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
2
Q
what two fields of biology are repeatedly linked?
A
cancer biology and ageing biology
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
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
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
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
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
8
Q
what might happen to stem cells as we age?
A
they may become less well controlled and become depleted
9
Q
by 2025 how many people will be over the age of 60?
A
1.2 billion
people are living longer
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
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
12
Q
name 5 diseases that are associated with ageing
A
- cardiovascular disease
- arthritis
- T2D
- pulmonary disease
- cancer
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
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
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
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
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
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
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
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
21
Q
how much does the ATP produced in muscles decline per decade?
A
by 5%
22
Q
what happens to mtDNA in the ageing process?
A
it becomes more damaged, levels of 8-oxoguanine increase
23
Q
what is 8-oxoguanine ?
A
a DNA lesion that results from ROS
it can lead to mismatch pairing with adenosine
24
Q
what three things are seen increasingly oxidised in the mitochondrial ageing process?
A
DNA
lipids
proteins
25
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?
they may feel pain and breathlessness
| they ae less likely to exercise and this makes them even more weak
26
what other four factors also affect skeletal muscle health?
- endocrine system
- neural system
- cardiovascular system
general health decline will have a knock on affect on skeletal muscle
27
why can circulatory system affect skeletal muscle?
it affects oxygen and nutrients availability
28
why is geriatric care complex?
when people age they may have several co-morbid conditions
29
changes in the muscle to fat ratio can lead to what?
- metabolic syndrome
a cluster of biochemical and physiological abnormalities which are associated with CV disease and T2D
- and insulin resistance
30
what is insulin resistance and what can it lead to?
when the body does not respond to insulin as efficiently as it should, this can lead to type 2 diabetes
31
what type of cells can generate ROS and release fatty acid into the blood?
fat cells
32
fatty acids in the blood are known to cause what?
muscle insulin resistance by inhibiting insulin stimulated glucose uptake and glycogen synthesis
33
what is seen in almost all old tissue?
inflammation
34
name a post mitotic cells in skeletal muscle
adult myofibres
35
name the stem cells in skeletal muscle and name a marker for them
skeletal muscle cells
| psx7
36
when stem cells in the skeletal muscle are stimulated to divide what do they do?
they fuse with damaged muscle fibres and regenerate myonuclei and locally regenerate tissue
37
what is seen about old satellite cells? and what two things might this be due to?
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
38
what is seen when old mice satellite cells at cultured in vitro?
- they produce less organised and more fragile myotubes
39
when satellite cells divide and make the wrong lineage, what affect does this have on tissue?
fibroblasts like cells wiggle into the tissue and disrupt the skeletal muscle structure
40
where are skeletal muscle cells found?
in contact with skeletal muscle fibre and basal lamina
41
define some contributing factors to the satellite cell niche (5)
- fat cells
- fibroblasts
- vasculature
- nerve cells
- muscle fibres
42
define some contributing factors to the ageing satellite cell niche (5)
- increase adipocytes
- thicker basal lamina and more ECM deposition which stiffen muscle
- decreased endothelial number
- impaired chemotaxis of macrophages
- increased fibroblasts
43
what happens to stem cell regulation in the ageing satellite cell niche?
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
44
what happens to the cross sectional area of myofibres as we age?
it is reduced
45
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?
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
46
what has parabiosis been shown to do?
- rejuvenate old satellite cells
| - they also showed the involvement of carconical Wnt signalling in this process
47
describe Wnt signalling
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
48
why might the results obtained from parasymbiosis experiments be hard to transfer into the clinic, and what may help overcome this?
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
49
when carconical Wnt signalling is decreased, what is seen?
this prevents aged satellite cells switching from myogenic to fibrogenic lineage as proliferate
50
what can injecting Wnt into repairing muscle lead to?
fibrosis
51
what can cleave the co-receptor of Wnt and drive Wnt signalling? and how is this relevant to ageing?
compliment
| C1q is found in old serum
52
what does the aged satellite cell niche disrupt?
quiescence
53
what is fgf2
a factor important in controlling cell division
54
what do aged muscle fibres express more of and what affect does this have on satellite cells?
fgf2 drives satellite cells out of quiescence and depletes them
55
why do old muscle fibres produce fgf2?
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
how old is an old mouse and why don't all papers use this age?
2-3 years
| its expensive
57
there are two models for whether all stem cell in an aged niche behave the same way, what are they?
>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
if the clonal selection model is true what does this suggest?
this suggests that different populations within a tissue are ageing at different rates, e.g. TA cells may age more rapidly
59
what happens in haematopoiesis as people age?
there is a bias towards the myeloid lineage as cell type and proportion control start to break down
60
what occurs Sarcopenia?
muscle atrophy and intramuscular adipose
61
what does Sarcopenia cause?
loss of muscle mass and changes in their strength and function
62
what are the symptoms of Sarcopenia? (5)
frailty, exhaustion, reduced physical activity, slow walking, reduced grip strength
63
what is a hige risk factor from mental health? and what may cause this?
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
what may cause Sarcopenia? (7)
- endocrine
- nutrition
- inactivity
- inflammation
- reduced activity of satellite cells
- medication
- cancer
65
why can exercise help prevent sarcopenia?
increasing ROS scavengers
66
how can cancer affect you risk of Sarcopenia?
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
when people age the are much less driven to each, what does this cause and what may this lead to?
- malnourishment
| - mental health problems
68
name 4 diseases that can cause Sarcopenia
diabetes
liver failure
obesity
anorexia
69
what is a good way to reduce frailty? (4)
- weight baring exercise
- anti-inflammatories
- hormones
- nutrition (supplements)
70
why do some old people become frail and others don’t?
this is not clear, we don’t know the genetic and environmental risk facts which influence frailty
71
name a risk factor for CV disease
age
72
what is the most common cause of death in the elderly in the western world?
