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Development > The genetics of ageing > Flashcards

The genetics of ageing Flashcards

1
Q

Closely related organisms can have vastly different lifespans. Give an example of this.

A

Humans can live to ~110, whereas chimps only to ~59.

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2
Q

What is the genetic approach to ageing?

A

Isolate mutants with abnormal ageing rates and determine genes involved.

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3
Q

S. cerevisae is a type of yeast. It is often used in ageing experiment. What is a problem with this?

A

It is not an animal (is a unicellular fungus) and may age very differently.

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4
Q

C. elegans is another model organism for ageing. Give 3 advantages of using it in experiments.

A
  1. Cheap and easy to work with
  2. Short lifespan of 2-3 weeks
  3. Well understood genome
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5
Q

Give 3 characteristic signs of ageing in C. elegans.

A
  1. Reduced movement and feeding
  2. Increased cuticular wrinkling
  3. Gonadal atrophy
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6
Q

Give 3 reasons why mice are good ageing models.

A
  1. Can look at inbreeding effects on ageing
  2. Suffers from age-related disease as humans do
  3. Well understood genome
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7
Q

What is the problem with studying short-lived mutants?

A

They may have died from disease not a shortened-lifespan, thus not accurate in ageing studies.

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8
Q

Tom Johnson in 1988 identified a mutant of which gene?

A

age-1

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9
Q

Mutations in the age-1 gene had what effect on mean lifespan?

A

65% increase.

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10
Q

Mutations in the age-1 gene had what effect on mamixmum lifespan?

A

110%

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11
Q

age-1 mutants appeared what?

A

Youthful for longer.

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12
Q

Cynthia Kenyon in 1993 discovered mutants of which gene?

A

Daf-2

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13
Q

Mutations in the daf-2 gene had what effect on lifespan? What effect did it specifically have on C. elegans?

A

Increased lifespan, a 7-fold increase in C. elegans.

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14
Q

What do age-1 and daf-2 mutants tell us about ageing?

A

It is not fixed.

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15
Q

What is a dauer larva?

A

A developmentally arrested stage 3 larva of C. elegans.

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16
Q

Under what conditions do dauer larvae form?

A

High population density, e.g. high temperature and low food. If these conditions are removed the larva will exit dauer stage and develop into adults.

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17
Q

Dauer larvae eat more than normal 3rd stage larvae. True or false?

A

False - the buccal cavity is sealed so dauer larvae must survive on stored food.

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18
Q

Why are dauer larvae studied in ageing experiments?

A

They can survive for over 2 months, which is longer than the usual lifespan of a reproductive adult. The length of time spent in dauer phase has no effect on the lifespan of the post-dauer adult. They are said to be ageless.

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19
Q

Dauer larvae show differential gene expression that allows them to surpass usual adult lifespan. Which gene are necessary for dauer formation?

A

Daf-2 and age-1.

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20
Q

Age-1 is the same as which gene?

A

Daf-23.

N.B. daf-2 and daf-23 form dauer larvae, as it means the same as daf-2 and age-1.

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21
Q

What does ‘daf-c’ mean?

A

Dauer constitutive, a dauer larva will form in non-dauer inducing conditions.

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22
Q

What does ‘daf-d’ mean?

A

Dauer defective, a dauer larva cannot form at all.

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23
Q

Which gene is crucial for longevity in dauer larvae in wild-type condition?

A

Daf-16

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24
Q

What is the human homologue of age-1?

A

A catalytic subunit of inositol 3-kinase.

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25
Q

What is the human homologue of daf-2?

A

IGF-1 receptor.

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26
Q

What is the human homologue of daf-16?

A

FOCO-class forkhead transcription factor.

27
Q

By looking at human homologues it becomes obvious that insulin-like signalling is crucial in the ageing pathway of nematodes. True or false?

A

True.

28
Q

It is disputed whether the role of insulin-like signalling in ageing is a) public or b) private. Explain what these terms mean.

A

a) Evolutionarily conserved across species

b) Unique to nematodes

29
Q

It appears that insulin-like signalling in ageing is a public strategy. Which animal was compared with a nematode to give this conclusion?

A

Drosophila.

30
Q

It appears that insulin-like signalling in ageing is a public strategy. Why does drosophila support this idea?

A

Nematode daf-2 is homologous to drosophila InR and the pathways are v. similar.

31
Q

It appears that insulin-like signalling in ageing is a public strategy. If you knock out InR in drosophila, what happens?

A

There is zero growth but an increase in longevity.

32
Q

It appears that insulin-like signalling in ageing is a public strategy. By what percentage does knocking out InR in drosophila increase mean female lifespan?

A

85%.

