AGING PROCESSAGING PROCESS

RA TUTY KUSWARDHANI RA TUTY KUSWARDHANI IGP SUKA ARYANA IGP SUKA ARYANA

GERIATRIC DIVISION, INTERNAL MEDICINE OF UDAYANA GERIATRIC DIVISION, INTERNAL MEDICINE OF UDAYANA UNIVERSITY/SANGLAH HOSPITAL, DENPASARUNIVERSITY/SANGLAH HOSPITAL, DENPASAR

MARIA ESTHER HEREDIA DE CAPOVILLA ,116 Y.O

EKUADOR (GUINNESS BOOK – DEC’ 2005)

NAMA: dr IGP SUKA ARYANA, SpPDNAMA: dr IGP SUKA ARYANA, SpPD STAF PENGAJAR DIVISI GERIATRI, STAF PENGAJAR DIVISI GERIATRI, BAGIAN/SMF ILMU PENYAKIT DALAM FK UNUD DENPASAR, BAGIAN/SMF ILMU PENYAKIT DALAM FK UNUD DENPASAR,

RSUP SANGLAHRSUP SANGLAH

PendidikanPendidikan Dokter umum: FK Unud 1997Dokter umum: FK Unud 1997 Spesialis Penyakit Dalam: FK Unud 2005Spesialis Penyakit Dalam: FK Unud 2005 Visiting research fellow Kobe Jepang 2002Visiting research fellow Kobe Jepang 2002

Penghargaan:Penghargaan: Nominator the Best Young Investigator Award AFES Singapura Nominator the Best Young Investigator Award AFES Singapura

20032003 Nominator the Best Young Investigator Award AFES Manila Nominator the Best Young Investigator Award AFES Manila

20052005 The Best Mustafa-Varon Award for the Best Free Paper On The Best Mustafa-Varon Award for the Best Free Paper On

shock and Critical Care shock and Critical Care 20052005 The Best Young Investigator Award, ASMIHA Surabaya 2005The Best Young Investigator Award, ASMIHA Surabaya 2005

KURIKULUM VITAEKURIKULUM VITAE

TOPICSTOPICS INTRODUCTIONINTRODUCTION

GERIATRIC DEFINITIONGERIATRIC DEFINITION DEMOGRAPHIC POPULATIONDEMOGRAPHIC POPULATION

AGING DEFINITIONAGING DEFINITION AGING AND SENESCENCEAGING AND SENESCENCE

THEORIES OF AGINGTHEORIES OF AGING

INTRODUCTIONINTRODUCTION GERONTOLOGY : GERONTOS AND LOGOSGERONTOLOGY : GERONTOS AND LOGOS

GERIATRY SCIENCE :A SCIENCE WHICH LEARNS THE GERIATRY SCIENCE :A SCIENCE WHICH LEARNS THE ELDERLY AND THE TREATMENTELDERLY AND THE TREATMENT

GEROS = ELDERLYGEROS = ELDERLYIATRY = TO TREATIATRY = TO TREATTHE TERM : THE TERM : IGNAS LEO VASCHERIGNAS LEO VASCHER (1909) (1909)

PROGRESSIVE DEVELOPMENT : PROGRESSIVE DEVELOPMENT : DR. MARJORI WARREN DR. MARJORI WARREN (THE PIONEER OF GERIATRY IN THE WORLD)(THE PIONEER OF GERIATRY IN THE WORLD)

ELDERLY POPULATIONELDERLY POPULATION INDONESIAINDONESIA : ≥ 60 Y.O: ≥ 60 Y.O W H OW H O : ≥ 60 Y.O: ≥ 60 Y.O DEVELOPED COUNTRYDEVELOPED COUNTRY : ≥ 60 Y.O: ≥ 60 Y.O ELDERLY PATIENTELDERLY PATIENT : ≥ 60 Y.O : ≥ 60 Y.O

+ MULTIPLE DISEASE/ + MULTIPLE DISEASE/ COMPLEXITYCOMPLEXITY

CHINACHINA 198. 343198. 343INDIAINDIA 107.713107.713INDONESIAINDONESIA 24.81624.816BRAZILBRAZIL 21.94521.945UKUK 12.91212.912MEXICOMEXICO 12.82912.829NIGERIANIGERIA 9.1159.115

THE PREDICTION OF THE THE PREDICTION OF THE ELDERLY POPULATION 2020ELDERLY POPULATION 2020

INDONESIA INDONESIA DEMOGRAPHYDEMOGRAPHYYEARS YEARS BALITA (< 5 yrs)BALITA (< 5 yrs) ELDERLY(> 60 yrs) ELDERLY(> 60 yrs)

