Cell Aging And Death

Question 1

What is clonal senescence and what evidence do we have for it?

Answer 1

All animals are genetically programmed to have a finite life expectancy even when kept under ideal conditions

Evidence:
- Embryogenesis, infancy, adolescence and maturity are genetically programmed
- Family members share statistically similar life expectancies
- Genetic conditions associated with abnormal rate of ageing

Question 2

What is replication senescence and what are its mechanisms?

Answer 2

“wear and tear” theory

Mechanisms:
- Damage to mitochondrial DNA: mechanisms that deal with DNA damage get less effective over time
- Telomere shortening

Question 3

What is the role of telomeres in cell senescence?

Answer 3

Telomeres cap and protect chromosomes from end to end fusions and chromosomal instability

They start out with multiple kilobases in length, and shorten after multiple replications

Question 4

Clinicopathological features of ageing:

Answer 4

Skin:
- Less elastic and collagen
- Thinner dermis

Cardiovascular:
- Ratio of elastin to collagen decreases

Immune cells:
- More memory cells, less naive cells (can’t properly respond to new pathogens)
- Thymus thins

Osteoarticular aging:
- Osteoporosis

Nervous system:
- Cerebrovascular disease

Question 5

Intrinsic apoptotic pathway:

Answer 5

Cytochrome C released during apoptosis and binds with:
- Apoptotic protease activating factor, ATP
- Pro-caspase 9
Altogether this makes an apoptosome

Apoptosome cleaves procaspase-9 into caspase 9, which cleaves procaspase 3 into caspase 3, this triggers cell death

Question 6

Extrinsic apoptotic pathways:

Answer 6

TNF (tumour necrosis factor) pathway:
- Binds to TNF receptor
- Triggers TNF receptor associated death domain (TRADD) and FAS associated death domain (FADD)
- Forms complex with procaspase 8 starting activation of caspase 8 and 3 triggering apoptosis

FAS (first apoptotic protein) pathway:
- Starts a complex of FADD, procaspase 8 / 10, this is called the death inducing signalling complex (DISC)
- Leads to caspase activation
- Initiates apoptosis

Question 7

How does caspase activation occur?

Answer 7

Intrinsic:
- Apoptosome cleaves procaspase 9 into caspase 9
- Caspase 9 cleaves procaspase 3 to active form (caspase 3)

Extrinsic:
TNF:
- TRADD and FADD form complex with procaspase 8 which activates caspase 8 and 3
FAS:
- Caused by DISC (FADD, procaspase 8/10 complex)

Question 8

Examples of apoptosis in aging physiology:

Answer 8

Skin:
- Sun damage

Cardiovascular:
- Increased systolic blood pressure

Osteoarticular aging:
- Prone to fractures

Nervous system:
- Dementia
- Parkinson’s