enabling replicative immortality

Question 1

what are the triggers for senescence?

Answer 1

accumulation of DNA damage with time

strong acute damage

Question 2

what is ‘the hayflick limit’?

Answer 2

the idea that normal human cells will divide a set number of times before they stop (normal human fibroblast cell lines will divide for 50-60 population doublings before viability begins to decrease

Question 3

what is senescence?

Answer 3

a terminal differentiation state in which metabolically active cells are permanently and irreversibly arrested, with distinct morphological changes

Question 4

what are the pathways to senescence?

Answer 4

• replicative senescence (telomere damage)

- stress induced premature senescence (oxidative stress, activation of oncogenes)

Question 5

what are telomeres?

Answer 5

repetitive DNA sequences (TTAGGG) that cap the chromosomes and protect their ends from erosion

Question 6

list markers of senescence

Answer 6

1- growth arrest 
2- SA-Bgal
3- DNA damage foci
4- heterochromatin foci 
5- p16INK4a
6- senescence associated

Question 7

list markers of senescence

Answer 7

1- growth arrest 
2- SA-Bgal
3- DNA damage foci
4- heterochromatin foci 
5- p16INK4a
6- senescence associated secretory phenotype

Question 8

what is ‘senescence associated B-gal’?

Answer 8

‘hallmark’ of senescence

most widely used senescence marker

Question 9

what are senescence associated heterochromatin foci?

Answer 9

-senescence is associated with large scale chromatin reorganisation

characterised by enrichment of repressive marks such as trimethylated H3K9 and heterochromatic protein 1

result of spatial reorganisation of pre-existing repressive marks rather than global changes in histone methylation

Question 10

what is meant by the senescence associated secretory phenotype (SASP)?

Answer 10

senescence is mediated by secretory factors e.g. inflammatory cytokines, chemokine, ECM proteases, growth factors and other signalling molecules secreted by senescent cells

Question 11

what functions are associated with the SASP?

Answer 11

• immune evasion
• immune surveillance
• wound healing acceleration
• tumour promotion
• cellular plasticity
• tissue dysfunction
• senescence re-enforcement
• paracrine senescence

Question 12

in what way could senescence promote cancer?

Answer 12

SASP stimulates cell growth and transformation

Question 13

what is meant by the term: antagonistic pleiotropy?

Answer 13

senescence controls more than one phenotypic trait in an organism (pleiotropy), at least one of them is beneficial and at least one is detrimental to the organisms fitness

Question 14

give examples of senescence related diseases?

Answer 14

• glaucoma
• macular degeneration
• disc degeneration
• brain aneurysm
• AD
• parkinsons
• obesity
• IBD
• sarcopenia
• liver fibrosis
• hypertension
• COPD
• renal disease

Question 15

what is therapy induced senescence?

Answer 15

radio/chemotherapy stresses the cells, some die, some senescence.
the senescent cancer cells survive -> tumour relapse

Question 16

how do cancer cells enable replicative immortality?

Answer 16

telomerase expression

inhibition of p53 and Rb

Question 17

what sort of therapies could be used to target aberrant senescence?

Answer 17

telomerase inhibitors

• SASP inhibitors (senostatics)
• anti-senescent drugs (senolytics)
• reactivate tumour suppressor pathways