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Regulation Of Gene Expression > Lesson 26 > Flashcards

Lesson 26 Flashcards

1
Q

what is aging defined as?

A

a time dependent decline of the function of tissues and organs → due to a loss of the physiological function of the organs

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2
Q

how are our bodies trying to contrast functional decline?

A

by compensatory responses the try to reestablish the homeostasis of tissues

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3
Q

what are the 9 candidate hallmarks of aging?

A
  1. genomic instability
  2. telomere attrition
  3. epigenetic alterations
  4. loss of proteostasis
  5. deregulated nutrient sensing
    6.mitochondrial dysfunction
  6. cellular senescence
  7. stem cell exhaustion
  8. altered intracellular communication
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4
Q

what is genomic instability caused by?

A

the accumulation of DNA damage caused by intrinsic or extrinsic factors

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5
Q

what are some cases of genomic instability?

A

Epigenomic modifications, loss of proteostasis, deregulation of new gene sensing (of the anabolic
pathways), mitochondrial dysfunction, cellular senescence, stem cell exhaustion

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6
Q

what are some extrinsic causes of genomic instability?

A

exogenous physical, chemical, biochemical, or pathological agents that trigger and promote DNA adhesion

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7
Q

what are some intrinsic causes of genomic instability?

A

accumulation of ROS or replication errors

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8
Q

what do intrinsic causes of genomic Instability lead to?

A

telomere shortening and gene distribution due to the reactivation of transposons or integration of viruses → mutations can affect nuclear DNA or mitochondrial DNA

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9
Q

why is the focus on the nuclear architecture so important?

A

the mutations in genes that encode for the nuclear lamina are quite important and give rise to genomic instability that is also structural Instability and premature aging syndromes (such as progeria)

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10
Q

what occurs when there is a deficiency in the DNA repair mechanism?

A

when a cell is trying to activate the DNA repair mechanism, the response is impaired or lost during aging which leads to the further accumulation of DNA damage

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11
Q

what is the DNA damage response activated by?

A

different sources of stress that cause SS or DS DNA breaks

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12
Q

what is the main and 1st mechanism activating the cellular senescence?

A

checkpoint arrest

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13
Q

what occurs when checkpoint arrest does not give rise to DNA repair?

A

cellular senescence

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14
Q

what is telomere attrition?

A

the deterioration of telomeres due to the progressive loss of the protective sequence

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15
Q

how are telomeres protected?

A

they are bound by shelterings that are going to protect complexes and prevent access of DNA repair machinery at the edge of the chromosomes

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16
Q

why is sheltering important to protect the edge of the chromosome?

A

if they are not protected, the chromosome is considered like a dsDNA with a break → DNA damage mechanism will come and try to fix the damage and the chromosome will be fused together to correct the gap and creates a fusion with another molecule of
DNA, so we will not have separate molecules or separate chromosomes, but instead we will have a
continuous DNA molecule of all the chromosomes fused together

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17
Q

what is aging characterized by?

A

imbalance in histone modification,
transcriptional changes, loss/gain of heterochromatin,
breakdown of nuclear lamina with the involvement of Lamin genes, global hypomethylation, focal hypermethylation (at a specific locus like polycomb locus), and general changes in chromatin remodelling.

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18
Q

what happens during the aging process in regards to methylation?

A

a global reduction in methylation creating transcriptional noise and there is a depression of transcription

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19
Q

what does the accumulation of unfolded or misfolded proteins caused by the decreased activity or chaperones or autophagy?

A

loss of proteostasis

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20
Q

what is the loss of proteostasis linked to?

A

reduced autophagy and decrease of chaperone expression → these processes are not properly functioning and the refolding of proteins and also the accumulation that is the consequence of all these steps of misfolded proteins within the cells gives rise to specific diseases

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21
Q

what is driven by GH and regulates the anabolic pathway?

A

somatotrophin axis

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22
Q

what is the central regulator of the somatotrophic axis?

A

mTOR

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23
Q

what two things have been used experimentally to reduce the somatotrophic pathway and prevent aging?

A

inhibition of the mTOR pathways and a low calorie diet → dietary restriction and pharmacological manipulation of this pathways is associated with the rejuvenation of organisms

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24
Q

what is mitohormesis?

