cell senescence and telomeres

features of senescence

stable cell cycle arrest
irreversible
metabolically active
SASP

effector programs of senescent cells

pDDR
cGAS/STING activation
SASP
autophagy

process of senescence

1. exposure to stress induces senescence

2. immune cells recruited to clear senescence

3. if not resolved, can lead to chronic inflammation, tumours, tissue degeneration and ageing

senescence in cell culture

present in primary cell culture but not immortalised or transformed cell culture

mouse model for OIS

hepatocytes expressing oncogenic NRAS undergo senescence and secrete SASP and cytokines to recruit immune cells
KO immune cells - tumorigenesis
identification of spectrum of phenotypes by scRNAseq

replicative senescence

cells reach hayflick limit
caused by telomere shortening

structure of telomeres

ends have 3’ overhangs due to end replication problem
protection - shelterin
maintenance - telomerase
only cancer cells, germ cells and some somatic cells are telomerase positive

pDDR at telomeres leads to senescence

DNA damage destabilises shelterin, exposing ends
ends recognised as DSBs leading to replicative senescence via p53
p53 loss = cells enter crisis = BFB cycles
reactivation of telomerase leads to crisis evasion and cancer development

mechanism of pDDR

1. telomere shortening or uncapping activates ATM/ATR

2. activates CHK1/2

3. activates p53

4. leads to apoptosis or p21 activation

5. cell cycle arrest and senescence

role of senescence in ageing

senescent cells may exceed capacity of immune cells
LINE1 expression induced by SIRT6 relocalisation leads to GIN and inflammation
SASP promotes inflammaging and disruption of tissue architecture

senotherapies

senomorphics inhibit SASP
senolytics kill senescent cells