Introduction to Ageing

Question 1

Why is ageing a key topic in neuroscience?

Answer 1

Neurons are incredibly long lived and ageing is a risk factor for many neurodegenerative diseases

Question 2

What human populations have been used to study ageing?

Answer 2

In the US - Framingham cohort have been studied for 60 years, however small community so little variability
- In Scotland - Lothian cohort, found that parental education was predictive of neurodegeneration

Question 3

What is ageing?

Answer 3

An interaction of genetic, environmental and lifestyle factors which influence longevity

Question 4

What does ageing cause?

Answer 4

Abnormal metabolism, damage to molecules structures and systems, and age-related pathologies

Question 5

What are the complications with using animal models to study ageing?

Answer 5

• Takes a long time, rates need to live 2 years to be truly aged
• Drosophila age quicker but are evolutionarily far removed from humans

Question 6

What are the four theories of ageing?

Answer 6

1. Programmed ageing - as there is programmed early development there is early ageing e.g most women go through menopause at 52
2. Rate of living hypothesis - the idea that the faster the metabolic rate the shorter the life (however parrots have fast metabolisms and long lives)
3. Nitric Oxide theory
4. Reactive Oxygen Species Theory

Question 7

What are free radicals?

Answer 7

• Compounds with unpaired electron

- By their nature are very reactive and can damage molecules and cells

Question 8

Which biological pathways can result in the production of ROS?

Answer 8

1. Mitochondrial electron transport (can be leaky)
2. Peroxisomal fatty acid metabolism
3. Cytochrome p-450 reactions
4. Phagocytic cells which destroy viruses can sometimes leak out

Question 9

How can the mitochonrial pathway lead to the production of superoxide (O2) and hydrogen peroxide (H2O2)

Answer 9

• If there is a high ATP:ADP ratio in the mitochondrial matrix then there is an inhibition of the citric acid cycle and less shuttling of electrons to the electron transport system to reduce production of ATP
• This leads to low matrix protons and high matrix electrons in the mitochondria
• As water cannot form without protons O2 is reduced to superoxide
• However SOD reduces superoxide to hydrogen peroxide and molecular oxygen and catalase further reduces hydrogen peroxide to water and oxygen

Question 10

How can hydrogen peroxide occur within the cytosol? How is it dealt with?

Answer 10

As a side product of fatty acid synthesis, can also be reduced by catalse or glutathionene peroxidase

Question 11

What do oxidants typically target?

Answer 11

• Lipids, which are very important for transport, when oxidised these can become brittle
• Nucleic acids, sugars in the DNA are particularly vulnerable, damage to the DNA leads to a higher rate of mutations and miscopying of the RNA
• Proteins very susceptible to oxidative stress, if missfolded cannot function properly or may aggregate

Question 12

What are age-associated trends?

Answer 12

• Accumulation of oxidative end products
• Oxidative depletion of key biological pools (proteins and lipids)
• Defence and repair systems malfunction
• Trends in oxidant generation

Question 13

Why is the nervous system particularly vulnerable to ageing?

Answer 13

• Needed for everything and interaction with the environment, very simple tasks require a healthy nervous system
• Neurons are not readily replaced (there is some neural genesis in the hippocampus)
• Central connections are not easily replaced
  The blood brain barrier means that interventions are technically demanding