8 - frailty Flashcards

1
Q

sarcopenia

A

loss of muscle mass, strength and quality

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2
Q

aging is a … process

A

heterogenous

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3
Q

how many hallmarks of aging

A

9

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4
Q

genomic instability

A

hallmark of aging
DNA damage accumulation
exogenous or endogenous cause
creates lesions

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5
Q

telomere attrition

A

shortening of telomeres

telomeres are required for normal cell divison

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6
Q

epigenetic alterations

A

changes in DNA methylation

changes in histone modification

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7
Q

loss of protestasis

A

proteins become unstable and unfolded

causes aggregation

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8
Q

deregulated nutrient sensing

A

caused by genetic polymorphisms

growth factors e.g. IGF-1
targets = FOXO/mTOR

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9
Q

mitochondrial dysfunction

A

destabilisation of ETC

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10
Q

cellular senescence

A

stable arrest of cell cycle

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11
Q

stem cell exhaustion

A

types of stem cell:

  • haematopoietic
  • mesenchymal
  • satellite
  • intestinal epithelial
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12
Q

altered intracellular communication

A

neuroendocrine dysfunction
inflammaging
immunosenescence

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13
Q

programmes theory of aging

A

deteriation is inevitable over time

  • programmed longevity
  • endocrine theory
  • immunological theory
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14
Q

programmed longevity

A

sequential switching on and off of switches over time causes deteroiration

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15
Q

damage and error theory consists of 5 parts

A
wear and tear
rate of living
cross-linking proteins
free radicals
somatic DNA damage
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16
Q

rate of living theory

A

greater metabolism = shorter life span

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17
Q

free radicals theory

A

cause oxidative damage to macromolecular cell components

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18
Q

what does ELISA stand for

A

enzyme-linked immunosoribent assay

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19
Q

what is ELISA

A

plate based assay technique

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20
Q

what does elisa used for

A

detecting and quantifying peptides, proteins, antibodies and hormones

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21
Q

rt-pcr stands for

A

reverse transcriptase polymerase chain reaction

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22
Q

rt-pcr steps

A
  1. convert RNA population to cDNA by reverse transcription

2. amplify cDNA by PCR

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23
Q

why is rt-pcr useful

A

allows more detailed study of original RNA species even if they are expressed in low abundance

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24
Q

uses of rt-pcr

A

detection of expressed genes
examination of transcript variants
generation of cDNA templates for cloning and sequencing

