMIN, COPPER, BETA CAROTEN & VITAMIN E - IN SERUMBETA CAROTEN & VITAMIN E - IN SERUM

ZINC in PLASMA, RBC & MONONUCLEARSZINC in PLASMA, RBC & MONONUCLEARS

IMMUNOLOGICAL STUDY METHODSIMMUNOLOGICAL STUDY METHODSDELAYED - TYPE HYPERSENSITIVITY (DTH) SKIN REACTIONS TO 7 ANTIGENS

WERE ASSESEDBY MULTITEST :

DELAYED - TYPE HYPERSENSITIVITY (DTH) SKIN REACTIONS TO 7 ANTIGENS

WERE ASSESEDBY MULTITEST :

;;;;;;;;

Tuberculin, Diphteria, Tetanus, Proteus, Streptococcus, Candida & Trichophyton

EFFECT OF ZINC SUPPLEMENTATION ON PLASMA, RBC & MNC ZINC

EFFECT OF ZINC SUPPLEMENTATION ON PLASMA, RBC & MNC ZINC

30

80

130

180

Z I N CZ I N CPLACEBO

PLASMA ug / dLPLASMA ug / dL

RBC

MNC

p = 0.01

EFFECT OF ZINC SUPPLEMENTATION ON DTH SKIN RESPONSES

EFFECT OF ZINC SUPPLEMENTATION ON DTH SKIN RESPONSES

0

1

2

3

4

5

N0

P < .001

ZINCZINC

PLACEBOPLACEBO

NUMBER OF POSITIVE RESPONSES

P < .001P < .001

EFFECT OF ZINC SUPPLEMENTATION ON DTH SKIN RESPONSES

EFFECT OF ZINC SUPPLEMENTATION ON DTH SKIN RESPONSES

0

5

10

15

20

P < .001

Z I N CZ I N C

PLACEBOPLACEBOPLACEBOPLACEBO

AVERAGE

TOTAL INDURATION

TOTALSCORETOTALSCORE

P < P < ..001001

CONCLUSIONS CONCLUSIONS

PROLONGED ZINC SUPPLEMENTATION IN

ADULTS IS REFLECTED IN INCREASED PLASMA ZINC CONCENTRATIONS

PROLONGED ZINC SUPPLEMENTATION IN

ADULTS IS REFLECTED IN INCREASED PLASMA ZINC CONCENTRATIONS

PROLONGED ZINC SUPPLEMENTATION MAY INHIBIT THE AGE- RELATED

DECLINE IN CELLULAR IMMUNITY (AT LEAST AS RELATED TO DTH SKIN TESTS)

PROLONGED ZINC SUPPLEMENTATION MAY INHIBIT THE AGE- RELATED

DECLINE IN CELLULAR IMMUNITY (AT LEAST AS RELATED TO DTH SKIN TESTS)