AGEING Flashcards
What is meant by ageing?
The progressive, irreversible decline in organismal performance
What is the current max life span and average life span of humans?
Max = 122 years (thus far)
Current average lifespan is 82 years old and is thought to have plateaued due to the lack of treatments for major killers like cancers and metabolic diseases
2 main factors that influence ageing?
GENOTYPE - genotype @ birth and the accumulation of mutations with age
ENVIRONMENT - diet, lifestyle, exposure to various external factors
Model organisms used to investigate ageing and why?
C.elegans, Drosophila and Mice
C. elegans and Dros are small and easy to culture, have a short lifespan, Genetically tractable (easy to control genetics) and easy to CONTROL ENVIRONMENT they are in
What is the problem with ‘measuring’ ageing? What is done instead of trying to measure ageing?
There is no direct method for measuring ageing as so many factors are involved and there are a lot of environmental impacts.
Instead, we measure age at death.
What is the median lifespan in animal models?
What is the purpose of Drosophila genetic screening
Median lifespan is the number of days into a study at which 50% of the population of models are still alive. This can be taken from a SURVIVAL CURVE which is plotted by keeping genetically identical animals in the same conditions.
Genetic screens are used in Drosophila to screen for genes that are involved in regulating life span
IGF/Insulin pathway - what is the purpose of the insulin hormone?
What is the important downstream effector of the insulin pathway?
Insulin pathway is highly conserved and ancient. Mammals, c.elegans and drosophila all have insulin and insulin-like peptides that are all involved in a highly conserved pathway.
Insulin binds InsulinRs and the intracellular component CHICO – this signals PI3K –> this ultimately impacts FOXO and S6K which have many effects.
DROSOPHILA LARGE-SCALE SCREEN - what does it consist of and what was shown regarding Chico
- DROSOPHILA underwent random mutagenesis
- Mutations in the Chico componant of the insulin pathway correlated with increased median lifespan
How does FOXO work and function, and what is the effect of insulin on FOXO
FOXO stimulates growth and lifespan by increasing transcription of genes which result in DNA repair, autophagy and decreased oxidative stress. Increase in all of these things will promote health and longevity!!!
Insulin causes DECREASE in FOXO stimulation. Therefore DECREASED INSULIN = INCREASED FOXO
Methuselah receptor – what does it code for? What was shown in Methusulah receptors in DROSOPHILA
What was shown by an antagonist of it BUT what is the problem with this?
Methuselah codes for a receptor that triggers insulin release in response to nutrients
Methuselah are LONG LIVED and a peptide antagonist of the receptor extends life span!
The antagonist extended life span BUT didn’t promote healthy ageing - i.e lived for longer but were’t more healthy and the adverse effects of ageing wasn’t reversed
What was shown as a result of DIETARY RESTRICTION in DROSOPHILA??
Modest dietary restriction was seen to extend life span across the species
Survival curve vs probability of death – which is used more and how do the curves differ?
Probability of death more widely used in DROSO studies - curve is seen to move upwards
Fully fed flies vs calorie restricted flies in probability of death?
Fully fed flies = increased probability of death
Dietary restricted flies showed a decreased mortality risk of death when calories were restricted AT ANY POINT
C.A.L.O.R.I.E - what is it?
Studies currently underway to investigate the long term effects of reducing energy intake
How does Dietary restriction impact the insulin pathway?
fewer calories –> less insulin secreted –> less inhibition of FOXO (therefore more FOXO) –> more autophagy/DNA repair/less oxidative stress –> HEALTH AND LONGEVITY
What other pathways are impacted by insulin and therefore could be contributing to increased lifespan?
- Inflammatory
- Adiposity
Alzheimer’s - how many people does it effect?
What charcterises it and what are the side effects?
Neurodegeneration disease effecting 7% of people above the age of 65.
Results in neuronal cell death and tissue atrophies.
Characterised by the build up of B-amyloid peptide but don’t know if this is the INITIAL CAUSE OR CONCEQUENCE
B-amyloid peptide - what does this being a neurotoxin allow?
Makes possible to screen for genes that decrease neurotoxicity.
UAS/Gal4 system used to INVESTIGATE Alzheim IN FLIES???
Make 2 fly strains - one strain where Gal4 expressed downstream of a promoter found in neurons
Second strain involves an overexpression system used to overexpress B-amyloid peptide (UAS upstream of B-Amlyoid peptide gene which is bound by Gal4 to increase transcription
Resultant bred strain means Gal4/B-amyloid expressed in all neurons
Overexpression strain of Drosophila – what does overexp. of B-amyloid allow?
Allows overexpression of B-amyloid which allows to screen for genes in drosophila that INCREASE LIFE SPAN IN FLIES WITH ‘ALZHEIMERS’
Drosophila eye - why a good model for observing decline that comes with ageing?
Can flourscently stain rhabdomeres and observe to see decline in their function in relation to neurodegenerative effects — look for genes that restore Rhabdomeres to a control level??
I.D.E - insulin degrading enzyme - what is it and what does it do?
I.D.E identified to degrade insulin and increase life span/decrease neurotoxicity
