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Cellular senescence and cancer and ageing Flashcards

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1
Q

who first described cellular senescence?

A

Hayflick, he observed that cultured fibroblasts cells could only proliferate for a set amount of times- this was called the hayflick limit. These cells remained viable but were unable to proliferate anymore

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2
Q

why did cellular senescence evolve?

A

as an anti cancer mechanism

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3
Q

what did multicellular organisms bring with them the need for?

A

renewable tissues which required proliferating cells which give rise to cancers. Therefore they needed anti cancer mechanisms

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4
Q

for what period of time do tumour suppressors need to be beneficial?

A

only for the reproductive lifespan of animals because after this point the deleterious effects will not be exposed to selection

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5
Q

what is the theory of antagonistic pleiotropy

A

the idea that genes and mechanisms that pose a selective advantage prior to reproduction may have antagonistic phenotypyes after this point

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6
Q

what type of cells does senescence occur in? why?

A

mitotic because this is where cancer can rise

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7
Q

what is the difference betweenn sen cells and quiescent cells?

A

quiescent cells can resume proliferation in response to appropriate signals, including the need for tissue repair or regeneration. sen cells are also resistant to apoptosis signals. they acquire widespread changes in gene expression

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8
Q

at what stage to sen cells normally arrest? when else can they?

A

G1 but sometimes they can at G2 or even S phase

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9
Q

generally, how do sen cells stop proliferating?

A

cell cycle inhibitors and their pathways are upregulated

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10
Q

can all sen cells acquire resistance to apoptosis? what cell type doesn’t?

A

no- human endothelial cells do not

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11
Q

what is thought to determine whether a cell undergoes sensencence or apoptosis?

A

cell type or type of stress

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12
Q

when a cell comes into stress or undergoes damage, what are the two options that it has?

A

sensence or apoptosis

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13
Q

what regulator do the apoptosis and sen pathways have in common?

A

p53

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14
Q

is it known how sen cells are resistant to apoptosis and what are the theories?

A

no but it is thought they might lose the proteins that are involved in the apoptic execution

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15
Q

what are the two main pathways involved in sen?

A

p53/p21 and p16/pRB

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16
Q

what do p21 and p16 do?

A

They ensure that pRB is kept active in its hypophosphorylated state

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17
Q

what type of genes are repressed in the sen cells?

A

replication-depdendent, c-FOS, cyclin A, cyclin B

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18
Q

what is one of the main transcription factors that is inhibited by pRB? what type of genes does this component normally activate?

A

E2F- it is inactivated and itnormaly encodes genes involved in cell cycle progression

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19
Q

name 6 markers of sen cells

A
  • lack of DNA rep (but doesn’t differentiate form quiescent cells)
  • beta galactosidase
  • p16 (in most but not all)
  • sen-associated DNA-damage foci
  • telomere induced foci
  • heterochromatin-associated histone modifications
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20
Q

what are the 4 main causes of sen?

A
  • strogn mitogenic signals
  • chromatin perturbations and other non genetics stresses
  • non-telomeric DNA dmage
  • dysfunctional telomeres
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21
Q

what is the sequence of telomere repeats?

A

TTAGGG +protein cap

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22
Q

what is the role of telomeres?

A

to prevent ends of chromosomes being mistaken for double strand breaks

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23
Q

what is the general structure of the end of a teller?

A

a t-loop

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24
Q

why do telomeres shorten?

A

DNA polymerases cannot completely replicate DNA ends - they lose 50-200 bps each S phase

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25
Q

how many bps are lost every S phase?

A

50-200

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26
Q

how many critically short telomeres are required to induce cellular sensencen?

A

just one

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27
Q

what do short telomeres trigger?

A

the DNA damage response- prolonged not transient

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28
Q

what can telomerase not prevent?

A

sen from telomere-indepdendent sen

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29
Q

give some evidence of telomerase not being sufficient to prevent sen

A

many mouse cells have long telomeres and express telomerase but sen in culture because of 20% oxygen levels which an DNA damage due to ROS

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30
Q

which of the two sen pathways normally stimulates sen after DNA damage? (telomere and non telomere)

A

p53

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31
Q

when is p16 expressed following DNA damage in the sen response ?

