1

Why do we get old?

1816 1840 1854 1880 1874

One trait in more detail: The evolution of ageing

The evolution of life histories

2

Demography of ageing

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0 20 40 60 80 100Age

% s

urvi

ving

MalesFemales

0.0001

0.001

0.01

0.1

1

0 20 40 60 80 100Age

Mor

talit

y ra

te

Ageing and mortality in humans (Switzerland 1988-93)

The decline in survival is mainly due to intrinsic mortality. Extrinsic mortality is low and plays hardly a role in modern societies.

3

A demographic definition of ageing

Ageing (= senescence): an intrinsic, irreversible increase of mortality and decline of fertility with advancing age

Fert

ility

Age [years]

Humans, Taiwan 1906

Mor

talit

y ra

te

Age [years]

00.020.040.060.08

0.10.120.14

0 10 20 30 40 50

Age [days from eclosion]

Mor

talit

y ra

te

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20

40

60

0 10 20 30 40 50Age [days from eclosion]

Ferti

lity

D. melanogaster, lab

4

Quantification of ageing: the reproductive value

Age [years]

Rep

rodu

ctiv

e va

lue

Humans, Taiwan 1906

Ageing can also be defined as the intrinsic, irreversible decline of the reproductive value with advancing age Reproductive value: the expected future contribution of an individual to the future gene pool of the population

5

Mechanistic explanations

for aging (proximate)

Lopez-Otin et al. Cell 2013

The 9 hallmarks of Aging

A few key words: •  somatic

mutations •  loss of telomers •  death of neurons •  osteoporosis •  menopause

6

Do we need an ultimate explanation for ageing? Asking for the evolutionary history and function

in terms of contribution to Darwinian fitness •  If development is possible, why wouldn�t maintenance be?

•  Our germ line does not age

•  Large differences between

genetically similar individuals

(e.g., Bee queen-workers)

•  Some organisms seem to age less

•  Large differences between related taxa in the rate of ageing

•  Genetic variation for the rate of ageing within populations

7

Large differences between related taxa in the rate of ageing

Mea

n an

d m

axim

al li

fesp

an (y

ears

)

8

Genetic variation for the rate of ageing within populations

The response of D. melanogaster populations to 4 generations of selection on lifespan.

Zwaan, B., R. et al. Evolution

Longevity (unmated)

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Males Females

Adul

t life

span

(day

s)

UpControlDown

Up = selection for longer life Down = selection for reduced life

9

The force of natural selection declines with age

The logic: •  the world is a dangerous place •  only few individuals survive to an advanced age •  good or bad conditions at an advanced age will rarely make a difference

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Human paleolitic population, females (reconstructed) (Hamilton 1966)

The force of natural selection declines with age

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A hypothetical species with no ageing: - constant mortality 5 % /year - constant fertility as of age 18

Force of selection on

mortality rate at age a

The force of selection is a measure of the strength of selection to alter this trait. The higher mortality, the stronger the decline in the force of infection.

The higher the mortality the steeper the decline of the curve.

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11

The force of natural selection declines with age

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Age a [years]

A hypothetical species with no ageing: - constant mortality 5 % /year or 3% per year - constant fertility as of age 18

Force of selection on

mortality rate at age a

The lower the extrinsic mortality the flatter the decline of the curve. Thus

with low extrinsic mortality we have a stronger force of

infection in higher age.

12

Available energy

Reproduction now

Somatic maintenance

and repair

Survival (if lucky)

and future reproduction

?

Hypothesis 1: The antagonistic pleiotropy theory of ageing

Ageing evolved through accumulation of alleles that are beneficial early, but deleterious late in life

More reproduction now

Insufficient somatic

maintenance and repair

Ageing

Available energy

Soma is disposable!

After: George Williams (1926 – 2010), an American evolutionary biologist.

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The disposable soma in extremum: semelparous organisms

Hypothesis 1: The antagonistic pleiotropy theory of ageing

14

Testing the antagonistic pleiotropy theory: Semelparous organisms have a much higher fertility

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Relative total seed mass (%)

Num

ber o

f spe

cies Perennial (N = 31)

Annual (N = 8)

Fertility of annual (semelparous) versus perennial (iteroparous) grasses

Hypothesis 1: The antagonistic pleiotropy theory of ageing

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Tests: Physiological manipulations and natural plasticity

•  Castration in semelparous animals (salmon, octopus) extends lifespan several-fold.

•  In many organisms, ageing is delayed when reproduction is prevented.

•  Dietary restriction slows down ageing but prevents reproduction in a variety of organisms (worms, flies, mammals).

