14. Ageing: Drosophila as a Model Flashcards
What is the definition of ageing?
Ageing is the progressive, irreversible decline in organismal performance
What are the 4 categories of cause of death in over 65’s?
- Cancer
- CV disease
- Respiratory disease
- Neurodegenerative disease
What is the maximum human lifespan?
How can we increase lifespan?
- 125 years - oldest person was 122 years old
- If we know what factors influence ageing
What are the factors influencing ageing?
- Genetics
- Genotype at birth and mutations accumulated through life - Environment
- Diet, lifestyle and exposure to external factors
2 factors can influence one another - e.g. exposure to external factors increases accumulation of mutations
What 3 model organisms are used to study ageing?
Why?
- C. Elegans, Drosophila, Mice
- All have short lifespan
- C. Elegans and drosophila are small and easy to keep
- Genetically tractable
- Easy to control environmental factors e.g. food intake
What is the method for measuring ageing?
There is no direct measure for ageing
- Ageing is a poorly defined concept of function - one part of body could age (eye) at time other parts of body are completely healthy
How do we measure age?
We measure age at death
- Animal models allow us to measure age of death in large cohorts of genetically identical animals
- Produces a survival curve which shows the % of animals alive over time compared to at the start of the study
What is median lifespan?
Age at which 50% of the population have died
What does the short lifespan of drosophila allow us to do?
- Perform genetic screens to identify genes regulating lifespan
- Mutagenise population of flies and identify mutants that have increased or decreased lifespans and identify gene that is mutated
What did a genetic screen in Drosophila identify about lifespan?
- Insulin/IGF-1 pathway is important in lifespan
- Flies with mutations in chico have significantly increased lifespan compared to WT
Describe the insulin/IGF-1 pathway.
Insulin/IGF-1 pathway has been highly conserved through evolution
- Insulin (mammals) or insulin-like peptides (drosophila) binds to insulin receptor and activates a protein bound to the cytosolic domain of the insulin receptor - IRS (mammals) or Chico (drosophila)
- IRS/Chico then activates PI-3K, which activates PDK-1, which activates Akt
- Activation of Akt leads to repression of FOXO TF
- FOXO normally activates a repressor of unwanted cell growth and decreased lifespan
How does a mutation in the insulin/IGF-1 pathway increase lifespan?
Any mutation that:
- Inactivates component of pathway that leads to repression of FOXO
- Overexpression of component of pathway that leads to repression of unwanted cell growth
How does insulin/IGF-1 pathway control lifespan?
- Decreased insulin results in increased FOXO
- This has 3 effects:
1. Increases autophagy - a self-degradative process that removes misfolded proteins, damaged organelles and IC pathogens
2. Increases DNA repair - reduces accumulation of mutations
3. Decreases oxidative stress - These 3 effects promote health and longevity
What was found about the methuselah gene?
- Methuselah encodes the receptor which triggers insulin secretion in response to nutrients
- Methuselah mutants (LoF) also show increased lifespan
- A peptide antagonist of methuselah increases lifespan, however these flies functional ability (measured by how long they could fly) is below control levels at old age
- Ie inhibiting methuselah increases lifespan but not healthy ageing
What environmental factors have previous studies suggested increases lifespan?
Dietary restriction and reduced nutrient intake
Does dietary restriction (DR) increase lifespan?
- Yes, drosophila with DR have significantly increased lifespans (55 days) compared to fully fed drosophila (35 days)
Is DR required throughout life to increase lifespan?
No, DR decreases mortality risk at any time
What experiments showed DR is not required throughout life to increase lifespan?
- When Drosophila are fully fed for 14 or 22 days and then switched to DR, probability of death decreases rapidly to that of Drosophila that are DR from day 0
- When Drosophila are DR for 14 or 22 days and then fully fed, probability of death increases rapidly to that of Drosophila fully fed from day 0
- ie DR in later life is sufficient to increase lifespan
How does DR control lifespan?
- DR causes decrease insulin and increased FOXO to increase health and longevity
- DR also decreases inflammation (decreases cancer) and decreases adiposity (decreases CV disease) to increase health and longevity
What is Alzheimer’s disease characterised by?
What accumulates in Alzheimer’s disease?
- Neurodegenration, neuronal cell death and tissue atrophy
- There is accumulation of B-amyloid peptide (unsure whether causal or consequence)
What does overexpression of B-amyloid in Drosophila cause?
Neurotoxicitity
Describe how the overexpression system UAS/Gal4 works.
- 1st strain of flies have transgene in which Gal4 is expressed under control of tissue-specific promoter (e.g. neuronal)
- 2nd strain of flies have transgene in which gene to be over expressed (e.g. B-amyloid) is expressed under control of UAS promoter
- Cross 2 strains and F1 flies will express Gal4 in neurones which will activate UAS promoter leading to overexpression of B-amyloid
How can UAS/Gal4 system be used?
- Overexpression of B-amyloid causes neurotoxicity and decreases lifespan
- Can perform mutagenesis screen to identify genes that reduce neurotoxicity and increase lifespan
What did the mutagenesis screen on B-amyloid ovexpressing flies show?
What does this suggest?
- Gene encoding the evolutionary conserved Insulin-degrading enzyme (IDE) reduces neurotoxicity induced by B-amyloid overexpression and increases lifespan
- Suggest insulin/IGF-1 pathway not only important for increasing lifespan but also increasing healthy ageing
How could DR increase healthy ageing?
Decreasing Alzheimer’s