A

normally a delayed response

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32
Q

for what type of tumours are chemotheraptuic drugs better for and why?

A

cells that express w ilf type p53 due to the fact these cells are more likely to senesce.

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33
Q

what type of chromatin perturbation can induce sen?

A

heterochromatin and euchromatin formation

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34
Q

what is the difference in the mouse response to chromatin perturbations and the human response ?

A

the human normally depends on pRB but in the mouse the p53 is more important

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35
Q

what particular oncogene has been shown to induce sen at high levels??

A

RAS and its pathway components such as MEK and BRAF

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36
Q

why would mitogenic signals trigger sen?

A

because these cells run the risk of increased mitogenic stimulation which increases the risk of oncogenic transformation

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37
Q

how can oncogenic RAS signalling trigger both pathways ?

A

it induces p16 but it also induces p53 via induces DNA strand breaks following lots of replication

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38
Q

what is the evidence for oncogenic signals stimulating sen in vivo?

A

activated oncogens in tissues cause benign lesions that consist of sen cells,

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39
Q

what kind of stressors can induce sen?

A

anti-proliferative cytokines such as interferon-beta by increasing intrcellular oxygen free radicals and activates p53
- TGF-beta promotes heterochromaitn formation and thus activates p16-pRB

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40
Q

do cells always sen from one pathway?

A

no some can sen from p16 and others from p53 in the same tissue- as a mosaic

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41
Q

which pathway can oxidative stress induce?

A

either!

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42
Q

what are the two pathways and how do they interact?

A
  1. sen signals-> ARF -] HDM2 -] p53 -> p21 -] cell cycle proteins and inhibits CDS in other pathway
  2. sen signals -> p16 -] CDKS -] pRB -] E2F -> cell proliferation (and activates ARF in other pathway)
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43
Q

how is it determined whether a cell will sen or whether the damage can be repaired and it doesn’t need to senesce? what type of cells will this only occur in?

A
  • one possibility os that DNA repair rapidly turns off the p53 or p21 pathway where as slow or faulty repair does not
  • only cells that dont express p16 or very low levels, as this pathway is irreversible
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44
Q

how do mouse and human sen response differ?

A

different stimuli can stimulate different pathways

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45
Q

what is the evidence for p16 and p21 not being equivalent or working in the same way?

A
  • cells that sen only due to p21 can be reversed in vitro
  • p16 is crucial to forming sen associated heterochoromatin foci which silence genes associated with proliferation- once this is formed, p16 signalling is no longer required to maintain
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46
Q

in which animals are sen cells found in many renewable tissue ?

A

rodents, primates and humans

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47
Q

what are 4 renewable tissues?

A

vasculature, haematopoetic system, epithelial organs and stroma

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48
Q

what is the link between sen cell and age?

A

very few cells expressing sen markers are found in young animals but many are found in older ones- they increase with age

49
Q

in sites of which diseases as sen cells found?

A

osteoarthritis and atherosclerosis, preneoplastic lesions

50
Q

which three hallmarks of ageing have p16 expressing cells been found in?

A

neurogenesis, haemtopoeiss and pancreatic function

51
Q

what is the link between p16 expressing cells and ageing?

A

the number of p16 expressing cells increases with age

52
Q

what happens in mice who are genetically engineered to lack p16 expression?

A

the age-related decline in stem- cell growth and issue regeneration is retarded

53
Q

what type of factors are scented by sen cells?

A

EXM degrading enzymes, inflammatory cytokines and growth factors which alter the microenvionrment

54
Q

what is the morphology of sen cells?

A

enlarged and flat

55
Q

what do sen cells maintain?

A

metabolic activity

56
Q

which of the two pathways is least understood and what is it stimulated by?

A
  • not DNA damage or telomeres- the p16 pathway
57
Q

what piece of evidence support the claim that older cells can divide less than younger cells?

A

cells from older tdonors replicate fewer times than cells from younger donors

58
Q

what is the minimum rate of thelomere shortening?

A

30-50 bps

59
Q

what opposes the argument that the number of divisions that cells undertake influences their age nd telomere shortening?

A
  • people are born with different lengths of telomeres and they can be degraded at different rates after birth and the factors such as ROS can shorten telomeres
60
Q

which age diseases have been associated with telomere shortening?

