Ex2 L5 - Cellular Senescence Flashcards
Sometimes “senescence” (not cellular senescence) is used as a synonym for…
aging
What happens in the S phase of the cell cycle?
duplicating of everything in the cell
The cell cycle forms…
2 identical daughter cells
What happens in interphase vs. mitosis?
interphase: preparing to divide
mitosis: dividing
Where are the cell cycle checkpoints and what are they checking for?
G1 - damaged DNA
S - unreplicated or damaged DNA
G2 - unreplicated or damaged DNA
Mitosis - chromosome misalignment
What is cellular senescence?
process where cells undergo permanent cell cycle arrest in response to certain stressors
What is the difference between senescence and quiescence?
senescence: permanent Go, possible to escape with more mutations
quiescence: temporary Go, can “easily” re-enter the cycle
Cellular senescence is a protective mechanism that…
allows cells to respond to potentially tumorigenic events, including:
- DNA damage
- activation/expression of oncogenes
- increased signals for growth (mitogens)
- oxidative stress
Senescent cells have a distinct ——- which includes 3 criteria:
phenotype:
- irreversible cell cycle arrest
- resist apoptosis
- altered cell function (metabolically active, but changes in function)
Senescent cells often have altered functions such as:
- chromatin rearrangement
- altered secretory function
-activation of tumor-suppressor genes
Describe senescence initiation
Senescence inducing signals like oncogene activation or DNA damage trigger the cell to exit the cell cycle permanently
Describe early senescence
- chromatin remodeling
- pancaked cells (flat, enlarged morphology)
- non uniform membrane
- loss of Lamin B1 (parallel to progeroid syndromes)
- more extensive Golgi (more secretion)
Describe late senescence
- triggered by aging or long-term damage
- after time, there is chronic inflammation (inflammaging) and diversification of the senescent phenotype
Before Hayflick, it was believed that cells…
were immortal
- Alexis Carrel (1912)
- said the limited capacity for cell division was thought to be an artifact of improper tissue culture technique
What is the Hayflick limit?
Leonard Hayflick, demonstrated a limited capacity for cell division
- found that after about 50 divisions cells enter a resting phase
The current belief about cell mortality is that…
- most cells undergo a finite number of divisions
- telomeres shorten with each division
- most cells undergo apoptosis or senescence when they reach the limit
- stem cells don’t have this limit, and cancer cells override it
What are the genes involved in senescence? What do they do?
- tumor suppressor genes promote senescence
- ex: p53 (detect DNA damage)
- ex: pRb (retinoblastoma protein, G1 checkpoint protein)
- induce cell cycle arrest in response to potentially tumorigenic events
What happened to mice without tumor suppressor genes?
they have high incidence of cancer at a younger age
Mutation of tumor suppressor genes –>
cancer
Cells from older individuals divide…
less frequently
Cells from individuals with progeroid syndromes divide…
less frequently
Senescent cells accumulate over time and cause…
age related pathologies
A hallmark trait of a senescent phenotype is:
altered cell function
- senescence-associated secretory phenotype (SASP)
What are SASPs? What do they cause?
senescence-associated secretory phenotype
- senescent cells secrete growth factors, inflammatory cytokines, ECM degrading enzymes, etc.
- pro-inflammatory: good for wound healing but bad for tossie and organ function
- ultimately contributes to aging and age-related pathologies
Regarding diabetes as an example, SASP causes release of growth factors/inflammatory cytokines and causes:
paracrine effects:
- tissue dysfunction
- diabetic complications
systemic effects:
- inflammation
- insulin resistance
both together worsen T2D
Senescent cells accumulate, and if something goes wrong…
they can acquire protumorigenic tissue mechanisms that allow them to escape senescence and cause cancer
To eliminate senolytic cells, we would want to create a drug that targeted…
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
What are the pros and cons of inhibiting senescence?
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
