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
