Comparative rates of aging:

Question: Why do different species age at different paces?

To investigate this question: need to accurately quantify the rate of aging:

- Using mortality rate doubling time (MRDT) calculations:

o But: available for a fraction of the species
o But: Not perfect estimate of aging
- Using tmax: maximum lifespan: argued that it represents the genetic potential for longevity
of each species = rate of aging. (Best measure)
o But: biases in sample size

Factors correlated with tmax Description Explanation

Body size Larger = longer. Ecological constraints:
Measure=allometry of lifespan: predation.
logarithmic relation between tmax
and body mass.
Importance: need to eliminate
effects of body mass in
comparative studies. (not genetic)

Caveat: In captivity- small animals

live longer (dogs/people)
Concllusion: bigger species longer
lived due to ecological constraints,
but smaller ones live longer in
protected environments?
Brain mass Heavier = longer.
Metabolic rate (mostly Kleiber’s rule (rate of living theory)
discarded) E.g. reptilians and amphibians live
longer because they have
decreased metabolic rates (cold-
blooded) 2. Mice: metabolic rate
higher
Hibernation Related to metabolic rates:
Less variation in brain
mass = does not prove
that causes of aging in
brain -> just correlation
(not even the best
correlator)
Exceptions: birds and bats
Marsupials (lower body
temp but live less than
eutherians)
Problem in measurement:
body mass.
Metabolic rates often
measured by oxygen
consumption, but
elephants will certainly
consume more O2 than a
mouse: if don’t eliminate
body mass correlation,
then will actually get body
mass relation with tmax.
After correction, find no
relation…
Or could be that hiding =
 metabolic torpor increase lifespan? reduce predation rates so
live longer?
Growth Longer it takes for a mammal to
reach sexual maturity, longer it will
live afterwards.
Grow slower = longer living
Development Body plan development affects Strong correlation, but
aging cannot prove causality- for
evolutionary reasons,
development may be
timed similarly to aging
even if relation is small
Cellular markers 1. Genes associated with Key shift: from
oxidoreduction and physiological traits to
mitochondria molecular biology as
2. Methionine residues in finding the required
mitochondrially encoded markers.
proteins higher in short-
lived species, while
cysteine residues depleted
3. Proteins involved in
protein degradation under
selection in lineages where
longevity increased
The evolutionary theory of aging:

Weismann’s 1891 hypothesis: aging evolved to the advantage of the species (group selection)

Weismann’s later formulation: aging occurs in organisms that segregate soma and germ because
additional resources need to be used to maintain the soma – renunciation of soma = aging.

Kirkwood’s reformulation of Weismann’s theory – the disposable soma theory: balance of resources
between reproduction and soma maintenance- aging is due to accumulation of damage during life.

Peter Medawar: force of selection declines with age = hazardous late-acting genes can exist.

George Williams Antagonistic pleiotropy model- maybe some genes are beneficial @ early ages but
harmful later – genes that increase survival to reproductive age will be favoured by NS even if it
increases likelihood of dying later. E.g. Peacock tail: Zahavi’s handicap theory.

2 models for how aging can evolve:

1. Genetic drift + mutation accumulation = loss of late-acting beneficial genes + appearance of

late-acting harmful genes
2. Williams: pleiotropic effect of some genes that are beneficial early on and then harmful later.

Broader theoretical framework of aging: Life history theory:

- Life history = study of the changes of organisms from birth to death, focusing on schedule of
reproduction and survival.
- r/K selection proposed by MacArthur and Wilson- organisms in hazardous environments
maximize reproduction = r selected, non-hazardous = K selected.
o R selected organsms: small size, rapid development, short lifespan
o K selected organisms: large size, delayed development, longer lifespan’
- Extreme life history strategies:
o Semelparous species- unstable environment
o Where juveniles live longer than adults – Mayfly
o Aging evolved for a purpose (group selection)

Testing the evolutionary theory of aging (fading force of natural selection);

1. Let Drosophila reproduce when older- find delay in aging: natural selection can operate on
older flies (+)
2. Steven Austad observed that opossums, a North American marsupial, living in a predator-
free island reproduced later (K-selected) than animals of the same species on the more
hazardous mainland (R-selected) – intraspecies variation in r/k selection. (+)
3. Modern theory of aging proposes that aging is multifactorial but: single gene knock outs in C.
elegans + delay aging without affecting reproduction + mating increases longevity in ant
queens + in guppies, where higher extrinsic mortality = mature earlier and invest more in
reproduction but DO NOT have earlier onset of reproductive aging + does not explain why
aging is similar among mammals.
4. Exceptions: animals that do not age (calassical evolutionary models of aging predict that all
species eventually age because all species must reproduce)
o Blanding turtles: increase reproductive output with age!
5. Some germ cells in mammals could originate in somatic cell precursors= soma and germ
discrimination too simplistic?

Aging in mammals:
 - Mammals evolved from reptiles, reptiles don’t age, but mammals age. Why?
Mammals age because of r-selection during dinosaur’s rule. Mammals were small
nocturnal animals then = high mortalities = short generation cycles = select for early
reproduction instead of survival: effects last till today.
- What is the process?
o Drift due to decrased evolutionary pressure at later stages?
o Mutation aaccumulation?
o Antagonistic pleiotropY

Human aging model systems:

1. Human cells
- Problem: measurement usually based on rate of cell proliferation, and rate of proliferation
doesn’t necessarily record vitality – cancer = excessive proliferation. Also, stress resistance is
used.. but is it really relevant to aging

Use of model organisms:

- Relevance? Private vs public aging mechanisms. Is the weakest pathway succumbing to

senescence the same in all organisms?
- Problem- all model organisms shorter-lived than humans- means that evolutionary processes
that acted on them are different, but selection for fertility (useful organisms in lab) = select
shorter lifespans = generate biases. Does this mean that life-extending gene variants in these
organisms simply restore lifespan to what is found in the wild??
- Different strains? Discrepancies between them significant?
- Human physiology very different from model organisms?
- Drosophila and C elegans composed mainly of post-mitotic cells = do not have cancer + other
age- related diseases but how useful are they? Can they be extrapolated to humans?
- E.g. telomere dysfunction effects vary from one organism to another. Impossible to
determine impact of telomeres and telomerase in human aging based on model systems.

Counterarguments:

- Aging is the corruption of life, so understand how life works is useful: many genes that
modulate aging have been identified in model organisms- useful starting point?

2. S. cerevisiae
3. C. elegans
4. D. melanogaster
5. Mice and rats (rodents)

Role of long-lived mammals:

- Sequencing of naked mle-rat:

a. Genes associated with oxidoreduction and mitochondria expressed at higher lelves
in naked mole rat = contribute to their long lifespan
 b. Resistance to cancer- anti-tumour mechanism? Resistane to experimental
tumorigenesis with oncogenes

Cellular senescence:

Hayflick and Moorhead’s 3 phases of cell culture: Primary culture- division in culture- slow division ->
hayflick limit (replicative senescence)

Cumulative population doublings

Markers of cell senescence: