15. ageing biology 1 Flashcards

1
Q

how has the field of ageing research changed?

A

people were looking for genes that drive the ageing process and now we are looking for genes that keep our genome healthy and resilient

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2
Q

what two fields of biology are repeatedly linked?

A

cancer biology and ageing biology

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3
Q

what is the number of risk factor for developing cancer? and what is one reason for this?

A

ageing

out defence against cancer decreases with age

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4
Q

what is happening in Japan and why is this a problem?

A

there are lots of old people and the birth rate is declining - how will these old people be supported if there are not young people to work and pay taxes for social care

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5
Q

what is the grandmother hypothesis?

A

it was useful to societies health to have a few grandmothers around, with spare energy to look after children and with wisdom

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6
Q

what is seen after natural disaster that proves the grandmother hypothesis?

A

old people are wiped out and so it takes society longer to re-develop as society has lost its historical knowledge

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7
Q

therapeutics that target the ageing process are not necessarily trying to increase life span, what are they trying to achieve?

A

a more healthy ageing process

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8
Q

what might happen to stem cells as we age?

A

they may become less well controlled and become depleted

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9
Q

by 2025 how many people will be over the age of 60?

A

1.2 billion

people are living longer

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10
Q

how do we define ageing?

A

in terms of resilience
when you are young and healthy your cells, tissues and genomes have lots of protection mechanism, if a stressor comes we can resit it
when you get older this ability decreases

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11
Q

what happens when a old tissue is stressed?

A

it is less able to handle the stress and less able to regernate afterwards

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12
Q

name 5 diseases that are associated with ageing

A
  1. cardiovascular disease
  2. arthritis
  3. T2D
  4. pulmonary disease
  5. cancer
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13
Q

in terms of therapeutics, what do we need to be careful about when we observe changes in old peoples physiology?

A

these changes may not actually be harmful, it may just be part of the tissue keeping itself going longer, if we try and reverse this it may lead to problems

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14
Q

why is studying the ageing process difficult? (5)

A
  • ageing is a gradual, dynamic process
  • there is lots of heterogeneity
  • there are external and internal influences on ageing
  • their is a lack of biomarkers for ageing
  • organs can age at different rates
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15
Q

what are being used more and more in the ageing biology field?

A

model animals like C elegans and Drosophila as humans and mice are expensive

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16
Q

when you pass the age of 50 what starts to happen to your skeletal muscle? (5) and what does this lead to?

A
  • loss of 1-2% of muscle per year
  • disorganisation
  • increased fibre size variability
  • protein aggregates
  • increased infiltration of non-contractile material like fat and connective tissue
    > this leads to reduced muscle strength and functional decline
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17
Q

what also have an effect on muscles in the ageing process?

A

decline in mitochondria number and function results in less energy available to muscle

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18
Q

what is observed about the appearance of mitochondria in old muscle tissue? (4)

A
  • there are fewer mit
  • they are larger
  • vacuolization of the matrix
  • shortened cristae
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19
Q

skeletal muscle may have a stress response that upregulates number of mitochondria, why may this still not be very good in old people? and what might also be observed?

A
  • mitochondria generated might be less functional

- a decline in number of mitochondria might also be observed

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20
Q

what is autophagy and how what happens to this in the ageing processes? giving an example

A

autophagy is hen cells can engulf dis-functioning organelles, break them down and make them safe again
this becomes less efficient in the ageing process
an example of this is mitochondria autophagy as we don’t want them leaking ROS

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21
Q

how much does the ATP produced in muscles decline per decade?

A

by 5%

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22
Q

what happens to mtDNA in the ageing process?

A

it becomes more damaged, levels of 8-oxoguanine increase

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23
Q

what is 8-oxoguanine ?

A

a DNA lesion that results from ROS

it can lead to mismatch pairing with adenosine

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24
Q

what three things are seen increasingly oxidised in the mitochondrial ageing process?

A

DNA
lipids
proteins

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25
Q

old people might produce a sufficient basal level of ATP, how does this make stress and exercise? and what may happen as a result of this?

A

they may feel pain and breathlessness

they ae less likely to exercise and this makes them even more weak

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26
Q

what other four factors also affect skeletal muscle health?

A
  • endocrine system
  • neural system
  • cardiovascular system
    general health decline will have a knock on affect on skeletal muscle
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27
Q

why can circulatory system affect skeletal muscle?

A

it affects oxygen and nutrients availability

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28
Q

why is geriatric care complex?

A

when people age they may have several co-morbid conditions

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29
Q

changes in the muscle to fat ratio can lead to what?

A
  • metabolic syndrome
    a cluster of biochemical and physiological abnormalities which are associated with CV disease and T2D
  • and insulin resistance
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30
Q

what is insulin resistance and what can it lead to?

