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A BMS 381 - Developmental neurobiology > Ageing > Flashcards

Ageing Flashcards

1
Q

What is ageing by definition?

A

The progressive, irreversible decline in organismal performance

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2
Q

What occurs in the organism as a result of ageing?

A

Failure of multiple systems

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3
Q

What are the main causes of death after 65 years old in the UK?

A
  • Cancer
  • Heart and lung problems
  • Alzheimers
  • Parkinsons
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4
Q

Can we prevent ageing?

A

Possible if we know the factors that influence ageing

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5
Q

What are the factors that influence ageing?

A

1) GENETICS (internal factors)

2) ENVIRONMENT (external factors)

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6
Q

What are the genetic factors leading to ageing?

A

Genotype at BIRTH

Accumulation of mutations with age

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7
Q

What are the environmental factors leading to ageing?

A

Diet
Lifestyle
Exposure to various external factors

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8
Q

What can/cannot be studied in model organisms in regards to ageing?

A

Can:
- GENETICS of ageing

Can’t:
- Environmental factors

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9
Q

What must model organisms be to study ageing?

A
  • Small, easy to culture
  • Short life span
  • Genetically tractable
  • Can be kept in a controllable environment
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10
Q

Why must model organisms be kept in a controllable environment?

A

To ensure that changes are dependant on GENETICS and not environment

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11
Q

What is the lifespan of c.elegans?

Drosophila?

Mouse?

A

Weeks

Months

Years

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12
Q

How can we measure ageing?

A

No direct method to measure ageing

Instead, measure age at DEATH

Demographic approached - large cohorts of identical animals –> build a survival curve

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13
Q

What can be identified using a survival curve?

A

Medial lifespan (on average how long a particular GENETIC COMBINATION lives)

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14
Q

What does the survival curve of drosophila show?

What other organisms show this?

A

Females live longer than males

Humans also show this

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15
Q

What makes drosophila a powerful tool to find the genes regulating LIFE SPAN?

A
  • Short-life span

- Can undergo genetic screens

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16
Q

What did screens of the drosophila show was important in ageing?

How?

A

The INSULIN/IGF-1 PATHWAY is important in ageing

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17
Q

As well as ageing, what does the insulin pathway impact on?(2)

A

1) Has a role in the regulation of brain function

2) Regulates human body homeostasis - important during development

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18
Q

What is the role of the insulin hormone?

A

Promotes the uptake of glucose from the blood for STORGAE

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19
Q

eIn this course, where has insulin been met before?

A

Energy balance

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20
Q

What is the insulin signalling pathway?

A

1) Insulin binds to insulin receptor
2) Intracellular cascade - PI3 –> Akt
3) Represses the function of FOXO AND promotes the function of S6K (through mTOR)

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21
Q

What is the normal function of FOXO?

A

INHIBITION of cell PROLIFERATION and NUMBER

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22
Q

What is the normal function of s6K?

A

INCREASE in cell SIZE (growth)

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23
Q

What did the first indication that the insulin pathway is involved in ageing?

What is thus protein?

A

With the chico protein

An insulin receptor substrate - functions in the insulin pathway in drosophila

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24
Q

What occurs in HETEROZYGOUS drosophila with chico mutant?

Why?

A

LONG lived (both males and females)

Pathway is REDUCED but not COMPLETELY ABOLISHED
–> longevity

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25
Q

What occurs in HOMOZYGOUS drosophila with chico mutant?

Why?

A

LETHAL

COMPLETELY abolishes the insulin pathway

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26
Q

Is the insulin/IGF-1 pathway conserved?

A

YES

HIGHLY conserved

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27
Q

What was shown after the original discovery of chico in longevity in drosophila?

A

Shown in other animals to have the SAME effect

Shown that other components of the pathway have the same roles

28
Q

What are components that ACTIVATE the insulin pathway?

What do HETERO mutations in these components show?