A

diabetes, CVD and alzheimers

61
Q

how can you see that telomere shortening increases with age?

A

telomere dysfunction induced foci increase with age

62
Q

which tissues would be particularly sensitive to telomere shortening?

A

cells with high turnover- renewable tissues

63
Q

how has telomere shortening been linked to stem cell pool exhaustion?

A

muscle satellite cells have been shown to be reduced by telomerase expression

64
Q

which two human progerois syndromes have been linked to telomere shortening?

A

Werner’s syndrome and Hutchinson-Gilford progeria syndrome- they both displayed ageing phenotype that ara accelerated - evidence has been presented of both that the accelerated sen is associated with increased rates of telomere shortening

65
Q

what is the problem with sen cell studies in vivo atm?

A

to date, no single and exclusive sen make has been found

66
Q

what is the problem with using beta galactosidase as a marker for sen cells?

A

sometimes non sen cells express it

67
Q

can sen cells be cleared by the immune system?

A

it is thought that early, non- mature sen cells can be which are involved in development but older mature sen cells can’t

68
Q

what percentage of dermal fibroblasts in old baboons showed sen phneotypes?

A

15% - p16 expression

69
Q

describe an example in which the presence of sen cells in a tissue has negatively been related to a condition? (3)

A
  • benign prostatic hyperplasia, the sen cells secrete cytokines IL-1alpha and IL-8 that stimulate stromal growth factors secretion which in turn correlates witth proliferation of the non-sen epithelial cells
  • altering the tissue microenvironment include the skin, where the secretion of growth factors, degradative enzymes and inflammatory cytokines by the aging dermal fibroblasts has been suggested to contribute to the characteristic aged skin morphology
  • Moreover, factors secreted by senescent cells have been shown to stimulate the growth and angiogenic activity of premalignant cells
70
Q

what does p16 inactivate to maintain pRB?

A

CDK4 and CDK6

71
Q

what can be delayed by CR?

A

increase in p16 expression with age

72
Q

what transcriptional regulator has been particularly implicated in p16 stimulation?

A

ETS1

73
Q

in what type os cells is p16 increase in expression particularly implicated in the age-related decline of? give a piece of evidence for this.

A

progenitor and stem cells
- cells that a=have lost BMi1 expressing which may inhibit p16 expression, shown a striking loss of hematopoetic cells which was associated with increased p16 expression and failure of stem cells

74
Q

what are the mechanisms by which the presence of sen cell in a tissue can be harmful?

A
  • cell autonomously0 the depletion of the functional cells from tissues- the depletion of stem cell pools
  • non cell autonomous effects such as secreting inflammatory factors, growth factors etc which lead to an alteration in the microenvironment and an affect on tissue function. these could cause ther cells to become sen which has been shown or cause them to behave in a strange way
75
Q

why can c.elegans and flies not be used to look at the effects of sen cells?

A

they are made from predominately post mitotic cells- only mitotic cells can be sen because they proliferate

76
Q

what is the difference between caretakers and gatekeepers?

A

caretakers are tumour suppressors that prevent cancer by protecting the genome from mutations. They act by preventing DNA damage and or optimising DNA repair.

Gate keepers prevent cancer by acting on intact cells- mitotic cells- that are at risk from neoplasmic transformation. The eliminate potential cancer cells by inducing apoptosis or cell sen

77
Q

why do cells with short tremors need to be dealt with?

A

the ends of the chromosomes will start to be lost which can cause cancerous deletions

78
Q

what does also of p53 cause?

A

delays or abboragtes cellular sen in human cells - this gives rise to the theory that dysfunctional telomeres trigger the same pathway as general DNA damage

79
Q

what is proof that telomere shortening sen requires p53

A

it depends on p53 in humans

80
Q

what happens in cells normally that dont have p53 but continue to replicate?

A

they eventually go into crisis and die

81
Q

because there are no common markers for sen cells, what doe this make it hard to do?

A

identify the difference between p53 and p16 induces sen cells

82
Q

why ar mice not that a good model for sen studies maybe- give examples

A

they vary in the cellular sen pathway response:

  • mouse cells can proliferate indefinitely in the right oxygen levels despite rising p16 and instant p53 levels- human cells cannot
  • the pRB state that is irreversible in humans can be reversed in mice
  • DNA damage can induce the p16 response and p53 in mice but just p53 in humans
  • mice cells are very low oxygen stress resistance
83
Q

what is the phenotype of CA p53 mice?

