Biology of Ageing 3

Question 1

Is ageing the driver or response of dysfunction?

Answer 1

Ageing reduces activation of mTORC1 signalling upon nutrient or exercise

Question 2

What happens when rapamycin is fed to mice LATE in life?

Answer 2

Extends lifespan

Question 3

What is the mTORC1 pathway?

Answer 3

Nutrients and growth factors activates mTORC1

mTORC1 inhibits ULK1 (Ser757)

mTORC1 phosphorylates S6K1

S6K1 phosphorylates S6 on ribosome

Protein synthesis

Question 4

What is activation of mTORC1 in aged muscle associated with?

Answer 4

Degenerative changes in human skeletal muscle

Question 5

Why is there degeneration in human skeletal muscle as we age?

Answer 5

Impaired nutrient sensing and anabolic response of muscle protein synthesis

Associated with S6K1 dyregulation in elderly humans

This means that mTORC1 pathway is activated even when under stress/starvation

This can lead to inefficient or excessive protein production, contributing to muscle protein breakdown rather than repair.

Question 6

Is the up-regulated mTORC1 signalling driving or responding to muscle ageing?***

Question 7

What happens when insulin binds its receptor?

Answer 7

Activation of tyrosine kinase = phosphoylation of insulin-receptor-substrate (IRS)

Phosphorylated IRS serves as docking site for PI3K = PIP3 formation and Akt activation

Question 8

What does Akt activation promote?

Answer 8

Nutrient utilization, storage and other ANABOLIC processes

Simultaneously suppresses catabolic pathways

Question 9

What is the function of the muscle clock?

Answer 9

Regulates muscle insulin sensitivity

Question 10

What are the 3 ways the muscle clock regulates muscle insulin sensivity?

Answer 10

Via protein levels and membrane translocation of insulin-sensitive GLUT4

AND via insulin signalling pathway via expression of SIRT1 (deacetylase)

Via histone acetylation of metabolic genes by histone deacetylase3 (HDAC3)

Question 11

What are the outcomes of time-restricted feeding?

Answer 11

Prevents body weight gain

Improves glucose tolerance

Question 12

Why do circadian misalignment and insufficient sleep play a role in obesity?

Answer 12

During sleep, energy is conserved

Insufficient sleep disrupts hormones = increase ghrelin and decrease leptin

Increased appetite increases energy intake