Midterm Distribution

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Midterm Distribution

• Mean 74.00
• N 68

Frequency ()
Grade ()
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Outline of Lectures on Ageing

• Evolutionary Tradeoffs Evolution of Ageing
• Cancer a Disease of Ageing
• Molecular Mechanisms of Ageing, and Mitigating
  its Effects (Sirtuins)

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Evolutionary and Mechanistic Theories of Ageing
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Questions from Reading

• Hughes, K. A. and Reynolds, R. M. 2005.
  Evolutionary and mechanistic theories of aging.
  Annual Review of Entomology. 50 421-445.
• Q What are some proposed evolutionary causes of
  ageing?
• Q What are some physiological mechanisms of
  ageing?
• Q How might selection act on a population to
  increase lifespan?

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Evolutionary Costs or Tradeoffs Ageing is an
example

• Adaptation is not perfect
• There is often a cost, and there are often
  tradeoffs
• One example of such a cost or tradeoff is Ageing

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What is ageing?

• Senescence decline in performance and fitness
  with advancing age

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Basic Evolutionary Concepts

• Natural Selection
• Pleiotropy
• Antagonistic Pleiotropy
• Evolutionary Tradeoffs

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Darwins Contribution

• Natural Selection

• Too many offspring are produced
• Limited resources and competition
• Variation in a population
• Better adapted individuals survive
• Survivors leave more offspring (fitness)
• Thus, the average composition of the population
  is altered
• Natural selection leads to adaptation

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• Population speciation through Natural Selection

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Mutation
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This mutation happens to be beneficial
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Individuals with this mutation happen to leave
more offspring (greater fitness)
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Ageing is not Universal

• Bacteria do not age they simply grow and divide
• Multicellular organisms tend to age and die
• Organisms that reproduce early in life are the
  ones that age faster

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Outline

• Evolutionary causes
• (WHY did it evolve?)
• Mechanistic causes
• (HOW does it occur? What physiological changes
  occur?)

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Outline

• Evolutionary causes (WHY)
• Mutational Accumulation
• Antagonistic Pleiotropy
• Disposable Soma
• Mechanistic causes (HOW)
• Oxidative Stress
• Other types of Stress
• Signal transduction pathways
• Role of Diet

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Causes of Ageing

• There might not be any adaptive reason for an
  individual to age
• It could be a tragic by-product of natural
  selection weakening with age
• Natural selection would act to reduce
  physiological damage
• Cellular ageing and death might occur to prevent
  excessive cell proliferation in multicellular
  organisms (discuss next time in lecture on
  evolution and cancer)

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• Evolutionary Causes
• Senescence occurs because the force of natural
  selection declines with age in populations that
  have age structure (individuals of different
  ages)
• Selection acts differently on different age
  groups (more effective before reproduction,
  declines with age)

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• Why would the action of natural selection weaken
  with age?
• Because natural selection acts
  deterministically individuals die for a reason
  selection acts when more adapted individuals have
  a greater probability of surviving and leaving
  offspring

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• Why would the action of natural selection weaken
  with increasing age?
• With increasing age, extrinsic mortality
  increases, that is death from random causes
  (accidents, non-age specific diseases, etc).
• These random deaths weaken the effect of natural
  selection (as deaths need to be caused by
  nonrandom forces for selection to act)
• Natural selection is less efficient when deaths
  are random, and not due to particular
  genetically-determined traits

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• So, as Natural Selection weakens with age (due to
  extrinsic mortality), traits that are harmful
  later in life do not get weeded out of the
  population
• Negative traits accumulate later in life

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Evolutionary Mechanisms

• General Model The ultimate evolutionary cause
  of aging is extrinsic mortality (WD Hamilton,
  1966)
• The hypothesized mechanisms by which ageing could
  evolve include
• Mutational Accumulation
• Antagonistic Pleiotropy
• Disposable Soma

