Lecture 19. Ageing 4. The Hallmarks of Ageing and Dietary Intervention

Question 1

What are the primary hallmarks of ageing?

Answer 1

The causes of cellular damage associated with ageing: specific alterations to DNA and proteins in the cell

Question 2

What are examples of the primary hallmarks of ageing?

Answer 2

Genomic instability
Loss of telomeres
Epigenetic alterations
Loss of proteostasis

Question 3

What causes DNA damage?

Answer 3

Exogenous threats (chemical and biological agents), and by endogenous threats (DNA replication errors, spontaneous hydrolytic reactions, and reactive oxygen species (ROS)

Question 4

What are examples of DNA repair mechanisms?

Answer 4

Those that repair damages inflicted to nuclear DNA
Mechanisms for maintaining the appropriate length and functionality of telomeres. Defects in the nuclear architecture, known as laminopathies, link these: they can cause genome instability and result in premature ageing syndromes
The integrity of mitochondrial DNA (mtDNA)

Question 5

What is telomere attrition?

Answer 5

Accompanied with normal ageing
Pathological telomere dysfunction accelerates ageing in mice and humans, whereas experimental stimulation of telomerase can delay ageing in mice

Question 6

What are telomeres?

Answer 6

Repetitive DNA sequences at the ends of metazoan chromosomes

Question 6

What are epigenetic changes?

Answer 6

Heritable changes in gene expression that are not caused by changes in DNA sequence

Question 7

What are examples of heritable changes?

Answer 7

DNA and histone methylation patterns
Acetylation of histones
Chromatin remodelling

Question 8

What does methylation of DNA and histones do?

Answer 8

Causes nucleosomes to pack together, hindering access of transcription factors: the genes are not expressed

Question 9

What does acetylation of histones lead to?

Answer 9

Loose packing of nucleosomes
Transcription factors have easy access, and the genes are expressed

Question 10

How are the epigenetic marks of the female passes?

Answer 10

To the ova

Question 11

What replaces the protamines associated with the sperm DNA?

Answer 11

Acetylated histones from the ovum’s cytoplasm and male DNA is then systematically demethylated
But some male epigenetic marks remain

Question 12

What are the antagonistic hallmarks of ageing?

Answer 12

Deregulated nutrient sensing
Mitochondrial dysfunction

Question 13

What is the somatotrophic axis in mammals comprised of?

Answer 13

Growth hormone (GH), which is produced by the anterior pituitary
And insulin-like growth factor 1 (IGF-1), produced in response to GH by many cell types, most notably hepatocytes.

Question 14

What signalling pathway does IGF-1 share?

Answer 14

The signalling pathway of IGF-1 is the same as that of insulin, which informs cells of the presence of glucose Nutrient sensing

Question 15

What is the name of the highly conserved ageing-controlled pathway in evolution?

Answer 15

The “insulin and IGF-1 signalling” (IIS) pathway

Question 16

What is the proposed model to explain the deregulation of the IIS pathway with age?

Answer 16

It is a defensive response to ageing, and not a cause of ageing
It minimises cell growth and metabolism and thus limits damage
An advantage to ageing organisms
An advantage when nutrient availability is low

Question 17

What are the integrative hallmarks of ageing?

Answer 17

The end result of the primary and antagonistic hallmarks and are ultimately responsible for the functional decline associated with ageing

Question 18

What are examples of the integrative hallmarks of ageing?

Answer 18

Cellular senescence
Stem cell exhaustion
Altered intracellular communication

Question 19

What is cellular senescence?

Answer 19

The processes by which the capacity for cell division, growth, and function is lost over time

Question 20

What does stem cell exhaustion cause?

Answer 20

HSCs (haematopoietic stem cells) which cause anaemia myelodysplasia
MSCs (mesenchymal stem cells) which cause osteoporosis and poor fracture repair
IESCs (intestinal epithelial stem cells) which cause reduced intestinal function
Satellite cells which cause poor muscle fibre repair

Question 21

What does altered intracellular communication cause?

Answer 21

Neuroendocrine dysfunction
Inflammation
Immunosenescence
Bystander effects

Question 22

What is the ‘Westernised’ lifestyle?

Answer 22

Low physical activity
High calorific activity
Low fruit, fibre and vegetable intake

Question 23

What are the pros of white adipose tissue (WAT)?

Answer 23

WAT stores energy
People with greater WAT mass have increased chances of survival in famine conditions
WAT regulates immune responses, gives mechanical protection, has endocrine functions, and regulates thermoregulation

Question 24

What are the cons of white adipose tissue?

Answer 24

A high-fat diet (HFD) induces obesity

Question 25

What is the effect of reducing the size of the stomach on relative telomere length?

Answer 25

~2% increase in the lengths of the leucocyte telomeres

Question 26

What is the Mediterranean diet?

Answer 26

A high intake of olive oil, fresh fruits, legumes and vegetables
A low intake of animal fat, meat, processed meat products and salty foods

Question 27

What does olive oil contain?

Answer 27

High levels of phenolic compounds, which possess strong antioxidant, and anti-inflammatory activities

Question 28

What does broccoli contain?

Answer 28

Glucosinolates and their degradation products which have health promoting benefits

Question 29

What is the mode of action of Nrf2?

Answer 29

Nrf2 is normally held inactive by Keap1, ubiquitylated and destroyed, keeping its concentration low. Under oxidative stress, Keap1 releases Nrf2, which then enters the nucleus and stimulates expression of catalase and superoxide dismutase

Question 30

What is the mode of action of sulforaphane?

Answer 30

Sulforaphane binds Keap1 and inhibits proteasome targeting. Result, increased anti-oxidant activity

Question 31

What is curcumin?

Answer 31

A polyphenolic bioactive compound from Curcuma longa, usually in the form of turmeric. Anti-ageing in most model organisms tested. It upregulates NRF2, so suppresses oxidative stress

Question 32

What is spermidine?

Answer 32

A polyamine that induces autophagy both in cultured cells and in vivo and has exceptional anti-ageing activity
It increases lifespan in both C. elegans and Drosophila, and reduces oxidative damage in mice
It may be a universal anti-ageing compound

Question 33

What are key sources of spermidine?

Answer 33

Vegetables (dried soybeans) and cheese (mature cheddar)