The genetics of ageing Flashcards
Closely related organisms can have vastly different lifespans. Give an example of this.
Humans can live to ~110, whereas chimps only to ~59.
What is the genetic approach to ageing?
Isolate mutants with abnormal ageing rates and determine genes involved.
S. cerevisae is a type of yeast. It is often used in ageing experiment. What is a problem with this?
It is not an animal (is a unicellular fungus) and may age very differently.
C. elegans is another model organism for ageing. Give 3 advantages of using it in experiments.
- Cheap and easy to work with
- Short lifespan of 2-3 weeks
- Well understood genome
Give 3 characteristic signs of ageing in C. elegans.
- Reduced movement and feeding
- Increased cuticular wrinkling
- Gonadal atrophy
Give 3 reasons why mice are good ageing models.
- Can look at inbreeding effects on ageing
- Suffers from age-related disease as humans do
- Well understood genome
What is the problem with studying short-lived mutants?
They may have died from disease not a shortened-lifespan, thus not accurate in ageing studies.
Tom Johnson in 1988 identified a mutant of which gene?
age-1
Mutations in the age-1 gene had what effect on mean lifespan?
65% increase.
Mutations in the age-1 gene had what effect on mamixmum lifespan?
110%
age-1 mutants appeared what?
Youthful for longer.
Cynthia Kenyon in 1993 discovered mutants of which gene?
Daf-2
Mutations in the daf-2 gene had what effect on lifespan? What effect did it specifically have on C. elegans?
Increased lifespan, a 7-fold increase in C. elegans.
What do age-1 and daf-2 mutants tell us about ageing?
It is not fixed.
What is a dauer larva?
A developmentally arrested stage 3 larva of C. elegans.
Under what conditions do dauer larvae form?
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.
Dauer larvae eat more than normal 3rd stage larvae. True or false?
False - the buccal cavity is sealed so dauer larvae must survive on stored food.
Why are dauer larvae studied in ageing experiments?
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.
Dauer larvae show differential gene expression that allows them to surpass usual adult lifespan. Which gene are necessary for dauer formation?
Daf-2 and age-1.
Age-1 is the same as which gene?
Daf-23.
N.B. daf-2 and daf-23 form dauer larvae, as it means the same as daf-2 and age-1.
What does ‘daf-c’ mean?
Dauer constitutive, a dauer larva will form in non-dauer inducing conditions.
What does ‘daf-d’ mean?
Dauer defective, a dauer larva cannot form at all.
Which gene is crucial for longevity in dauer larvae in wild-type condition?
Daf-16
What is the human homologue of age-1?
A catalytic subunit of inositol 3-kinase.
What is the human homologue of daf-2?
IGF-1 receptor.
What is the human homologue of daf-16?
FOCO-class forkhead transcription factor.
By looking at human homologues it becomes obvious that insulin-like signalling is crucial in the ageing pathway of nematodes. True or false?
True.
It is disputed whether the role of insulin-like signalling in ageing is a) public or b) private. Explain what these terms mean.
a) Evolutionarily conserved across species
b) Unique to nematodes
It appears that insulin-like signalling in ageing is a public strategy. Which animal was compared with a nematode to give this conclusion?
Drosophila.
It appears that insulin-like signalling in ageing is a public strategy. Why does drosophila support this idea?
Nematode daf-2 is homologous to drosophila InR and the pathways are v. similar.
It appears that insulin-like signalling in ageing is a public strategy. If you knock out InR in drosophila, what happens?
There is zero growth but an increase in longevity.
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?
85%.
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?
48%.
It appears that insulin-like signalling in ageing is a public strategy. Why is this more complicated in mammals?
Nematodes and drosophila only have 1 insulin/insulin receptor, whereas mammals have many.
A reduction in insulin-like signalling in nematodes and drosophila increases ageing. True or false?
False - it massively reduces ageing.
What does FIRKO stand for?
Fat-specific Insulin Receptor Knock Out.
In 2003 John Kahn produced a FIRKO mouse that lacked insulin receptors in its adipose tissue. What effect did this have and why?
It increased mean lifespan by 18%. This is because the mouse was protected against age-related obesity.
Define the somatotropic axis.
The role of GH, IGFs and their control of metabolic and physiological processes. Essentially controls body size.
Where is GH produced?
The anterior pituitary.
What functions do IGFs (insulin-like growth factors) have?
Promotes cell survival, growth and puberty, gonadal function and reduced adiposity (body fat).
What conclusion can we come to about insulin-like signalling and ageing in mammals?
Insulin-like signalling in mammals does not promote ageing, but the lack of it certainly increases longevity.
Give examples of where insulin knock out mammals have resulted in increased longevity.
FIRKO mouse and Ames dwarf mice.
What is an Ames dwarf mouse?
A mouse with combined pituitary hormone deficiency that is dwarfed as a result.
Which hormones is Ames dwarf mouse missing?
GH, thyroid-stimulation hormone and prolactin.
What is responsible for the hormone deficiency in Ames dwarf mice?
A mutation in Prop-1, a transcription factor required for normal development of the anterior pituitary.
Ames dwarf mice have a wide variety of negative symptoms. Give 3 examples.
- Obesity
- Reduced fertility
- Dwarfism
Describe the insulin conditions of Ames dwarf mice.
- Very low circulatory insulin and glucose
2. Undetectable levels of IGF-1
The Ames dwarf mouse displays decreased insulin signalling. What effect does this have on longevity?
Their mean lifespan is increased by 70-80%.
What is the IGF-1 receptor responsible for in mice?
The regulation of lifespan and oxidative stress. Heterozygotes are resistant to oxidative stress and thus longer lived.
Being heterozygous for the IGF-1 receptor increases the mean lifespan of both male and female mice. True or false?
False - it increases that of female mice by 33% but has no effect on male lifespan.
What do GH and IGF-1 do in humans?
Controls body size.
What kind of correlation is there in humans between GH/IGF-1 levels and longevity?
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.
There are allelic polymorphisms of both GH and IGF genes. What is characteristic of people with allele A of IGF-1R?
Low plasma IGF-1, tend to be longer-lived.
What factors are associated with FOXO3A G?
Increased longevity and reduced incidence of cancer or CV disease.
What is FOXO3A G?
An allele of the Forkhead Box O3 gene.
What is Forkhead Box O3?
A family of transcription factors with a characteristic forkhead DNA binding domain.
In the genetic approach to ageing, which kind of mutants are more informative?
Long-lived (as opposed to short-lived) mutants.
The daf (dauer formation) genes are organised into a complex, branched pathway. True or false?
True.
Mutations in daf-2 are temperature sensitive. True or false?
True.
All age-1 mutants are long-lived. True or false?
True.
The daf-16 increases longevity in wild-type. In mutants it decreases lifespan. Why?
It suppresses the life extension effects of daf-2.
The C. elegans genome has a single longevity programme. True or false?
False - there are 2 separate programmes, one for dauer larvae and one for adults.
What is the general consensus regarding the IGF-1 receptor and ageing?
It accelerates ageing.
How are allelic frequency studies helpful in ageing?
Alleles promoting longevity will increase in frequency with increasing age, thus compare frequency of different alleles in young and old populations.