A

Insulin receptor
Insulin
PI3K
mTOR

Mutations –> promote longevity

29
Q

What are components that INACTIVATE the insulin pathway?

What do OVEREXPRESSION in these components show?

A

PTEN
FOXO

Over expression –> reduce activity of the pathway –> promote longevity

30
Q

How does a reduction in the insulin pathway increase longevity? (2)

How?

A

On the whole organism level:

1) Increases autophagy and DNA repair –> less accumulation of mutation and less senesence
2) Reduction in oxidative stress
- By inhibiting mTOR that normally acts to increase cell size (by blocking autophagy) and by inhibiting the inhibition FOXO (now activated) that acts to REDUCE cell proliferation (ROS involved in cell proliferation)

–> Ultimately increasing health and longevity

31
Q

What does Methuselah do?

A

A gene that encodes the receptor that triggers insulin release –> activates the insulin pathway in response to NUTRIENTS

32
Q

What happens the methuselah mutants?

A

Long lived

33
Q

What does a peptide antagonist of methuselah do?

On the other hand?

A

EXTENDS life-span

BUT:
- Functional abilities are BELOW the CONTROL level at old ages (flies live longer but they are less healthy and perform WORSE when they are old compared to control)

  • Control flies live shorter lives but they are HEALTHIER - more active, longer flight duration
34
Q

What impact does dietary restriction have on life-span? What effect does this show?

On the other hand?

A

MODEST dietary restriction (reduced nutrient intake –> extends lifespan)
Shows ENVIRONMENTAL EFFECTS

But if food concentration is TOO LOW –> flies die

35
Q

What is another way to measure longevity of life?

What does this show?

A

The PROBABILITY of death at each age (taken from the survival curve)

Shows:
- Probability of death increases exponentially with age

36
Q

What can be produced from the probability curve?

What does this show?

A

Plot on a log scale:
- Produces a straight line

Shows:
- Probability of death is LINEAR with age

37
Q

What were the experiments performed by scientists to see if dietary restriction can extend life when applied at a particular point or throughout life?

Conclusion:

A

Fully fed flies:

  • Higher mortality rate than dietary restricted flies
  • Switch flies to dietary restriction @ day 14 or day 22

SAW: mortality rate reduced dramatically to the level the same as flies that were kept on dietary restriction throughout their lifetime

Then - reverse experiment:
- Switch dietary restriction to fully fed at day 14 or day 22

SAW:
- Flies started to die as quickly as flies that were kept on fully fed diet throughout life

CONCLUSION:
- DR reduces mortality risk at any time of life

38
Q

When is middle aged for a fly?

39
Q

What is CALORIE?

A

Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy

40
Q

Where are insulin receptors found?

A

In the hypothalamus

41
Q

As well as insulin, what acts on the insulin receptors?

What happens when this binds to insulin receptors in the hypothamus? (2)

A

LEPTIN:

  • Regulates food hunger, food intake and feeding behaviour
  • INDIRECTLY regulates INSULIN SECRETION
42
Q

How does insulin act in the brain?

A

Acts in the hypothalamus to control glucose metabolism

43
Q

What does the evidence show that is regulating lifespan?

A

Insulin receptors in the hypothlamus

44
Q

What is IGF-1?

A

Insulin Growth Factor-1

45
Q

What is IGF-1 production simulated by?

A

Hypothalamus GHRH (growth hormone releasing hormone)

46
Q

Why is Alzheimer’s do demanding?

A
  • Increasing number of people diagnosed

- Large strain on the economy

47
Q

What occurs in Alzheimer’s? (2)

A

1) Neurodegeneration, cell death, tissue atrophy –> impairs cognitive function
2) Accumulation of beta-amyloid peptides in the cells of the brain –> over expression in drosophila is neurotoxicity

48
Q

How does known information of Alzheimer’s be used to promote healthy ageing?

A

Can screen for genes that potentially REDUCE neurotoxicity/beta-amyloid peptides –> used for drug targets?

49
Q

How can over express a gene using the UAS/Gal4 system?

