Lecture 1
The human ageing population continues to increase. Detailed understanding of biology of
ageing and longevity is urgently needed survival rate increased throughout the years, but
then die within a short time.
Ageing = the total effect of those intrinsic changes that accumulate in the course of life that
negatively affect the vitality of the organism, and that makes it more susceptible to the
factors that cause death
Frailty = a measure for this increased vulnerability someone is “frail” when he or she has
more of the following: muscle weakness, slow waling speed, exhaustion, low physical activity
levels
Longevity = maximum lifespan and/or exceptionally long-life
Al er géén veroudering is, is de kans om dood te gaan
onafhankelijk van de chronologische leeftijd (blauw =
no ageing, rood = ageing).
Relationship between age and mortality rate.
The ageing process is characterised by a decline in
organismal functioning that makes the individual more susceptible to factors that cause
death.
Mortality is the sum of intrinsic and extrinsic factors:
mtotal=menvironment + mintrinsic
LET OP! Houdt rekening met de omgeving, om de intrinsieke veroudering zichtbaar te
maken.
There has been a transition from
mortality rates that are dominated
by external causes, to mortality
rates that are mainly caused by
internal causes hygiëne, betere
huisvesting, veiliger voedsel, gelijker
verdelen van rijkdom en welvaart.
Ageing is rare in natural populations
of organisms because external mortality sources (such as predation, starvation, accidents)
are much larger than the internal causes of mortality (i.e. ageing) full extent of ageing in a
population will become clear when most external death hazards are removed (in laboratory
conditions for example) lifespan becomes greatly extended.
1
,So ageing in nature is rare extrinsic mortality dominates. Ageing becomes visible when
extrinsic mortality is (largely) removed. DUS: Ageing is largely a unique human problem in
natural environments.
Lifespan seems to be under genetic control, while at the same time accumulation of
damage undoubtedly contributes to increased mortality rates.
Why do we age?
Ageing limits the reproductive potential of an individual and should be opposed by natural
selection accumulation of damage in molecules, cells and tissues over the total lifetime of
an organism diminishes capacity of organism to maintain homeostasis under stressful
environments greater risk for many complex and common diseases and premature
mortality.
Cell senescence = accumulation of DNA damage and epigenetic changes in DNA structure
that affect correct gene expression and lead to altered cell function
Progerias = a group of diseases characterized by a premature aging phenotype and
are a model for studying aging-associated genetic changes develop features of
accelerated aging caused by mutations in genes implicated in genetic stability.
Premature senescence (gray hair, atherosclerosis, increased risk of cancer), skin
changes (atrophy, ulcer, hyperkeratosis), metabolic disorders (diabetes,
hyperlipidemia) and senile dementia.
There is little to distinguish biological ageing from a disease state 3 goals for treatment
for ageing:
Compressed morbidity: develop cures that protect against illnesses later in life
without dealing with the underlying ageing process (improve health among elderly
without any major extension of lifespan and a reduction of the period of disability
experienced by elderly people) only make sense if ageing and age-related disease
are clearly distinguishable (mostly not the case)
Arrested ageing: involves stopping ageing entirely, or even reversing it (not possible
with current knowledge)
Decelerated ageing: slow ageing is possible!
LET OP! However, ageing can still not be considered as a disease. But here the evolutionary
theory may help according to the evolutionary theory, ageing = consequence of a
reduction in the force of selection against mutations with deleterious effects later in life
leads to accumulation within populations of alleles with deleterious effects later in life.
2
,Evolutionary explanation
Zelfs als een organisme intrinsiek onsterfelijk is, heeft het een niet-nulkans om te overlijden
vanwege extrinsieke oorzaken zoals verhongering, predatie en ongelukken
overlevingskans neemt in de loop van het leven af, en aangezien natuurlijke selectie alleen
effectief is via de reproductieve output van overlevende individuen, neemt de kracht van
natuurlijke selectie af met de leeftijd.
LET OP! De kracht van natuurlijke selectie neemt af met de leeftijd, zelfs zonder veroudering.
Dit komt door 2 mogelijke scenario’s:
1. Mutaties met specifieke effecten op late leeftijd zijn onderhevig aan zwakkere
selectie dan mutaties met specifieke effecten op jonge leeftijd laatwerkende
schadelijke mutaties kunnen moeilijk worden verwijderd; individuen hebben zich
gereproduceerd voordat ze die dergelijke mutaties dragen vallen in selectie
schaduw
2. Genen met gunstige effecten op fitheid op jonge leeftijd, maar nadelige effecten op
fitheid op latere leeftijd, worden geselecteerd vanwege de afnemende kracht van
natuurlijke selectie met de leeftijd
Antagonistic pleiotropy (AP) of ageing veroudering is geëvolueerd als een
bijproduct van natuurlijke selectie voor gunstige effecten op de vroege
reproductieve output
Disposable soma (DS) theory legt nadruk op wisselwerking tussen
reproductie en somatisch herstel en onderhoud
(A) Survival (lx) and reproductive rate
(mx), and (B) the probability of
reproduction and proportion of
reproduction remaining for an individual
aged x, for a hypothetical non-ageing
population. The probability of
reproduction at age x, is taken as the
product of lx and mx. The proportion of
reproduction remaining can be taken as a
measure for the strength of natural
selection at age x. It appears that the
strength of natural selection declines with
age even in the absence of ageing. Genes
can escape the scrutiny of natural
selection if their effects occur in the
selection shadow.
3
, What explains variation in lifespan and ageing?
De kans om dood te gaan is enorm gedaald “72 is the new 30”. Een 72 jarige nu heeft
dezelfde overlevingskans dan een 30 jarige in 1750.
Mortality reduction has been experienced by only about 4 of the roughly 8000 human
generations thus, increase achieved by environmental changes! However, variation in
lifespan and ageing is still there.
Factors that influence ageing:
Environment
Stochasticity (= the quality of lacking any predictable order or plan)
Genetics
What is the relationship between disease
and ageing? Er zijn 3 mogelijke scenario’s:
Raakvlakken tussen de 3
processen, maar ook verschillend
(meest waarschijnlijk)
Veroudering en ziekte zijn 2
verschillende processen.
Gezond ouder worden staat apart
van snelle veroudering en ziek
worden.
Is ageing a programmed process? Genetische factoren hoeft niet te resulteren in een vast
geprogrammeerd programma. Stochasticiteit is een
sterk element speelt door de geprogrammeerde
programma’s van genetics heen.
Stochatsticiteit = fluctuaties in fysische,
chemische, biologische en ecologische
processen als gevolg van de natuurlijke
variabiliteit en inherente willekeurigheid
Accumulation of damage Genetic control
Stochastic Variation
Irreversile Death rate reversible
These two sides are in contrast to each other. Genetic controle, is the more optimistic side,
because this could be influenced by science.
4
The human ageing population continues to increase. Detailed understanding of biology of
ageing and longevity is urgently needed survival rate increased throughout the years, but
then die within a short time.
Ageing = the total effect of those intrinsic changes that accumulate in the course of life that
negatively affect the vitality of the organism, and that makes it more susceptible to the
factors that cause death
Frailty = a measure for this increased vulnerability someone is “frail” when he or she has
more of the following: muscle weakness, slow waling speed, exhaustion, low physical activity
levels
Longevity = maximum lifespan and/or exceptionally long-life
Al er géén veroudering is, is de kans om dood te gaan
onafhankelijk van de chronologische leeftijd (blauw =
no ageing, rood = ageing).
Relationship between age and mortality rate.
The ageing process is characterised by a decline in
organismal functioning that makes the individual more susceptible to factors that cause
death.
Mortality is the sum of intrinsic and extrinsic factors:
mtotal=menvironment + mintrinsic
LET OP! Houdt rekening met de omgeving, om de intrinsieke veroudering zichtbaar te
maken.
There has been a transition from
mortality rates that are dominated
by external causes, to mortality
rates that are mainly caused by
internal causes hygiëne, betere
huisvesting, veiliger voedsel, gelijker
verdelen van rijkdom en welvaart.
Ageing is rare in natural populations
of organisms because external mortality sources (such as predation, starvation, accidents)
are much larger than the internal causes of mortality (i.e. ageing) full extent of ageing in a
population will become clear when most external death hazards are removed (in laboratory
conditions for example) lifespan becomes greatly extended.
1
,So ageing in nature is rare extrinsic mortality dominates. Ageing becomes visible when
extrinsic mortality is (largely) removed. DUS: Ageing is largely a unique human problem in
natural environments.
Lifespan seems to be under genetic control, while at the same time accumulation of
damage undoubtedly contributes to increased mortality rates.
Why do we age?
Ageing limits the reproductive potential of an individual and should be opposed by natural
selection accumulation of damage in molecules, cells and tissues over the total lifetime of
an organism diminishes capacity of organism to maintain homeostasis under stressful
environments greater risk for many complex and common diseases and premature
mortality.