A

a hermetic response → the mitochondria is strung to regenerate and rebalance the ROS to reach homeostasis

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25
Q

what is cellular senescence?

A

the stable arrest of the cell cycle coupled to stereotyped phenotypic changes

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26
Q

what are the two portions of cellular senescence?

A

the accumulation of senescent cells and a decreased function of the immune system

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27
Q

what occurs when the senescence is transient?

A

the cell uses it to stop the proliferation of aberrant cells and through the production of inflammatory cytokines recruits immune system cells (which then clear aberrant cells)

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28
Q

what is senescence the basis of?

A

the main surveillance of cancer and involved in tissue regeneration, tissue development, and homeostasis

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29
Q

what does prolonged senescence cause?

A

gives rise to a compensatory response which is no longer balanced → the immune cells have impaired function that leads to the accumulation and propagation of damaged and senescent cells

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30
Q

what is a way to preserve the genomic instability an to preserve the long-term function of a cell?

A

quiescence

31
Q

describe the quiescent cell state:

A

in the state of quiescence the cell state is reversible, so the cell triggers based on the stimuli and can reverse to the cell cycle state

32
Q

in what state is a senescent cell usually in?

A

the state of cell cycle arrest → either immune cells are recruited and they can clear the senescent cells or the senescent cells accumulate

33
Q

what happens when stem cells are exhausted?

A

they go through differentiation and they lose their self-renewal potential

34
Q

what a common hallmark of senescent cells?

A

a higher activity of β-galactosidase (can distinguish between a senescent cell and a quiescent one)

35
Q

what is a way to see if a cell is going through the process of quiescence?

A

the expression of specific cell cycle inhibitors such as p53, p16, p21, or DNA damage

36
Q

with is SASP?

A

senescence-associated secretory phenotype → associated with inflammatory cytokines that are produced by senescent cells

“good senescence” → transient

37
Q

what is one of the most important effectors along with cyclin dependent kinase that gives rise to stem cell exhaustion?

A

p53

38
Q

when comparing old somatic cells to newer ones, what can we see?

A

overexpression of cell cycle inhibitors proteins like p16, as well as shorter telomeres

39
Q

what happens when there is an excessive proliferation of stem cells?

A

they lose their self-renewing capacity → gives rise to different defects in different organs depending on the type of stem cells (bone marrow= osteoporosis, muscle fibers= sarcopenia)

40
Q

what gives rise to an overall, systemic deterioration of the system?

A

the aging-dependent deterioration of multiple tissues caused by inter-organ communication

41
Q

what term is tied into the concept of intercellular communication and cellular aging?

A

inflammaging → a condition characterized by high levels of inflammatory cytokines and a higher susceptibility of chronic disease

42
Q

what are the four primary hallmarks of cellular aging?

A
  1. genomic instability
  2. telomere attrition
  3. epigenetic alterations
  4. loss of proteostasis
43
Q

what are the primary hallmarks tied to?

A

tied to the cause of aging and can be considered unequivocally negative

44
Q

what are antagonistic hallmarks?

A

activated as a response to damage → cellular senescence is not detrimental mechanism, but when it is persistent and the immune system cannot be
properly recruited to clear the cells, the hallmark is negative as it gives rise to aging factors

45
Q

what are the three antagonistic hallmarks?

A
  1. deregulated nutrient sensing
  2. mitochondrial dysfunction
  3. cellular senescence
46
Q

what are the two integrative hallmarks?

A
  1. stem cell exhaustion
  2. altered intracellular communication
47
Q

what are integrative hallmarks?

A

they effect tissues architecture, homeostasis, and function

48
Q

what is premature aging syndrome?

A

when mutations affect the different genes that are involved in the architecture of the nuclear lamina or
genes that are involved in RNA replication and transcription

48
Q

describe primature aging syndrome:

A

aging seems accelerated and these patents die very early in life

49
Q

what is Hutchinson-Gilford progeria (HGPS)?

A

characterized by accelerated aging, abnormalities on a multi-organ level

50
Q

what causes HGPS?

A

due to a mutation in the lamin genes coding for the nuclear filament protein lamin → gives rise to shortened truncated proteins and the accumulation of aberrant proteins in the nuclear periphery

51
Q

what happens when the Farnesyl tail is not removed in HGPS?

