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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
what can ROS cause in the cell?
molecular damage - lipids, DNA and proteins
26
what types of mtDNA repair can take place?
- direct reversal - base pair excision - mismatch repair - double strand break repair
27
problems in the mtDNA repair system may contribute to what? and why is this?
ageing | >damage to mtDNA changes the function of mitochondria and its ATP production
28
define the mitochondrial free radical theory of aging
>ROS generated during respiration causes macromolecular damage that accumulates and drives ageing
29
ROS damage increases as we age but does it cause ageing?
there is mixed evidence for this
30
what does the oxidative stress theory of ageing predict? and what is challenging this?
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
31
how does over expression of antioxidant enzymes, including SOD1, SOD2 and catalyse affect vertebrates and mice lifespan?
increases vertebrates life | >has no affect on mice
32
what is seen in mice that are heterozygous for an enzyme that that reduces membrane bound lipid hydroperoxides, what have we assumed from this?
>they have a longer lifespan despite having high levels of oxidative damage >we have assumed that heterozygousity means less activity
33
how long do naked mole rates live
over 30 years
34
what is special about naked mole rats? and what does this show us?
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
what fails to shorten life of mice models?
increasing ROS
36
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?
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
what are naked mole rats very good at doing? and what might this explain?
maintaining their telomeres | >this might explain why they live long and don't get cancer
38
what might cancer resistance in naked mole rats be due to? and what happens when this is KO?
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
what ROS be useful in doing? and what effect might this have?
signalling to nucleus that the mit are very active | >might upregulate transcription, translated precursor proteins for important into pre-existing mitochondria
40
athletes used to be advised to take antioxidants after training, why is this bad?
it interfere with this communication between the mitochondria and the nucleus >exercise induces mitochondrial biogenesis in skeletal muscle through ROS signalling
41
define some evidence for MFRTA, an deception is there for this?
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
why do we need to be cautious about results obtained from C. elgans?
>C. elegans live in soil with hypoxia and anaerobic energy production >this may affect how their ETC is set up
43
compare SOD1 null C. elgans and flies
worms are fine and longer lived | flies have severely shortened lives
44
what affect does apoptosis inducing factors AIF have on ETC? what happens when it is KO in muscle and liver?
it is found on the inner mit membrane and so stabilises ETC | >reduces obesity and diabetes
45
give one more ways indirectly affecting ETC can affect lifespan
mice lacking SURF1- a putative complex IV assemble factors have increased lifespan
46
what affect did deleting complex IV in neurones have?
reduced oxidative stress in neurones and reduced amyloid plaque load in Alzheimer's disease model
47
how might dampening down ETC affect mitochondria biogenesis and turnover?
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
ROS releases what transcription factor and what affect does this have?
NF-κB - this drives cells into senescence
49
what can happen to mitochondria as we age? (7) (clue: 3 regarding mtDNA)
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
what affect does releasing cytochrome C have on cells?
activates caspase 3 and triggers apoptosis
51
what is seen about mt in old tissue? and what have we not determined about this?
there are less of them and they are more fragile | >is this driving ageing or is this a result of ageing?
52
why do we inherit mtDNA from and how might this affect us
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
what is mitochondrial replacement therapy and why might it be used?
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
why does the cell need to clear away faulty mit?
they release ROS | they may release cytochrome C
55
what is the amplification of damage loop in mit?
mtDNA damage leads to ROS which leads to more damage
56
what three mechanisms can be used to clear away damaged mt?
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
name the channel on lysosomes that cytosolic chaperones bring proteins for lysosomal degradation
LAMP-2a
58
why is the autophagy process less efficient when we age? and what does this mean?
some factors involved decline e.g. LAMP-2a declines with age >this leads to increased risk of proteins aggregates
59
what are speculated to be the cause of neurodegenerative diseases such as Alzheimer’s disease?
protein aggregates
60
how are misfolded proteins removed from the cell?
either degraded by the proteasomes or the lysosome
61
clearing away senescent cells themselves can reduce ageing, how has this been seen? and what was this the first paper to suggest?
this has been seen using progeroid models - saw prolonged health of fat, skeletal muscle and eye >senescent cells are not passive
62
what might senescent cells release?
growth factors, cytokines and protease
63
what is GATA4? and how is this implicated in old tissue
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
what does TOR motor?
nutrients availability
65
when there are high levels of nutrients what does TOR signalling feed into?
the mit and this can signal with ROS to the nucleus
66
what can TOR signalling inhibit?
autophagy in nutrient rich conditions
67
what does TOR trigger in starvation/CR?
autophagy - this can release energy for the cell to use
68
what evidence links autophagy and ageing?
there is lots of evidence that increasing autophagy ability increases lifespan in C. elegans and Drosophila
69
what do mice null in some autophagy genes show?
neurodegeneration
70
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?
TOR inhibitor rapamycin - these show some anti-ageing properties >neurodegeneration - proteins aggregate near nucleus which leads to neurodegeneration >TOR inhibitors have immunosuppressive effects
71
what medication is taken for bipolar? and what can it do?
LiCL | >activate autophagy in an TOR independent manner
72
what has LiCL been shown to do?
reduces neurodegeneration in Drosophila models of Huntington’s disease >it also delays the progression in ALS mouse models
73
what might work well in combination with LiCL and why?
rapamycin | LICL inhibits GSK3 which reduces autophagy
74
why is it quicker to repurpose drugs than develop new ones? and how may this be useful in ageing?
that are already cleared form human use | >we can look for useful side effects to reduce the symptoms of ageing
75
why must we be careful when therapeutically trying to manipulate autophagy?
it is hard to predict what effect this may have
76
there is a therapeutic that increases autophagy but also inhibits HAT, how can we reduce off target effects in therapeutics?
develop cell type specific drugs
77
what affect does removing damaged organelles and proteins have on a cell?
improve the metabolic fitness of cells and keep proteome functional
78
what three things can lead to proteins being misfolded?
heat shock, ER stress and oxidative stress
79
what happens to the ER as we age?
ER stress - the ER becomes less efficient and so the quality control of the proteins and their folding becomes less efficient
80
what happens if misfolded proteins are not disposed of?
you might start to see the symptoms of ageing

SCRA (19 decks)

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