Transcript Lecture 16-POSTED-BISC441-2012

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)
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?
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 > 60 years was 605 million
• By 2050, number is expected to reach almost 2 billion
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
Before
After
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 ->
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
Examples of age-specific rates of survival and reproduction
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
LATE-ONSET MUTATIONS ARE NOT
ELIMINATED BY NATURAL SELECTION
EXAMPLE: Huntington’s 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
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
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
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 Early +
Late rates at later ages.
 There is a tradeoff (antagonism) between fitness
components early in life and later in life
Example of antagonistic
pleiotropy
Mature age 3,
die by age 16,
expected RS 2.419
A pleiotropic mutation
affects two different life
history characteristics->
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
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
Predictions of evolutionary models of senescence
(1) Patterns of aging have a genetic basis:
-artificial selection for late-life reproduction leads to
delayed senescence in Drosophila (Rose 1984)->
-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 ->
(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
EXPERIMENTAL EVIDENCE FOR
ANTAGONISTIC PLEIOTROPY - Drosophila
artificial selection in the lab
LATE REPRODUCTION
EARLY
REPRODUCTION
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)
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.
MOLECULAR AND PHYSIOLOGICAL
(proximate) MECHANISMS OF AGING
(1) 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 ->
findings falsify one prediction of antagonistic pleiotropy,
because aging is largely underlain by one system
BUT WHAT ABOUT TRADE-OFFS AND LIFE-HISTORY
THEORY?
Integrating molecular mechanisms with life-history theory
(1) 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:
Another important form of trade-off: between cancer risk
and senescence via cumulative loss of functioning cells
Judy Campisi,
UC Berkeley
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 >45%)
Bad News! The m allele appears to have a cost in terms of aging
(die off sooner than p53+/+ wild types)
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 (<200k years ago)
E4 allele confers higher risk
of Alzheimer’s disease
and cardiovascular disease
Advantage of E3? Delay
cognitive and cardiovascular
disease? E4 persistence?
The Oxidative-Damage/Free-Radical
Hypothesis Of Aging
Self–perpetuating
Cycle of Impaired
Function
↓
Increased Oxygen
-free radicals
-DNA Damage
-Cross-linking
proteins
-Mitochondria
Damage
-Form age
pigments
Oxidative cell
damage
↓
Mitochondrial
Damage
Be careful not to confuse
proximate with ultimate
explanations for aging!
Oxygen-free
radicals release
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
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
Tennyson’s poem “Tithonus”:
“Man comes and tills the field and lies beneath,
And after many a summer dies the swan.
Me only cruel immortality
Consumes: I wither slowly in thine arms”
Living longer without youthful vitality is not a good idea