Lecture 17 - Regulation Of Cardiac Senescence In Health And Disease

Question 1

How many people in the uk are living with heart and circulatory diseases?

Answer 1

7.4million

Question 2

What is the total annual health cost of heart and circulatory disease in the UK?

Answer 2

9 billion

Question 3

What age is more likely to survive a heart attack - 50 or 85?

Answer 3

Someone who is 50

Question 4

What is age related heart failure?

Answer 4

Decline in cardiac function

Question 5

What is at risk when a “healthy patient” has a heart attack?

Answer 5

Increased motility and increase in severity

Question 6

What are age-dependent changes that occur to cardiovascular tissues?

Answer 6

Diastolic dysfunction and systolic dysfunction and age remodelling

Question 7

What is some examples of age remodelling?

Answer 7

Fibrosis, hypertrophy, decreased cardiomyocytes, inflammation, ischaemic areas and impaired regeneration

Question 8

What is accumulated cellular senescence associated with?

Answer 8

Age related tissue dysfunction

Question 9

What happens when senescence cells are moved from a mouse?

Answer 9

They mouse is healthier and you get

Question 10

What type of expression is only seen in senescence cells?

Answer 10

P16

Question 11

What is senescence cells driven by?

Answer 11

Cellular stress or replicated stress like telomeres

Question 12

What can cause cellular stress?

Answer 12

DNA damage

Question 13

What do cytokindependent inhibitors do?

Answer 13

Make the cell exit the cell cycle

Question 14

What does SASP stand for?

Answer 14

Senescence associated secretory phenotype

Question 15

What is antagonistic pleiotrophy?

Answer 15

A process that is beneficial earlier in life, it becomes detrimental in order life when there is no selective pressure

Question 16

What are examples of chronic senescence?

Answer 16

Replicative failure/stem cell dysfunction, tissue remodelling, inflammation and senescence propagation

Question 17

What can senescence occur as a result as?

Answer 17

Persistent DDR - (DNA damage response)

Question 18

What are senescence cells casual to?

Answer 18

Age related pathophysiologies in multiple tissues and organs

Question 19

What are the pathophysiologies due to?

Answer 19

Cell cycle exit - effecting tissue homeostasis and regeneration and SASP - propagating the senescent phenotype and inducing tissue remodelling and inflammation

Question 20

What does cardiomyocyte senescence accumulate with?

Answer 20

Age

Question 21

What happens when you induce senescence experimentally?

Answer 21

You get a young mouse with an old heart

Question 22

What happens if you over express genes in cardiomyocytes that delay senescence?

Answer 22

You delay the heart ageing process

Question 23

Switch on senescence?

Answer 23

High heart ageing

Question 24

Switch off senescence?

Answer 24

Low heart ageing

Question 25

What do mouse models that demonstrate myocardial remodelling cause?

Answer 25

Myocardial remodelling characteristic of ageing

Question 26

What do the teleports protect during continuous cell proliferation?

Answer 26

Teleports protect the chromosome

Question 27

Where are telomeres found?

Answer 27

At the end of chromosomes

Question 28

What happens when a cell divides?

Answer 28

It replicates it DNA, every time you replicate the DNA you lose a bit from the end

Question 29

What happens to telomeres every time DNA is replicated?

Answer 29

Telomeres shorten

Question 30

What happens during stem cell dysfunction?

Answer 30

Exhaustion of the stem cell pool, reduced potential maintain tissue homeostasis

Question 31

What does both telomere shortening and stem cell dysfunction lead to?

Answer 31

Tissue degeneration

Question 32

What happens during a heart attack (as a post mitotic organ)?

Answer 32

Remodelling not regeneration, cardiomyocytes loss

Question 33

What is TAF?

Answer 33

Telomere associate DNA damage

Question 34

What are the stresses involved with TAF?

Answer 34

Oxidative stress

Question 35

What does TAF contribute to?

Answer 35

Senescent phenotype

Question 36

Does AF occur independently or dependently?

Answer 36

Independently of cell proliferation

Question 37

What is a persistent form of DNA damage?

Answer 37

TAF

Question 38

What are the favoured targets of persistent DNA damage?

Answer 38

Telomeres, if the damage occurs in the T region, the DNA damage response wont get in so wont be able to repair

Question 39

Does TAF accumulate during cardiomyocytes ageing?

Answer 39

There is an increase in TAFs in older individuals

Question 40

Could TAF contribute to senescence in a rarely cycling cardiomyocyte?

Answer 40

When you induce damage to the telomeres you get scenscence, TAF can occur independently of proliferation but itself can drive the senescence in the cardiomyocyte

Question 41

What effect does exit from the cell cycle have on the post mitotic heart?

Answer 41

It has little effect on the post mitotic heart

Question 42

What do senescent CMs produce?

Answer 42

A senescence associated secretory phenotype (SASP)

Question 43

What do aged cardiomyocyte express?

Answer 43

A non typical senescence associated secretory phenotype (SASP)

Question 44

What do secreted proteins up regulate in?

Answer 44

Aged cardiomyocytes

Question 45

What do secreted factors from cultured aged cardiomyocytes express?

Answer 45

They inhibit proliferation and promote expression of marks of myofibroblast differentiation/fibrosis

Question 46

What can senescence cardiac cells induce?

Answer 46

Senescence in other cells “bystander effect”

Question 47

What does TAFs lead to?

Answer 47

Expression of SASP which leads to fibrosis and inflammation

Question 48

What are senescent cells primed for?

Answer 48

Apoptosis

Question 49

What do inhibitors of senescence do?

Answer 49

Try to stop the apoptosis process

Question 50

What is hypertrophy reduced in?

Answer 50

Aged ink-ATTAC mice

Question 51

What is an example of a drug that clears senescence cells?

Answer 51

Navitoclax - reduces SASP and clears senescence cells

Question 52

What does navitoclax target?

Answer 52

Bcl2 to induce apoptosis

Question 53

What does navitoclax do?

Answer 53

It cleats senescent cells and attenuates myocardial remodelling in vivo.

Question 54

What are the benefits for navitoclax?

Answer 54

Fewer senescence cells, reduced fibrosis and hypertrophy

Question 55

What did pre-treatment with Navitoclax and then give subject a heart attack show?

Answer 55

Improved survival and recovery post heart attack