1971 1971 19,1 mil (16,1 %) 19,1 mil (16,1 %) 5,3 mil(4,5 %)5,3 mil(4,5 %)1980 1980 21,2 mil (14,4 %) 21,2 mil (14,4 %) 8,0 mil (5,5 %)8,0 mil (5,5 %)1985 1985 21,6 mil (13,4 %) 21,6 mil (13,4 %) 9,4 mil (5,8 %)9,4 mil (5,8 %)1990 1990 21,0 mil (11,7 %) 21,0 mil (11,7 %) 11,2 mil (6,3 %)11,2 mil (6,3 %)1995 1995 21,6 mil (11,0 %) 21,6 mil (11,0 %) 13,6 mil (6,9 %) 13,6 mil (6,9 %) 2000 2000 21,2 mil (10,1 %) 21,2 mil (10,1 %) 15,9 mil (7,6 %) 15,9 mil (7,6 %) 2005 2005 21,1 mil ( 9,5 %) 21,1 mil ( 9,5 %) 18,3 mil (8,2 %) 18,3 mil (8,2 %) 2015 2015 18,8 mil ( 7,6 %) 18,8 mil ( 7,6 %) 24,4 mil (10,0 %)24,4 mil (10,0 %)

The importance of genetics in the The importance of genetics in the regulation of biologic aging is regulation of biologic aging is demonstrated by the characteristic demonstrated by the characteristic longevity of each animal species. longevity of each animal species.

Several theories of aging have been Several theories of aging have been promulgated and recently reviewed promulgated and recently reviewed (Goldstein, 1989; Abrass, 1991). (Goldstein, 1989; Abrass, 1991).

These theories fall into two general These theories fall into two general categories: accumulation of damaged to categories: accumulation of damaged to informational molecules, or the regulation informational molecules, or the regulation of specific genes of specific genes

BIOLOGIC AGINGBIOLOGIC AGING

AGING PROCESS AGING PROCESS DEFINITIONDEFINITION

Aging is a process of the loosing of ability the Aging is a process of the loosing of ability the tissue slowly to develop it self and to maintain tissue slowly to develop it self and to maintain the structure and the normal function; so it the structure and the normal function; so it can not stand towards the trauma to develop can not stand towards the trauma to develop the damage. (Constantine 1994)the damage. (Constantine 1994)

AGING: A process of gradual and spontaneus AGING: A process of gradual and spontaneus change resulting in maturation through change resulting in maturation through childhood, puberty and young adulthood and childhood, puberty and young adulthood and then decline through middle and late agingthen decline through middle and late aging

SENESCENCE: The process by which SENESCENCE: The process by which the capacity for cell division, growth and the capacity for cell division, growth and function is lost over time, ultimately function is lost over time, ultimately leading to an incompatibility with life i.e leading to an incompatibility with life i.e the process of senescence terminates in the process of senescence terminates in death.death.

DISEASE vs aging DISEASE vs aging In both aging and In both aging and senescence, many physiology function senescence, many physiology function decline but normal decline is not usually decline but normal decline is not usually considere the same as disease. So ??considere the same as disease. So ??

Progressively the human will loose Progressively the human will loose the defence of infection & it will the defence of infection & it will accumulate more metabolic and accumulate more metabolic and structural distortion which is called :structural distortion which is called :““DEGENERATIVE DISEASE”DEGENERATIVE DISEASE”

WHY DO WE AGE?WHY DO WE AGE?

WHY DO WE LIVE AS WHY DO WE LIVE AS LONG AS WE DO?LONG AS WE DO?

WHY DO WE DIE?WHY DO WE DIE?

THEORIES OF AGING THEORIES OF AGING PROCESS PROCESS

AGING IS EXTREMELY COMPLEX AND AGING IS EXTREMELY COMPLEX AND MULTIFACTORIAL PROCESSMULTIFACTORIAL PROCESS

SEVERAL PROCESSES MAY INTERACT SEVERAL PROCESSES MAY INTERACT SIMULTANEOUSLYSIMULTANEOUSLY

AGING PROCESS MAY OPERATE AT MANY AGING PROCESS MAY OPERATE AT MANY

LEVEL OF FUNCTIONAL ORGANISMLEVEL OF FUNCTIONAL ORGANISM

MAJOR THEORIES ON AGINGMAJOR THEORIES ON AGING(focus on proces)(focus on proces)

Theory Theory Mechanisms Mechanisms Manifestations Manifestations

Accumulation of Accumulation of damaged to damaged to informational informational molecules molecules (demage and (demage and error)error)

