Ageing and senescence Flashcards
What is senescence?
An age related decline in function
What is the disposable soma theory?
As soon as an individual can’t increase the number/chance of survival of its offspring any further there is no natural selection against decline in that individual
What is a senescence factor?
Something that drives ageing
What are the major senescence factors? (3)
- Metabolism
- Reactive oxygen species (ROS)
- DNA damage (Progeria syndromes)
What are the major factors that increase lifespan? (3)
- Dietary restriction
- Environmental stresses
- Signals from the somatic gonad
What is the rate of living theory? (2)
- Animals with a high metabolism have a shorter lifespan
- Large animals live longer, cold blooded animals live longer at lower temperatures
What is the ROS theory of ageing?
Oxygen molecules with an unpaired electron cause oxidative damage which causes ageing
What happens if you give an animal more ROS?
Increases lifespan - goes against the theory
What do longevity genes do?
Induce resistance to oxidative stress
What is the DNA damage theory of ageing? (2)
- Unrepaired/unrepairable DNA may accumulate in non-replicating cells and cause ageing (not higher mutation rate)
- NAD depletion via excessive PARP activation could result in senescent cells
What is the role of PARP?
PARP is an enzyme that responds to DNA damage and requires co-factor NAD
What is a senescent cell?
A cell which is aged no longer divides but isn’t dead (zombie cell)
How might senescent cells drive ageing? (2)
- Could be hogging the stem cell niches and getting in the way
- Secretion of SASP factors
What are the actions of SASP secretions? (3)
- Pro-inflammatory
- Cause tissue remodelling
- Induce senescence in neighbouring cells
How does dietary restriction affect lifespan?
Appears to increase lifespan
How do environmental stresses affect lifespan? (2)
- Stresses e.g. heat, ROS generators appear to increase lifespan
- Hormesis
What is hormesis?
Low level stresses activate protective mechanisms
How might ROS levels increase lifespan? (3)
- Low ROS levels are fine
- An increase above normal allows activation of protective mechanisms
- Taking high levels of antioxidants would negatively interfere with this system
Which pathways are involved in ageing? (3)
- IGF
- TOR
- Sirtuins
How is the IGF pathway involved in ageing?
Blocking IGF increases lifespan
How is the TOR pathway involved in ageing?
Blocking TOR increases lifespan
How is the Sirtuins pathway involved in ageing?
Overexpression of Sirtuins increases lifespan
What happens to C.elegans if you block IGF signalling?
Enters dauer stage and lives longer
What does the IGF pathway do?
Blocks the nuclear localisation of DAF16/FOXO
What is the mammalian version of DAF16?
FOXO
What is DAF16/FOXO?
A transcription factor that enters the nucleus and promotes anti-ageing functions
How does dietary restriction increase lifespan?
Blocks the IGF pathway
What genes does DAF16/FOXO activate? (4)
- Antioxidant genes
- Metabolic genes
- Chaperone genes
- Antibacterial genes
What does TOR signalling do?
TOR kinase is a nutrient sensor that stimulates growth and blocks repair pathways e.g. autophagy when food is plentiful
What is the TOR pathway? (3)
- TOR activates S6K1 and inhibits 4E-BP1
- S6K1 stimulates growth, 4E-BP1 inhibits growth and activates autophagy
- TOR is blocked by TSC1-TSC2 kinases which are activated by stress and blocked by growth factors and amino acids
How is IGF linked to TOR signalling?
IGF is one of the growth factors that blocks TSC1-TSC2, therefore activating TOR
What is the effect of rapamycin on lifespan?
Blocks TOR kinase and extends lifespan
How can the TOR pathway be manipulated to extend lifespan? (3)
- Block S6K1
- Overexpress 4E-BP1
- Block TOR
What are the Sirtuins?
NAD+ dependent protein deacetylases
How do the Sirtuins increase lifespan? (2)
- Activates FOXO/DAF16 and UPR-mt response, requires NAD as a cofactor
- May downregulate IGF pathway
What is the UPR-mt response? (2)
- Mitochondrial unfolded protein response
- Mitochondrial stress response which is linked to longevity
What is the NAD depletion theory of ageing? (2)
- NAD levels decline with age
- Unrepaired DNA damage causes NAD depletion via excessive PARP activation
How do signals from the somatic gonad affect lifespan? (2)
- Removal of the germ cells extends lifespan
- Steroidal hormones dafachronic acid and DAF12 act on DAF16/FOXO in an unknown manner
