Ageing and senescence

Question 1

What is senescence?

Answer 1

An age related decline in function

Question 2

What is the disposable soma theory?

Answer 2

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

Question 3

What is a senescence factor?

Answer 3

Something that drives ageing

Question 4

What are the major senescence factors? (3)

Answer 4

• Metabolism
• Reactive oxygen species (ROS)
• DNA damage (Progeria syndromes)

Question 5

What are the major factors that increase lifespan? (3)

Answer 5

• Dietary restriction
• Environmental stresses
• Signals from the somatic gonad

Question 6

What is the rate of living theory? (2)

Answer 6

• Animals with a high metabolism have a shorter lifespan
• Large animals live longer, cold blooded animals live longer at lower temperatures

Question 7

What is the ROS theory of ageing?

Answer 7

Oxygen molecules with an unpaired electron cause oxidative damage which causes ageing

Question 8

What happens if you give an animal more ROS?

Answer 8

Increases lifespan - goes against the theory

Question 9

What do longevity genes do?

Answer 9

Induce resistance to oxidative stress

Question 10

What is the DNA damage theory of ageing? (2)

Answer 10

• 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

Question 11

What is the role of PARP?

Answer 11

PARP is an enzyme that responds to DNA damage and requires co-factor NAD

Question 12

What is a senescent cell?

Answer 12

A cell which is aged no longer divides but isn’t dead (zombie cell)

Question 13

How might senescent cells drive ageing? (2)

Answer 13

• Could be hogging the stem cell niches and getting in the way
• Secretion of SASP factors

Question 14

What are the actions of SASP secretions? (3)

Answer 14

• Pro-inflammatory
• Cause tissue remodelling
• Induce senescence in neighbouring cells

Question 15

How does dietary restriction affect lifespan?

Answer 15

Appears to increase lifespan

Question 16

How do environmental stresses affect lifespan? (2)

Answer 16

• Stresses e.g. heat, ROS generators appear to increase lifespan
• Hormesis

Question 17

What is hormesis?

Answer 17

Low level stresses activate protective mechanisms

Question 18

How might ROS levels increase lifespan? (3)

Answer 18

• 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

Question 19

Which pathways are involved in ageing? (3)

Answer 19

• IGF
• TOR
• Sirtuins

Question 20

How is the IGF pathway involved in ageing?

Answer 20

Blocking IGF increases lifespan

Question 21

How is the TOR pathway involved in ageing?

Answer 21

Blocking TOR increases lifespan

Question 22

How is the Sirtuins pathway involved in ageing?

Answer 22

Overexpression of Sirtuins increases lifespan

Question 23

What happens to C.elegans if you block IGF signalling?

Answer 23

Enters dauer stage and lives longer

Question 24

What does the IGF pathway do?

Answer 24

Blocks the nuclear localisation of DAF16/FOXO

Question 25

What is the mammalian version of DAF16?

Answer 25

FOXO

Question 26

What is DAF16/FOXO?

Answer 26

A transcription factor that enters the nucleus and promotes anti-ageing functions

Question 27

How does dietary restriction increase lifespan?

Answer 27

Blocks the IGF pathway

Question 28

What genes does DAF16/FOXO activate? (4)

Answer 28

- Antioxidant genes - Metabolic genes - Chaperone genes - Antibacterial genes

Question 29

What does TOR signalling do?

Answer 29

TOR kinase is a nutrient sensor that stimulates growth and blocks repair pathways e.g. autophagy when food is plentiful

Question 30

What is the TOR pathway? (3)

Answer 30

- 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

Question 31

How is IGF linked to TOR signalling?

Answer 31

IGF is one of the growth factors that blocks TSC1-TSC2, therefore activating TOR

Question 32

What is the effect of rapamycin on lifespan?

Answer 32

Blocks TOR kinase and extends lifespan

Question 33

How can the TOR pathway be manipulated to extend lifespan? (3)

Answer 33

- Block S6K1 - Overexpress 4E-BP1 - Block TOR

Question 34

What are the Sirtuins?

Answer 34

NAD+ dependent protein deacetylases

Question 35

How do the Sirtuins increase lifespan? (2)

Answer 35

- Activates FOXO/DAF16 and UPR-mt response, requires NAD as a cofactor - May downregulate IGF pathway

Question 36

What is the UPR-mt response? (2)

Answer 36

- Mitochondrial unfolded protein response - Mitochondrial stress response which is linked to longevity

Question 37

What is the NAD depletion theory of ageing? (2)

Answer 37

- NAD levels decline with age - Unrepaired DNA damage causes NAD depletion via excessive PARP activation

Question 38

How do signals from the somatic gonad affect lifespan? (2)

Answer 38

- Removal of the germ cells extends lifespan - Steroidal hormones dafachronic acid and DAF12 act on DAF16/FOXO in an unknown manner