Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

CORE II Block 4 > Aging and senescence > Flashcards

Aging and senescence Flashcards

1
Q

Definition of aging?

A
  • loss of homeostasis at the cellular level
  • increased vulnerability of the organism (to disease)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Why does mortality rate increase with age?

A

Because vulnerability increases with age

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Is aging a disease?

A

No, it is an increased vulnerability to disease.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

How can selective pressure on early life events result in species-specific differences in longevity?

A

each species evolves based on its environmental niche. Lifespan is just a side-effect

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Describe the common pathway involved in lifespan in yeast, worms, flies, and mammals.

A

mTOR signaling and insuiin/insulin-like pathways. Lifespan extensions are due to single gene mutations.

Because mTOR is a nutrient-sensing pathway effector, a restrictive diet can increase longevity.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Example of lifespan pathway that diverged from worms to mammals?

A

Worms have Daf-2 insulin-like growth factor receptor, and humans have IGF-1R and GHR

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What issues contribute to aging-related vulnerability?

A
  • hormonal changes
  • loss of tissue-specific architecture
  • decline in immune function and increased inflammation

all due to stem cell loss and cellular damage

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Term for cellular mechanisms of aging?

A

senescence

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Hayflick limit?

A
  • normal fibroblasts arrest following a defined number of population doublings
  • immortal lines like tumors do not have a limit
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What events induce senescence?

A
  1. telomere attrition (recognized as DNA damage)
  2. oncogene conversion
  3. stress (O2)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Can human cells spontaneously immortalize? Mouse cells?

A

Human cells cannot spontaneously immortalize, but mouse cells can. Therefore, when culturing mouse cells it is important to choose the right density of cells to work with. At low density, mouse cells senesce. We normally choose middle density cells (3T3) because they maintain normalcy.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What is the effect of viral proteins on human cell immortalization and out of senescence?

A

adding viral protein induces crisis in cells, leading to apoptosis. Out of the same population, leftover cells will become immortal/tumorigenic.

  • SV40T antigen: causes inhibitory binding to p53 and pRb, causes cell transformation
  • papilloma virus E6 and E7 proteins: E6 inhibits p53, E7 inhibits pRB
  • Li Fraumeni syndrome: heterozygous mutation of p53
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Under normal conditions, what is the inhibitor of p53?

A

Mdm2 binds and inhibits unphosphorylated p53 and targets it to the proteosome, so that p53 is constantly turned over in the absence of DNA damage

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Structure and modifications of p53?

A

tetramer – mutant p53 is dominant.

can be phosphorylated, acetylated, and ubiquitinated to regulate activity and localization

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Effect of mono- and poly-ubiquitination on p53?

A

Monoubiquitination: promotes cytoplasmic localization

Polyubiquitination: promotes degradation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

p53 modification that leads to senescence?

A

phosphorylation of serine 15. Activates p21, a CDKi which inhibits cyclin D and E complexes, leading to G1 arrest (senescence)

17
Q

Effect when p53 modifications lead it to be upregulated too long?

A

p53 will cause transcriptional activation of PUMA. This causes apoptotic gene activation: BCL2, mitochondrial transition pore, cytochrome C release from mito, caspase 9 activation

18
Q

Differences between apoptosis and senescence?

A
19
Q

describe telomere attrition

A

-at 5’ end of lagging strand, DNA pol can’t fill in the 3’ overhang once the RNA primer is removed. This is eventually recognized as DNA damage.

Causes senescence:

  • DNA damage response – p53 activation
  • DNA damage response protein accumulation: p53BP1, H2AX foci
  • telomere-induced damage foci (TIF)
20
Q

What is T loop formation, and why is it necessary?

A

T loops are formed to hide the linear overhang so it is not recognized as damage

  • TRF1 and TRF2 bind the telomere and allow the 5’ end to invade the 3’ end.
  • the telomere cap structure also contains DNA repair proteins Ku70/80 and DNAPK (deletion of Ku in humans causes telomere fusion with other chromosomes)
21
Q

How do telomeres differ between species?

A

mice: large, have telomerase activity in somatic cells
human: small, only telomerase in germ cells (present but inactive in somatic cells)
yeast: anchored to nuclear membrane

22
Q

telomerase structure?

A
  • TERT enzyme protein
  • TLC1 template in vitro
23
Q

What do southern blots of telomeres tell us about senescence?

A

That telomere length decreases with senescence.

24
Q

How have we experimentally allowed unlimited growth in human somatic cells?

A

by introducing telomerase. We see the telomere smear length by southern blotting increases in size.

25
Q

How is access of telomerase to the telomere regulated?

A

Not entirely known, but TRF1 may play a role:

  • deletion increases telomere length
  • overexpression decreases telomere length
26
Q

Effect of oncogenic Ras on immortal (mouse) cells? Normal human cells?

A

In immortal cells, oncogenic Ras causes transformation.

In normal human cells, oncogenic Ras causes senescence, We know this because of increase in p53, p21, and p16 senescence markers via western blotting

27
Q

How does oncogene activation lead to senescence in normal human fibroblasts?

A

Ras v12 induces hyper-replication in normal cells, thus activating the DNA damage response. Over-firing of DNA origins without proper signals causes cells to senesce.

28
Q

Describe chromatin remodeling during senescence?

A

chromatin DAPI staining is condensed and irregular in senescent cells. why?

  • stress causes S phase arrest
  • pRb binds E2F genes involved in S phase
  • laminin B1 expression is decreased
  • p53 increase PML expression, which are docking sites for histone chaperones HP-1 and HIRA.
  • this causes senescence-associated heterochromatin foci (SAHF)
29
Q

Describe senescence-associated heterochromatin foci (SAHF).

A
  • pericentromeric and telomeric regions located at SAHF periphery
  • contains markers of heterochromatin including hypoacetylated histones and H3K9m3 and HP1
  • does not contain all heterochromatin markers
30
Q

Which protein is one of the best senescent markers?

A

p16

31
Q

What are the consequences/significance of senescent cells in tissues?

A
  • decreased wound healing (CCN1 matrix protein-ROS senescence)
  • altered secretory profile (p21, IGF-BP3, collagenase, cytokine production increase, IL-6, Rantes, IL-2, IL-8) – contributes to tumorigenesis and immune clearance
32
Q

Role of senescent cells in tumorigenesis?

A
  • tumor formation is stimulated by senescent fibroblasts
  • conducted in mouse fat pads
  • possibly due to altered secretory profile
33
Q

Relationship between later life disease and senescent cells?

A

late life disease positively correlates with the number of senescent cells in the tissue

34
Q

How would we expect immune clearance of senescent cells to affect lifespan?

A

We would expect clearance of senescent cells to extend lifespand.

35
Q

How can we therapeutically target senescen cells for clearance?

A

can add caspase9 downstream of a p16 promotor. This has been shown to extend lifespan in mice, and improves cardiac function.

36
Q

Relationship between pluripotency txn factors and senescence?

A

Low amounts of oct4, sox2, klf4, c-myc induce senescence

CORE II Block 4 (6 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions