Memory is short, and braine is dry.

1
Memory is short, and braine is dry. My
Almond-tree (gray haires) doth flourish now, And
back, once straight, begins apace to bow. My
grinders now are few, my sight doth faile My
skin is wrinkled, and my cheeks are pale. No
more rejoyce, at musickes pleasant noyse.




Anne Bradstreet (1612-1672)
Anne Bradstreet (1612-1672)
2
EVOLUTION OF SENESCENCE

• Why do we age and die?
• Why do we have a particular
• suite of age-related diseases?
• Can we delay aging and/or make it more
  successful?
• What can evolutionary biology
• contribute to understanding
• aging and our aging population?

3
(No Transcript)
4
The Challenges of GLOBAL AGING

• 20th century saw a global phenomenon of
  longevity a triumph and a challenge
• Average life expectancy at birth- increased
  by 20 years since 1950
  to 66 years
• Is expected to increase another 10 years by 2050
• By 2050, the population of older people will
  exceed that of children (0-14 yrs)
• Is a social phenomenon without historical
  precedent
• In 2002, number of persons gt 60 years was 605
  million
• By 2050, number is expected to reach almost 2
  billion

5

• Defining and measuring aging
• SENESCENCE/AGING deteriorative changes
• that occur in an individual with increasing age -
  
• increase with age in probability that an organism
  
• will die from internal reasons, and decrease with
  
• age in rate of reproduction
• Examples of deteriorative changes hair loss
• or greying, slowed reactions times, memory loss,
• increasing cancer rates and type 2 diabetes rates
• Can quantify via age-specific rates of
• survival and reproduction - is property of
• populations and species -gt
• Life-span is not a good measure of aging, as it
  includes extrinsic mortality risk (eg accidental
  death) -eliminate these risks and life span would
  change but senescence rate would not (in short
  term)
• Without aging/senescence, and with physiological
  peak performance, life expectancy would be about
  5000 years

Before After
6
Examples of age-specific rates of survival and
reproduction
7
EEK! SENESCENCE REDUCES SURVIVAL AND REPRODUCTION
- SO WHY DO WE SENESCE? FIRST, THE INTENSITY OF
NATURAL SELECTION INEVITABLY DECLINES WITH AGE,
BECAUSE THERE ARE FEWER OLDER INDIVIDUALS (DUE
TO EXTRINSIC MORTALITY), AND LESS OF THEIR
REPRDUCTION IS AHEAD OF THEM
the forces of natural selection weakens with
increasing age . If a genetical disaster
happens late enough in individual life, its
consequences may be completely unimportant. Even
in such a crude and unqualified form, this
dispensation may have a real bearing on the
origin of innate deterioration with increasing
age. Medawar, 1952
8
LATE-ONSET MUTATIONS ARE NOT ELIMINATED BY
NATURAL SELECTION
EXAMPLE Huntingtons chorea disabling disorder
of the nervous system caused by a dominant
mutation that is not expressed until the age of
35 40.
George Sumner Huntington
9
Another example Hereditary nonpolyposis colon
cancer

• A heritable genetic disease causing colon cancer
• The median age of diagnosis is 48, well after the
  typical reproductive age in humans

10
Evolutionary hypothesis of aging

• Aging is not due to unavoidable cellular and
  tissue damage, but is instead associated with
  failures to completely repair damage complete
  repair should be entirely feasible, in theory
• Incomplete repair may be due to
• Deleterious mutations
• Trade-offs between repair and reproduction, or
  between other pairs of factors

11
MUTATION ACCUMULATION HYPOTHESIS
Early o Late -

• Senescence occurs because of mutations that have
  no effect early in life, but deleterious effects
  late in life these are nearly neutral and can
  drift to appreciable frequency, accumulating in
  genomes over evolutionary time

ANTAGONISTIC PLEIOTROPY HYPOTHESIS

• Senescence occurs because of the pleiotropic
  effects of genes.
• Selection for alleles which enhance survivorship
  and/or reproductive rate at early reproductive
  ages may also lower survivorship and reproductive
  rates at later ages.
• There is a tradeoff (antagonism) between fitness
  components early in life and later in life

Early Late -
12
Example of antagonistic pleiotropy Mature age 3,
die by age 16, expected RS 2.419
A pleiotropic mutation affects two different
life history characteristics-gt
Mature age 2, die by age 10, expected RS 2.663
Benefits of early reproduction may be selected
for while selection against reduced lifespan may
be minimal
13
Kirkwood developed the Disposable Soma Theory as
a general mechanism for the operation of
antagonistic pleiotropy Organisms face tradeoffs
between reproduction and maintenance/repair
(soma) Alleles and physiological mechanisms
increasing allocation to reproduction compromise
somatic maintenance and repair (eg testosterone
immunity eg castration can extend
life) Genetic tradeoffs physiologies that are
genetically different (eg genetic change
increases fertility but shortens
life) Physiological tradeoffs tradeoffs within
individual depending on conditions (eg have more
kids, have shorter life)
"The secret of life is enjoying the passage of
time. James Taylor
14