A

when the body does not respond to insulin as efficiently as it should, this can lead to type 2 diabetes

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31
Q

what type of cells can generate ROS and release fatty acid into the blood?

A

fat cells

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32
Q

fatty acids in the blood are known to cause what?

A

muscle insulin resistance by inhibiting insulin stimulated glucose uptake and glycogen synthesis

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33
Q

what is seen in almost all old tissue?

A

inflammation

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34
Q

name a post mitotic cells in skeletal muscle

A

adult myofibres

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35
Q

name the stem cells in skeletal muscle and name a marker for them

A

skeletal muscle cells

psx7

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36
Q

when stem cells in the skeletal muscle are stimulated to divide what do they do?

A

they fuse with damaged muscle fibres and regenerate myonuclei and locally regenerate tissue

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37
Q

what is seen about old satellite cells? and what two things might this be due to?

A

there are less of them and they divide less/come out of G0 less
- they divide and make the wrong lineages (more fibrotic and less myogenic)
>it might be due to changes in the niche or changes in the satellite cells genome

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38
Q

what is seen when old mice satellite cells at cultured in vitro?

A
  • they produce less organised and more fragile myotubes
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39
Q

when satellite cells divide and make the wrong lineage, what affect does this have on tissue?

A

fibroblasts like cells wiggle into the tissue and disrupt the skeletal muscle structure

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40
Q

where are skeletal muscle cells found?

A

in contact with skeletal muscle fibre and basal lamina

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41
Q

define some contributing factors to the satellite cell niche (5)

A
  • fat cells
  • fibroblasts
  • vasculature
  • nerve cells
  • muscle fibres
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42
Q

define some contributing factors to the ageing satellite cell niche (5)

A
  • increase adipocytes
  • thicker basal lamina and more ECM deposition which stiffen muscle
  • decreased endothelial number
  • impaired chemotaxis of macrophages
  • increased fibroblasts
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43
Q

what happens to stem cell regulation in the ageing satellite cell niche?

A

there is less positive and more negative regulation of stem cells
factors that regulate stem cells are deregulated and so satellites do not know when to divide

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44
Q

what happens to the cross sectional area of myofibres as we age?

A

it is reduced

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45
Q

what is seen when old mice hind limb muscle is put into a young mouse? and what is seen when a young muscle is put into an old mouse?

A

old hind limb muscle into young hose can regenerate like a young muscle
young muscle in old host cant regenerate as normally would
this shows that intrinsic and extrinsic factors change as we age

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46
Q

what has parabiosis been shown to do?

A
  • rejuvenate old satellite cells

- they also showed the involvement of carconical Wnt signalling in this process

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47
Q

describe Wnt signalling

A

when Wnt bids Frizzled receptor, APC and GSK3 are localised to the membrane, beta catenin is stabilised and can enter nucleus, bind TCF/LEF and promote gene expression and cell division

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48
Q

why might the results obtained from parasymbiosis experiments be hard to transfer into the clinic, and what may help overcome this?

A

if rejuvenation is due to Wnt signalling, it will be hard to influence this without increasing risk of cancer
this may be overcome by delivering treatment more locally

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49
Q

when carconical Wnt signalling is decreased, what is seen?

A

this prevents aged satellite cells switching from myogenic to fibrogenic lineage as proliferate

50
Q

what can injecting Wnt into repairing muscle lead to?

A

fibrosis

51
Q

what can cleave the co-receptor of Wnt and drive Wnt signalling? and how is this relevant to ageing?

A

compliment

C1q is found in old serum

52
Q

what does the aged satellite cell niche disrupt?

A

quiescence

53
Q

what is fgf2

A

a factor important in controlling cell division

54
Q

what do aged muscle fibres express more of and what affect does this have on satellite cells?

A

fgf2 drives satellite cells out of quiescence and depletes them

55
Q

why do old muscle fibres produce fgf2?

A

it is not clear why the old muscle fibre is doing this, perhaps the muscle fibres is expressing more fgf2 to try and counteract age related changes

56
Q

how old is an old mouse and why don’t all papers use this age?

A

2-3 years

its expensive

57
Q

there are two models for whether all stem cell in an aged niche behave the same way, what are they?

A

> the shift population model
all stem cells change with development and ageing
the clonal selection model
different clones are affected in different ways, changes in the niche may only affect certain lineages within a tissue

58
Q

if the clonal selection model is true what does this suggest?

A

this suggests that different populations within a tissue are ageing at different rates, e.g. TA cells may age more rapidly

59
Q

what happens in haematopoiesis as people age?

A

there is a bias towards the myeloid lineage as cell type and proportion control start to break down

60
Q

what occurs Sarcopenia?