CV disease
73
what occurs to heart function as we age and what can contribute to this?
- the heart has reduced function
| - the rest of the body ageing can put a strain on the heart
74
what happens to heart tissue to reduce its function?
- 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
what causes exercise intolerance?
reduced heart function
76
when the heart muscles walls thicken, what is this called and why does this happen? what might some of the thickening be?
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
what is present in healthy cardiac muscle and what does this allow?
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
what about cardiac muscles may be challenging about stimulating them to divide?
they are bi-nuclear
79
what happens in heart fibrosis? (5)
- 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
what is cardiomyopathy? and what can it be associated with?
disease of the heart muscle
| age
81
what happens to the mitochondria in the aged heart? (6)
- 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
what causes mitochondrial swelling, collapse of membrane potential, ATP depletion and apoptosis?
increase mitochondria permeability transition pore on the inner membrane
83
what affect does reducing IGF1 signalling have on the heart?
cardiovascular performance in drosophila
| and reduced age-associated cardiomyocytes dysfunction in mice
84
what increases the risk of heart failure in elderly people?
low serum IGF1 level
85
what affect does growth hormone have on the heart?
can improve heart failure recovery and reduce age-associated blood pressure dysfunction
86
what is the only widely accepted method to reduce the bad effects of aging? and why is this?
calorie restriction
| it reduces cellular activity, less activity means less damage to organs and organelles
87
what type of cells in the heart are controversial?
stem cells
88
in the putative stem cells that have been proposed in the heart, what happens to these cells during ageing?
- more apoptosis
- shortened telomeres
- increased senescence
89
when heart muscles was 14C labelled to show turnover and renewal rate of cardiomyocytes, what was observed at 25 years and 75 years?
at 25 year turnover rate was around 1% annually decreases to 0.45% at 75 years
90
what happens to arteries and capillaries as we age? (2)
- they become stiff
| - they also become dilated
91
why do arteries and capillaries become stiff? and what affect does this have on them?
increased cross linked ECM
> this makes them less resilient and less able to cope with exertion
> it also affects mechanosensitive gene expression
92
angiogenesis decreases in what organ as we age? and what has been seen to improve this in rats?
the brain
| GH has been seen to improve this
93
endothelial progenitor cells in capillaries are less active when old, what might this be due to?
inflammation and down regulation of insulin signalling
94
give an example of an indirect way that calorie restriction can be beneficial to organ health
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
give three examples of an direct way that calorie restriction can be beneficial to organ health
1. upregulate eNOS (endothelial nitric acid synthase)
2. reduce endothelial ROS
3. reduce pro-inflammatory pathways
96
what has the serum of calorie restructured animals been shown to do?
protect cardiovascular cells in culture
97
what has seen to regulate function of the ageing heart? and what does this show?
vinculin network-mediated cytoskeleton remodelling
| >this shows that hearts can protect themselves as we age
98
what is vinculin? and what happens to it in the aged heart?
it is part of the adhesion complex that interacts with the cytoskeleton
>it is upregulated in the aged heart
99
what does the upregulation of vinculin in the ageing heart do?
it reinforces the cytoskeleton and helps maintain myocyte organisation and contractile function for longer
> and so it is a protective mechanism
100
what can potentially be therapeutically exploited in the ageing process?
the fact that as we age, out organs changes protein expression to help us age well
101
what is hypotrophy? and what organ can this be seen in?
the enlargement of an organ or tissue from the increase in size of its cells
> this can be seen in the heart
102
what is ischemia? and what may this lead to?
the restriction of blood flow to an organ, this might lead to a heart attack
103
what is seen about brain function as we age?
cognitive decline
104
what percentage of people over 80 have Alzheimer's?
50%
105
when an old brain and an Alzheimer's are compared what can be seen? and what does this show?
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
what becomes less efficient in the ageing brain? and what might this be due to?
cross-communication between different regions of the brain
| > this might be due to glia cells and changes in myelination of oligodendrocytes
107
what changes can occur in the brain as we age?
- 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
HDAC inhibitors were given to mice, what did this promote and what did it do?
neural plasticity and recovered memories
109
what does a decline in autophagy lead to?
misfolded proteins, leaky mt and other dysfunctional organelles.
110
why is autophagy important for the brain?
neurones need lots of ATP
111
what are some of the biomarkers for Alzheimer’s? (4) and what does this lead to?
neuronal loss, synapse loss, amyloid plaques and neurofibrillary tangles
> this leads to cognitive decline
112
what has been seen to extend lifespan of neurones in drosophila?
reduced ETC
113
when an enzyme that is necessary for ubiquinone synthesis is homozygous WT/mutant in mice, what is observed?
mice neurones live longer
114
what has been shown to reduce the speed of ageing in the brain?
calming down neuronal activity reduces stress on neurones and reduces speed of aging
115
gene associated with Parkinson's disease are almost always associated with what? and what does this highlight?
the mitochondria
| this highlights the role of ATP in dopaminergic neurones
116
name three genes are associated with Parkinson's disease and how this affects the disease?
- 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
what happens when you lose 50-70% of you DN? and what happens before this point?
you start getting the shakes
| > you will lose your sense of smell, constipation and disrupted REM sleep
118
where are people suggesting Parkinson's may arise?
in the gut
119
what affect has young blood been seen to have on the brain in heterochronic parasymbiosis experiments?
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
what might be interesting to tests in relation to the parasymbiosis experiments?
to see what affect heterochronic blood would have on the cells which die in Alzheimer’s and Parkinson’s