33
Q

It appears that insulin-like signalling in ageing is a public strategy. Mutating chic in drosophila, an insulin receptor substrate, increases lifespan by how much?

A

48%.

34
Q

It appears that insulin-like signalling in ageing is a public strategy. Why is this more complicated in mammals?

A

Nematodes and drosophila only have 1 insulin/insulin receptor, whereas mammals have many.

35
Q

A reduction in insulin-like signalling in nematodes and drosophila increases ageing. True or false?

A

False - it massively reduces ageing.

36
Q

What does FIRKO stand for?

A

Fat-specific Insulin Receptor Knock Out.

37
Q

In 2003 John Kahn produced a FIRKO mouse that lacked insulin receptors in its adipose tissue. What effect did this have and why?

A

It increased mean lifespan by 18%. This is because the mouse was protected against age-related obesity.

38
Q

Define the somatotropic axis.

A

The role of GH, IGFs and their control of metabolic and physiological processes. Essentially controls body size.

39
Q

Where is GH produced?

A

The anterior pituitary.

40
Q

What functions do IGFs (insulin-like growth factors) have?

A

Promotes cell survival, growth and puberty, gonadal function and reduced adiposity (body fat).

41
Q

What conclusion can we come to about insulin-like signalling and ageing in mammals?

A

Insulin-like signalling in mammals does not promote ageing, but the lack of it certainly increases longevity.

42
Q

Give examples of where insulin knock out mammals have resulted in increased longevity.

A

FIRKO mouse and Ames dwarf mice.

43
Q

What is an Ames dwarf mouse?

A

A mouse with combined pituitary hormone deficiency that is dwarfed as a result.

44
Q

Which hormones is Ames dwarf mouse missing?

A

GH, thyroid-stimulation hormone and prolactin.

45
Q

What is responsible for the hormone deficiency in Ames dwarf mice?

A

A mutation in Prop-1, a transcription factor required for normal development of the anterior pituitary.

46
Q

Ames dwarf mice have a wide variety of negative symptoms. Give 3 examples.

A
  1. Obesity
  2. Reduced fertility
  3. Dwarfism
47
Q

Describe the insulin conditions of Ames dwarf mice.

A
  1. Very low circulatory insulin and glucose

2. Undetectable levels of IGF-1

48
Q

The Ames dwarf mouse displays decreased insulin signalling. What effect does this have on longevity?

A

Their mean lifespan is increased by 70-80%.

49
Q

What is the IGF-1 receptor responsible for in mice?

A

The regulation of lifespan and oxidative stress. Heterozygotes are resistant to oxidative stress and thus longer lived.

50
Q

Being heterozygous for the IGF-1 receptor increases the mean lifespan of both male and female mice. True or false?

A

False - it increases that of female mice by 33% but has no effect on male lifespan.

51
Q

What do GH and IGF-1 do in humans?

A

Controls body size.

52
Q

What kind of correlation is there in humans between GH/IGF-1 levels and longevity?

A

It varies between populations. In populations where variation reflects nutritional status there is a positive correlation. In affluent populations where body size is due to the somatotropic axis there is a negative correlation.

BASICALLY, when nutrition is not a limiting factor on body size, elevated levels of GH/IGF that produce larger humans causes a decrease in longevity.

53
Q

There are allelic polymorphisms of both GH and IGF genes. What is characteristic of people with allele A of IGF-1R?

A

Low plasma IGF-1, tend to be longer-lived.

54
Q

What factors are associated with FOXO3A G?

A

Increased longevity and reduced incidence of cancer or CV disease.

55
Q

What is FOXO3A G?

A

An allele of the Forkhead Box O3 gene.

56
Q

What is Forkhead Box O3?

A

A family of transcription factors with a characteristic forkhead DNA binding domain.

57
Q

In the genetic approach to ageing, which kind of mutants are more informative?

A

Long-lived (as opposed to short-lived) mutants.

58
Q

The daf (dauer formation) genes are organised into a complex, branched pathway. True or false?

A

True.

59
Q

Mutations in daf-2 are temperature sensitive. True or false?

A

True.

60
Q

All age-1 mutants are long-lived. True or false?

A

True.

61
Q

The daf-16 increases longevity in wild-type. In mutants it decreases lifespan. Why?

A

It suppresses the life extension effects of daf-2.

62
Q

The C. elegans genome has a single longevity programme. True or false?

A

False - there are 2 separate programmes, one for dauer larvae and one for adults.

63
Q

What is the general consensus regarding the IGF-1 receptor and ageing?

A

It accelerates ageing.

64
Q

How are allelic frequency studies helpful in ageing?

A

Alleles promoting longevity will increase in frequency with increasing age, thus compare frequency of different alleles in young and old populations.

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