A

muscle atrophy and intramuscular adipose

61
Q

what does Sarcopenia cause?

A

loss of muscle mass and changes in their strength and function

62
Q

what are the symptoms of Sarcopenia? (5)

A

frailty, exhaustion, reduced physical activity, slow walking, reduced grip strength

63
Q

what is a hige risk factor from mental health? and what may cause this?

A

people withdrawing from society

people with Sarcopenia fall over a lot as their muscles don’t support them, this may stop them from going out

64
Q

what may cause Sarcopenia? (7)

A
  • endocrine
  • nutrition
  • inactivity
  • inflammation
  • reduced activity of satellite cells
  • medication
  • cancer
65
Q

why can exercise help prevent sarcopenia?

A

increasing ROS scavengers

66
Q

how can cancer affect you risk of Sarcopenia?

A

cancer does weird things to the body, you accumulate lots of fluid and can start to break down organs as the cancer is so hungry for nutrients - including skeletal muscle

67
Q

when people age the are much less driven to each, what does this cause and what may this lead to?

A
  • malnourishment

- mental health problems

68
Q

name 4 diseases that can cause Sarcopenia

A

diabetes
liver failure
obesity
anorexia

69
Q

what is a good way to reduce frailty? (4)

A
  • weight baring exercise
  • anti-inflammatories
  • hormones
  • nutrition (supplements)
70
Q

why do some old people become frail and others don’t?

A

this is not clear, we don’t know the genetic and environmental risk facts which influence frailty

71
Q

name a risk factor for CV disease

A

age

72
Q

what is the most common cause of death in the elderly in the western world?

A

CV disease

73
Q

what occurs to heart function as we age and what can contribute to this?

A
  • the heart has reduced function

- the rest of the body ageing can put a strain on the heart

74
Q

what happens to heart tissue to reduce its function?

A
  • tissue is less organised
  • fibrous ECM gets laid down
  • left ventricle has thicker wall
  • ventricle filling declines
    >which means it can contract less efficiently
75
Q

what causes exercise intolerance?

A

reduced heart function

76
Q

when the heart muscles walls thicken, what is this called and why does this happen? what might some of the thickening be?

A

hypertrophic cardiomyopathy occurs when the heart is trying to retain strength and in doing so causes reduced ventricle size and contractile ability
>some of the thickening may be fibrous material as well

77
Q

what is present in healthy cardiac muscle and what does this allow?

A

in healthy cardiac muscle there are complicated adhesions complexes that keep fibres together and allows contraction to pass although the sheet of tissue really rapidly and with good strength of contraction.

78
Q

what about cardiac muscles may be challenging about stimulating them to divide?

A

they are bi-nuclear

79
Q

what happens in heart fibrosis? (5)

A
  • cells lay down fibrous ECM in the heart to try and keep itself strong
  • thickening and hardening of the arteries
  • sarcomeres collapse
  • vascularisation of the cytoplasm
  • variable and increased volume of myocyte fibre size
80
Q

what is cardiomyopathy? and what can it be associated with?

A

disease of the heart muscle

age

81
Q

what happens to the mitochondria in the aged heart? (6)

A
  • increased mt protein oxidation
  • increase mtDNA damage
  • increased mt biogenesis
  • more ROS released
  • decreased mt SERC2 protein - regulates calcijm mediated coupling of heart cells
  • increased mt permeability transition pore
82
Q

what causes mitochondrial swelling, collapse of membrane potential, ATP depletion and apoptosis?

A

increase mitochondria permeability transition pore on the inner membrane

83
Q

what affect does reducing IGF1 signalling have on the heart?

A

cardiovascular performance in drosophila

and reduced age-associated cardiomyocytes dysfunction in mice

84
Q

what increases the risk of heart failure in elderly people?

A

low serum IGF1 level

85
Q

what affect does growth hormone have on the heart?

A

can improve heart failure recovery and reduce age-associated blood pressure dysfunction

86
Q

what is the only widely accepted method to reduce the bad effects of aging? and why is this?

A

calorie restriction

it reduces cellular activity, less activity means less damage to organs and organelles

87
Q

what type of cells in the heart are controversial?

A

stem cells

88
Q

in the putative stem cells that have been proposed in the heart, what happens to these cells during ageing?

A
  • more apoptosis
  • shortened telomeres
  • increased senescence
89
Q

when heart muscles was 14C labelled to show turnover and renewal rate of cardiomyocytes, what was observed at 25 years and 75 years?

A

at 25 year turnover rate was around 1% annually decreases to 0.45% at 75 years

90
Q

what happens to arteries and capillaries as we age? (2)

A
  • they become stiff

- they also become dilated

91
Q

why do arteries and capillaries become stiff? and what affect does this have on them?