A
  • no cancer but die early
  • increase apoptosis and sen
  • activated IGF signalling pathway !!!
84
Q

describe a piece of evidencee showing that sen cells can alter the function of cells

A

sen cells reduced milk protein expression by normal mammary epithelial cells

85
Q

describe an experiment that showed that the removal of sen cells could ameliorate ageing patholgies?

A

To address these fundamental questions, we made use of a biomarker for senescence, p16(Ink4a), to design a novel transgene, INK-ATTAC, for inducible elimination of p16(Ink4a)-positive senescent cells upon administration of a drug. Here we show that in the BubR1 progeroid mouse background, INK-ATTAC removes p16(Ink4a)-positive senescent cells upon drug treatment. In tissues–such as adipose tissue, skeletal muscle and eye–in which p16(Ink4a) contributes to the acquisition of age-related pathologies, life-long removal of p16(Ink4a)-expressing cells delayed onset of these phenotypes. Furthermore, late-life clearance attenuated progression of already established age-related disorders. These data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan.

86
Q

what have fibroblastic sen cells been shown to secrete?

A
  • matrix metalloporoteases, epithelial growth factors, inflammatory cytokines
87
Q

what type of cell does the fibroblastic sen cell resemble?

A

fibroblasts associated with carcinomas

88
Q

how could the presence of sen cells affect cancer formation

A

. Fur- ther, many cells with oncogenic mutations are kept in check by the tissue microenvironment (Park et al., 2000). It is possible, therefore, that changes in the mi- croenvironment caused by senescent cells can fuel the growth and progression of such cells toward malig- nancy

89
Q

how can it be that sen cells could induce cancer in cells by secreting growth factors etc but still be selected for?

A

cancer mutations accumulate with time so earlier the presence of the sen cells is not a problem- less triggering, but later in when there are more sen cells and more cancerous mutations- this is very different

90
Q

describe a key piece of evidence which suggests sen cells can be carcinogenic?

A

sen fibroblasts create a local tissue environment that promotes the growth of initiated or preneoplastci epithelial cells in culture and in vivo

91
Q

what are the two ways that sen cells can affect stem cell pools?

A

First, it could deplete tissues of stem or progenitor cell pools. From mouse models, such as mice genetically engineered to lack telomerase activity, and human conditions, such as the hereditary telome- rase deficiency syndrome dyskeratosis congenita, it is clear that replicative exhaustion of proliferating pools can result in some features of premature aging, includ- ing increased cancer incidence (Rudolph et al., 1999; Wong and Collins, 2003). Second, the presence of se- nescent cells, whether stem cells themselves or sur- rounding cells in stem cell niches, could disrupt the stem cell microenvironment. The senescent microenvi- ronment in turn could alter the proliferation, differentia- tion, and/or mobilization the resident stem cells.

92
Q

what are the dangers o chemo in relation to sen cells?

A

if you induce tumours to den vi DNA damage then you are producing cells that can damage again and cause cancers etc.

93
Q

what is BRAF?

A

it is a component of the ERK pathway that can stimulate DNA damage independent senesce

94
Q

what is a non neoplasm mitogen that can stimulate sen?

A

interferon-beta

95
Q

what are the difference thoughts of the combination of p16 and p53 in cells

A

some claim that even though the timing can vary, cells end up expressing both but then other argue that cells will only express one or the other

96
Q

what is the link between sen cells and progeroid mice cells?

A

they show increased ageing and express increased levels of p16, p21, p53 and ARF

97
Q

how can in vivo experiments which show that p53 and p21 expression prevented cell sen and age related pathologies?

A
  • cells that are coping with a lot of damage and stress can increase the length of the cell cycle by relying on p21 pathaway which gives them more time to repair- but if too much damage then will sense— maybe
98
Q

what remains to be looked at in sen research?

