Lecture 18. Ageing 3. Proteostasis and Caloric Restriction Flashcards
What is the protein turnover rate of cartilage collagen?
~120 years
What is the protein turnover rate of ornithine decarboxylase?
11 minutes
What are proteasomes?
Multi-subunit particles with a barrel-shaped catalytic core (protease activity) capped with regulatory particles
Found in the cytosol and around the nuclear pore complexes. Each of our cells has about 30,000 proteasome
How do porteasomes work?
Proteins destined for destruction are unfolded by the regulatory particles, and then are degraded in the core particle and expelled as peptides
The peptides can be displayed at the cell surface (immunological function) or further degraded by cellular proteases into amino acids
What do leaked electrons not captured by oxidative phosphorylation directly react with oxygen to form?
Superoxide anion radicals (O₂*)
What can O₂* modify and damage?
O₂* can modify proteins (usually unfolding them) and damage metal prosthetic groups of enzymes (Cu, Fe)
These modified proteins age the cell
What can degrade the oxidised and unfolded proteins?
The 20S core (unregulated) proteasome
What are the roles of autophagy?
Removal of aggregates, damaged organelles and invading microbes
Developmental remodelling
Providing amino acids nucleotides, lipids and sugars under low nutrient conditions
What happens during autophagy?
An isolation membrane captures cytoplasmic contents forming an autophagosome which fuses with a lysosome forming an autolysosome that digests the cytoplasmic cargo
What does microautophagy involve?
Direct targeting into a lysosome
What does chaperone-mediated autophagy involve?
Via a membrane channel
What is the primary source of the isolation memebrane?
The omegasome
How is macroautography selective?
LC3-II protein recruited to the isolation membrane captures a cargo receptor that captures cargo
How does LC3-II capture cargo receptors?
LC3-II captures cargo receptors that contain an LC3-interacting region (LIR) motif
The cargo receptor then recruits cargo
Is autophagy rapid or slow?
Rapid
What are the pros of autophagy in neurodegeneration?
Autophagy reduces build-up of toxic aggregates
What are the cons of autophagy in neurodegeneration?
Upregulated autophagosomes may process amyloid into the toxic Aβ form
What are the pros of autophagy in cancer?
Autophagy suppresses tumours by removing damaged organelles and growth factors
What are the cons of autophagy in cancer?
Autophagy can help cancer cells survive in low nutrient conditions
What are the pros of autophagy in infection and immunity?
Some intracellular bacteria and viruses can be digested
What are the cons of autophagy in infection and immunity?
Some microbes subvert autophagy to establish a replicative niche (e.g. Legionella pneumophila)
What are the pros of autophagy in ageing?
Autophagy removes damaged organelles and can limit production of ROS
What is rapamycin?
A macrolide antifungal agent produced by the bacterium Streptomyces hygroscopicus, isolated for the first time in 1972 from samples of S. hygroscopicus found on Easter Island
Does rapamycin increase lifespan in mice?
Yes
2009: Rapamycin extends lifespan in mice
2011: Mechanism – it reduces the incidence of cancers in mice
