Download Death: the Ultimate Genotype

Death: the Ultimate
Phenotype
Genomics of Aging
Studying Aging in Model Systems


1)
2)
3)
4)
yeast- caloric restriction slows aging
living systems tend to delay reproduction
until food is plentiful
worms- 4 other signaling pathways that
prolong life:
hormonal signaling- Daf2 makes worms
more resistant to stress
reproductive cells- gamete formation
mitochondrial signals slow metabolism
tyrosine kinase mutants live 60% longer
More Model Systems
fliesmethusela mutation can prolong life by 35%
gene encodes a G-protein coupled integral
membrane protein
No orthologs of this protein have been found
 miceAmes dwarf mice live longer than normal
These mice have altered hormonal levels
Another mutation, in p66shc, changes the
stress response

Why Do We Age?


1)
2)
If the selection pressure is to produce as
many offspring as possible- evolution should
favor longer and longer lifespan
Two hypotheses have been put forth:
mutation accumulation- mutations
accumulate gradually and become fixed by
genetic drift (adaptation to 1 environment is
not related to loss of adaptation in a different
one)
antagonistic pleiotrophy- a mutation which
produced a benefit in 1 environment may be
detrimental in another
Trade-offs for Longer Life
Age-1 is a mutation in C. elegans which
affects a kinase involved in insulin signaling
 Gordon Lithgow (Manchester) tested the
survival of worms in populations with different
proportions of age-1 mutants
 The ratios of age-1 to wt were .9 (black), .5
(gray), or .1 (blue)
 Worms were given unlimited amounts of food
and were maintained at 20o C
 The results supported the mutation
accumulation hypothesis

Another Interpretation
Lithgow realized that the experimental
conditions did not mimic conditions in nature
 Worms don’t usually have unlimited supplies
of food
 His lab repeated the experiments, this time
feeding the worms a large amount of food and
then starving them for four days
 They started with a 50:50 mix of age-1 and wt
 Only young adults laid eggs during starvation
 Their results now supported the antagonistic
pleiotrophy hypothesis

Aging Studies Using Bacteria
Richard Lenski (MSU) has grown E. coli for
20,000 generations (since 1988)
 His lab grows bacteria in glucose as its only C
source and then switches to other C sources to
test for the loss of catabolic function
 Fitness = improved metabolism in glucose
 If AP is correct- loss of catabolic function will be
inversely proportional to gains in fitness
 If MA is correct- loss of catabolic function will
occur at an independent rate

Antagonistic Pleiotrophy
A mutation which produces a selective
advantage early in life may accumulate a cost
that is exhibited late in life
 In many cases, reduced fitness appears to be a
trade-off for increased longevity
 A genetically engineered mouse that was
smarter than average mice was more sensitive
to chronic pain
 Animal models of the genomics of aging are not
perfect since humans do not live in controlled
environments
