Lecture 1 – Theories and Evolution of Ageing
Ageing a unique problem
-The human ageing population continues to increase: understanding of biology of aging en longevity.
-Ageing: total effect of intrinsic changes that accumulate in the course of life that negatively affect
The vitality of the organism and that makes it more susceptible to factors that cause death.
-Complex, gradual process: affects many systems with an accumulation of damage.
-Mortality: m(total) = m(environment) + m(intrinsic factors).
-Decreasing environmental mortality reveals ageing in humans as well.
-Ageing in natural settings is quite rare because extrinsic mortality dominates.
-Ageing therefore becomes visible when extrinsic mortality is (largely) removed.
-So ageing is largely a unique human problem in natural environments -> neg effects of it.
-So variation in lifespan and ageing is explained by environmental changes. (only 4 out of 8000
human generation experienced mortality reduction which rules out genetics as explanation).
-Senescence: changes that are deteriorative and cause increased mortality.
Identifying the main questions
-Why do we age?
-Is ageing beneficial?
-Why is the integrity of the soma not maintained?
-Species-specific longevities have a genetic basis and ability to avoid or cope with internal
And external damage has evolved
-What explains variation in lifespan?
-Cell senescence as consequence of gradual accumulation of DNA damage and epigenetic
Changes in DNA that affects correct gene expression and leads to altered cell function.
-What are the factors that influence ageing?
-Genetic, environmental and stochasticity. Which all interact with each other.
-What is the relationship between disease and ageing?
-Is ageing a programmed process?
Evolutionary theories of ageing
-Key traits: reproduction and survival: determine the strength of natural selection.
-From individual perspective, ageing is not good. For group survival it is.
-MA theory: ageing is consequence of reduction in force of selection against mutations
With deleterious effects in life -> leads to accumulation of alleles particularly in reproduction.
-Mutations with deleterious effects on survival and fertility early in life will be swiftly
eliminated from the population, late-acting mutations not since most of these individuals will
have reproduced before these mutations have the chance to take effect -> course of
evolution, extrinsic mortality is reduced -> now the late-acting deleterious mutations are
visible.
-Natural selection: maximal reproductive output with the natural lifespan.
-Strong early in life, very weak later in life -> leads to selection shadow.
-Constraining environmental mortality has exposed this life in the selection shadow.
-AP theory: genes with beneficial effects on fitness early in live, but detrimental effects on fitness
late in life are selected because of the diminishing power of NS with age -> so ageing has
evolved as by-product of natural selection for beneficial effects on early reproductive output.
-DS theory: trade-off between reproduction and somatic repair and maintenance.
-Evolutionary theories explain origin of ageing: immortality of soma is sacrifice for reproduction.
-Balance between reproduction and survival.
, -Ageing is non-adaptive and mechanisms evolved via two main routes:
-Public – shared: strong selection for early life fitness at the expense of late-life health,
Late-life consequences, selection for genes with antagonistic pleotropic effects,
Common principles: public phenotypes and mechanisms.
-Shared across species (AP and DS theory).
-Private – Unique: lack of selection late-life, no early-life consequences, accumulation of
Deleterious mutations with late-life effects, contingency: private phenotypes.
-Mechanisms specific to particular species or lineages of species. (MA theory)
From theory to experiments
-Is ageing a universal property of life in multicellular organisms?
-If there is an increase in reproduction with age -> organisms are larger -> intensity of
selection may decrease slower as possible or even increase again -> no ageing signs.
-Greenland shark and ocean quahog.
-How the decreasing power of natural selection with age relates to the genetics of ageing?
-Two groups of fruit flies: ER and LR
-If AP is correct we select for longer lived individuals -> less ER.
-If ER: no cost early in life = same rep rate early in life = MA theory correct.
-Interesting: adding females later to males show mating is risky.
-Adding females = quick decrease in survival rate: mating = energy cost.
-So lifespan can only be increased at the expense of reproduction.
Lecture 2 – Mechanisms and Pathways of Ageing
Experiments to mechanisms
“Dauer” genes in C. elegans: normal life <-> in extreme environment Dauer state.
o Dauer mutants (age-1 mutation) have a much longer life span but reproduce less =
trade-off according to y-shaped model.
o Either somatic precursor and Germ-line precursor cells (reproductive cells).
o Check the slide of daf-2 mammalian insulin receptor homologue.
When germ-line cells are disabled = long life span = Dauer mutants.
Y-shaped model of trade-off: Resource -> acquisition -> Allocation of either more trait 1 or 2.
o Maintenance repair or Reproduction for example due to natural selection.
Insulin/IGF signalling pathway regulates the life history by integrating external and internal
signals of nutritional status.
Chico mutant lives longer then wild-type. However the benefit of the mutant depends on
the environment in which the organisms live. For example food. (slide 26).
Why are life span mutants not selected in nature? : move away from culture vial and petri.
Ageing and longevity are determined by genetic & environmental factors + their interaction.
o Variation in lifespan and ageing in humans due to thrifty genotype:
1). Evolutionary mismatch: our genomes are expressed in environments
they were not adapted to through natural selection (HW babies).
2). Developmental mismatch: predictive adaptive responses +
developmental origin of health and disease. (PAR + DOHAD).