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25
one step rt-pcr
``` single tube combines cDNA synthesis and PCR otgether reduces variation reduces contamination quicker ```
26
two step rt-pcr
cDNA synthesis and PCR in separate tubes and reaction s used for detecting multiple genes in the same sample can reach optimum reaction conditions longer workflow less contamination
27
how do you test for different genes in the same sample with rt-pcr
2 step method | make different specific primers for each time you run PCR
28
define senescence
loss of a cell's power to divide and grow
29
main mechanism of senescence
telomere shortening
30
why do telomeres shorten
linear DNA is not completely replicated every mitosis
31
DNA damage response
when telomeres reach a critically short length | they become dysfunctional
32
hayflick limit
when a cell has reached its maximum amount of times it can divide
33
why are cancer and stem cells immortal
their DNA doesnt shorten no hayflick limit they express telomerase
34
telomerase
adds telomere back on when lost
35
effect of DNA damage/telomere malfunction
premature senescence
36
benefit of senescence
helps prevent tumours
37
cons of senescence
causes ageing age-releated diseases prevents tissues reparing well
38
accumulation of senescence
negatively affects tissue structure and fucntion leading to frailty
39
Senescence associated secretory phenotype
secreted factors by senescing cells | e..g proinflammatory cytokines, chemokines, proteases, growth factors
40
immunosenescence
gradual deterioration of the immune system with age
41
immunosenescence cellular effects
defects in haematopoietic stem cells | defects in peripheral lymphocyte migration, maturation and function
42
overall effects of immunosenescence
increased infection , cancer and autoimmune disease
43
why does immunosenescence cause decreased adaptive immune resposne
causes decreased antigen presentation
44
thymic involution
immunosenescence causes decrease in thymuc tissue mass | leads to loss of naive t cells
45
inflammaging
chronic inflammation associated with age | chronic inflammatory cytokine production
46
process of inflammaging
irritation causes cell membrane damage causes arachidonic acid to be cut into leukotrienes and prostaglandins inflammatory leukotrienes cause free radical damage
47
effect of free radicals produced by inflammaging
cause elastase and collagenase to affect skin and destruct skin structure
48
role of inflammaging in cancer
reduces immune response to new antigens
49
direct ELISA
target antigen bound to bottom of well complementary primary labelled antibody added antibody binds to antigen enzyme label catalyses colour change reaction
50
advantages of direct elisa
cross-reactivity of secondary antibody eliminated | not max reactivity as antibody is labelled
51
indirect elisa
antigen bound to bottom primary antibody added and binds to antigen well washed to remove any non-bound antibodies secondary enzyme-linked antibody added - complementary to constant region of primary antibdy enzyme label causes colour chnage
52
advantages of inirect elisa
maximum immuno-reactivity of primary antibody as it isnt labelled
53
sandwich elisa
``` antibody bound to bottom of well target antigen added and binds well washed - removes non-bound antigen secondary enzyme-labelled antibody added colour change measured ```
54
advantages of sandwich elisa
allows concentration of unknown substances to be measured most common one
55
characteristics of apoptosis process
chromatin condensation nuclear fragmentation blebbing and cell shrinkage release of apoptotic bodies
56
extrinsic apoptosis pathway
``` Fas binds to death receptor transautophosphrylation of RTK death inducing complex formed activation of caspase-8 activation of effector caspases e.g. caspase-3 apoptosis ```
57
intrinsic apoptosis pathway
``` intracellular damage/ no growth factor Bad not phosphorylated Bcl-2 inihibited mitochondrial dysfunction release of cytochrome-c into cytosol caspase-9 activated effector caspases activated - eg caspase-3 apoptosis ```
58
Bad protein in presence of trophic factor
Bad gets phosphorylated binds to Bcl-2 no apoptosis
59
process of necrosis
``` cell swells chromatin digested organelle membranes disrupted cells lyse and spill contetns hydrolytic enzymes damage neighbouring cells inflammation ```
60
cause of auto-phagy
response to cell starvation and stress or if organelles wear out source of energy for cell
61
autophagy in cellular homeostasis
digestion of intracellular components | degradation products transloacted to cytoplasm
62
microautophagy
invagination of lysosomal membrane | sequesters proteins and degrades
63
macroautophagy steps
isolation membrane vesicle elongates to form phagophore autophagosome formation - double membrane LC3 allows binding to lysosome autolysosome forms contents broken down by acid proteases/hydrolytic enzymes
64
defects in autophagy
prevent cells from clearing unwanted proteins/microbes | allow disease manifestation
65
principal mechanism for protein catabolism
ubiquitin proteasome pathway
66
role of E1-activating enzyme
binds to Ub primes Ub adds ATP
67
role of E2-conjugating enzyme
binds to Ub and replaces E1 | escorts Ub to E3 enzyme
68
role of E3-ubiquitin ligase enzyme
acts as a platform fro E2-Ub complex to bind to targeted protein Ub is then transferred to protein
69
type I skeletal muscle fibres
``` slow twitch fibres red aerobic respiration slow-contracting low myosin ATPase activity ```
70
type IIa skeletal muscle fibres
``` fast oxidative fibres red aerobic respiration fast-contracting higher myosin ATPase activity ```
71
type llb skeletal muscle fibres
``` fast glycolytic fibres white fast-contracting anaerobic respiration lower capactiy for ATP production sparser capillary network less sustainable ```
72
what triggers contraction of cardiac muscle
calcium induced calcium release | triggers opening of ryanodine receptor
73
characteristics of cardiac muscle
involuntary | striated - intercalated disks
74
cardiomyocyte
heart muscle cell
75
diseases of cardiac muscle
caused by restriction to blood supply angina myocardial infarction
76
t-tubules in cardiac muscle
bigger/wider than skeletal muscle transmit action potentials to cells core regulate Ca2+ conc in excitation-contraction coupling
77
angina
obstruction to coronary arteries reduces blood flow to heart heart cant contract properly chest pain
78
PI3/Akt pathway until PIP3 is activated
signal binds to RTK receptor dimerisation and transautophosphorylation PI3 recruited via SH2 domain PIP2 converted to PIP3
79
PI3/Akt pathway once PIP3 is activated
PIP3 recruits Akt and PDK-1 via their PH domains PIP3 binds to Akt Akt phosphorylated by MTORC2 and PDK-1 Akt downstream affects
80
3 downstream effects of phosphorylated Akt
1 - activation of Rheb by inactivation of TSC2 MTORC1 activated - growth 2 - activation of AIP (apoptosis inhibiting) by inactivating Bad - cell survival 3 - inactivation of FOXO (T. factor) which prevents transcription of atrogenes in myofibres (prevents autophagy)
81
3 overall effects of PIP2/Akt pahway
activation of MTORC1 - cell growth inhibition of apoptosis - cell survival inhibition of autophagy
82
PI3-Kinase
converts PIP2 to PIP3
83
mTOR
mammalian target of rapamycin
84
mTOR involevd in
cell growth, proliferation
85
regulation of mTOR
growth factors, insulin, glucose
86
inactivated TSC2
activated Rheb | activated MTORC1
87
mTOR pathway in presence of growth factor
``` Akt causes inactivation of TSC2 activation of Rheb (Rheb-GTP) activae mTOR cell growth ```
88
mTOR in absence of growth factor
``` TSC2 active acts as a GAP to Rheb Rheb-GDP (inactive) inactive mTOR no cell growth ```
89
myostatin
protein produced and released by myocytes that inhibits myogenesis
90
myogenesis
determines muscle fibre number in development and muscle size in adults
91
increased myostatin
decreased muscle mass
92
effect of myostatin on Akt
inhibits Akt inhibition of protein synthesis myofibirl degradation muscle atrophy
93
inhibition of myostatin as a therapuetic
for sarcopenia (prevent muscle wasting)
94
IGF-1
insulin like growth factor produced in liver stimualted by growth hormone binds to RTK
95
IGF-1 pathway
``` IGF-1 binds to RTK receptor dimerisation and transautophosphorylation activation of PI3-K via SH domain PIP2 to PIP3 Akt recruited mTOR pathway initiated protein synthesis etc ```
96
effects of IGF-1
protein synthesis inhibition of proteolysis stimulates nutrient uptake
97
IRS-1
signalling adaptor protein has a PH domain binds to RTKs
98
IRS-1 pathway
ligand binds to RTKs transautophosphorytion IRS-1 binds via PH domain recruits docking proteins bind via SH2 domains e.g. grb2 and PI3-K Activates downstream pathways e.g. MAPK and PI3-K/Akt