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SCRA > 18. ageing biology 4 > Flashcards

18. ageing biology 4 Flashcards

1
Q

what types of yeast can we used to study ageing? and what are the specifically useful to study?

A

budding yeast

>central biochemistry behind nutrient sensing

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2
Q

what are the pros of using budding yeast?(4)

A
  • small sequenced genome
  • cheep
  • quick
  • easy to genetically manipulate
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3
Q

why are results obtained from budding yeast useful to us?

A

many gene orthologues in humans

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4
Q

discuss budding yeast life span

A

they have a finite replicative capacity - their replicative lifespan

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5
Q

what is CLS?

A

the chronological lifespan of budding yeast - this is how long they can survive in a non-diving state

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6
Q

describe old budding yeast (4)

A
  • they are larger
  • cell cycle and proteins synthesis slower
  • cells surface looks loose and wrinkled
  • show apoptotic markers
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7
Q

what can use suggest when looking at irregular less plump yeast?

A

they are accumulating more dysfunctional proteins/their genome is stressed

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8
Q

what can increase lifespan in yeast?

A

dietary restriction - reduced glucose and/or amino acids in their broth

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9
Q

when calorie restriction was done on yeast, what % were their calories reduced by?

A

30/40%

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10
Q

what are sirtuins?

A

they act as nutrients sensors that are regulated by NAD+

>they regulate many aspects of biology

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11
Q

what functions can sirtuins have?

A

> deacetylate histones and compact DNA

>deacetylate TFs and regulate gene expression

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12
Q

what does SIRT1 signalling do?

A

it leads to increase insulin secretion form the pancreas

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13
Q

SIRT1 may increase senescence and apoptosis, but what may it also increase?

A

resilience and autophagy

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14
Q

SIRTs can regulate TFs and gene expression, what sort of processes can these regulate?

A
  • glucose production in the liver
  • fat metabolism
  • angiogenesis
  • neuronal development
  • resistance to neurodegeneration
  • increased insulin secretion from pancreas
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15
Q

what affects does SIRT1 have on ageing? and what implication does this have on therapeutics?

A

+ and - effects

>we may need to look at tissue specific regulation for preventing ageing phenotype

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16
Q

what happen when there is lots of nutrients available?

A
  • high metabolism, less NAD+
  • sir2 inactive
  • normal reproductive rate
  • normal lifespan
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17
Q

what happen when there is low nutrients available?

A
  • low metabolism, high NAD+
  • SIr2 active
  • stress response - it is good to stress you tissue slightly
  • reduced fertility
  • longer lifespan
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18
Q

what choices can be made in increase lifespan?

A

not to reproduce and have non-essential activity

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19
Q

how many SIRTs are there in mammals?

A

7

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20
Q

what processes do SIRTs influence? (7) (note: they have different effects in different tissues)

A
  • senescence
  • stem cells maintenance
  • DNA damage repair
  • metabolic regulation
  • tumourigenesis
  • neurogenesis
  • inflammation
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21
Q

what genes was identified in yeast when they were looking for genes of longevity and what does it do?

A

TOR - serine threonine kinase
high nutrients = high activity
inhibits stress response
regulates cell growth and proliferation

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22
Q

what nutrients is TOR activated in response to?

A

oxygen, ATP, glucose, insulin and cytokines

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23
Q

what does decreased TOR activity in yeast lead to?

A

increases RLS and CLS

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24
Q

what happens when you starve cells and TOR activity is reduced?

A

stress response factors enter the nucleus

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25
Q

if signalling from mit to nucleus is reduced due to mit dysfunction, what is seen in yeast?

A

reduced RLS

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26
Q

what represses autophagy and what affect does this have on yeast?

A

TOR

in decreased CLS

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27
Q

what two things can increase yeast lifespan? and what does this link to? and what is this conserved in? and how are they different?

A

TOR inhibition
Sir overexpression
>the most robust way to increase lifespan is calorie restriction
> conserved in worms, flies and mammals >they are unicellular, short lived, different DNA modification, no telomeres shortening

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28
Q

which second model animal shows functional senescence?

A

Drosophila e.g. heart, learn less well, explore less

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29
Q

how are Drosophila similar to us?

A
  • they have gene structure
  • they have kidney like structures
  • neurons can develop protein aggregates
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30
Q

stress resistant Drosophila mutants live…

A

longer

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31
Q

what had CR and less reproduction shown in Drosophila?

A

increased lifespan

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32
Q

what has also been seen to reduced flies lifespan?

A

reducing insulin signalling

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33
Q

describe C elegans (4)

A
  • transparent
  • 1 mm
  • cheap
  • dead if stop moving
  • sequenced genome - orthologues but lack Shh
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34
Q

what is seen in old worms? (3)

A

muscle dystrophy, reduced skin elasticity, venerable to infection
>they show signs of ageing

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35
Q

how long does it take for a C elegan to go from egg to adult?

A

4 days

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36
Q

how many stages are there in the laval development on C elgans?

A

4 stages

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37
Q

what happens when C elegans are starved in the 3rd laval stage?

