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SCRA > 17. ageing biology 3 > Flashcards

17. ageing biology 3 Flashcards

1
Q

what is autophagy and define one type of this

A

organelle destruction and turn over

mitophagy - the destruction of mitochondria

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2
Q

what is proteostasis? and what does it ensure?

A

the homeostasis of proteins - how the cell ensures that correct proteins are produced and correctly folded
- it also ensures that faulty proteins are recognised and disposed of

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3
Q

how is homeostasis affected by ageing

A

it is reduced

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4
Q

in what sort of cells do mitochondria need to be really robust in?

A

energy hungry cells, like neurones in the brain

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5
Q

glucose is oxidised during glycolysis, what is produced? and what does the mitochondria do with them?

A

co enzymes are reduced to NADH and FADH2
>they are oxidised by the mitochondria - electron flow down ETC and this is coupled with an electrochemical gradient across inner mit membrane

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6
Q

how is energy generated in the mitochondria?

A

proton gradient across inner mit membrane generates electrochemical gradient which complex V uses to generate ATP

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7
Q

where can free radical leak from?

A

the complexes in the mit - the ETC has proven to be leaky

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8
Q

what type of free radical are produced by the ETC?

A

superoxide anion radicals - dismutase transformed these to hydrogen peroxide that can further react to make hydroxyl radical

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9
Q

what can reduced ROS leaking from the mit? and what does this have a similar effect to?

A

dampening down ETC

>calorie restriction

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10
Q

how did we come about to have mitochondria in our cells and what have we had to adapt to?

A

mitochondria were engulfed many years ago, we have evolved ways to reduce the effects of free radicals which they produce

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11
Q

what are the two systems employed to reduce the effects of ROS?

A

SOD enzymes and non-enzymatic mechanisms

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12
Q

what does the SOD enzymes do and where are they found?

A

they convert superoxide to hydrogen peroxide
>SOD1 in the mit
>sod2 in the cytosol

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13
Q

what does SOD stand for?

A

superoxide dismutase

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14
Q

what deactivated hydrogen peroxide?

A

catalyse reduced hydrogen peroxide to water

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15
Q

how does non-enzymatic removal of ROS occur? and what are these?

A

micronutrients obtained from food safely absorb energy from free radicals
>these are antioxidants

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16
Q

what sort of micronutrients can absorb energy from ROS?

A

hydrophilic - like ascorbate and glutathione

lipophilic - carotenoids and ubiquinol

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17
Q

what happens when these macronutrients are KO in mice?

A

they are much more sensitive to oxidative stress

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18
Q

describe mtDNA

A

small number of genes

codes for 4 out of 5 of the complexes for oxidative P

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19
Q

what type of damage are mt venerable to?

A

mtDNA damage - even though they can undergo some repair

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20
Q

where is mtDNA found in Mit and what implication does this have?

A

near inner mitochondrial membrane – close to where ROS will be produced

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21
Q

what types of lesions do ROS cause in mtDNA?

A

oxidised bases, abasic sites, single and double strand breaks

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22
Q

what is mtDNA not protected by and what implication does this have?

A

not protected by histones – these are thought to protect genomic DNA by ten folds

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23
Q

what is a common marker of oxidative stress in mtDNA?

A

8-oxoG

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24
Q

what can ROS modulate in the cell? and how do they do this? and what might happen is this is deregulated?

A

signalling pathways - kinases, phosphatases and TFs
>covalent modifications to redox sensitive cysteine which alters proteins activity but is reversible
>if deregulated this may cause disease

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25
Q

what can ROS cause in the cell?

A

molecular damage - lipids, DNA and proteins

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26
Q

what types of mtDNA repair can take place?

A
  • direct reversal
  • base pair excision
  • mismatch repair
  • double strand break repair
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27
Q

problems in the mtDNA repair system may contribute to what? and why is this?

A

ageing

>damage to mtDNA changes the function of mitochondria and its ATP production

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28
Q

define the mitochondrial free radical theory of aging

A

> ROS generated during respiration causes macromolecular damage that accumulates and drives ageing

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29
Q

ROS damage increases as we age but does it cause ageing?