Spontaneous mutagenesisSpontaneous mutagenesisFailure inFailure in DNA repair systemsDNA repair systemsErrors in DNA, Errors in DNA, RNA, and protein synthesis RNA, and protein synthesis Superoxide radicals and loss of Superoxide radicals and loss of scavenging enzymesscavenging enzymes

Copying errorsCopying errors

Error catastropheError catastrophe

Oxidative cellular Oxidative cellular damagedamage

Regulation of Regulation of specific genes specific genes (program)(program)

Appearance of specific Appearance of specific protein(s) protein(s)

Genetically Genetically programmed programmed senescene senescene

CLASSIFICATION THEORIES OF AGING CLASSIFICATION THEORIES OF AGING

(focus on level)(focus on level) EVOLUTIONARYEVOLUTIONARY

MUTATION ACCUMULATIONMUTATION ACCUMULATION mutation effect healht at older age mutation effect healht at older age DISPOSABLE SOMADISPOSABLE SOMAafter reproductive somatic cell become disposableafter reproductive somatic cell become disposable ANTAGONISTIC PLEIOTROPY ANTAGONISTIC PLEIOTROPY genes beneficial at younger, deleterious at older genes beneficial at younger, deleterious at older

MOLECULARMOLECULAR GENE REGULATION GENE REGULATION change regulating development and aging change regulating development and aging CODON RESTRICTION CODON RESTRICTION inability decode codoninability decode codonimpaired translation mRNAimpaired translation mRNA ERROR CATASTROPHE ERROR CATASTROPHE decline fidelity of gene expresion decline fidelity of gene expresion increased abnormal increased abnormal

proteinprotein SOMATIC MUTATION SOMATIC MUTATION accumulated molecular demage (DNA/genetic material)accumulated molecular demage (DNA/genetic material) DYSDIFFERENTIATION DYSDIFFERENTIATION accumulated molecular demage accumulated molecular demage impairs gene expresionimpairs gene expresion

CELLULARCELLULAR CELLULAR SENESCENCE-TELOMERE THEORYCELLULAR SENESCENCE-TELOMERE THEORY FREE RADICALFREE RADICAL WEAR AND TEAR WEAR AND TEAR accumulation of normal injuryaccumulation of normal injury APOPTOSISAPOPTOSISprogrammed cell dead from genetic event /genome crisisprogrammed cell dead from genetic event /genome crisis

SYSTEMSYSTEM NEUROENDOCRINE NEUROENDOCRINE alteration control homeostasis alteration control homeostasis aging related physiological aging related physiological

change change IMMUNOLOGIC IMMUNOLOGIC decline immune function decline immune function increased autoimmunityincreased autoimmunity RATE OF LIVING RATE OF LIVING fixed amount of metabolic potential for every living (live fastfixed amount of metabolic potential for every living (live fastdie die

young)young)

AGING PROCESS THEORYAGING PROCESS THEORY1. GENETIC CLOCK THEORY1. GENETIC CLOCK THEORY In this theory In this theory aging has been programmed aging has been programmed

genetically for certain species.genetically for certain species. Every species has nucleus like a genetic clock Every species has nucleus like a genetic clock

which has been winded according to a certain which has been winded according to a certain replication.replication.

This clock will count the mytocysThis clock will count the mytocysMytocys Mytocys will stop cell replication if it is will stop cell replication if it is

not windednot winded PROGRAMMED THEORYPROGRAMMED THEORY

Why on some species get a real Why on some species get a real different of life expectationdifferent of life expectation

Figure 1. Record in life span (Eudililin et al, 1993)Figure 1. Record in life span (Eudililin et al, 1993)

Turtle Turtle 170 y.o170 y.o

ElephantElephant 70 y.o70 y.o

HorseHorse 62 y.o62 y.o

GorillaGorilla 48 y.o48 y.o

BearBear 47 y.o47 y.o

CatCat 30 y.o30 y.o

DogDog 27 y.o27 y.o

Theoritically Theoritically it is possible to rewind it is possible to rewind this clock eventhough just for small time, this clock eventhough just for small time, with external interverences, such as :with external interverences, such as :

Health developmentHealth development Disease prevention with medicine/ Disease prevention with medicine/

treatmenttreatment

• The theory supported by experiment : The theory supported by experiment : nucleus which determines the replication nucleus which determines the replication Aging Aging Death Death

2. THE SHORTENING OF TELOMERE THEORY.

The shortening of DNA telomere will The shortening of DNA telomere will cause the death of the cell. cause the death of the cell.