• Predictions of evolutionary models of senescence
• Patterns of aging have a genetic basis
• -artificial selection for late-life reproduction
  leads to
• delayed senescence in Drosophila (Rose 1984)-gt
• -lifespan is heritable in humans (30-50)
• (2) Higher extrinsic mortality risk should be
  associated
• with accelerated senescence, and vice versa
  (accidental
• death determines strength of selection on
  age-specific
• survival and reproduction)
• -experimental tests with possums -gt
• (3) Mutations with age-specific effects are
  common
• -some evidence but need more
• (4) Many genes each of small effect are expected
  to
• underlie antagonistic pleiotropy effects

15
EXPERIMENTAL EVIDENCE FOR ANTAGONISTIC
PLEIOTROPY - Drosophila artificial selection in
the lab
LATE REPRODUCTION
EARLY REPRODUCTION
16
A natural experiment on the evolution of aging
with the Virginia Opossum (Austad 1993)

• Sources of mortality
• Ecological
• Intrinsic
• In populations with low ecological mortality,
  selection may favor delayed senescence (and
  eliminate deleterious late-acting alleles)
• Study compared island population (low ecological
  mortality) to mainland population (high
  ecological mortality)

17
Island individuals show evidence of delayed
senescence
Differences in mortality rates
Differences in parental investment
Differences in rates of physiological aging?
Do differences reflect trade-offs between
reproduction and repair? If ecological mortality
is high, best strategy may be for early
reproduction.
18

• MOLECULAR AND PHYSIOLOGICAL
• (proximate) MECHANISMS OF AGING
• Dietary restriction after adulthood reduces
  effects
• of aging leads to increased lifespan, in lab
  animals
• (yeast, worms, Daphnia, Drosophila, mice,
  primates).
• Molecular basis of this effect is rapidly being
  uncovered
• (2) Insulin/IGF-1 signalling pathway genes are
  strongly
• implicated in aging effects - these genes
  regulate metabolism
• and stress responses, affect maintenance
  functions -gt
• findings falsify one prediction of antagonistic
  pleiotropy,
• because aging is largely underlain by one system
• BUT WHAT ABOUT TRADE-OFFS AND LIFE-HISTORY
• THEORY?

19

• Integrating molecular mechanisms with
  life-history theory
• Insulin/IGF1 (growth hormones) pathway appears
  to strongly
• regulate tradeoffs between growth, maintenance
  and reproduction,
• via adaptive responses in allocation
• patterns to different environmental signals
• -poor environment (eg dietary restriction) -
• increase maintenance (survival), reduce
• growth and/or reproduction
• -good environment - increase growth
• and/or reproduction, decrease maintenance
• (2) In lab, life-span extending mutations
• have pleiotropic effects that involve substantial
  costs in terms of other
• fitness components - fits with presence of
  trade-offs in humans,
• insulin/IGF mutants do poorly do not show
  evidence of long lives.
• However

20
Another important form of trade-off between
cancer risk and senescence via cumulative loss
of functioning cells
Judy Campisi, UC Berkeley
21
p53 gene, cancer risk, and aging in mice
p53 alleles in this mouse strain wild
type - loss of function m mutation
Good news! The m allele appears to confer
resistance to tumors (6 vs gt45) Bad News!
The m allele appears to have a cost in terms of
aging (die off sooner than p53/ wild types)
22
Genetic basis of aging the APOE
example Apolipoprotein E (APOE) transports
cholesterol Humans have 3 alleles, E2 (0-15),
E3 (50-90), E4 (5-40) with different binding
affinities to low-density lipoprotein receptor
E4 is ancestral, E3 and E2 arose recently (lt200k
years ago) E4 allele confers higher risk of
Alzheimers disease and cardiovascular
disease Advantage of E3? Delay cognitive and
cardiovascular disease? E4 persistence?
23
The Oxidative-Damage/Free-Radical Hypothesis Of
Aging
Be careful not to confuse proximate with
ultimate explanations for aging!
24
Human aging and evolution Humans have
quite-recently evolved a much longer lifespan,
based on comparative-phylogenetic studies of
primates the genetic basis of this extension
remains to be elucidated and requires studies of
positive selection This longer lifespan (and the
alleles underlying it) evolved in ancestral
human environments quite different from those
today early-acting beneficial genes in ancestral
environments may be irrelevant in modern
environments and late-acting effects may not be
deleterious In developed and developing
countries, females are reproducing much later in
life, which his expected to lead to delayed
senescence across generations There is no
physiological or evolutionary reason to think
that we cannot break the trade-offs that
underly senescence and live a very very long
time
25

• The Greek God Zeus granted Tithonus
• the gift of immortality, but not of perpetual
• youth, when requested by his wife Eos.
• Tithonus grew progressively ancient, and
• begged for death to overcome him
• Tennysons poem Tithonus
• Man comes and tills the field and lies
  beneath, And after many a summer dies the
  swan.Me only cruel immortalityConsumes I
  wither slowly in thine arms
• Living longer without youthful vitality is not a
  good idea