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Evolutionary Mechanisms

• General Model The ultimate evolutionary cause
  of aging is extrinsic mortality (WD Hamilton,
  1966)
• The hypothesized mechanisms by which extrinsic
  mortality (i.e. ineffective selection) causes
  ageing to evolve include
• Mutational Accumulation
• Due to ineffective selection later in life,
  deleterious mutations accumulate
• Antagonistic Pleiotropy
• Mutations that are favored by selection early in
  life, might be harmful later, but selection is
  ineffective later in life
• Disposable Soma
• Selection early in life favors reproduction,
  ineffective selection later in life will not
  favor maintenance and repair

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• The reduction in natural selection later in life
  (due to extrinsic mortality, i.e. random deaths)
  might result in aging due to
• Mutational accumulation
• Antagonistic pleiotropy
• Disposable Soma
• That is, ineffective selection later in life
  might lead to senescence (ageing) due to one of
  the mechanisms above.

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(1) Mutational AccumulationMedawar (1952)

• Deleterious mutations expressed at a young age
  are severely selected against, due to their high
  negative impact on fitness (number of offspring
  produced).
• On the other hand, deleterious mutations
  expressed only later in life are neutral to
  selection, because their bearers have already
  transmitted their genes to the next generation.
• Because genes have already been passed on,
  selection is weaker later in life, and thus
  mutations accumulate, and the negative effects
  are manifested as ageing.

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(2) Antagonistic PleiotropyWilliams (1957)

• Pleiotropy phenomenon where a gene affects
  several different traits
• Antagonistic Pleiotropy where a gene has a
  positive effect on one trait but a negative
  effect on another trait (example a gene that
  increases heat tolerance but reduces cold
  tolerance)
• Antagonistic Pleiotropy Theory of Aging
  Mutations that are beneficial early in life
  (before reproduction), but are deleterious later
  in life do not get selected out of a population
  because selection is less efficient later in life
• Antagonistic pleiotropy could leads to
  evolutionary trade-offs (sometimes between
  fecundity and longevity)

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Pleiotropy when a gene affects many traits or
functions
Gene Network

• Selection might not be able to act on trait if
  the gene that codes it also affects many other
  traits, and the change negatively affects the
  other traits

• Conversely, a seemingly unbeneficial trait might
  get selected for because the gene that codes for
  it also enhances fitness

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• Antagonistic Pleiotropy could lead to
  evolutionary tradeoffs such as
• Degeneration during Aging A trait that is
  beneficial early in life might be deleterious
  (bad) later in life

Or Not.
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• Antagonistic Pleiotropy Theory of Aging
  Mutations that are beneficial early in life
  (before reproduction) will be selected for even
  if they are deleterious later in life

Adult reproduction
Post reproduction
Birth
Juvenile
Death
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• Antagonistic Pleiotropy Theory of Aging
  Mutations that are beneficial early in life
  (before reproduction) will be selected for even
  if they are deleterious later in life

Adult reproduction
Post reproduction
Birth
Juvenile
Death

• Genes that affect reproduction early in life
  might have negative health effects later in life
• Example high estrogen -gt high fecundity when
  young, but increased chance of breast cancer
  later in life tradeoffs between fecundity and
  ageing

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(3) Disposable Soma (a special case of
antagonist pleiotropy)

• Somatic maintenance and repair are metabolically
  costly
• Metabolic resources devoted to reproduction are
  not available for maintenance and repair
  (tradeoff between reproduction vs repair)
• Selective advantage to devote resources to
  reproduction and allocate just enough somatic
  maintenance to keep the organism alive and good
  enough condition for as long as needed (for
  fitness of offspring)
• Senescence results from accumulation of
  unrepaired somatic damage

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Tests of Theories

• Effect of extrinsic mortality --gt ineffective
  selection --gt
• Role of mutation accumulation
• Role of Antagonistic Pleiotropy

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Tests of Theories

• Effect of extrinsic mortality
• Prediction if extrinsic mortality is reduced
  and natural selection could act on a population,
  the rate of aging should go down
• Evidence
• Organisms in low-risk environments age more
  slowly
• Artificial experiments that selectively bred
  older individuals, allowing natural selection to
  act at later life stages, increased life span
  (cited in Hughes p. 426)

