Ageing

Question 1

Outline ageing - what does it affect?

Answer 1

Gradual decline in normal physiological functions in a time-dependent manner, affecting all biological systems: molecular interactions, cellular function, tissue structure, systemic physiology

Question 2

What does ageing lead to?

Answer 2

Impaired function
Decreased ability to cope with environmental stressors
Increased incidence of age-related diseases
Increased vulnerability to death

Question 3

How do you define a hallmark of ageing?

Answer 3

It should manifest during normal ageing
It’s experimental aggravation should accelerate ageing
It’s experimental improvement should slow down ageing and increase rate of healthy ageing

Question 4

What are the 3 hallmarks (groups) of ageing?

Answer 4

Primary hallmarks - causes of damage
Antagonistic hallmarks - response to damage
Integrative hallmarks - linked to phenotype of ageing

Question 5

What are the 4 primary hallmarks of ageing?

Answer 5

Genomic instability (increased damage/no repair)
Telomere attrition (no replication)
Epigenetic alteration (loss of translation/transcription)
Loss of proteostasis (misfolding/structural changes)

Question 6

What are the 3 antagonistic hallmarks of ageing?

Answer 6

Mitochondrial dysfunction
Cellular senescence (frozen in time)
Deregulated nutrient sensing

Question 7

What are the 2 integrative hallmarks of ageing?

Answer 7

Stem cell exhaustion (no new cells)

Altered communication

Question 8

How can healthy ageing be promoted?

Answer 8

Stem cell based therapies
Anti-inflammatory drugs
Elimination of damaged cells
Telomerase reactivation
Epigenetic drugs
Clearance of senescent cells
Activation of chaperones and proteolytic systems

Question 9

What are some broad functional physiological changes with age?

Answer 9

CNS and PNS: slowed central processing/speech/cognition and reduced nerve conduction
GI: impaired drug metabolism, insulin secretion, Ca2+ Vit D absorption
Cardio: L ventricular hypertrophy, AF, chronic heart failure, raised systolic bp
Renal: increased excretion of proteins and reduced creatinine clearance
Bones/Joints: osteoporosis, reduced bone density, thickened cartilage, stiffness of cartilage matrix
Muscles: sarcopenia, increased type 1 % muscle fibres

Question 10

What’s the terminology of ageing - the 3 categories of age

Answer 10

Young old: 60s and early 70s who are active and healthy
Old: 70s and 80s with chronic illnesses who are slowing down due to symptoms
Old-old: those who are often sick or disabled or perhaps nearing death

Question 11

What’s the difference between lifespan and healthspan?

Answer 11

Lifespan = maximum length of time an organism is expected, or known to survive

Healthspan = the % of individuals life during which they are generally in good health

Life expectancy = average length of time an organism is expected to survive

Question 12

Define health

Answer 12

State of complete physical, mental and social wellbeing and not merely the absence of disease or infirmity (WHO)

Question 13

What are some processes of ageing

Answer 13

Inflammation
Oxidative stress
Mitochondrial dysfunction
Cellular senescence
Stem cell exhaustion 
Epigenetic alterations
Genomic instability

Question 14

Outline genomic instability

Answer 14

Changes in the genetic code due to exogenous damage (UV/chemicals) or endogenous damage (ROS/replication errors)

Genome becomes unstable by structural changes (in lamins - proteins that provide structural function and transcriptional regulation in the cell nucleus)

Question 15

What are telomeres? Outline telomere wearing?

Answer 15

Telomeres = repetitive nucleotide sequences at the end of chromosomes - protect end of chromosome from decay and fusion with other chromosomes

Telomere wearing obviously removes this protective effect leading to a theory of ageing

Question 16

Outline epigenetic alterations in ageing

Answer 16

Epigenetic factors are those causing a heritable change in gene expression in the absence of change in DNA

DNA methylation at CpG dinucleotides
Histone modifications (acetylation)
Non coding RNAs (ncRNA)

Question 17

What’s the Hovarth clock of ageing?

Answer 17

Biochemical test based on DNA methylation at CPG dinucleotides to measure biological (vs chronological) age
It’s the only available method that measures biological age in different tissues

Question 18

What is proteostasis? Outline how a loss of it leads to ageing

Answer 18

Process by which cells control the abundance and folding of the proteome

In young/healthy tissues misfolded protein is disposed of by protein quality control systems
In ageing cells the protein quality control systems are overloaded = accumulation of misfolded proteins and loss of proteostasis

Question 19

Which diseases show loss of proteostasis?

Answer 19

Alzheimer’s and Parkinson’s

Appearance of non-native protein aggregates is a common feature of degenerative diseases

Question 20

What’s cellular senescence? What’s its primary purpose in healthy tissues?

Answer 20

A process that imposes permanent proliferative arrest on cells in response to various stressors, leading to formation of senescent cells with specific phenotypic characteristics

Purpose to prevent progress of damaged cells and trigger their removal

Question 21

How does cellular senescence link to other hallmarks of ageing and cancer?

Answer 21

Senescent cell accumulation = ageing

Cellular connection, progenitor exhaustion, intercellular communication, immune system

Question 22

Outline the stem cell theory of ageing

Answer 22

Stem cell exhaustion = inability of stem cells (or progenitor cells) to replenish the tissue of an organism

Exhaustion can be caused by decline in ability of stem cells to proliferate (senescence) or due to excessive proliferation leading to stem cell exhaustion and premature ageing

Question 23

Why does systolic blood pressure increase with age?

Answer 23

Collagen and calcium deposition and loss of elastic fibres in the medial layer of larger arteries = vessel diameter narrows and loss of stretchability means resistance increases

Question 24

Why can ageing increase the risk of left ventricular hypertrophy, chronic heart failure and atrial fibrillation?

Answer 24

VO2max declines with age - reduction in peak heart rate and pulmonary function

Cardiovascular performance during exercise is reduced - reduced cardiac B-adrenergic density and efficiency of B-adrenergic signalling

= reduction in physiological functional capacity

Question 25

What are some changes in GI structure with ageing?

Answer 25

Reduced liver size and blood flow
Reduced saliva production and impaired response to gastric mucosal injury
Reduced pancreatic mass and enzyme reserve
Decrease in effective colonic contractions
Decrease in gut associated lymphoid tissue

Question 26

What are some changes in GI function with ageing?

Answer 26

Reduced stomach acid production
Impaired acid clearance
Slowing of gastric emptying
Reduced absorption of vitamin D/Ca2+
Delay in colonic transit
Reduced insulin secretion
Reduced tensile strength of rectal and colonic walls

Question 27

What are some renal structural and functional changes with ageing?

Answer 27

Kidney size decreases, nephrons decrease
Glomerular basement membrane thickens
Increase in glomerular basement membrane permeability

Increase in glomerular basement membrane permeability = increased excretion of proteins (albumin)
GFR declines after 4th decade
Reduced kidney mass = reduced creatinine clearance

Question 28

Outline changes to bones with ageing

Answer 28

Reduced bone density -> osteoporosis
Reduced osteoclast formation -> reduced bone remodelling
Increased adipocyte formation in bone marrow
Slower healing of fractures
Decreased vitamin D absorption

Question 29

How do muscles change with age?

Answer 29

Muscle mass and strength declines with age
Distribution of muscle fibre type changes with age
Increased % of type I fibres in aged

Type I fibres = small, slow contracting, low tension output fibres

Sarcopenia = degenerative loss of skeletal muscle mass, quality and strength associated with age