A

increased cross linked ECM
> this makes them less resilient and less able to cope with exertion
> it also affects mechanosensitive gene expression

92
Q

angiogenesis decreases in what organ as we age? and what has been seen to improve this in rats?

A

the brain

GH has been seen to improve this

93
Q

endothelial progenitor cells in capillaries are less active when old, what might this be due to?

A

inflammation and down regulation of insulin signalling

94
Q

give an example of an indirect way that calorie restriction can be beneficial to organ health

A

fasting glucose and insulin levels reduce risk of arthrosclerosis, this is when arteries become clogged with a fatty substance
it also reduces blood pressure

95
Q

give three examples of an direct way that calorie restriction can be beneficial to organ health

A
  1. upregulate eNOS (endothelial nitric acid synthase)
  2. reduce endothelial ROS
  3. reduce pro-inflammatory pathways
96
Q

what has the serum of calorie restructured animals been shown to do?

A

protect cardiovascular cells in culture

97
Q

what has seen to regulate function of the ageing heart? and what does this show?

A

vinculin network-mediated cytoskeleton remodelling

>this shows that hearts can protect themselves as we age

98
Q

what is vinculin? and what happens to it in the aged heart?

A

it is part of the adhesion complex that interacts with the cytoskeleton
>it is upregulated in the aged heart

99
Q

what does the upregulation of vinculin in the ageing heart do?

A

it reinforces the cytoskeleton and helps maintain myocyte organisation and contractile function for longer
> and so it is a protective mechanism

100
Q

what can potentially be therapeutically exploited in the ageing process?

A

the fact that as we age, out organs changes protein expression to help us age well

101
Q

what is hypotrophy? and what organ can this be seen in?

A

the enlargement of an organ or tissue from the increase in size of its cells
> this can be seen in the heart

102
Q

what is ischemia? and what may this lead to?

A

the restriction of blood flow to an organ, this might lead to a heart attack

103
Q

what is seen about brain function as we age?

A

cognitive decline

104
Q

what percentage of people over 80 have Alzheimer’s?

A

50%

105
Q

when an old brain and an Alzheimer’s are compared what can be seen? and what does this show?

A

they can look very similar, you can see some of the classic markers for AD in brains and they have no cognitive decline
this shows that ageing in the brain has varying affects on people

106
Q

what becomes less efficient in the ageing brain? and what might this be due to?

A

cross-communication between different regions of the brain

> this might be due to glia cells and changes in myelination of oligodendrocytes

107
Q

what changes can occur in the brain as we age?

A
  • changes in synapses - the balance between inhibition and excitation is altered
  • myelination
  • epigenetics - could be due to oxidative stress
  • decline in autophagy - leads to protein aggregates
108
Q

HDAC inhibitors were given to mice, what did this promote and what did it do?

A

neural plasticity and recovered memories

109
Q

what does a decline in autophagy lead to?

A

misfolded proteins, leaky mt and other dysfunctional organelles.

110
Q

why is autophagy important for the brain?

A

neurones need lots of ATP

111
Q

what are some of the biomarkers for Alzheimer’s? (4) and what does this lead to?

A

neuronal loss, synapse loss, amyloid plaques and neurofibrillary tangles
> this leads to cognitive decline

112
Q

what has been seen to extend lifespan of neurones in drosophila?

A

reduced ETC

113
Q

when an enzyme that is necessary for ubiquinone synthesis is homozygous WT/mutant in mice, what is observed?

A

mice neurones live longer

114
Q

what has been shown to reduce the speed of ageing in the brain?

A

calming down neuronal activity reduces stress on neurones and reduces speed of aging

115
Q

gene associated with Parkinson’s disease are almost always associated with what? and what does this highlight?

A

the mitochondria

this highlights the role of ATP in dopaminergic neurones

116
Q

name three genes are associated with Parkinson’s disease and how this affects the disease?

A
  • DJ-1 is an antioxidant protein that can quench ROS
  • PINK is involved in regulating mitochondrial mediated apoptosis
  • Parkin E3 ubiquitin ligase - maintains mitochondrial function and reduces oxidative stress
117
Q

what happens when you lose 50-70% of you DN? and what happens before this point?

A

you start getting the shakes

> you will lose your sense of smell, constipation and disrupted REM sleep

118
Q

where are people suggesting Parkinson’s may arise?

A

in the gut

119
Q

what affect has young blood been seen to have on the brain in heterochronic parasymbiosis experiments?

A

young blood reverses age related impairments in cognitive function and synaptic plasticity in mice
> young blood can rescue production of new neurones in the hippocampus

120
Q

what might be interesting to tests in relation to the parasymbiosis experiments?

A

to see what affect heterochronic blood would have on the cells which die in Alzheimer’s and Parkinson’s