Biology of Ageing 2 Flashcards
Name a cellular component that can’t be degraded by autophagy
Genomic DNA
Describe an autophagolysosome
When autophagosome fuses with lysosome, it becomes a one layered membrane that is dark-coloured on electron micrograph because of dense material
Why would autophagy need to degrade lysosomes?
Lysosomes seal enzymes inside, if there was a lysosomal disease the membrane could be damaged releasing these degradative enzymes
What are AMPK and mTORC1?
Both kinases
What triggers AMPK and mTORC1 activation and what is the outcome?
Under starvation and stress AMPK is turned on and initiates autophagy by phosphorylating ULK1
In the presence of nutrients, growth factors & amino acids, mTORC1 phosphorylates ULK1 inhibiting it from initiating autophagy
What physiological conditions promote autophagy and why?
When a cell is under stress or starvation, autophagy is increased, and other systems are shut off
Autophagy removes toxic or obsolete proteins and organelles and recycles the degradation products for use as sources of energy and metabolites in anabolic pathway
What is another function of AMPK?
Stimulates the insulin-independent glucose transporter = GLUT2
What would glucose starvation cause?
Activation of AMPK because ATP levels would be low and AMP would be high
AMPK would phosphorylate ULK1 initiating autophagy
How many AMPKs do we have vs yeast?
Humans = AMPK 1 & 2 so would need a double KO to inhibit the function
Yeast = 1 AMPK
What are the sites on ULK1 that AMPK phosphorylates?
Ser 317 & Ser 777
This is in response to glucose starvation
No glucose = AMPK phosphoylation occurs
How does mTORC1 prevent autophagy?
Disrupting the ULK1-AMPK interaction by phosphorylating the Ser 757 on ULK1
What is rapamycin?
mTORC1 inhibitor = enhances the interaction of endogenous ULK1 and AMPK
Rapamycin increases autophagy activity
What does TSC1 do?
TSC1 is the upstream inhibitor of mTROC1
KO of TSC1 causes hyperactivated mTORC1 that is INSENSITIVE to nutrient availability
How does ULK1 iniate autophagy?
ULK1 phosphorylates LC3
Which is necessary for LC3 to conjugate and modify the autophagosome membrane
Where is mTOR found?
Cytoplasm not plasma membrane
Nutrient signal is passed through the presence of whether there are amino acids in the lysosomes or not
What does metformin do?
Activates AMPK but not sure by what mechanism
Why is it beneficial to suppress mTOR to a certain degree?
mTOR promotes anabolic signalling
Slowing this down means the rate of synthesis can also be slowed, so there is more time for the checkpoints to check allowing the quality control to increase
Why are dogs considered a good ageing model?
They live with us so are exposed to a similar environment leading to a similar microbiome
They have a shorter lifespan than us so a quicker model to observe
Rapa has already been tested on dogs
What was the outcome of calorie restriction?
20% calorie restriction increased both female and male lifespan
But 40% CR had a detrimental effect on both, but more severely on females, killing them earlier
What are the important signalling pathways to study?
Evolutionarily conserved nutrient signalling pathways that regulate longevity
[insert examples]
What causes Laron syndrome?
Deficiency in growth hormone receptor = prevents their bodies from properly using the hormone
What levels of GH and IGF-1 do people with Laron syndrome have?
They have normal or high levels of GH
Low levels of IGF-1
What is the role of IGF-1?
Normally helps growth hormone (GH) promote the growth of bones and tissues
GH causes IGF-1 release
What is the GH-IGF1 axis?
GH is released from the pituitary
Binds to GHR on the liver
Liver releases IGF-1
What is a benefit of laron syndrome?
Protects from some age-related syndromes
Growth hormone receptor deficient subjects display lower serum glucose, insulin, blood pressure, smaller cardiac dimensions, similar pulse wave velocity etc
Conclusion: GHRD have normal or improved levels of CVD risk factors compared to their relatives
What is a daf-2 mutants?
Mutation in the insulin-like growth factor receptor (IGFR) in WORMS
Loss-of-funciton mutation
This causes daf-2 mutants to be long-lived so increases the proportion of time spent in a frail state compared to WT