How is this used to study ageing?

A

Fly 1:
- Sequence coding for Gal4 under the regulation of a promoter expressed in a particular TISSUE or a particular TIME (eg. brain)

Fly 2:
- UAS (upstream activating sequence promoter) fused to the coding system of interest OR an interfering construct targeting a gene of interest

CROSS FLIES TOGETHER:
- Gal4 produces where the promoter is expressed (specific tissue/time)

  • Gal4 binds to the UAS promoter –> produces the gene of interest

Study ageing:

  • Can over express beta-amyloid peptide in SPECIFIC NEURONAL CELLS
  • THEN, can screen for genes that increase life span or prevent the degeneration of these neurons
50
Q

What is used to score the effect of the genes that increase life span/prevent neurodegeneration? Why?

A

Drosophila eye

Easy to score

51
Q

What is the structure of the drosophila eye?

How can this model be scored easily?

A
  • Compound structure of ~750 individual units (ommatidia)
  • Each ommatidia - has 8 photoreceptors
  • Photosensitive membrane in each photoreceptor - rhabdomere

Scored easily:
- Can shine red light on the flies - see the photoreceptors under the microscope without needing to dissect/fix/prepare tissue

  • Can COUNT how many photoreceptors/neurons are remaining
52
Q

What is the difference between WT and the disease model (when over express beta-amyloid peptide)?

A

Disease model:

- Over-half of the photoreceptors are GONE

53
Q

What is IDE?

What does it do?

A

Insulin degrading enzyme:
- Evolutionally conserved metalloendopeptidase

  • Binds to insulin molecules before they bind to the receptor and REDUCES insulin pathway signalling
54
Q

Where is IDE in the body?

A

Expressed by cells and secreted extracellularily

55
Q

How does IDE interact with beta-amyloid peptidase?

A

Over-expression of beta-amyloid peptidase induces neurotoxicity (shown by reduction in photoR/neurons in the drosophila eye)

IDE reduces this induced neurotoxicity and increases lifespan (but not at long as WT flies)

56
Q

Describe the experiment with Beta-amyloid peptide

A

Beta-amyloid overexpressed specifically in all fly neurons using elav
At the same time, elav expresses GFP

–> Reduces the lifespan

57
Q

What is elav?

A

The promoter which expressed GAL4 in all neuronal cells

58
Q

What happens when express beta-amyloid peptide with HUMAN IDE in flies?

What does this suggest?

A

REDUCES the lifespan of the flies to their counterparts
–> prevents neurodegeneration and increases lifespan

Suggests:
- Decrease of insulin signalling potentially decrease Alzheimers?

59
Q

What is the role of the hypothalamus?

A

Important for regulating insulin production and calorie intake

Can speculate hypothalamic function is important in the onset and progression of Alzhemier’s

60
Q

What mediates the increase in lifespan by DR in the drosophila?

A

Nutrient sensing pathways (insulin/IGF1 pathway) and TOR pathway

61
Q

How is the mTOR pathway activated?

How is it inhibited?
What does this lead to?How?

A

By nutrients

Inhibited by RAPAMYCIN 
Extension of life span due to:
- Autophagy and DNA repair
OR
- Reduction of cancer??
62
Q

What is the action of sirtuins?

What does this cause?

A

ACTIVATE FOXO

Increase longevity

63
Q

SO, what leads to INCREASE in longevity?

A

INCREASE IN:

  • FOXO
  • Sirtuins
  • PTEN

DECREASE (NOT COMPLETE ABLATION OF) IN:

  • mTOR and S6K
  • Insulin
  • Insulin R
  • Chico
  • Mth gene (receptor that results in insulin release in response to nutrients)
64
Q

What is chico?

A

An insulin receptor substrate - functions in the insulin pathway in drosophila

65
Q

Why does this reduction in insulin signalling increase longevity?

A

Drosophila go into a reproductive diapause

A BMS 381 - Developmental neurobiology (17 decks)

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