A

there is mixed evidence for this

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30
Q

what does the oxidative stress theory of ageing predict? and what is challenging this?

A

differential rates of aging among species may be caused by inherited differences in oxidative damage accrual
>there are growing number of exceptions to this theory

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31
Q

how does over expression of antioxidant enzymes, including SOD1, SOD2 and catalyse affect vertebrates and mice lifespan?

A

increases vertebrates life

>has no affect on mice

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32
Q

what is seen in mice that are heterozygous for an enzyme that that reduces membrane bound lipid hydroperoxides, what have we assumed from this?

A

> they have a longer lifespan despite having high levels of oxidative damage
we have assumed that heterozygousity means less activity

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33
Q

how long do naked mole rates live

A

over 30 years

34
Q

what is special about naked mole rats? and what does this show us?

A

they live ten times longer than other rats
>they have very high ROS and oxidative damage
>they do nit get cancer
>this shows us that they are able to tolerate oxidative damage well

35
Q

what fails to shorten life of mice models?

A

increasing ROS

36
Q

what type of mice have a 40% increased lifespan than other mice? and what is seen in these mice? and why can we not say what we are seeing is due to ROS?

A

ames dwarf mice
>they have higher ROS in their cardiovascular system by they appear to be able to resist this
>these mice also lack anabolic hormones

37
Q

what are naked mole rats very good at doing? and what might this explain?

A

maintaining their telomeres

>this might explain why they live long and don’t get cancer

38
Q

what might cancer resistance in naked mole rats be due to? and what happens when this is KO?

A

high molecular weight HA secreted from fibroblasts that accumulates in rats tissue (they also have reduced activity in HA degradation enzymes)
>rats become susceptible to cancer

39
Q

what ROS be useful in doing? and what effect might this have?

A

signalling to nucleus that the mit are very active

>might upregulate transcription, translated precursor proteins for important into pre-existing mitochondria

40
Q

athletes used to be advised to take antioxidants after training, why is this bad?

A

it interfere with this communication between the mitochondria and the nucleus
>exercise induces mitochondrial biogenesis in skeletal muscle through ROS signalling

41
Q

define some evidence for MFRTA, an deception is there for this?

A

altering components of the ETC in C elgans has some affect on their lifespan
>using RNAi to KO complexes increases lifespan
>when complex II is KO this results in more ROS and a shortened lifespan

42
Q

why do we need to be cautious about results obtained from C. elgans?

A

> C. elegans live in soil with hypoxia and anaerobic energy production
this may affect how their ETC is set up

43
Q

compare SOD1 null C. elgans and flies

A

worms are fine and longer lived

flies have severely shortened lives

44
Q

what affect does apoptosis inducing factors AIF have on ETC? what happens when it is KO in muscle and liver?

A

it is found on the inner mit membrane and so stabilises ETC

>reduces obesity and diabetes

45
Q

give one more ways indirectly affecting ETC can affect lifespan

A

mice lacking SURF1- a putative complex IV assemble factors have increased lifespan

46
Q

what affect did deleting complex IV in neurones have?

A

reduced oxidative stress in neurones and reduced amyloid plaque load in Alzheimer’s disease model

47
Q

how might dampening down ETC affect mitochondria biogenesis and turnover?

A

reduced activity might be sensed as a reduction of function - this will trigger cells to dispose of some mit and to proliferate ones that are functioning at a higher rate

48
Q

ROS releases what transcription factor and what affect does this have?

A

NF-κB - this drives cells into senescence

49
Q

what can happen to mitochondria as we age? (7) (clue: 3 regarding mtDNA)

A
  1. biogenesis decreases
  2. releases more cytochrome C from membrane
  3. increasing release AIF
  4. accumulate mtDNA mutations
  5. decrease mtDNA copy number
  6. lower expression of mtDNA
  7. failing mt can trigger senescence
50
Q

what affect does releasing cytochrome C have on cells?

A

activates caspase 3 and triggers apoptosis

51
Q

what is seen about mt in old tissue? and what have we not determined about this?

A

there are less of them and they are more fragile

>is this driving ageing or is this a result of ageing?