The DNA replication leads to telomere The DNA replication leads to telomere shortening because DNA polymerase shortening because DNA polymerase cannot replicated the very end of DNA cannot replicated the very end of DNA molecule. molecule.

Telomerase elongates the chromosome Telomerase elongates the chromosome through de novo sequerell addition.through de novo sequerell addition.

3. THE DAMAGED BY FREE RADICAL.

Teory was first proposed in 1957, its one of best teory

All organism live contain free radical (ROS)

For aerobic organism, the free radical is

mainly formulated while respirating (aerob) in mitochondria.

The free radical are : super oxide (OThe free radical are : super oxide (O22), Hydroxcyl ), Hydroxcyl radical (COH), Hydrogen peroxide (Hradical (COH), Hydrogen peroxide (H2 2 OO22).).

Free radical is destroyer Free radical is destroyer it can react to DNA it can react to DNA cumulative demage cumulative demage aging and senescenceaging and senescence

The body itself is able to prevent free radical with The body itself is able to prevent free radical with

its enzymes : superoxide dismutase (SOD) : Zn, Cu, Mnits enzymes : superoxide dismutase (SOD) : Zn, Cu, Mn

2 O2 O22-- + 2H+ 2H+ SOD+ SOD H H22 O O22 + O + O22

*Catalase enzyme with Fe element in the “haem” *Catalase enzyme with Fe element in the “haem” to to burst burst hydrogen peroxide become water & oxygen hydrogen peroxide become water & oxygen : :

CATALASECATALASE

2H2H2 2 OO2 2 22HH22OO + O+ O22

*Glutathion peroxide enzyme with selenium (Se) *Glutathion peroxide enzyme with selenium (Se) element element burst peroxide hydrogen through the burst peroxide hydrogen through the reaction :reaction :

HH22OO2 2 + GSH GSSH +H+ GSH GSSH +H22O O

Also can be netralised by vit C, A and EAlso can be netralised by vit C, A and E

4. METABOLIC AGING THEORY4. METABOLIC AGING THEORY

From the experiment From the experiment it get a longer life it get a longer life span caused by the retriction of the calorie. span caused by the retriction of the calorie. It is caused by one of metabolism process It is caused by one of metabolism process increase insulin sensitivity, increase insulin sensitivity, neuroendocrine and immune responneuroendocrine and immune respon

The modification of under exercise to be The modification of under exercise to be more active will cause the longer life spanmore active will cause the longer life span

Calaric retriction Calaric retriction delayed growth and delayed growth and failure of sexual maturationfailure of sexual maturation

5. THE DAMAGE OF IMMUNE SYSTEM5. THE DAMAGE OF IMMUNE SYSTEM

The repeated mutation/ the changing protein post The repeated mutation/ the changing protein post translation translation decrease the immune system decrease the immune system decreased ability of self recognitiondecreased ability of self recognition

The somatic mutation The somatic mutation change antigen in the surface change antigen in the surface cell cell immune system treat the changing cell as a immune system treat the changing cell as a strange cell and destroy it strange cell and destroy it AUTO IMMUNE AUTO IMMUNE PROCESSPROCESS

All somatic cell will set aging process, except sexual All somatic cell will set aging process, except sexual cell & cancer cell. cell & cancer cell.

6. WEAR-AND-TEAR THEORY6. WEAR-AND-TEAR THEORY Supports the concept that aging is a Supports the concept that aging is a

programmed process. programmed process. each animal-each each animal-each cell, has a specific amount of metabolic cell, has a specific amount of metabolic energy available to it & that the rate at energy available to it & that the rate at whish this energy is used determines the whish this energy is used determines the animal’s length of life.animal’s length of life.

In addition to the depletion of available In addition to the depletion of available energy, wear-and-tear theories energy, wear-and-tear theories include include the effects of the accumulation of harmful by the effects of the accumulation of harmful by products of metabolism & of faulty enzymes products of metabolism & of faulty enzymes due to random errors as contributing to due to random errors as contributing to aging changesaging changes

MODEL MODEL HEALTHY AGINGHEALTHY AGING

Endogenic aging

Cellular Tisue Anatomical Organ

Environment Life Style

Exogenic factor

Healthy aging(menua sehat)

HEALTY AGING CONCEPTHEALTY AGING CONCEPT

““GERONTOLOGY IS GERONTOLOGY IS CONCERNED PRIMARILY CONCERNED PRIMARILY WITH PROBLEM OF WITH PROBLEM OF HEALTHY AGING HEALTHY AGING RATHER THAN THE RATHER THAN THE PREVENTION OF AGINGPREVENTION OF AGING” ”