Ferrari & Aprile: Lecture XXVII Flashcards

Molecular Mechanisms of Aging: Changes and mTOR singaling

1
Q

What is the epigenetic clock?

A

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

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2
Q

Describe the state of chromatin in young vs old:

A

young have a more condensed, repressive state

old have a more open, active, euchromatic state

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3
Q

What is the acetylation of the histone tail associated with?

A

different states in different organisms

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4
Q

What is nutrient sensing linked to?

A

the epigenetic landscape

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5
Q

What is cellular senescence strictly linked to?

A

epigenetic mechanisms

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6
Q

How is the epigenome influenced by metabolism?

A

it has been shown that caloric restriction can lead to rejuvenation

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

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7
Q

Describe what could be seen in animals under caloric restriction:

A

downregulation of P16

repression of sirtuins

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8
Q

An increase in glycolysis in cells gives rise to ___.

A

accelerated aging phenotype

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9
Q

An overexpression of FAO (fatty acid oxidation) ___.

A

extends lifespan

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10
Q

Describe the interplay between the epigenome and mitochondria:

A

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

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11
Q

What is NAD involved in?

A

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

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12
Q

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

A

activation of nuclear processes

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13
Q

What does an increase of ROS give rise to?

A

deregulation and changes of expression of mitochondrial genes

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14
Q

What does the genral loss of heterochromatin result in?

A

reactivation of transposons

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15
Q

What is inflammaging?

A

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

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16
Q

What is an example of premature aging syndrome?

A

Werner syndrome

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17
Q

What causes werner syndrome (WS)?

A

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

18
Q

What does WRN associate with?

A

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

19
Q

What is the role of WRN?

A

maintaining heterochromatin stability

20
Q

What could be a potential determinant of human aging?

A

heterochromatin disorganizzation

21
Q

Review the following in regards to WS:

A
22
Q

When does the onset of WS usually occur?

A

after 30 years

23
Q

What characterizes WS?

A

accelerated aging → osteoporosis in premature age

short status

hormonal defects

diabetes

blindness

premature death

24
Q

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

A

3 layers of differentiation:

ectoderm
mesoderm
endoderm

25
Q

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

A

Senescence

β-galactosidase (also associated with the cell cycle)

26
Q

What is an inflammatory cytokine?

A

SASP

27
Q

How is heterochromatin organization checked?

A

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

28
Q

How were they able to demonstrate the molecular mechanism?

A

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

29
Q

What is mTOR a crosspath for?

A

anabolic and catabolic pathways

30
Q

What is mTOR?

A

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

31
Q

What does Rapamycin do?

A

inhibits cellular functions and has an immunosuppressing role

it also promotes autophagy

32
Q

How does Rapamycin act?

A

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

33
Q

What is mTORC1 involved in?

A

cell cycle and cellular growth

34
Q

Review the mTOR pathway:

A

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

35
Q

How is mTORC1 involved in aging?

A

protein synthesis

acts on transcription initiation factors

ribosome biogenesis

anabolism

36
Q

What reduces catabolism activity?

A

mTORC activity

37
Q

Where is mTORC located?

A

cytosol near lysosomes

38
Q

How is mTORC involved in metabolic syndrome?

A

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

39
Q

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

A

over 80%

40
Q

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

A

lifespan was increased

41
Q

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

A

mTOR activity was impacted and prevented the aging of animals

42
Q

Review the following points:

A