Cellular ageing Flashcards
(47 cards)
1
Q
Define ageing
A
Progressive deterioration of an organism over its lifetime
- decreased fitness and function
- increased susceptibility to disease and death
2
Q
How much is the UK life expectancy increasing per year?
A
0.22 years
3
Q
What % of human death in the UK is due to ageing?
A
> 80%
4
Q
What diseases is ageing a primary risk factor for?
A
Cancer
Diabetes
Cardiovascular disorders
Neuroegenerative diseases
5
Q
What % of GDP does ageing cost?
A
25%
6
Q
What is the mortality doubling time?
A
8 years
7
Q
How much has the average lifespan increased over the last 200 years?
A
2x
8
Q
What evolutionary explanations are there for ageing?
A
- wild animals die from extrinsic causes before age significantly -> no significant selection pressure against ageing
- little selective pressure to live beyond reproductive age
- Antagonistic pleiotropy: growth and reproduction early in life may induce damage and use up resources required to prevent/repair/replace damage -> ageing later in life
9
Q
What are the commonalities of ageing?
A
- near universality of ageing
- survival curves have similar shape
- increased disease and death
- organ functions decline eg muscles particularly in mammals
- cell loss including stem cells
- cellular changes eg DNA damage, protein turnover slows
10
Q
What factors should be considered for model organisms in ageing?
A
- Rate of ageing - quickly so that factors that modify this can be identified
- Relevance to humans
11
Q
What differs in ageing?
A
- Rate of ageing
- Diseases of ageing
- Cause of death
12
Q
What is the average lifespan of yeast?
A
6 days
13
Q
What is the average lifespan of worms?
A
18 days
14
Q
What is the average lifespan of Drosophila?
A
75 days
15
Q
What is the average lifespan of mice?
A
800 days
16
Q
What is the average lifespan of humans?
A
20,000 days
17
Q
What is the main cause of death in yeast?
A
bud scarring
18
Q
What is the main cause of death in worms?
A
Gut bacteria proliferation
19
Q
What is the main cause of death in flies?
A
mechanical damage
20
Q
What is the main cause of death in mice?
A
cancer
21
Q
What is the main cause of death in rats?
A
cancer
kidney disease
22
Q
What is the main cause of death in humans?
A
Heart disease
Cancer
Stroke
Dementia
23
Q
How many mechanistic theories are there for ageing?
A
> 200
24
Q
What are the causes of damage?
A
- Genomic instability
- Telomere shortening
- Epigenetic alterations
- loss of proteostasis (protein damage and aggregation)
25
What are the responses to damage?
- deregulated nutrient sensing
- mitochondrial dysfunction
- cell sensescence
26
What therapies are there to intervene/prevent processes associated with increased ageing?
- Clearance of senescent cells
- stem cell based therapies
- anti-inflammatory drugs, blood born rejuvenation factors
- removal of damaged cells
- telomerase reactivation
- epigenetic drugs
- activation of chaperones and proteolytic systems
- dietary restriction
- mitohormetics, mitophagy
27
How does telomere shortening lead to ageing?
- telomeres shorten with age as most cells do not express telomerase
- senescence in key cell populations eg stem cells
28
What evidence is therefore for the telomere shortening theory?
- telomeres shorten with age
- senescent cells increase with age
- stem cell proliferation decreases with age
- cells taken from human foetus and 71 year old -> telomeres from 71 yo shorter and more variable, cell senescence occurs more quickly in cells from 71 yo
- correlation between the numbers of doublings when senescence occurs and the lifespan of the animal that the cells were taken from -> suggests connection between lifespan and maximum times cells divde
29
What evidence is there against the telomere shortening theory?
- some animals (eg rabbits) have no telomere shortening but still age
- ageing can occur in humans without telomere shortening eg Hutchinson-Gilford progeria
- ageing occurs in non-dividing cells
30
Which cells express telomerase?
germ cells
some stem cells
cancer cells
31
How does the telomere length from the cells from human foetus vs 71 yo compare?
Telomeres from 71 yo shorter and more variable
| 5-10 kb vs 7/8-15 kb
32
How quickly do cells from 71 yo senescence?
40 divisions
33
How quickly do cells from the human foetus senescence?
80 divisions
34
How quickly do telomeres shorten?
10-15 kb -> 3-5 kb over 50-60 doublings
35
why does telomere shortening lead to cell senescence?
- when 1-few telomeres become critically short (4kb in humans)
- sensed as DNA damage by the p53 checkpoint -> growth arrest, heterochromatin gene silencing, may induce apoptosis
36
After how many doublings do mouse cells sensescence?
20
37
After how many doublings do humans cells senescence?
60
38
After how many doublings do Galapagos tortoise cells senescence?
125
39
What is used as a marker for cell senescence and why?
-increased beta-galactosidase activity
40
How can senescence block proliferation?
-due to p21, p16 and/or ARF
41
Which pathway is particularly involved in senescence that accumulates with age?
p16
42
What is the senescent associated secretory phenotype?
Senescent cells secrete pro-inflammatory factors
43
What is the flow of the p21 pathway?
Stress -> ATM/ATR kinase or ARF -> p53 -> p21 -> inhibits CDK2 -> prevents cdk2 inhibiting Rb -> cell cycle arrest -> either repair or senescence
44
What is the flow of the p16 pathway?
stress -> p16 -> inhibits CDK4/6 -> prevents CDK4/6 from inhibiting Rb -> cell cycle arrest -> senescence
45
What evidence is there that senescent cells may be damaging?
- p16 and ARF expression increases with age
- p16 KO mice -> extended proliferation/function of stem cells
- removal of p16-expressing senescent cells delays ageing in mice (caspase 8 fused to FKBP under control of p16 specific promoter, addition of drug causes FKBP to dimerise activating caspase 8)
- muscle stem cells become senescent with age -> KD of p16^Ink4a in old muscle stem cells increases self-renewal and muscle formation
- senescent cells express p53, FOXO4 normally binds p53 to prevent apoptosis, inhibiting this interaction induces in senescent cells and reversed loss of fur/kidney function/endurance
46
What evidence is there that senescent cells can contribute to age related pathology?
- p16 expressing lgia accumulate in brain with age
- more p16 expressing glia in mice expressing tau mutant that induces dementia (P301S tau)
- removing p16 expressing senescent cells reduces neuronal loss and dementia in these mice
47
What factors can cause senescence?
-Epigenetic factors
Telomere erosion
DNA damage
mitochondria dysfunction