Cell senescence = accumulation of DNA damage and epigenetic changes in DNA structure
that affect correct gene expression and lead to altered cell function
Progerias = a group of diseases characterized by a premature aging phenotype and
are a model for studying aging-associated genetic changes develop features of
accelerated aging caused by mutations in genes implicated in genetic stability.
Premature senescence (gray hair, atherosclerosis, increased risk of cancer), skin
changes (atrophy, ulcer, hyperkeratosis), metabolic disorders (diabetes,
hyperlipidemia) and senile dementia.
There is little to distinguish biological ageing from a disease state 3 goals for treatment
for ageing:
Compressed morbidity: develop cures that protect against illnesses later in life
without dealing with the underlying ageing process (improve health among elderly
without any major extension of lifespan and a reduction of the period of disability
experienced by elderly people) only make sense if ageing and age-related disease
are clearly distinguishable (mostly not the case)
Arrested ageing: involves stopping ageing entirely, or even reversing it (not possible
with current knowledge)
Decelerated ageing: slow ageing is possible!
LET OP! However, ageing can still not be considered as a disease. But here the evolutionary
theory may help according to the evolutionary theory, ageing = consequence of a
reduction in the force of selection against mutations with deleterious effects later in life
leads to accumulation within populations of alleles with deleterious effects later in life.
2
,Evolutionary explanation
Zelfs als een organisme intrinsiek onsterfelijk is, heeft het een niet-nulkans om te overlijden
vanwege extrinsieke oorzaken zoals verhongering, predatie en ongelukken
overlevingskans neemt in de loop van het leven af, en aangezien natuurlijke selectie alleen
effectief is via de reproductieve output van overlevende individuen, neemt de kracht van
natuurlijke selectie af met de leeftijd.
LET OP! De kracht van natuurlijke selectie neemt af met de leeftijd, zelfs zonder veroudering.
Dit komt door 2 mogelijke scenario’s:
1. Mutaties met specifieke effecten op late leeftijd zijn onderhevig aan zwakkere
selectie dan mutaties met specifieke effecten op jonge leeftijd laatwerkende
schadelijke mutaties kunnen moeilijk worden verwijderd; individuen hebben zich
gereproduceerd voordat ze die dergelijke mutaties dragen vallen in selectie
schaduw
2. Genen met gunstige effecten op fitheid op jonge leeftijd, maar nadelige effecten op
fitheid op latere leeftijd, worden geselecteerd vanwege de afnemende kracht van
natuurlijke selectie met de leeftijd
Antagonistic pleiotropy (AP) of ageing veroudering is geëvolueerd als een
bijproduct van natuurlijke selectie voor gunstige effecten op de vroege
reproductieve output
Disposable soma (DS) theory legt nadruk op wisselwerking tussen
reproductie en somatisch herstel en onderhoud
(A) Survival (lx) and reproductive rate
(mx), and (B) the probability of
reproduction and proportion of
reproduction remaining for an individual
aged x, for a hypothetical non-ageing
population. The probability of
reproduction at age x, is taken as the
product of lx and mx. The proportion of
reproduction remaining can be taken as a
measure for the strength of natural
selection at age x. It appears that the
strength of natural selection declines with
age even in the absence of ageing. Genes
can escape the scrutiny of natural
selection if their effects occur in the
selection shadow.
3
, What explains variation in lifespan and ageing?
De kans om dood te gaan is enorm gedaald “72 is the new 30”. Een 72 jarige nu heeft
dezelfde overlevingskans dan een 30 jarige in 1750.
Mortality reduction has been experienced by only about 4 of the roughly 8000 human
generations thus, increase achieved by environmental changes! However, variation in
lifespan and ageing is still there.
Factors that influence ageing:
Environment
Stochasticity (= the quality of lacking any predictable order or plan)
Genetics
What is the relationship between disease
and ageing? Er zijn 3 mogelijke scenario’s:
Raakvlakken tussen de 3
processen, maar ook verschillend
(meest waarschijnlijk)
Veroudering en ziekte zijn 2
verschillende processen.
Gezond ouder worden staat apart
van snelle veroudering en ziek
worden.
Is ageing a programmed process? Genetische factoren hoeft niet te resulteren in een vast
geprogrammeerd programma. Stochasticiteit is een
sterk element speelt door de geprogrammeerde
programma’s van genetics heen.
Stochatsticiteit = fluctuaties in fysische,
chemische, biologische en ecologische
processen als gevolg van de natuurlijke
variabiliteit en inherente willekeurigheid
Accumulation of damage Genetic control
Stochastic Variation
Irreversile Death rate reversible
These two sides are in contrast to each other. Genetic controle, is the more optimistic side,
because this could be influenced by science.
4
