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BS131: Health & the Community > Lecture 18. Ageing 3. Proteostasis and Caloric Restriction > Flashcards

Lecture 18. Ageing 3. Proteostasis and Caloric Restriction Flashcards

1
Q

What is the protein turnover rate of cartilage collagen?

A

~120 years

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2
Q

What is the protein turnover rate of ornithine decarboxylase?

A

11 minutes

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3
Q

What are proteasomes?

A

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

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4
Q

How do porteasomes work?

A

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

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5
Q

What do leaked electrons not captured by oxidative phosphorylation directly react with oxygen to form?

A

Superoxide anion radicals (O₂*)

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6
Q

What can O₂* modify and damage?

A

O₂* can modify proteins (usually unfolding them) and damage metal prosthetic groups of enzymes (Cu, Fe)
These modified proteins age the cell

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7
Q

What can degrade the oxidised and unfolded proteins?

A

The 20S core (unregulated) proteasome

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8
Q

What are the roles of autophagy?

A

Removal of aggregates, damaged organelles and invading microbes
Developmental remodelling
Providing amino acids nucleotides, lipids and sugars under low nutrient conditions

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9
Q

What happens during autophagy?

A

An isolation membrane captures cytoplasmic contents forming an autophagosome which fuses with a lysosome forming an autolysosome that digests the cytoplasmic cargo

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10
Q

What does microautophagy involve?

A

Direct targeting into a lysosome

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11
Q

What does chaperone-mediated autophagy involve?

A

Via a membrane channel

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12
Q

What is the primary source of the isolation memebrane?

A

The omegasome

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13
Q

How is macroautography selective?

A

LC3-II protein recruited to the isolation membrane captures a cargo receptor that captures cargo

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14
Q

How does LC3-II capture cargo receptors?

A

LC3-II captures cargo receptors that contain an LC3-interacting region (LIR) motif
The cargo receptor then recruits cargo

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15
Q

Is autophagy rapid or slow?

A

Rapid

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16
Q

What are the pros of autophagy in neurodegeneration?

A

Autophagy reduces build-up of toxic aggregates

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17
Q

What are the cons of autophagy in neurodegeneration?

A

Upregulated autophagosomes may process amyloid into the toxic Aβ form

18
Q

What are the pros of autophagy in cancer?

A

Autophagy suppresses tumours by removing damaged organelles and growth factors

19
Q

What are the cons of autophagy in cancer?

A

Autophagy can help cancer cells survive in low nutrient conditions

20
Q

What are the pros of autophagy in infection and immunity?

A

Some intracellular bacteria and viruses can be digested

21
Q

What are the cons of autophagy in infection and immunity?

A

Some microbes subvert autophagy to establish a replicative niche (e.g. Legionella pneumophila)

22
Q

What are the pros of autophagy in ageing?

A

Autophagy removes damaged organelles and can limit production of ROS

23
Q

What is rapamycin?

A

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

24
Q

Does rapamycin increase lifespan in mice?

A

Yes
2009: Rapamycin extends lifespan in mice
2011: Mechanism – it reduces the incidence of cancers in mice

25
Q

Why don’t people take rapamycin?

A

It is an immunosuppressant, inhibiting activation of T cells and B cells by making them less sensitive to interleukin-2

26
Q

What happens in phase 0 of a clinical trial?

A

The earliest trials, small number of people, very small dose. Does the drug reach the target? Is there any target response? How does the drug behave in vivo?

27
Q

What happens in phase 1 of a clinical trial?

A

Small trials, only a few patients, typically with dose escalation as the trial progresses. What is the safe dose? Are there side effects? How do patients cope?

28
Q

What happens in phase 2 of a clinical trial?

A

Larger trials. More about side effects and how to manage them. More about the best dose to use

29
Q

What happens in phase 3 of a clinical trial?

A

Often very large, randomised, double blind. Compare with a control group (new treatment vs standard treatment, comparing different doses)

30
Q

What happens in phase 4 of clinical trials?

A

Done after a drug has been shown to work and has been granted a licence. More about side effects and safety, long term risks and benefits

31
Q

What does mTOR complex 1 (mTORC1) inhibit?

A

Autophagy

32
Q

What is resveratrol (RSV)?

A

A polyphenol found in the skin of grapes so its concentration is high in red wine (also found in the skins of blueberries, raspberries and mulberries)

33
Q

What does resveratrol compete with?

A

ATP for the ATP-binding site of mTOR

34
Q

What does resveratrol also do?

A

Reduces weight gain of mice on high caloric diets, extends the lifespan of mice on high fat diets and improves motor skills and co-ordination

35
Q

Does resveratrol increase the lifespan in humans?

A

Little evidence of lifespan increase

36
Q

What is dietary/caloric restriction?

A

The reduced intake of food without malnutrition which increases the lifespan of many organisms, from yeast to mammals

37
Q

What did the Wisconsin trial show?

A

Macaques on a restricted diet live longer than the control group

38
Q

What did the NIA (National Institute on Aging) trial show?

A

Initially found no difference in the survival rates of their animals, which cast doubt on the entire premise. But CR here was started in some juveniles (where it increased death rates)

39
Q

What was the 2 year CALERIE trial?

A

200 healthy non-obese volunteers reduced their calorific content for 2 years by 15%, showed average weight loss of 9kg and a reduction in base metabolic rate

40
Q

What are the negative effects of calorific restriction?

A

Gaunt appearance, significant decreases in strength and stamina, body temperature, heart rate and sex drive Fatigue, irritability, social withdrawal depression and apathy: some self-mutilation

41
Q

What was the Minnesota Starvation Experiment in November 1944?

A

36 male, single, physically healthy and mentally healthy conscientious objectors to war volunteered to lose 25% of their body weights and only eat vegetables

BS131: Health & the Community (23 decks)

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