Senescence Flashcards

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1
Q

aging is?

A

the inevitable time-dependent decline in physiological organ function that eventually leads to death

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2
Q

changes in life expectancy throughout human history

A

-changes in the environment, nutrition, and medical care –> can extend expected survival age

-the average age expectancy continues to increase
-the area under the curves has dramatically increased

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3
Q

the ______ lifespan appears to be unchanged?

A

maximum

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4
Q

central nervous system effects from aging

A

extreme shrinkage of the cerebral cortex

severely enlarged ventricles

shrinkage of hippocampus : learning and memory

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5
Q

respiratory system effects from aging

A

-clogged and deformed alveoli
(fewer and large)

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6
Q

timeline of ageing research

A

caloric restriction enhances lifespan in mice and rats (1930s)

The 1950s - medewar accumulation theory, Williams antagonistic pleiotropy

1960s- Hayflick limit

1990s- senescence observed in human aging

2000s- SASP identified: senescence-associated sensitive phenotype
, first senolytics clinical trial

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7
Q

9 hallmarks of aging, grouped into 3 categories

A
  1. the primary causes of cellular damage
    -genomic instability
    -telomere attrition
    -epigenetic alteration
    -loss of proteostasis
  2. compensatory or antagonistic responses to the damages
    -cellular senescence
    -mitochondrial dysfunction
    -deregulated nutrient sensing
  3. the consequences of aging cues: hallmarks group 1-2
    responsible for the functional decline associated with aging
    -stem cell exhaustion
    -altered intercellular communication
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8
Q

Alexis Carrel

A

studied phenomenon of senescence or aging

“on the permanent life of tissue outside of the organism”

-tissue from embryonic chicken heart, the cultures were supplied with nutrients regularly

-tissue were maintained for over 20 years– this is longer than a chicken’s normal lifespan

“all cells continued to grow indefinitely”- this was widely accepted in the 20th century

an image of a thirty-day-old culture of connective tissue. in the center there was debris of old plasma, around it is a ring of concentric layers of very active new tissue

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9
Q

primary cells

A

cells obtained from original tissue that have been cultivated in vitro for the first time

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10
Q

cell strains

A

cells were derived from animal tissue, sub-cultivated more than once in vitro (diploid)

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11
Q

cell lines

A

immortal cells that have been grown in vitro for extended periods of time (years) (heteroploid)

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12
Q

cultured normal human cells have a limited capacity to divide

A

-around 40-60 doubling before entering a senescence phase

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13
Q

cell alteration

A

phase 1: or primary culture: the beginning of culture. cells are isolated from the original tissue
-this phase terminates with the formation of the first confluent sheet

phase 2: the luxuriant growth period where cells are continuously proliferating
-cells in this phase are termed “cell strains”

  • an alteration may occur at any time giving rise to a “cell line” -whose potential life is infinite

phase 3: the period where cell replication rate slows, a phenomenon named “senescence”
-cell strains enter phase 3 and are lost after a finite period of time

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14
Q

primary causes of cellular damage

A

genomic instability, telomere attrition, epigenetic alteration, loss of proteostasis

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15
Q

compensatory or antagonistic responses

A

cellular senescence or ageing

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16
Q

eukaryotic cell

A

10 to 100 um
-can see the nucleus
-condensed chromatin
-an extension of nuclear envelope

cytoplasm: fluid within the cell that surrounds the organelles

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17
Q

building blocks of life

A

DNA, RNA, and protein

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18
Q

liquid-liquid phase separation (LLPS)

A

-underlies the formation of membrane-less organelles (MLOs)

-LLPS leads to a conversion of homogenous solution into a dense phase and a dilute phase

-intrinsically disordered proteins (IDP’s) containing, LCDs, PLDs (PrLDs) etc bind to multivalent polymers such as RNA and DNA as well as proteins

-MLOs function to concentrate proteins, and nucleic acids, and regulate gene expression

nucleolus and paraspeckles are nuclear MLOS

stress granules (SGs), RNA transport granules, and P-bodies are cytoplasmic MLO’s

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19
Q

Paraspeckle is involved in?

A

gene expression regulation, RNA processing

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20
Q

stress granule is involved in?

A

translational regulation, antiviral defense, response to stresses, store some mRNA and proteins

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21
Q

Nucleolus is involved in?

A

ribosome biogenesis

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22
Q

cajal body is involved in?

A

pre-mRNA and pre-rRNA processing

23
Q

the p body is involved in?

A

post-transcriptional modification, response to stress

24
Q

nuclear pore complex?

