Ex2 L5 - Cellular Senescence

Question 1

Sometimes “senescence” (not cellular senescence) is used as a synonym for…

Answer 1

aging

Question 2

What happens in the S phase of the cell cycle?

Answer 2

duplicating of everything in the cell

Question 3

The cell cycle forms…

Answer 3

2 identical daughter cells

Question 4

What happens in interphase vs. mitosis?

Answer 4

interphase: preparing to divide
mitosis: dividing

Question 5

Where are the cell cycle checkpoints and what are they checking for?

Answer 5

G1 - damaged DNA
S - unreplicated or damaged DNA
G2 - unreplicated or damaged DNA
Mitosis - chromosome misalignment

Question 6

What is cellular senescence?

Answer 6

the process through which cells undergo permanent cell cycle arrest in response to certain stressors - permanent Go

Question 7

What is the difference between senescence and quiescence?

Answer 7

senescence: permanent Go, possible to escape with more mutations

quiescence: temporary Go, can “easily” re-enter the cycle

Question 8

Cellular senescence is also a protective mechanism that…

Answer 8

allows cells to respond to potentially tumorigenic events, including: DNA damage, activation/expression of oncogenes, increased signals for growth (mitogens), and oxidative stress

Question 9

Senescent cells have a distinct ——- which includes 3 criteria:

Answer 9

phenotype:
- irreversible arrest of cell proliferation (exit cell cycle)
- resistance to apoptosis (don’t die)
- altered cell function (metabolically active, change in function)

Question 10

Senescent cells often have altered functions such as:

Answer 10

• chromatin rearrangement
• altered secretory function
  -activation of tumor-suppressor genes

Question 11

Describe senescence initiation

Answer 11

Senescence inducing signals like oncogene activation or DNA damage trigger the cell to exit the cell cycle permanently

Question 12

Describe early senescence

Answer 12

• progressive chromatin remodeling
• implementation of the senescence program
• pancaked cells (flat, enlarged morphology)
• loss of Lamin B1 (parallel to progeroid syndromes)
• more extensive Golgi that leads to more secretion and SASPs

Question 13

Describe late senescence

Answer 13

• triggered by aging or long-term unscheduled damage
• after time, there is chronic inflammation (inflammaging) and diversification of the senescent phenotype

Question 14

Before Hayflick, it was believed that cells…

Answer 14

were immortal
- Alexis Carrel (1912)
- said the limited capacity for cell division was thought to be an artifact of improper tissue culture technique

Question 15

Who was Hayflick?

Answer 15

Leonard Hayflick, demonstrated a limited capacity for cell division (1961)
- found that after about 50 divisions cells enter a resting phase

Question 16

The current belief about cell mortality is that…

Answer 16

• most cells undergo a finite number of divisions
• telomeres shorted with each dividion
• most cells eventually reach the end of their replicative life span
• stem cells don’t have this limit, and cancer cells override it

Question 17

What are the genes involved in senescence?

Answer 17

• tumor suppressor genes promote senescence
• ex: p53 (detect DNA damage)
• ex: pRb (retinoblastoma protein, G1 checkpoint protein)
• these induce cell cycle arrest in response to potentially tumorigenic events

Question 18

What happened to mice without tumor suppressor genes?

Answer 18

they have high incidence of cancer at a younger age

Question 19

Mutation of tumor suppressor genes –>

Answer 19

cancer

Question 20

Cells from older individuals divide…

Answer 20

less frequently

Question 21

Cells from individuals with progeroid syndromes divide…

Answer 21

less frequently

Question 22

Senescent cells accumulate over time and cause…

Answer 22

age related pathologies

Question 23

A hallmark trait of a senescent phenotype is:

Answer 23

altered cell function
- senescence-associated secretory phenotype (SASP)

Question 24

What are SASPs?

Answer 24

senescence-associated secretory phenotype

• senescent cells secrete growth factors, inflammatory cytokines, ECM degrading enzymes, etc.
• leads to a decline in tissue and organ function
• ultimately contributes to aging and age-related pathologies
• can be beneficial for wound healing, but not good all the time

Question 25

Regarding diabetes as an example, SASP causes release of growth factors/inflammatory cytokines and causes:

Answer 25

paracrine effects:
- tissue dysfunction
- diabetic complications

systemic effects:
- inflammation
- insulin resistance

both together worsen T2D

Question 26

Senescent cells accumulate, and if something goes wrong…

Answer 26

they can acquire protumorigenic tissue mechanisms that allow them to escape senescence and cause cancer

Question 27

To eliminate senolytic cells, we would want to create a drug that targeted…

Answer 27

the pathways that block apoptosis in senescent cells - this way it doesn’t affect healthy cells because they do not have the anti-apoptotic pathways

Question 28

What are the pros and cons of inhibiting senescence?

Answer 28

pros:
- reduce inflammation that leads to age-related diseases
- eliminate cells that have the potential to escape senescence and form tumors

cons:
- cells that should become senescent (because they have DNA damage, etc.) will remain active and continue dividing - could cause many issues or cancer
- eliminating senescent cells can impair wound healing