A

they can survive for months without food
they have low metabolism
limited protein synthesis
survive of fat stores

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38
Q

how can genes be KO in C elegans?

A

feed them bacteria expressing RNAi

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39
Q

how many genes have shown to regulate lifespan in C elgans?

A

300+

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40
Q

what are the major pathways in regulating C elegans lifespan?

A

insulin like signalling - central way of monitoring nutrients availability
germline signalling

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41
Q

name the 1 insulin like receptor in C elegan and what does this receptor bind?

A

daf2

>this bind insulin and IGF1 with different dynamics

42
Q

what happens in C elegans when nutrients is low?

A

daf16 enters the nucleus as it is not P - this is part of the stress response

43
Q

what happens when daf2 is activated?

A

there is a signalling pathways that results in activated AKT, this P Daf16, meaning it cannot enter the nucleus

44
Q

what is daf16?

A

a TF
>represses growth and reproduction genes
>increases expression of genes for stress defence and altered metabolism

45
Q

in yeast, C. elegans, drosophila, mammals: mutations in what lead to increased lifespan?

A

mutations that lower glucose or insulin signalling

46
Q

what does nutrients excess cause?

A

> reduced lifespan
obesity
metabolic problems

47
Q

nutrients sensing is an important regulator of ageing, what decision do cells make in regard to this?

A

whether to be active and reproduce or to not be very active

48
Q

when nutrients receptor on yeast is activated, what happens?

A

kinases phosphorylate and inactivate transcription factors by excluding them from the nucleus
>this down regulates genes involved in stress response

49
Q

what is downstream of the nutrient receptor in yeast and what happens when this is KO?

A

Ras
CLS increased by 2 times
by allowing transcription of stress response genes

50
Q

in addition to allowing transcription of stress response genes, what else can reducing nutrient signalling do?

A

more glycerol leads to increased antioxidant activity - nutrient sensing and ROS can be linked

51
Q

what can low glucose also stop? and what choice is this?

A

cell cycle - the growth vs anti-ageing choice

52
Q

how much longer lived are daf2 mutants and what do they also show?

A

60-100% longer lived

resistant to behavioural decline

53
Q

what genes are daf16 involved in?

A

ROS scavengers
heat shock proteins
change metabolism - switches to hypometabolic state and start storing excess nutrients as fats and glycogen

54
Q

what are heat shock proteins?

A

and folding of proteins, under stressful conditions, these are upregulated to protect and stabilise unfolded proteins, this gives the cell time to repair and re-synthesise damaged proteins

55
Q

what can reducing the nutrient signalling pathway do in terms of immunity and senescence?

A

also boosts innate immunity and reduces cell senescence

56
Q

how many ligands are there for the Drosophila sensing receptor? and what do they all diverge onto?

A

7

>dFOXO

57
Q

what happens when you mutate drosophila nutrient signalling receptor? (4)

A

longer life
reduced cardiac ageing
store nutrients
upregulate SOD

58
Q

what happens when dFOXO is upregulated? and what does this have similar affect to?

A

longer life

>KO the players in the pathway that reduced nutrient signalling

59
Q

why is nutrient sensing more complex in mammals?

A

we have more signals and more forms of the receptor

>there are three receptors in mice - they bind different proteins but share much of the same downstream signalling

60
Q

what is insulin level a read out of?

A

nutritional state of the whole organism

61
Q

what do insulin receptors converge on?

A

four Forkhead TFs (FOXO 1 3 4 6)

62
Q

nutrient signalling is conserved between what?

A

yeast, worms, flies and mice

63
Q

why is less known about human nutrient signalling?

A

not many complete body assays have been done in mammals/humans

64
Q

stress may be due to reduction in nutrients, what does this lead to in humans?

A 
FOXO enters the nucleus 
>inhibits cell cycle 
>regulates metabolism 
>resists further stress 
i.e. help contribute to resilience
65
Q

what is necessary for the proliferation and self-renewal of NSC and what happens when this is reduced? why is this?

A

FOXO
NSC are depleted
>FOXO maintains self-renewal and constrains proliferation

66
Q

what happens in brains of FOXO deficient mice?

A

they are initially larger, this is followed by decline in NSC pool and neurogenesis in the adult brain

67
Q

what happens when nutrients are decreased in mammals? (3)

A

> less reproduction
more stress response
slower aging process

68
Q

why does daf16 increase preserve post mitotic tissue?

A

by altering metabolism and increasing stress resistance

>this increases lifespan of worm

69
Q

FOXO increases self-renewal in stem cells, what does this mean in terms of HSC and NSC? what might FOXO increase in general?

A

> HSC decrease in ROS
NSC decrease in ROS, altered metabolism, decreased Wnt signalling and altered cell cycle regulation
tissue repair and lifespan

70
Q

how does the cell decide whether to calm down metabolism or go ahead as if it has lots of nutrients?

A

FOXO and TCF mediated gene expression both compete for limited pool of beta catenin.
>during ageing and oxidative stress, production of ROS leads to increased FOXO mediated gene expression
>when nutrient signalling is present, FOXO is excluded from the nucleus and Wnt signalling can use beta catenin
>nutrient signalling also enhances nuclear beta catenin

71
Q

what is a robust way to improve health of tissue?

