Ferrari & Aprile: Lecture XXVII

Question 1

What is the epigenetic clock?

Answer 1

describes how there is a complete change in the heterochromatin state that can be predicted analyzing DNA de-methylation

Question 2

Describe the state of chromatin in young vs old:

Answer 2

young have a more condensed, repressive state

old have a more open, active, euchromatic state

Question 3

What is the acetylation of the histone tail associated with?

Answer 3

different states in different organisms

Question 4

What is nutrient sensing linked to?

Answer 4

the epigenetic landscape

Question 5

What is cellular senescence strictly linked to?

Answer 5

epigenetic mechanisms

Question 6

How is the epigenome influenced by metabolism?

Answer 6

it has been shown that caloric restriction can lead to rejuvenation

*animals tested also had a different landscape of both methylation and histone acetylation

Question 7

Describe what could be seen in animals under caloric restriction:

Answer 7

downregulation of P16

repression of sirtuins

Question 8

An increase in glycolysis in cells gives rise to ___.

Answer 8

accelerated aging phenotype

Question 9

An overexpression of FAO (fatty acid oxidation) ___.

Answer 9

extends lifespan

Question 10

Describe the interplay between the epigenome and mitochondria:

Answer 10

there is an interplay between the product of metabolism inside the mitochondria and how the product can control the nucleus’ different processes

Question 11

What is NAD involved in?

Answer 11

it is a co-factor for sirtuins and a mitochondrial product that is used to control histone deacetylase

Question 12

What does the increase of 𝛼-ketoglutarate give rise to?

Answer 12

activation of nuclear processes

Question 13

What does an increase of ROS give rise to?

Answer 13

deregulation and changes of expression of mitochondrial genes

Question 14

What does the genral loss of heterochromatin result in?

Answer 14

reactivation of transposons

Question 15

What is inflammaging?

Answer 15

all the changes that give rise to the accumulation of pro-inflammatory cytokines the epigenetic changes can induce a pro-inflammatory phenotype in the cells

Question 16

What is an example of premature aging syndrome?

Answer 16

Werner syndrome

Question 17

What causes werner syndrome (WS)?

Answer 17

WRN protein deficiency (chromosme 8), which is a DNA helicase

Question 18

What does WRN associate with?

Answer 18

heterochromatin proteins SUV39H1 and HP1𝛼 and nuclear lamina-heterochromatin anchoring protein LAP2β

Question 19

What is the role of WRN?

Answer 19

maintaining heterochromatin stability

Question 20

What could be a potential determinant of human aging?

Answer 20

heterochromatin disorganizzation

Question 21

Review the following in regards to WS:

Answer 21

Question 22

When does the onset of WS usually occur?

Answer 22

after 30 years

Question 23

What characterizes WS?

Answer 23

accelerated aging → osteoporosis in premature age

short status

hormonal defects

diabetes

blindness

premature death

Question 24

What were the WRN KO ESCs able to give rise to?

Answer 24

3 layers of differentiation:

ectoderm
mesoderm
endoderm

Question 25

_____ is a hallmark of aging and _____ is a feature of senescence.

Answer 25

Senescence β-galactosidase (also associated with the cell cycle)

Question 26

What is an inflammatory cytokine?

Answer 26

SASP

Question 27

How is heterochromatin organization checked?

Answer 27

they performed a ChIP and saw there is a general enrichment of histone modification but a decrease in H3K9me3

Question 28

How were they able to demonstrate the molecular mechanism?

Answer 28

using chromatin immunoprecipitation, the WRN protein precipitated and they saw it interacted with SUV39H1

Question 29

What is mTOR a crosspath for?

Answer 29

anabolic and catabolic pathways

Question 30

What is mTOR?

Answer 30

serine threonine protein kinase that is part of the PI3 kinase family in mammals, mTOR is the catalytic subunit of 2 different complexes that are mTORC1 and mTORC2

Question 31

What does Rapamycin do?

Answer 31

inhibits cellular functions and has an immunosuppressing role it also promotes autophagy

Question 32

How does Rapamycin act?

Answer 32

binds FKBP12 and forms a complex with mTORC1 and sometimes also with mTORC2

Question 33

What is mTORC1 involved in?

Answer 33

cell cycle and cellular growth

Question 34

Review the mTOR pathway:

Answer 34

https://www.youtube.com/watch?v=ytfQJlC5gjQ

Question 35

How is mTORC1 involved in aging?

Answer 35

protein synthesis acts on transcription initiation factors ribosome biogenesis anabolism

Question 36

What reduces catabolism activity?

Answer 36

mTORC activity

Question 37

Where is mTORC located?

Answer 37

cytosol near lysosomes

Question 38

How is mTORC involved in metabolic syndrome?

Answer 38

mTORC is activated by insulin and GH (obesity and diabetes have been associated with mTORC activity)

Question 39

What percentage of cancer has been associated with the hyperactive state of mTOR?

Answer 39

over 80%

Question 40

In an experimental model, what happened when there was a genetic inhibition of mTOR?

Answer 40

lifespan was increased

Question 41

What happened when mice and monkeys were put on caloric restriction?

Answer 41

mTOR activity was impacted and prevented the aging of animals

Question 42

Review the following points:

Answer 42