A

there is an accumulation of the aberrant protein that gives rise to aberrant shape of the nuclear lamina leading to severe disease

52
Q

what does an aberrant shape of the nuclear lamina cause?

A

activation of different mechanisms such as telomere shortening, ROS accumulation, accumulation of DNA damage, and cellular senescence

53
Q

what is progeria?

A

aberrant lamin protein

54
Q

what can help to prevent or reverse the aging phenotype?

A

exercise, diet, caloric restriction, and mechanism targeting

55
Q

what is the most used way to study senescence in humans?

A

whole genome sequencing

56
Q

what is at the top of the hematopoietic hierarchy?

A

long term hematopoietic stem cells (LT-HSC)

57
Q

what is the microenvironment in which LT-HSCs are regulated and finely tuned in terms of function?

A

bone marrow niche → where they are interacting with other hematopoietic and mature cells, but also with cells of completely different origins

58
Q

what happens to the hematopoietic system during aging?

A

Hematopoietic stem cells start to
proliferate and expand, but ALSO exhaust their functional activity:

-They have a decreased homing capacity to the marrow, so there are more circulating hematopoietic cells in the peripheral blood.
-They start to imbalance their capacity to give rise to homeostatic output of mature cells → increased platelets production and an increased myeloid-biased, whereas the lymphoid one is much lower

59
Q

describe cell-intrinsic aging:

A

cell-autonomous → important in aging since all the defects that are present in the top of the hierarchy part are then transmitted to the progeny and are affecting how these (stem) cells are able to give rise to differentiated progeny

60
Q

what are some examples of cell-intrinsic aging issues?

A

o Epigenetic dysregulation
o Replication stress
o Deficient DNA repair (accumulation of DNA damage)
o Metabolic changes
o Defective autophagy
o Altered protein homeostasis
o Telomere shortening
o Increased ROS production and oxidative damage

61
Q

describe cell-extrinsic aging:

A

bone marrow niche-driven

62
Q

what are some examples of cell-extrinsic aging?

A

o Decreased bone formation since aging is associated also to osteopenia, there is a
decreased bone formation, and this can affect hematopoietic stem cells because of the
osteo-lineage crosstalk to the HSC
o Increased adipogenesis
o Increased plasma levels of CXCL12 (CXCL12 is the stromal cell-derived factor 1à
it attracts hematopoietic stem cells to the niche)
o Loss of stromal osteopontin
o Loss of beta-adrenergic innervation of the bone marrow
o Loss of endothelial Jag2 and mTOR

63
Q

what other mechanisms are involved in hematopoietic stem cell aging?

A

epigenetic changes

64
Q

what are some niche contributions to aging?

A
  • increase in ROS levels
  • decrease of retention factors and function of the sympathetic nervous system
  • stiffness of the ECM
65
Q

what is considered to be one of the most important non-hematopoietic populations affecting HSC function and retention?

A

sympathetic nervous system

66
Q

what are label-retaining cells?

A

the ones not proliferating and dividing

67
Q

what protects HSCs from aging in perisinusoidal niches?

A

endothelial Jag2

68
Q

what is the Dox off system?

A

it allows the silencing of gene expression through the administration of doxycycline

69
Q

when compared to other cell types, where are HSC in relation to the bone?

A

they are the more distant - there are no differences between young and old→ all the HSCs are becoming distant from different structure but they are preserved quite close to the sinusoidal vesicles

70
Q

what else besides bone are HSCs distant from?

A
  • they are distant from arterioles
  • they are distant from megakaryocytes
  • they are distant from Nestinhigh stromal cells
71
Q

what do HSCs remain close to?

A
  • they remain close to sinusoids
  • they are close to Nestinlow cells
72
Q

what is the signaling that preserves HSC quiescence in sinusoids?

A

notch signaling pathway, specifically Jag2 which is a ligand of Notch k

73
Q

did they discover that there are cell-intrinsic or cell-extrinsic mechanisms for HSC aging?

A

cell extrinsic mechanism → it depends on the mutations of HSCs, on mitochondrial activity of HSCs, and by the surrounding environment

Regulation Of Gene Expression (28 decks)

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