Health and community ageing

Question 1

What is mortality shock

Answer 1

A reduction in life expectancy with a quick recovery

Question 2

What causes a mortality shock

Answer 2

• Natural disasters e.g. Haiti earthquake
• Emergence of disease e.g. Nepalese peacekeepers brought cholera to Haiti
• Conflicts e.g. IS where prolonged conflict stops recovery

Question 3

3 ageing diseases

Answer 3

1. Hutchinson-Gilford syndorme
2. Werner syndrome
3. Down’s syndrome

Question 4

What is Hutchinson gilford syndrome

Answer 4

• A genetic disorder where ageing manifests at a very early stage.
• Average age of death is 13
• Fragile body, large head, loss of hair, dwarfism

Question 5

Causes of Hutchinson gilford syndrome

Answer 5

• A mutated lamin A protein, called prgerin. Has the last 50 amino acids missing.
• Causes a change in nuclear shape.
• Lamin A promotes genetic stability by maintain proteins in DNA repair
• There is an inability to repair DNA damage causing premature ageing.

Question 6

Why is HGPS not a good model for ageing

Answer 6

• No increase risk of cancer
• High blood pressure is rare
• Dont suffer from mental degeneration or get Alzheimers

Question 7

What is Werner syndrome

Answer 7

• Normal growth until puberty, then accelerated ageing
• Autosomal recessive
• Live to 40s - 50s
• Common cause of death is cancer and atherosclerosis (Build up of plaque in arteries)

Question 8

Causes of werner syndrome

Answer 8

Limited cellular division capacity:

• Fibroblasts have fewer divisions
• Result in a loss of function in WRN, a DNA helicase

Faulty DNA replication at telomeres:
-WRN has a role in efficient replication of telomeres

Question 9

Why is werner not a good model for ageing

Answer 9

• No high blood pressure
• No stroke
• No mental degeneration and Alzheimers

Question 10

What is Down’s syndrome symptoms

Answer 10

• Greying/ loss of hair
• Early onset of vascular disease
• Early onset of Alzheimer’s disease
• Build of plaques and tangles (hallmarks)

Question 11

3 types of downs syndrome

Answer 11

1. Trisomy 21: An extra chromosome 21
2. Translocation downs: Extra chromosome 21 attached to another chromosome
3. Mosaic Down’s: Some cells are trisomic, others are not

Question 12

Causes of Down’s syndrome

Answer 12

• Fibroblasts proliferate slowly
• There is downregulation of USP 16 which a critical regulator of DNA damage by removing ubiquitin from histones. Ubiquinated histones recruit DNA repair enzymes at sites of double breaks

Question 13

Mutated age-1 gene

Answer 13

It encodes catalytic subunit of PI3K.
Leads to dysregulation of glucose metabolism
Linked to diet and caloric restriction

Question 14

daf-2 gene

Answer 14

Allows C.elegans to enter a dauer state which double life span

Question 15

APOE-4 allele

Answer 15

A risk factor for Alzheimer’s.
APOE removes plaque (amyloid beta)
APOE 4 Binds poorly to plaque (amyloid beta) and so there is a build up.

Question 16

How to interfere with IIS pathway to decrease ageing

Answer 16

• Phagocytosis

- Caloric restriction (limiting damage due to oxidative phosphorlyation)

Question 17

2 removal mechanisms

Answer 17

• Proteasome mediated

- Autophagy

Question 18

How are proteins damaged

Answer 18

• Misfolded

- Reactive oxygen species (formed by leaked elctrons reacting with oxygen)

Question 19

How do proteasomes degrade damage proteins

Answer 19

Made of a regulatory particle and a core particle. Where proteins are unfolded by the regulatory particle and degraded by the core particle.

Question 20

Role of Autophagy

Answer 20

• Removes aggregates and damage organelles

- Also provides nucleotides, lipids and sugars under low nutrient conditions

Question 21

Stages of macroautophagy

Answer 21

1. Isolation membrane captures cytoplasmic contents forming an autophagosome
2. Fuses with a lysosome becoming an autolysosme
3. Hydrolytic enzymes degrade cytoplasmic cargo

Question 22

What is microautophagy

Answer 22

Direct targeting of the lysosme

Question 23

What is chaperone mediated autophagy

Answer 23

Via membrane channel

Question 24

How is macroautophagy selective

Answer 24

Recruits a LC3-II protein that acts as a receptor for ubiquinated substrates

Question 25

What is autophagy stimulated by and inhibited by

Answer 25

Stimulated by FOXO-3a

Inhibited by mTORC I

Question 26

What does rampomycin do

Answer 26

Inhibits mTORC I

Question 27

What does resveratrol do

Answer 27

Stimulates autophagy by activating SIRT 1 which activates FOXO 3a

Question 28

Clinical trials

Answer 28

Phase 0: see if response from small does on a small number of people
Phase 1: Increase dose and see if it is safe, check for side effects
Phase 2: Find best dose
Phase 3: Compare with control group, double blind
Phase 4: look for long term effects, negative and positive

Question 29

Primary hallmarks

Answer 29

1. Genomic instability
2. Loss of telomeres
3. Epigenetic alterations
4. Loss of proteostatsis

Question 30

Antagonistic hallmarks of ageing

Answer 30

1. Deregulated nutrient sensing (decline of IFG1 with age)

2. Mitochondrial dysfunction (more electron leakage, ROS triggers survival in stress conditions)

Question 31

Integrative hallmarks

Answer 31

1. Cellular senescence
2. Stem cell exhaustion
3. Altered intracellular communication

Question 32

How does olive oil reduce ageing

Answer 32

Antioxidant and anti-inflammatory

Question 33

Broccoli

Answer 33

Activation of NRF2 and FOXO. Mediated by sulforaphane.

Question 34

NRF2 function

Answer 34

When uderstress or sulforaphane binds, Keap 1 releases NRF2 stimulating expression of catalase and superoxide dismutase

Question 35

Role of cucumin

Answer 35

Upregulates NRF2

Question 36

Role of spermidine

Answer 36

Induces autophagy