14. Ageing: Drosophila as a Model Flashcards Preview

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Flashcards in 14. Ageing: Drosophila as a Model Deck (25)
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1
Q

What is the definition of ageing?

A

Ageing is the progressive, irreversible decline in organismal performance

2
Q

What are the 4 categories of cause of death in over 65’s?

A
  • Cancer
  • CV disease
  • Respiratory disease
  • Neurodegenerative disease
3
Q

What is the maximum human lifespan?

How can we increase lifespan?

A
  • 125 years - oldest person was 122 years old

- If we know what factors influence ageing

4
Q

What are the factors influencing ageing?

A
  1. Genetics
    - Genotype at birth and mutations accumulated through life
  2. Environment
    - Diet, lifestyle and exposure to external factors

2 factors can influence one another - e.g. exposure to external factors increases accumulation of mutations

5
Q

What 3 model organisms are used to study ageing?

Why?

A
  • 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
6
Q

What is the method for measuring ageing?

A

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

7
Q

How do we measure age?

A

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
8
Q

What is median lifespan?

A

Age at which 50% of the population have died

9
Q

What does the short lifespan of drosophila allow us to do?

A
  • 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
10
Q

What did a genetic screen in Drosophila identify about lifespan?

A
  • Insulin/IGF-1 pathway is important in lifespan

- Flies with mutations in chico have significantly increased lifespan compared to WT

11
Q

Describe the insulin/IGF-1 pathway.

A

Insulin/IGF-1 pathway has been highly conserved through evolution

  1. 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)
  2. IRS/Chico then activates PI-3K, which activates PDK-1, which activates Akt
  3. Activation of Akt leads to repression of FOXO TF
    - FOXO normally activates a repressor of unwanted cell growth and decreased lifespan
12
Q

How does a mutation in the insulin/IGF-1 pathway increase lifespan?

A

Any mutation that:

  1. Inactivates component of pathway that leads to repression of FOXO
  2. Overexpression of component of pathway that leads to repression of unwanted cell growth
13
Q

How does insulin/IGF-1 pathway control lifespan?

A
  • 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
14
Q

What was found about the methuselah gene?

A
  • 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
15
Q

What environmental factors have previous studies suggested increases lifespan?

A

Dietary restriction and reduced nutrient intake

16
Q

Does dietary restriction (DR) increase lifespan?

A
  • Yes, drosophila with DR have significantly increased lifespans (55 days) compared to fully fed drosophila (35 days)
17
Q

Is DR required throughout life to increase lifespan?

A

No, DR decreases mortality risk at any time

18
Q

What experiments showed DR is not required throughout life to increase lifespan?

A
  • 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
19
Q

How does DR control lifespan?

A
  • 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
20
Q

What is Alzheimer’s disease characterised by?

What accumulates in Alzheimer’s disease?

A
  • Neurodegenration, neuronal cell death and tissue atrophy

- There is accumulation of B-amyloid peptide (unsure whether causal or consequence)

21
Q

What does overexpression of B-amyloid in Drosophila cause?

A

Neurotoxicitity

22
Q

Describe how the overexpression system UAS/Gal4 works.

A
  1. 1st strain of flies have transgene in which Gal4 is expressed under control of tissue-specific promoter (e.g. neuronal)
  2. 2nd strain of flies have transgene in which gene to be over expressed (e.g. B-amyloid) is expressed under control of UAS promoter
  3. Cross 2 strains and F1 flies will express Gal4 in neurones which will activate UAS promoter leading to overexpression of B-amyloid
23
Q

How can UAS/Gal4 system be used?

A
  • Overexpression of B-amyloid causes neurotoxicity and decreases lifespan
  • Can perform mutagenesis screen to identify genes that reduce neurotoxicity and increase lifespan
24
Q

What did the mutagenesis screen on B-amyloid ovexpressing flies show?
What does this suggest?

A
  • 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
25
Q

How could DR increase healthy ageing?

A

Decreasing Alzheimer’s