Ageing a unique problem
-The human ageing population continues to increase: understanding of biology of aging en longevity.
-Ageing: total effect of intrinsic changes that accumulate in the course of life that negatively affect
The vitality of the organism and that makes it more susceptible to factors that cause death.
-Complex, gradual process: affects many systems with an accumulation of damage.
-Mortality: m(total) = m(environment) + m(intrinsic factors).
-Decreasing environmental mortality reveals ageing in humans as well.
-Ageing in natural settings is quite rare because extrinsic mortality dominates.
-Ageing therefore becomes visible when extrinsic mortality is (largely) removed.
-So ageing is largely a unique human problem in natural environments -> neg effects of it.
-So variation in lifespan and ageing is explained by environmental changes. (only 4 out of 8000
human generation experienced mortality reduction which rules out genetics as explanation).
-Senescence: changes that are deteriorative and cause increased mortality.
Identifying the main questions
-Why do we age?
-Is ageing beneficial?
-Why is the integrity of the soma not maintained?
-Species-specific longevities have a genetic basis and ability to avoid or cope with internal
And external damage has evolved
-What explains variation in lifespan?
-Cell senescence as consequence of gradual accumulation of DNA damage and epigenetic
Changes in DNA that affects correct gene expression and leads to altered cell function.
-What are the factors that influence ageing?
-Genetic, environmental and stochasticity. Which all interact with each other.
-What is the relationship between disease and ageing?
-Is ageing a programmed process?
Evolutionary theories of ageing
-Key traits: reproduction and survival: determine the strength of natural selection.
-From individual perspective, ageing is not good. For group survival it is.
-MA theory: ageing is consequence of reduction in force of selection against mutations
With deleterious effects in life -> leads to accumulation of alleles particularly in reproduction.
-Mutations with deleterious effects on survival and fertility early in life will be swiftly
eliminated from the population, late-acting mutations not since most of these individuals will
have reproduced before these mutations have the chance to take effect -> course of
evolution, extrinsic mortality is reduced -> now the late-acting deleterious mutations are
visible.
-Natural selection: maximal reproductive output with the natural lifespan.
-Strong early in life, very weak later in life -> leads to selection shadow.
-Constraining environmental mortality has exposed this life in the selection shadow.
-AP theory: genes with beneficial effects on fitness early in live, but detrimental effects on fitness
late in life are selected because of the diminishing power of NS with age -> so ageing has
evolved as by-product of natural selection for beneficial effects on early reproductive output.
-DS theory: trade-off between reproduction and somatic repair and maintenance.
-Evolutionary theories explain origin of ageing: immortality of soma is sacrifice for reproduction.
-Balance between reproduction and survival.
, -Ageing is non-adaptive and mechanisms evolved via two main routes:
-Public – shared: strong selection for early life fitness at the expense of late-life health,
Late-life consequences, selection for genes with antagonistic pleotropic effects,
Common principles: public phenotypes and mechanisms.
-Shared across species (AP and DS theory).
-Private – Unique: lack of selection late-life, no early-life consequences, accumulation of
Deleterious mutations with late-life effects, contingency: private phenotypes.
-Mechanisms specific to particular species or lineages of species. (MA theory)
From theory to experiments
-Is ageing a universal property of life in multicellular organisms?
-If there is an increase in reproduction with age -> organisms are larger -> intensity of
selection may decrease slower as possible or even increase again -> no ageing signs.
-Greenland shark and ocean quahog.
-How the decreasing power of natural selection with age relates to the genetics of ageing?
-Two groups of fruit flies: ER and LR
-If AP is correct we select for longer lived individuals -> less ER.
-If ER: no cost early in life = same rep rate early in life = MA theory correct.
-Interesting: adding females later to males show mating is risky.
-Adding females = quick decrease in survival rate: mating = energy cost.
-So lifespan can only be increased at the expense of reproduction.
Lecture 2 – Mechanisms and Pathways of Ageing
Experiments to mechanisms
“Dauer” genes in C. elegans: normal life <-> in extreme environment Dauer state.
o Dauer mutants (age-1 mutation) have a much longer life span but reproduce less =
trade-off according to y-shaped model.
o Either somatic precursor and Germ-line precursor cells (reproductive cells).
o Check the slide of daf-2 mammalian insulin receptor homologue.
When germ-line cells are disabled = long life span = Dauer mutants.
Y-shaped model of trade-off: Resource -> acquisition -> Allocation of either more trait 1 or 2.
o Maintenance repair or Reproduction for example due to natural selection.
Insulin/IGF signalling pathway regulates the life history by integrating external and internal
signals of nutritional status.
Chico mutant lives longer then wild-type. However the benefit of the mutant depends on
the environment in which the organisms live. For example food. (slide 26).
Why are life span mutants not selected in nature? : move away from culture vial and petri.
Ageing and longevity are determined by genetic & environmental factors + their interaction.
o Variation in lifespan and ageing in humans due to thrifty genotype:
1). Evolutionary mismatch: our genomes are expressed in environments
they were not adapted to through natural selection (HW babies).
2). Developmental mismatch: predictive adaptive responses +
developmental origin of health and disease. (PAR + DOHAD).