A
  • need to look into the different phenotypes that rise from different stresses in different tissues relying on different pathway
99
Q

describe how senescence is a multi-process step

A
  • it is thought that the properties of a sen cell continually change and progress
  • The initiating step is the transi- tion of temporal to stable cell-cycle arrest, which typically involves prolonged inhibition of Cdk–cyclin activity by p21, p16Ink4a, or both. A change in p53 expression from intermittent to continuous may be a critical event in the transition from temporal to persistent growth arrest. these cells release cytokines which are tough to allow them to be recognised by the immune system and for them to be cleared.
    For the progression to full senescence, it seems that lamin B1 downregula-
    tion triggers both global and local modifications in chromatin methylation.ome mammalian cell types form regions of highly condensed chro- matin called senescence-associated heterochromatin foci. This is consistent with the idea that p53 mechanisms can be reversed but then if chronic then the p16 signalling come sin an makes it irreversible. As the organism ages, the immune system becomes worse which means that they sen cells are lesslikley to bec cleared so they accumulate
100
Q

what factors are upregulated in sen cells?

A

cytokines and chemokines with proinflammatory prop- erties, as well as various growth factors and proteases that together alter tissue structure and function

101
Q

can the scented proteins vary in sen cells depending on what activate sen?

A

yes

102
Q

how does the ageing of the immune system impact sen accumulation ?

A

because the immune system ages- sen cells are less likely to get cleared with age

103
Q

in additon to ageing, what are sen cells related to? what is the role of these sen cells here? how are they cleared.

A

wound repair and recovery from liver injury. to promote the breakdown of ECM to promote healing or : vascular remodelling in uterine neovascularaisaiton. They re cleared very efficiently

104
Q

why is the study of there of p53 and p16 hard to do?

A

if you KO then animals die of cancer very early

105
Q

how can sen cells induce sen in other cells?

A

scereting TGF-beta and chemokine ligands

106
Q

how can the secretion of metaloproteases be harmful?

A

can alter ECM or cleave membrane bound receptors

107
Q

what causes the ends of chromosomes to be lost after replication?

A

• Replication of the lagging strand of DNA requires RNA primers which are then degraded, leaving Okazaki fragments, which are then ligated. Problem: it is impossible to replicate the end of the lagging strand, because of the requirement for an RNA primer. Chromosome ends will get shorter each round of division.

108
Q

what is the link between the size of the animal and the hay flick limit? what did they find in relation to hay flick limit and longevity?

A

cells from bigger animals tend to have a larger hay flick limit because larger animals require more cells but there isn’t a correlation between hay flick number and species longevity . This basically means that the number of times a cell can divide is not dependent on time and that the study which showed older donor’s cells could divide less may be wrong

109
Q

what cell type was hay flicks test done on?

A

cultured fibroblasts

110
Q

what is the problem itht eh argument that telomeres shorten with age and that older animals have shorter telomere and so this is a cause of ageing?

A

the end replication problem is not the only factor with contributes to telomere shortening, things such as oxidative damage do too so some cells from youngr organisms will have shorter telomeres than some in others, if this is the case then how can this case ageing?

111
Q

what are examples of a gatekeeper?

A

SOD catalase detoxification enzymes, turnover processes

112
Q

describe the experiments which looked at the BubR1 mouse

A

BubR1 mouse expresses progeroid- accelerated ageing. p16(ink4a) homo mutants reduces sen cell number and suppresses progeria in BubR1 mice- when they ablate p16 expressing cells, they ameliorate symptoms

113
Q

what are the two components thought to make up the molecular clock in somite formation?

A

cell autonomous expression of Notch and Wnt oscillations

114
Q

what does chromatin remodelling result in?

A

profound changes in genes expression

115
Q

how long does it take for a cell to sen and then for how long does t remain viable?

A
  • a few weeks and then a few months
116
Q

what cells sen at the point of wound healing and why

A

upon wound closure, myofibroblasts suddenly undergo sen to limit excess firbosis at the site of insjurt

117
Q

give two examples of p16 cells being addressds and the effects in mice

A

genetic inactivation of p16 in skeletal mysce, eye anf fat attentuated the onset of age related pathologies in prgerois mice - also p16cell were ablated in mice progeroud - attenuated progresison of ageing

118
Q

what signals do sen cells secrete which cause other cells to sen?

A

TGF-beta and IL-1beta

Biology Of Ageing (8 decks)

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