Transcript Lecture PPT - Carol Lee Lab

Midterm Distribution
25
Frequency (#)
20
Mean = 74.00
15
N = 68
10
5
0
90-100 80-90
70-80
60-70
Grade (%)
50-60
<50
Outline of Lectures on Ageing
Evolutionary Tradeoffs: Evolution of Ageing
Cancer: a Disease of Ageing
Molecular Mechanisms of Ageing, and Mitigating its Effects
(Sirtuins)
Evolutionary and Mechanistic
Theories of Ageing
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?
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
What is ageing?
Senescence: decline in performance
and fitness with advancing age
Basic Evolutionary Concepts
Natural Selection
Pleiotropy
Antagonistic Pleiotropy
Evolutionary Tradeoffs
Darwin’s Contribution:
Natural Selection
• Too many offspring are produced
• Limited resources and competition
• Variation in a population
• Better adapted individuals survive
“Of course, long before you mature,
most of you will be eaten”
• Survivors leave more offspring (“fitness)
• Thus, the average composition of the population is altered
• Natural selection leads to adaptation
“Population speciation through
Natural Selection”
Mutation
This mutation
happens to be
beneficial
Individuals with this mutation
happen to leave more offspring
(greater “fitness”)
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
Outline
• Evolutionary causes
(WHY did it evolve?)
• Mechanistic causes
(HOW does it occur? What physiological
changes occur?)
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
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)
• 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)
• 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
• 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
• 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
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
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
• 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.
(1) Mutational Accumulation
Medawar (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.
(2) Antagonistic Pleiotropy
Williams (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)
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
• 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….
• 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
Birth Juvenile
Adult
reproduction
Post
reproduction
Death
• 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
Birth Juvenile
Adult
reproduction
Post
reproduction
Death
• Genes that affect reproduction early in life might have
negative health effects later in life
• Example: high estrogen -> high fecundity when young,
but increased chance of breast cancer later in life;
tradeoffs between fecundity and ageing
(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
Tests of Theories
• Effect of extrinsic mortality -->
ineffective selection -->
– Role of mutation accumulation
– Role of Antagonistic Pleiotropy
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)
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.
Tests of Theories
– Role of Antagonistic Pleiotropy
– Prediction: selection on enhanced late life
reproduction should select against earlylife reproduction
– Evidence: see Hughes, p. 427. Several
studies support this prediction
Test of Theories
• Based on current evidence, it appears
nearly certain that antagonist pleiotropy
is a cause of senescence, while
mutation accumulation likely contributes
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
Mechanistic Causes:
• Oxidative Stress
• Other types of Stress
• Signal transduction pathways
• Role of Diet (not well understood)
– dietary restriction and lifespan
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)
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
Several enzymes (antioxidants) such
as superoxide dismutase (SOD) and
Catalase (CAT) will convert the free
radicals into less harmful products
Evolution at genes that code for these
enzymes have been found
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)
Transgenic and mutant studies that examined effects
of over-expression of single genes on Lifespan
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)
Mechanistic Causes:
•
•
•
•
Oxidative Stress
Other types of Stress
Signal transduction pathways
Dietary restriction and lifespan
• 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)
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)
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