M.

AryadiArsyad

CELL CYCLE
CELLCYCLE
Howaretheprocessesof
How are the processes of
proliferation,differentiation,
apoptosiscoordinated?
i
di
d?

Cell cycle
Cellcycle
Twomajorsub
divisions
Two major subdivisions
Mphaseandinterphase

MPhase:eventsofmitosis,nuclear
h
f i i
l
division

Interphase:allotherstagesofthecell
cycle
growthphasesG1andG2
S phase: DNA synthesis
Sphase:DNAsynthesis

Cell Cycle Check Points

CellCycleCheckPoints

Determination
Determination
Determinationdescribesthesituationwhere
Determination describes the situation where
thedevelopmentalstate(differentiated
phenotype) of a cell has been preset
phenotype)ofacellhasbeen
preset ,
howeverthecellhasyettodisplayanytraits
of the differentiated lineage
ofthedifferentiatedlineage

Differentiation
Differentiation
Regulatedprocessbywhichcellsgainand
Regulated process by which cells gain and
losespecialised characteristics:canbe
morphological and biochemical
morphologicalandbiochemical
Centralprocessintheformationof
specialised tissuesandorgans
tissues and organs

Determination and Differentiation

DeterminationandDifferentiation

Adipocyte differentiation

Rapid growth
Rapidgrowth

Predifferentiation
growtharrest

Nonterminal
differentiation

Terminal
differentiation

Apoptosis
Apoptosis
DNADamage(KerusakanDNA)
DNA Damage (Kerusakan DNA)
DNArepairimpair
Freeradicalandoxidation
Free radical and oxidation
MitochondrialDNA
Radiation
R di ti
Telomereshortening

Physiological changes
Physiologicalchanges

Neuralsystem
Neural system
Respiratorysystem
Cardiovascular system
Cardiovascularsystem
Digestivesystem
M
Musculoskeletalsystem
l k l t l t
Endocrinesystem
Reproductionsystem

Nervous system
Nervoussystem

Decreaseinbrainvolume
Decrease in brain volume
Lossofcellsincertainareas
Morphologiccellularchanges
h l i
ll l h
Changesinhormonalneurotransmitters
Synaptictransmissionslowswithage
Decrease in nerve conduction velocity
Decreaseinnerveconductionvelocity
Slowingofreactiontime

Impact
Impact
Brainatrophy
Brain atrophy
Declineinvisionandhearing
Impairmentofsmell,taste,touchandpain
i
f
ll
h d i
Lossofsensationsmayleadtodelaysin
seekingcare
Decreaseincognitiveabilities
g
Decreaseinmotorskillsorfrankparesisor
paralysis

Respiratory system
Respiratorysystem
ec ease u g capac ty
Decreaselungcapacity
Decreaserespiratoryvolume
Cough mechanism less efficient
Coughmechanismlessefficient
DecreaseoflocallyprotectiveIg Ainnasaland
respiratorymucosa
p
y
Decreaseinlaryngealprotectivereflex
p
Increaseriskofaspirationoforalsecretions
DecreaseinarterialO2contentwithnormal
breathing

Impact
Impact
Lungassociatedheartdisease
Lung associated heart disease
Muscleweaknesscancausebreathing
problems
COPD:emphysema,chronicbronchitis,
asthmaticbronchitis
h
i b
hi i

Cardivascular system
system

Lowcardiacoutput
Low cardiac output
Majorvalvular changes
Majorcinduction
j
i d i problems
bl
Differenceincoronaryarterydiseaseoutcome
Hypertensionrisk
Heart failure
Heartfailure

Gastrointestinal system
Gastrointestinalsystem

Atrophyofmucosa
Atrophy of mucosa
Decreasesecretionsofenzymes
Disorderedmotility
i d d
ili
Impairedabsorption
Increaseinneoplasias

Impact
Impact

Achalasia
Oesophagal spasm
Dysphagia
h i
Decreaseinvitamin&mineralabsorption
Decreasedetoxification
Increase incidence of gall stones
Increaseincidenceofgallstones

Musculoskeletal system
Musculoskeletalsystem
Highlimitationofactivitydueto
High limitation of activity due to
musculoskeletalproblems:muscleatrophy
Osteoporosisduetobonedecalcification
Osteoporosis due to bone decalcification
Degenerativejointdisease

Urogenitalia system

Decreaseinrenalblod
Decrease in renal blod flow
Decreaseintubularmass
DecreaseGFR
G
Decreasekidneymass
SlowingofpHmetabolicadjustment

Impact
Impact

Asymptomaticpyelonephritis
Asymptomatic pyelonephritis
Resistanturinarytractinfections
Prostatichypertrophy(male)
i h
h ( l )
Cystocele (female)

Endocrine system
Endocrinesystem
Decreaseintyroid
Decrease in tyroid production
Decreaseinadrenalhormoneproduction
Decreaseintestisandovaryprod
i
i
d
d