A

nuclear import and export, tumor, immune

25
Q

cellular senescence

A
  1. well-established driver of aging and age-related diseases
  2. refers to the irreversible growth arrest that occurs when cells become exposed to a variety of stressors
26
Q

cell growth

A

the increase in size (mass accumulation)

27
Q

cell division:

A

the division of a mother cell into 2 daughter cells (cytokinesis)

28
Q

cell proliferation

A

the process of generating an increased number of cells through cell division

29
Q

eukaryotic cell division cycle

A

interphase: duplication of its entire cellular contents

M phase: creation of genetically identical cells

two main events
1. DNA replication (S phase)
2. segregation of the DNA (cytokinesis)

check points
G1 and G2 phases: commit to enter the next cycle
M phase: mitotic exit

30
Q

A snapshot of dividing cells

A

HEK293 is a human embyronic kidney cell line

-invitro cell culture model for tauopathies (e.g. Alzheimer’s)

immunocytochemistry

lamin b1: protein of nuclear lamina which is a meshwork of proteins inside the inner layer of the NE

Hoechst 33342 (nuclei) a blue fluorescent dye for DNA stains

31
Q

HEK293 expressing Dox:

A

GFP-tau (isoform 0N4R) is a microtubule binding protein

32
Q

progression of the cell cycle

A

CDK: cyclin-dependent kinase in inactivated form

cyc: cyclin binding to CDK- promotes entry into the cell cycle

p16, p21, p27 : CDK inhibitors

E2F: transcription factor

RB, tumor supressor retinoblastoma in active form

33
Q

cell division cycle withdrawal

A
  1. Quiescent cells
  2. terminally differentiated cells
  3. senescent cells
34
Q

Quiescence

A

cell cycle: reversible arrest

macromolecular damage: no

signaling: p27kipi dependant

secretion: no

35
Q

differentiation

A

cell cycle: genetically irreversible arrest

macromolcular damage: no

secretion: yes/no

36
Q

senescence

A

generally irreversible arrest

macromolecular damage: yes

secretion: yes

paracrine/autocrine signaling

37
Q

genomic dna damage an telomere shortening

A

persistent DDR signaling -> cellular senescence and altered stemness and differentiation -> inflammation and fibrosis

all considered aging

-impair stem cells properties and alter its differentiation

38
Q

mutation types

A

point, DNA amplification and chromosomal rearrangement

substitution: change the code of the single triplet

insertion: changes the genetic code of all triplets following

deletion: changes genetic code of all triplets following

39
Q

a individual cell can suffer up to ________ DNA changes per day?

A

one million

40
Q

mutations and chromosome aberrations can lead to?

A

cancer, ageing, inborn disease

41
Q

inhibition of _______ leads to apoptosis (cell death)

A

transcription, replication, chromosome segregation

42
Q

homologous recombination

A

simultaneous action of large numbers of molecules (multiple protein complex)

43
Q

cohesins

A

facilitate the identification of homologous sequence from the sister chromatid

44
Q

RAD51

A

exchange the ssdNA with the same sequence from dsDNA

45
Q

end joining (alternative)

A

simply links ends of DSB together (KU70/80)
-associated with gain or loss of a few nucleotides

46
Q

DNA replication and associated proteins at the replication fork

A

topoisomerase: removes

helicase: unwinds

SSBs: coat

ligase: seals

pol E: synthesize

47
Q

telomere

A

short nucleotide sequences found at the end of linear chromosomes

telomerase (TERT gene) : a reverse-transcriptase

telomerase binds to the 3’ end of the telomere sequence, along with an RNA template

telomerase catalyzes the addition of bases restoring the telomere length

DNA polymerase extends and seals the DNA strands

48
Q

proliferating tissues

A

telomeres are shortened, when critically short, they trigger a DDR

49
Q

post mitotic tissues

A

telomere dysfunction can be driven by irreparable DD within telomeres

50
Q

persistent DDR (DNA damage response) activation

A

senescent phenotype
1) arrested proliferation and 2) SASP activation

inhibition of DNA damage repair at telomeres
-accumulation of DD at telomeres –> DDR–> cell cycle arrest or senescence or senescence like phenotype

51
Q

post mitotic tissues

A

cardiomyocyte, adipocyte, neuron, osteocyte

52
Q

how stem cells age?

A

stem-cell number and self-renewal do not necessarily decline with aging, but function does decline

young stem cells -> many progenitors-> many effectors

after physiological ageing, mutagen exposure or forced regeneration

old cells-> less progenitors -> less effectors

53
Q

fates of damaged stem cells

A

stem cell-> RAF mutation, p53 loss (mutations or tumor suppressors) -> transformation->cancer

stem cell-> telomere dysfunction->senescence -> regenerative failure, SA-SP

stem cell-> unrepaired DSBs-> apoptosis-> tissue dysfunction and failure

stem cell-> y chromosome or 5q- loss, Tert gene -> dysfunction -> tissue dysfunction and failure (e,g. Myelodysplasia (MDS))