Topic07 - Epigenetics of Aging

Question 1

What are the two main theories of aging?

Answer 1

1. Programmed theory of aging

2. Damage or Error theory of aging

Question 2

State the subcategories of the Programmed theory of aging

Answer 2

1. Programmed longevity
2. Endocrine theory
3. Immunological theory

Question 3

State the subcategories of the Damage/Error theory of aging

Answer 3

1. Wear and tear theory
2. Rate of living theory
3. Cross-linking theory
4. Free-radicals theory
5. Somatic DNA damage theory

Question 4

Define programmed longevity

Answer 4

The programmed longevity theory poses aging as a result of a sequential switching on and off of certain genes, explaining aging as a primary disorder instigated by inner coordination and control mechanisms.

Question 5

Define senescence

Answer 5

Senescence is defined as the combination of processes of deterioration which follow the period of development. In other words, it is the process by which a cell loses its ability to divide, grow, and function

Question 6

Define cellular senescence

Answer 6

The state at which a cell in the body can no longer divide.

Question 7

What are SASPs?

Answer 7

Senescent cells can assume a special secretory form (SASP) in which they release various chemical signals that harm the health of nearby cells.

Question 8

Briefly discuss the epigenetic changes involved in the formation of senescent cells.

Answer 8

1. Histone deacetylation occurs
2. macroH2A enriches histones
3. Histone methylation occurs

In short, heterochromatin is irreversibly formed at senescence-associated heterochromatin foci (SAHF). As proliferation-related genes are located within SAHF, proliferation is halted in senescent cells.

Question 9

Briefly discuss DNA methylation in terms of aging

Answer 9

DNA methylation is globally reduced, but local DNA methylation increases.
Hypomethylation of LINEs and SINEs increases transposition, resulting in decreased DNA stability

Question 10

Define the term epigenetic clock

Answer 10

An epigenetic clock is a biological clock to help in predicting the aging process

Question 11

Define the term hazard ratio

Answer 11

A hazard ratio is the probability of an event in some experimental group at a given time, divided by the probability of the same event in a control group.
A hazard ratio of 1 means there is no difference, a hazard ratio of 2 means there is twice the risk

Question 12

When does age acceleration slow?

Answer 12

Around adulthood (20 yrs)

Question 13

What is the percentage of age acceleration in babies?

Answer 13

100%

Question 14

List the three biological clocks.

Answer 14

1. Horvath’s clock
2. Hannum’s clock
3. Levine’s clock

Question 15

State the epigenetic changes monitored by the Horvath’s, Hannum’s and Levine’s clock

Answer 15

DNA methylation-based biomarkers

Question 16

State the tissue(s) involved in Hannum’s clock

Answer 16

Whole blood tissue (single tissue)

Question 17

State the tissue(s) involved in Horvath’s clock

Answer 17

It is a multi-tissue age estimator, taking into account 51 types of tissues.

Question 18

Discuss the performance of Hannum’s clock versus Horvath’s clock

Answer 18

Hannum’s clock performs better in predicting biological age, while Horvath’s clock performs better in predicting lifespan

Question 19

Briefly describe Levine’s clock

Answer 19

Levine’s clock takes into account the weighted average of 10 clinical characteristics, regressed on DNA methylation levels in blood.

Question 20

State the clinical characteristics used in constructing Levine’s clock

Answer 20

1. Chronological age
2. Albumin
3. Creatine
4. Glucose
5. C-reactive protein levels
6. Lymphocyte percentage
7. Mean cell volume
8. RBC distribution width
9. Alkaline phosphatase
10. WBC count

Question 21

Briefly explain the heterochromatin-loss model of aging

Answer 21

This model suggests that the loss of heterochromatin that accompanies aging leads to changes in global nuclear architecture and the expression of genes residing in those regions.
This causes transcriptional and genomic instability.
An abnormal chromatin state causes a feedback loop, causing more epimutations.

Question 22

The heterochromatin-loss model is currently outdated. TRUE or FALSE?

Answer 22

TRUE. It is updated with the heterochromatin-reorganisation model.

Question 23

Briefly explain the heterochromatin-reorganisation model

Answer 23

Heterochromatin marks are redistributed during aging (e.g. heterochromatin formation at SAHF).
Decondensation of heterochromatin occurs alongside condensation of euchromatin

Question 24

Briefly discuss the effect of core histone protein loss in aging

Answer 24

The loss of core histone proteins have been shown to be a cause of aging in yeast.
Notably, all genomic regions showed transcriptional up-regulation, due to increased access of transcription machinery to DNA sequences.

Question 25

State the three ways in which chromatin stability can be rescued.

Answer 25

1. Addition of extra histones
2. Knockdown of Alu RNAs (involved in retrotransposition)
3. Calorie restriction

All three ways essentially reduce transposition events of LINEs and SINEs.

Question 26

State the histone variant that accumulates with age

Answer 26

H3.3

Question 27

State the prominent histone modifications involved in aging

Answer 27

Lysine acetylation and methylation

Question 28

List the environmental factors affecting the epigenome during aging

Answer 28

1. Diet
2. Circadian cycle
3. Exercise
4. Pheromones
5. Systemic factors (e.g. sex steroid hormones)

Question 29

What are sirtuins?

Answer 29

Sirtuins are a novel therapeutic target to treat age-associated diseases

Question 30

What is SIRT1?

Answer 30

SIRT1 is an NAD dependent histone deacetylase that catalyses the removal of acetyl groups from a number of non-histone targets.

Question 31

State the effects of SIRT1

Answer 31

SIRT1 is an NAD dependent HDAC. SIRT1 decreases apoptosis and inflammation and increases genome stability, gene silencing, insulin sensitivity, mitochondrial biogenesis.
In essence, SIRT1 increases life span