Genetics of ageing Flashcards
(19 cards)
How can we study genetics of ageing?
Using a classical genetic approach by using model organisms with mutations resulting in altered rates of ageing. Map, clone and sequence the affected gene to identify lifespan determining proteins and mechanisms.
Which model organisms are good to study ageing?
Yeast, c. elegans, drosophila, mice
Why are c. elegans good model organisms?
- They display signs of ageing - reduced fertility, increased molecular damage, organ deterioration.
- No inbreeding effects as seen in drosophila
- Cheap and easy
- Short lifespan
What were the breakthrough discoveries for genetics of ageing?
- Michael Klass (1983) - Isolated the first longlived mutants
- Tom Johnson (1988) - Isolated and identified age-1 mutant which showed 65% increase in mean lifespan and 110% increase in max lifespan
- Cynthia Kenyon (1993) - Isolated daf-2 mutant which show doubled lifespan
Better to study long lived than short lived as short lived more likely to be due to other factors.
What is dauer formation?
Developmentally arrested alternative third stage of larva. It forms in response to high population density, high temperature or low food. During this time, they are non-ageing but then continue normal lifespan after.
What does daf mean?
Dauer abnormal formation
Why were people interested in looking for mutants which affect dauer formation?
The dauer phenotype seems to resemble deferred ageing so whatever is involved in forming the dauer phase may increase lifespan.
What two genes arose from looking at mutations which affect dauer formation?
- Daf-c (dauer constitutive always dauer) - daf2, age1
- Daf-d (dauer defective no dauer formation) - daf-16
Therefore daf-16 wildtype extends longevity and daf-2 inhibits daf-16.
How are daf-2, age-1 and daf-16 relevant to other species which don’t have dauer formation?
When sequenced, found human homologues.
- Age-1 = catalytic subunit of PI3K
- Daf2 = Insulin of IGF1 receptor
- Daf-c = FOXO-class forkhead transcription factor
What is the daf-2 pathways?
Daf2 encodes PI3k which converts PIP2 to PIP3. PIP3 recruits PDK1 and PKB so PKB phosphorylated and activated. PKB phosphorylates FOXO1 TF preventing it from transcribing genes associated with dauer formation and longevity.
How was the insulin pathway in c. elegans explored to see if it is conserved in other animals?
Look at insulin/IGF-1 signalling pathway in flies. They found chico mutants (IRS) and dNIR (homologues to daf2 receptor) were both long-lived. Increased lifespan by 85%
What about mammals?
Mammals are more complicated because they have 3 insulin pathways. Reduced functions of insulin receptors in human causes diabetes, and KO mice lethal so insulin unlikely to be involved in ageing in humans. But did find KO of fat-specific insulin receptors increased lifespan by 18% then turned on IGF1 so maybe.
What about in humans?
We know IGF1 has role in growth which is related to longevity in mice, rats and dogs - clear negative correlation between body size and lifespan. Data is more complicated with humans - Ecuadorian dwarfs.
Why are DNA repair protein genes relevant?
Proteins which regulate DNA repair and cell division may be important regulators of age.
What is the effect on longevity in species whose cells have more efficient DNA repair enzymes?
Live longer
What is progeria?
an extremely rare genetic disorder in which symptoms resembling aspects of aging are manifested at a very early age
How are DNA repair enzymes related to progeria?
Appear to be caused by mutations in DNA repair enzymes.
- Hutchinson-Gilford progeria - symptoms of human senescence (age spots, hair loss)
- Klotho gene mutation in mice prolong by 30%
How is p53 important in ageing?
TF which regulates cell cycle. Can stop the cell cycle, cause cellular senescence in rapidly dividing cells, instruct Bax to initiate apoptosis, activate DNA repair enzymes.
How are sirtuin genes involved in ageing?
Encode histone deactylation proteins which guard genome from being expressed at wrong time and place. When DNA breaks, sirtuin fix breaks, prevent ageing.
In yeast, show SIRT2 assists in the repair of DNA and regulates genes that undergo altered expression with age
