Transcript Cell Death

Death: the Ultimate
Genomics of Aging
Studying Aging in Model Systems
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?
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
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