52
Q

why do we inherit mtDNA from and how might this affect us

A

our mother
>fitness of mt genome can affect lifespan
>mutations transmitted can reduce lifespan by speeding up the ageing process
>it can also impair brain development

53
Q

what is mitochondrial replacement therapy and why might it be used?

A

during IVF the mit comes from a third party - this may be chosen due to fitness of DNA and will affect rate of ageing

54
Q

why does the cell need to clear away faulty mit?

A

they release ROS

they may release cytochrome C

55
Q

what is the amplification of damage loop in mit?

A

mtDNA damage leads to ROS which leads to more damage

56
Q

what three mechanisms can be used to clear away damaged mt?

A
  1. they can be fused with ok mitochondria - healthy genome can compensate for the failed one
  2. proteases can degrade entire mit
  3. mitochondria can fus with lysosome and be degraded
57
Q

name the channel on lysosomes that cytosolic chaperones bring proteins for lysosomal degradation

A

LAMP-2a

58
Q

why is the autophagy process less efficient when we age? and what does this mean?

A

some factors involved decline
e.g. LAMP-2a declines with age
>this leads to increased risk of proteins aggregates

59
Q

what are speculated to be the cause of neurodegenerative diseases such as Alzheimer’s disease?

A

protein aggregates

60
Q

how are misfolded proteins removed from the cell?

A

either degraded by the proteasomes or the lysosome

61
Q

clearing away senescent cells themselves can reduce ageing, how has this been seen? and what was this the first paper to suggest?

A

this has been seen using progeroid models - saw prolonged health of fat, skeletal muscle and eye
>senescent cells are not passive

62
Q

what might senescent cells release?

A

growth factors, cytokines and protease

63
Q

what is GATA4? and how is this implicated in old tissue

A

this is P by ATR when DNA damage is sensed, it is a TF that blocks cell cycle progression
>activates NF-κB which triggers inflammation and senescence
>GATA4 accumulates in older tissue including the brain

64
Q

what does TOR motor?

A

nutrients availability

65
Q

when there are high levels of nutrients what does TOR signalling feed into?

A

the mit and this can signal with ROS to the nucleus

66
Q

what can TOR signalling inhibit?

A

autophagy in nutrient rich conditions

67
Q

what does TOR trigger in starvation/CR?

A

autophagy - this can release energy for the cell to use

68
Q

what evidence links autophagy and ageing?

A

there is lots of evidence that increasing autophagy ability increases lifespan in C. elegans and Drosophila

69
Q

what do mice null in some autophagy genes show?

A

neurodegeneration

70
Q

what therapeutics are available to increases autophagy and prevent ageing? and what might this be especially useful in? and what bad side affects have these show?

A

TOR inhibitor rapamycin - these show some anti-ageing properties
>neurodegeneration - proteins aggregate near nucleus which leads to neurodegeneration
>TOR inhibitors have immunosuppressive effects

71
Q

what medication is taken for bipolar? and what can it do?

A

LiCL

>activate autophagy in an TOR independent manner

72
Q

what has LiCL been shown to do?

A

reduces neurodegeneration in Drosophila models of Huntington’s disease
>it also delays the progression in ALS mouse models

73
Q

what might work well in combination with LiCL and why?

A

rapamycin

LICL inhibits GSK3 which reduces autophagy

74
Q

why is it quicker to repurpose drugs than develop new ones? and how may this be useful in ageing?

A

that are already cleared form human use

>we can look for useful side effects to reduce the symptoms of ageing

75
Q

why must we be careful when therapeutically trying to manipulate autophagy?

A

it is hard to predict what effect this may have

76
Q

there is a therapeutic that increases autophagy but also inhibits HAT, how can we reduce off target effects in therapeutics?

A

develop cell type specific drugs

77
Q

what affect does removing damaged organelles and proteins have on a cell?

A

improve the metabolic fitness of cells and keep proteome functional

78
Q

what three things can lead to proteins being misfolded?

A

heat shock, ER stress and oxidative stress

79
Q

what happens to the ER as we age?

A

ER stress - the ER becomes less efficient and so the quality control of the proteins and their folding becomes less efficient

80
Q

what happens if misfolded proteins are not disposed of?

A

you might start to see the symptoms of ageing

SCRA (19 decks)

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