DNA Damaging and Senescence

Question 1

Give examples of species commonly used in a lab

Answer 1

• C. elegans
• rats
• drosophila

Question 2

What does stochastic mean?

Answer 2

the outcome is probable and can be influenced by genetics and environment

Question 3

What does the wear and tear theory of ageing suggest?

Answer 3

ageing results from a gradual deterioration of the cells and tissues of the body via wear and tear, oxidative stress, exposure to radiation, toxins, or other deteriorative processes

Question 4

Give examples of programmed theories of age

Answer 4

• hormonal
• programmed senescence
• immunologic
• telomere shortening

Question 5

Give examples of stochastic theories of age

Answer 5

• metabolic rate
• glycation
• somatic mutation
• wear and tear
• oxygen free radicals

Question 6

What are ageotypes?

Answer 6

different types of ageing patterns in different individuals

Question 7

What are the 9 hallmarks of ageing?

Answer 7

• genomic instability
• telomere attrition
• epigenetic alterations
• loss of proteostasis
• dysregulated nutrient sensing
• mitochondrial dysfunction
• cellular senescence
• stem cell exhaustion
• altered intercellular communication

Question 8

Give an example of functional connections between the hallmarks of ageing

Answer 8

telomere shortening leads to cellular senescence

Question 9

What are the primary hallmarks of ageing?

Answer 9

causes of damage:
- loss of proteolysis
- epigenetic alterations
- telomere attrition
- genomic instability

Question 10

What are the antagonistic hallmarks of ageing?

Answer 10

responses to damage:
- dysregulated nutrient sensing
- cellular senescence

Question 11

What are the integrative hallmarks of ageing?

Answer 11

culprits of phenotypes:
- stem cell exhaustion
- altered intercellular communication

Question 12

What is senescence?

Answer 12

a deteriorative process that follows development and maturation

Question 13

What is replicative senescence?

Answer 13

when cells can no longer be replicated in culture

Question 14

What is the primary role of senescence?

Answer 14

eliminating unwanted cells by inducing tissue remodelling

Question 15

What are the 3 sequential processes involved in inducing tissue remodelling?

Answer 15

1. stable proliferative arrest
2. a secretory phenotype that recruits immune cells and modifies the ECM
3. the mobilisation of nearby progenitors that populate the tissue

Question 16

What are the 2 outcomes of cell cycle arrest?

Answer 16

stress relief or repair depending on the extent of damage or stress

Question 17

What are the 2 types of senescence?

Answer 17

acute and chronic

Question 18

What is acute senescence?

Answer 18

the scheduled clearance of unwanted cells e.g. wound healing, oncogene induced senescence (OIS), development (tissue patterning, cell plasticity)

Question 19

What is chronic senescence?

Answer 19

when there is a gradual increase in stress over time and can happen in any cell that is dividing; it is unscheduled clearance of non-specific cells

Question 20

What does early senescence involve?

Answer 20

lamin B1 downregulation, chromatin remodelling and SASP

Question 21

What does late (deep) senescence involve?

Answer 21

SASP moderation, retrotransposition, chromatin budding and histone proteolysis

Question 22

Give an example of when senescence can be beneficial

Answer 22

developmental processes e.g. neural tube closure

Question 23

What would happen if cells during brain development did not undergo senescence?

Answer 23

the brain would be enlarged and the embryos would die in utero

Question 24

Why do cataracts happen?

Answer 24

proteins within the lens begin to break down and vision becomes cloudy

Question 25

Give examples of senescence-related diseases

Answer 25

- cancer - fibrosis - metabolic disorders - bone and cartilage disorders

Question 26

Where is disease-related senescence common?

Answer 26

in individuals who smoke since there is higher damage to the epithelial cells of the lungs

Question 27

Where is therapy-induced senescence common?

Answer 27

- chemotherapy - kidney transplant

Question 28

What do commonly used markers of senescence derive from?

Answer 28

expansion and cell-cycle arrest stimuli

Question 29

Give examples of cell signals to arrest

Answer 29

- epigenetic changes - DNA damage - cell-cycle inhibitors expression - HMGB1 nuclear exclusion - mitochondria

Question 30

Give examples of cell signals to expand

Answer 30

- mitochondrial mass increase - karyomegaly - increase in cell soma size

Question 31

Give an example of pathways that regulate senescence-mediated arrest

Answer 31

DNA damage response from repair-resistant DNA segments with chromatin alterations reinforcing senesce (DNA-SCARS)

Question 32

What are the environmental factors that influence lifespan and ageing?

Answer 32

- temperature - food availability - disposable soma theory - DNA repair capacity

Question 33

What is the disposable soma theory?

Answer 33

the correlation between longevity and the number of resources applied to somatic maintenance and repair

Question 34

What is Dauer?

Answer 34

an alternative stage of development whereby the larva goes into a type of stasis and can survive harsh conditions

Question 35

What is a consequence of DNA damage?

Answer 35

cell cycle arrest which can be temporary or permanent depending on the type and extent of damage

Question 36

What are the 3 tiers of defence against DNA damage?

Answer 36

1. regulation of toxic molecules e.g. free radicals 2. DNA repair 3. pots-repair defence e.g. apoptosis or senescence

Question 37

What does BER deal with?

Answer 37

neurodegeneration

Question 38

What does mismatch repair deal with?

Answer 38

cancer

Question 39

Give examples of senescence signals

Answer 39

- p53 - p21 - Rb - p16

Question 40

What are the 3 mechanisms by which DNA damage can drive ageing?

Answer 40

- driving cells to senescence - exhausting regenerative capacity - impacting mitochondrial function - introducing protein aggregation

Question 41

How can cells be driven to senescence?

Answer 41

metabolism alterations, secretion of proinflammatory factors and local tissue environment alterations

Question 42

What does DNA damage drive?

Answer 42

ageing

Question 43

Give examples of molecular consequences of DNA damage

Answer 43

- DNA/RNA polymerase stalling - dysfunctional telomeres - aneuploidy

Question 44

Give examples of cellular consequences of DNA damage

Answer 44

- cellular senescence - stem cell exhaustion

Question 45

Give examples of systemic consequences of DNA damage

Answer 45

- signalling mechanisms - inflammation - deregulated nutrient sensing

Question 46

What can DNA damage be?

Answer 46

- exogenous (UV, chemicals, X-rays, chemotherapy) - endogenous (ROS, aldehydes, H2O)

Question 47

Give examples of how DNA repair defects accelerate human ageing

Answer 47

- progeroid syndromes - osteoporosis in premature ageing systems - neurodegeneration

Question 48

Give examples of progeroid syndromes

Answer 48

- Werner Syndrome - Bloom syndrome - Hutchison-Gilford progeria syndrome

Question 49

What happens once damage occurs/senescence kicks in?

Answer 49

there are very few functional cells; damaged/dysfunctional/senescent cells accumulate