A

calorie restriction

72
Q

what is seen in IGFR+/- mice?

A

only females are longer lived

73
Q

what might explain gender specific responses?

A
  • due to the protective effects of oestrogen
74
Q

why must studies on nutrient signalling be done on multiple strains? and what is this most important in?

A

there is variation between strains/genetic backgrounds

>in subtle neurological disorders – different strains can really effect responses

75
Q

what is seen when the nutrient signalling receptor is KO in mice?

A

would expect tissue to be resilient
>but lack of insulin signalling has knock on effects
>much sorter lives due to excessive keto acids in their blood

76
Q

what affect can the dysregulation of insulin signalling in humans have?

A

T2D and cancer

77
Q

we would expect that disrupting insulin signalling would have beneficial ageing affects, but this is not always the case, what implication does this have on therapy? give an example

A

developing tissue specific treatments/tissue specific restriction/modulation of insulin
>adipose tissue is very sensitive to insulin signalling. people trying to tackle obesity and diabetes are looking at ways to modulate insulin signalling in adipose tissue

78
Q

what happens when insulin receptor is KO in neurones? and what does this mean in terms of therapy?

A

> mice were overweight and insulin resistant
but lifespan extended
we need to decide if these side effects are worth tolerating or can be corrected

79
Q

what happens when insulin receptors are KO in fat tissue?

A

> longer life

>leaner and have increases insulin sensitivity

80
Q

what was seen when the pituitary gland was removed from rats and what does this suggest?

A

they lived longer but the mice was smaller

>growth hormone may be a factor in the ageing process - if you don’t grow you might be more resilient to stress

81
Q

in addition to growth, what does GH also stimulate?

A

Igf-1 release from liver

82
Q

Ames dwarf mice, are small and live longer, why is this?

A

mutation in prop1 - this affects pituitary gland differentiation and so they have no GH in circulation and no plasma Igf1

83
Q

name another mouse with similar phenotypes of Ames dwarf mice and what mutation is causing this?

A

Snell dwarf mice
mutations in Pit1 (downstream of Prop1) - this affects pituitary gland differentiation and so they have no GH in circulation and no plasma Igf1

84
Q

what do Ames dwarf mice and Snell dwarf mice suggest?

A

maybe small size and reduced growth hormone may be useful in prolonging lifespan

85
Q

what does reduced GH lead to in mice? (7)

A
  1. small size
  2. longer life
  3. reduces insulin
  4. increased insulin sensitivity
  5. reduced fertility
  6. reduces anabolism
  7. reduces ROS
86
Q

what happens to GH and IGF1 as we age? and what does this lead to?

A

they fall and lead to
>muscle weakness
>changes in body fat (similar to GH deficiency)

87
Q

what can increase muscle mass and reduce fat in old people? and what does this suggest?

A

GH treatment

>GH might rejuvenate

88
Q

statically studies have shown what about reducing GH and Igf1?

A

there is no lifespan effects

89
Q

what was concluded from GH/igf-1 signalling studies in humans?

A

more GH/igf-1 signalling can prevent some ageing symptoms but not increase lifespan

90
Q

what is dietary restriction?

A

reduction in one/total nutrient level (no malnutrition)

- generally calorie restriction

91
Q

how can calorie restriction of 30-40% in mice affect lifespan? and does this have the same affect in most species?

A

extends lifespan by up to 50%

>yes, most but not all species

92
Q

why might we have evolved CR signalling?

A

to resist molecular stress/cell stress during periods of starvation

93
Q

what evidence is there that TOR is involved in DR signalling?

A
  • TOR inhibition mimics DR and prolong life

- TOR mutants are not further affected by DR

94
Q

how does TOR regulate translation?

A

upregulates ribosomal subunit and inhibits translation of its inhibitor

95
Q

what does high metabolic rate mean? and what therapeutic idea stems from this?

A

> more proteins
more organelles
more leaking ETC
= the idea of translation inhibitors which might dampen down translation and reduce the effects of ageing

96
Q

what two things are reduced during DR? and what question can be asked from this?

A

TOR activity

translation - is decreased translation necessary for lifespan extension?

97
Q

human trials looking at the effect on CR took place in 2007. they lasted for 6 months. what was observed and what were the limitations?

A

> muscle punch biopsy showed upregulation of SIRT1
increased mit number
reduced DNA damage
- this study was done on young not obese people for only 6 months

98
Q

are anti-ageing pathways linear? and what does this mean?

A

no, there is cross talk between pathways

>this means there is not one drugable target

99
Q

what might longevity be a side effect of? what might also be affecting this?

A

CR survival mechanism
>other stresses: temperature, reproductive signals, respiration and translation
>cells is monitoring other stresses not just at the nutrients levels, they will all be feeding into these pathways

100
Q

name 6 things that happen in a low nutrients response

A

stopping cell division, using energy stores, reducing translation, up regulating chaperones, increasing autophagy, reducing fertility

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