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Tests of Theories

• Role of Mutation Accumulation
• Prediction because of the accumulation of
  deleterious mutations (most of which will be
  recessive), inbreeding depression (due to
  homozygous recessive alleles coming together)
  should increase with age. Genetic variance and
  dominance variance should also increase (because
  of the new recessive mutations)
• Evidence see Hughes, p. 427. A few studies
  support this prediction. Further studies are
  needed to conclusively test this hypothesis.

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Tests of Theories

• Role of Antagonistic Pleiotropy
• Prediction selection on enhanced late life
  reproduction should select against early-life
  reproduction
• Evidence see Hughes, p. 427. Several studies
  support this prediction

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Test of Theories

• Based on current evidence, it appears nearly
  certain that antagonist pleiotropy is a cause of
  senescence, while mutation accumulation likely
  contributes

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Mechanistic Causes of Ageing

• How does ageing occur (physiologically)?
• We talked about deleterious mutations
  accumulating-and not getting selected out (via MA
  and AP) what mutations are accumulating? Which
  traits are affected by mutations? Which traits
  are experiencing tradeoffs?
• Hundreds of theories
• Oxidative Stress
• Other types of Stress
• Signal transduction pathways
• Role of Diet

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Mechanistic Causes

• Oxidative Stress
• Other types of Stress
• Signal transduction pathways
• Role of Diet (not well understood)
• dietary restriction and lifespan

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Mechanistic Causes

• Oxidative Stress
• Ageing is a consequence of cellular damage caused
  by reactive oxygen species (ROS)
• ROS generation in animals occurs mainly within
  mitochondria, where more than 90 of oxygen used
  by cells is consumed (as an electron acceptor
  during respiration)

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Production of Free Radicals

• Electrons escape from the electron transport
  chain
• These electrons latch on to oxygens, creating
  superoxides and peroxides
• These free radicals causes cellular damage

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• Several enzymes (antioxidants) such as superoxide
  dismutase (SOD) and Catalase (CAT) will convert
  the free radicals into less harmful products

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• Evolution at genes that code for these enzymes
  have been found

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• Tests of the Oxidative Stress Theory
• Artificial selection experiment selection for
  late life reproduction in Drosophila resulted in
  populations with increased life span and
  increased resistance to oxidative stress.
  Selection acted to increase gene expression of
  SOD or CAT genes
• Transgenic experiment overexpression of SOD
  genes resulted in lifespan increases (Table 1,
  next slide)

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Transgenic and mutant studies that examined
effects of over-expression of single genes on
Lifespan
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Evolutionary changes that would mitigate
Oxidative Stress

• Evolution of genes that mitigate oxidative stress
  (SOD, CAT)
• Reduce damage by reducing amount of ROS (free
  radical) production
• Increase respiration efficiency
• Repair of oxidative damage (Example methionine
  sulfoxide reductase--increased gene expression
  led to longer lifespan)

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Mechanistic Causes

• Oxidative Stress
• Other types of Stress
• Signal transduction pathways
• Dietary restriction and lifespan

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• Mutations in signal transduction pathways were
  found to extend lifespan in yeast, C. elegans,
  and D. melanogaster
• Insulin signaling pathway mutations that
  decrease signaling through this pathway lead to
  increased longevity (and sometimes
  nonreproductive-- tradeoff)

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Mechanistic Causes

• Oxidative Stress
• Other types of Stress
• Signal transduction pathways
• Dietary restriction and lifespan
• (talk about this in the next lecture when I
  discuss sirtuins)

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Role of Diet

• Dietary restriction (DR) has been found to
  increase life span in many organisms
• Caloric Reduction by 30 greatly increases
  lifespan
• Mechanism is not fully understood
• HYPOTHESIS DR affects insulin/IGF pathway that
  regulates a trade-off between fecundity and
  longevity

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