Impact
Impact
Menopause
Menopause
Andropause

Future projects
Futureprojects

MaladaptiveEffectsofSenescence
l d
ff
f
Physiologicaldisintegration:Progressive lossofhomeostasis;the
equilibriumbetweenfunctionsofdifferentbutinterdependent
elementsofanorganism.(PrimaryfocusofLongevityMedicine)
Intrinsic Disease:Progression ofphysiologicaldisintegration
increasesriskfordevelopmentofintrinsicdiseasesuchasdiabetes,
heart disease, osteoporosis, high blood pressure & stroke, etc.
heartdisease,osteoporosis,highbloodpressure&stroke,etc.
(PrimaryfocusofTraditionalMedicine)
Lethalgene
g
expression:Activation
p
ofgenesthatcauselethal
g
diseasessuchascertaincancers(oncogenes),Alzheimers,
Huntingtons,etc.thatinvariablykilltheorganism.(Focusof
TraditionalMedicine)

 Unlikelethalgeneexpression,physiological
disintegration is an expression of the aging
disintegrationisanexpressionoftheaging
processandthus,isonefocusofLongevity
Medicine Another focus is upon genetic
Medicine.Anotherfocusisupongenetic
expressionof theagingmechanismitself.

Theseinterventionfocideterminethe
hi h
i
di i h
extenttowhichLongevityMedicinehas
thepotentialtoprolonglifespan

1.Withinbiologicallimits(Determinatelife
extension)
t i )
2.Beyondbiologicallimits(Indeterminatelife
extension)

LimitsofLifeExtensionTherapies
f f
h
Extenttowhichlifecanbeextendeddepends
uponthetypeofclinicalinterventionthatis
employed
PhysiologicalInterventionhaspotentialtoachieve
Physiological
Intervention has potential to achieve
determinatelifeextension
GeneticInterventionhaspotentialtoachieve
indeterminatelifeextension

DeterminateorLimitedLifeExtension
Compensatesforphysiologicaldeclinethrough
replacementofessentialcompounds,lifestyle
changes, detoxification, neutralization of reactive
changes,detoxification,neutralizationofreactive
metabolites(contemporaryinterventionsinaging)
Doesnotaltermechanismforagingorprogressionof
senescence
Agerelateddecayofformandfunctionisnotabated,
althoughonsetofintrinsicdiseasemaybedelayed
causingmorbiditytobecompresseduntillateinlife
i
bidi
b
d
il l
i lif
anddeathdelayed
Maximumspeciesspecificlifespanisachieved
p
p
p

DeterminateorLimitedLifeExtension
d f

PreventionofIntrinsicDiseasecanExtendLife
toitsBiologicallyDeterminedLimitsSurvival
i Bi l i ll D
i d Li i S i l

IndeterminateorUnlimited
LifeExtension
f
Stopsorslowsexpressionofthegeneticmechanismthat
affectspersistentchangebeyondyoungadulthoodthat
resultsinsenescence(futureinterventionsinaging)
Physiologicalconsequencesofsenescenceareopposed
therebyslowingorpreventingonsetofintrinsicdisease
Frailtyanddecayofinternalorderthatcausesomatic
Frailty and decay of internal order that cause somatic
agingare slowedorstoppedresultinginpersistently
youthfulanatomy andphysiology.
Mortalityduetofrailtyandinfectionisdelayedor
Mortality due to frailty and infection is delayed or
preventedresultinginlifeextensionbeyondbiological
limits

IndeterminateorUnlimitedLife
Extension

Isthereanyevidencethat
Is
there any evidence that
indeterminatelifeextensionis
possible?

Yes!

GeneTherapyAllows
ExtensionofLife
Beyond Biologically
BeyondBiologically
DeterminedLimits

Indy(Imnotdeadyet)
geneencodesaNa+
dicarboxylatecotransporter
ofKrebscycles
intermediatestofacilitate
storageoffat,glycogen
andprotein
d
i
Metabolismandrateof
developmentand
maturationareslowedin
i
l
di
Indymutants

C ElegansLife ExtensionGenesIdentified
Extension Genes Identified
C.ElegansLife
CynthiaKenyon,PhD,
Fewyearsago,usingDNAmicroarraytechnology,Kenyon's
teamdiscoveredthatasinglemutationinthedaf2gene,
which encodes a hormone receptor similar to the human
whichencodesahormonereceptorsimilartothehuman
receptorsforinsulinandIGF1,stoppeddevelopment
resultinginapersistentlyimmatureanimal.Thesameor
related hormone pathways have since been shown to affect
relatedhormonepathwayshavesincebeenshowntoaffect
lifespaninfruitfliesandmice,andthereforemayinfluence
developmentandaginginhumansaswell.Herlabfound
thatdaf2affectslifespanthroughasecondgene,knownas
p
g
g
daf16,whosefunctionwasknowntocontrolthe
expressionofothergenes.

IIsthereanyreasontobelievethat
h
b li
h
thesefindingsarerelevanttohuman
g
beingsandforeveryoungcancome
true ?
true?

Hopefully!!!

this present
thispresent