•  Some organisms have a facultative life stage with no reproduction and much-delayed ageing (diapause in insects, dauer larva in the nematode worm C. elegans).

Hypothesis 1: The antagonistic pleiotropy theory of ageing

16

Tests: Correlated responses to selection

Mode of selection Response Source Late reproduction ↑Longevity ↓Early fecundity 1

Late reproduction ↑Longevity ↓Early fecundity 2 Late reproduction ↑Longevity ↓Larval viability 3 Extrinsic mortality ↑Longevity ↓Early fecundity; ↑Dev. time 4 Long lifespan ↑Longevity ↓Fecundity 5

Selection experiments involving lifespan in D. melanogaster

1Rose and Charlesworth 1980, Nature 287:141-142; 2Buck et al. 2000, J. Gerontol. A 55:B292-301; 3Partridge et al. 1999, Proc. R. Soc. Lond. B 266:255-261; 4Stearns et al. 2000, PNAS 97:3309-3313; 5Zwaan et al. 1995, Evolution 49:649-659

Hypothesis 1: The antagonistic pleiotropy theory of ageing

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Hypothesis 2: The mutation accumulation theory of ageing

Mutations with no effects early in life and deleterious effects at an advanced age are effectively neutral (they are not seen by natural selection, as the force of selection is too weak in an advanced age). Accumulation of such mutations have contributed to the evolution of ageing.

After Peter Brian Medawar (1915 – 1987), a British biologist.

18

Test: Genetic variance for age-specific reproductive success increases with age in Drosophila

Hughes et al. 2002, PNAS

Additive variance

Gen

etic

var

iatio

n of

re

prod

uctiv

e su

cces

s

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Age from eclosion [days]

Inbr

eedi

ng d

epre

ssio

n

Age from eclosion [days]

Hypothesis 2: The mutation accumulation theory of ageing

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General predictions of the evolutionary theory of ageing Low extrinsic mortality favours delayed ageing

Extrinsic mortality rate [year-1]

Rat

e of

age

ing

[yea

r-1]

A comparative analysis of birds and mammals

(Ricklefs, R., Am. Nat. 152 20

Ficus indica Calcutta Botanical Gardens

Experimental evolution in Drosophila melanogaster

Selection regimes: High extrinsic adult mortality (HAM): 99 % killed/week Low extrinsic adult mortality (LAM): 36 % killed/week Age-specific intrinsic mortality after 5 years of selection:

Stearns et al 2000 PNAS

Intrinsic mortality

rate [day-1]

HAM LAM

General predictions of the evolutionary theory of ageing Low extrinsic mortality favours delayed ageing

Age [days from egg]

21

General predictions of the evolutionary theory of ageing Ageing requires a parent-offspring asymmetry

Parent: ages, i.e., accumulates damage Offspring: is born young, doesn't inherit the age of the parent

•  Unicellulars with symmetric division would not show ageing •  Some multicellular modular organisms with no clear

delineation of parent and offspring show no ageing •  Unicellulars with asymmetric division show ageing

22

A prokaryote that shows ageing:Caulobacter crescentus

swarmer cell stalked cell

birth age at secondreproduction

age at first reproduction

flagellum

swarmer cell

stalked cellstalkholdfast

a)

b)

parent

offspring

The rate of offspring production declines with age

Ackermann et al. 2003. Science

23

General predictions of the evolutionary theory of ageing There should be many mechanisms of ageing (Ford T principle)

24

Conclusions: Ageing

•  Ageing is a product of evolution

•  It does not have a function

•  Death is not "programmed"

•  It is a price of high survival and fertility at young age

•  It evolved because the force of natural selection declines with age

•  Two hypotheses can exlain aging: antagonistic pleiotropy and the

accumulation of deleterious mutations with age specific effect.

25 Lopez-Otin et al. Cell 2013

26

Summary: The evolution of life histories

•  Life history traits are shaped by differential fecundity and survival. Life tables are an easy to use tool to study age dependes of survival and fecundity.

•  Population growth rate , r and the net reproductive rate of increase, R0 are useful measures of fitness and can be calculated from life tables.

•  Trade-offs play an important role in life history evolution. Examples are: •  cost of reproduction •  evolution of parasite virulence •  early versus late fecundity.

•  As a consequence of trade-offs, most life history traits are under balancing selection. (e.g. birth weight in humans, clutch size in great tits). Directional selection often happens after a change in the environment (guppy example).

•  Trade-offs may explain the evolution of traits with apparently no function, e.g. ageing.

•  Phenotypic plasticity is a way to express different phenotypes under different environmental conditions.