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Block 3 > Ageing > Flashcards

Ageing Flashcards

1
Q

What is ageing?

A

Gradual decline in normal physiological functions and integrity in a time-dependent manner affecting all biological systems such as molecular interactions, cellular function, tissue structure and systemic physiological homeostasis

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2
Q

Why are people more likely to die in old age?

A

Decreased ability to cope with stressors of the environment leading to increased incidence of age-related diseases and conditions and increased vulnerability to death

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3
Q

What is Gerontology?

A

Scientific study of the process and problems of ageing

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4
Q

What old age classifications exist?

A

Young-old: people in their 60s-early 70s who are active and healthy

Old: people in their
70s-80s with chronic illnesses slowing down due to symptoms

Oldest-old: people who are often sick, disabled and perhaps near death

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5
Q

What is happening to our population in terms of ageing?

A

We are an ageing population i.e. there is a higher percentage of people living in older age than there was previously

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6
Q

What types of diseases/conditions are ageing patients more at risk of?

A

Shift from acute to chronic diseases e.g. NCDs and disability:

  • Neurodegenerative diseases e.g. dementia
  • Osteoporosis (=falls)
  • Frailty
  • Hearing loss
  • Incontinence
  • Diabetes
  • Depression
  • Cancer
  • CVD
  • Cerebrovascular disease
  • COPD
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7
Q

What is a chronic condition?

A

Conditions that persist and require on-going management over a period of years or decades - not normally transmissible directly from one person to another

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8
Q

What is a non-communicable disease (NCD)? Why do they predominantly affect older adults?

A

Diseases characterised by slow progression and long duration thus, the clinical manifestation and burden will inevitably disproportionally affect older adults

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9
Q

Why is ageing and associated illness relevant to the healthcare profession?

A

Multimorbidity increases in the elderly and a person with multiple chronic conditions has more complex treatment needs than a person with one condition so training and investment must go into the care and management of them sufficiently increasing costs

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10
Q

What is the difference between lifespan and life expectancy?

A

Lifespan is the max length of time an organism is expected or known to survive e.g. 125yrs in humans HOWEVER, life expectancy is the average length of time an organism is expected to live e.g. ~80yrs for UK

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11
Q

What is health span?

A

Percentage of individuals life during which they are generally in good health - has not been improved in conjunction with lifespan

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12
Q

What can be targeted to reduce diseases in the aging population?

A

Target MOLECULAR and PHYSIOLOGICAL changes associated with normal ageing

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13
Q

How do we define a hallmark of ageing?

A
  1. It should manifest during normal healthy ageing
  2. Its experimental aggravation should accelerate ageing causing premature ageing
  3. Its experimental improvement should slow down ageing rate and enhance health ageing
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14
Q

What are the 3 subheadings of the 9 hallmarks of ageing?

A
  1. Primary: cause of damage (-ve)
  2. Antagonistic: response to damage (+ve/-ve)
  3. Integrative: link to phenotype of ageing (physiological changes)
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15
Q

What determines if a cellular hallmark is positive or negative?

A 
\+ve = acute and short-term
-ve = long-term and chronic accelerating ageing
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16
Q

What are the 4 primary cellular hallmarks of ageing?

A
  1. Genomic instability: increased damage/mutations and no repair
  2. Telomere attrition: no replication
  3. Epigenetic alteration: loss of translation/transcription
  4. Loss of proteostasis: misfolding/structural changes
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17
Q

What are the 3 antagonistic cellular hallmarks of ageing?

A
  1. Mitochondrial dysfunction: no energy
  2. Deregulated nutrient sensing: reducing nutrient uptake to reduce overload to damaged cells
  3. Cellular senescence: frozen in time
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18
Q

What are the 2 integrative cellular hallmarks of ageing?

A
  1. Stem cell exhaustion: no new cells

2. Altered communication: no co-ordination

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19
Q

How can a change in the genetic code cause genomic instability?

A

DNA lesions e.g. single base mutations, translocations, duplications or inversions can occur in the genetic material due to exogenous (chemicals, UV/IR) or endogenous (ROS, replication errors, spontaneous reactions) damage - this can sometimes be repaired by the repair pathway

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20
Q

What are reactive oxygen species (ROS)?

A

Highly reactive molecules with the ability to oxidize cell structures and biomolecules and consequently, cause DNA damage, lipid peroxidation and protein modification that can harm the cell integrity

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21
Q

How can structural changes cause genomic instability?

A

Changes in lamins due to ROS (free radical theory): proteins providing structural function and transcriptional regulation in the cell nucleus as they interact with membrane-associated proteins to form the nuclear lamina on the interior of the nuclear envelop providing a scaffold for chromatin/protein complexes and condensing DNA regulating genomic stability and regulation so lamin instability can impact DNA/chromatin packing and what genes are active/inactive (genes associated with lamins not heavily expressed normally)

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22
Q

What is the free radical theory? Why is the evidence against this theory?

A

Ageing is caused by accumulation of damage inflicted by ROS HOWEVER, anti-oxidant gene KO in mice has no impact on lifespan

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23
Q

What are telomeres?

A

Repetitive nucleotide sequences at the end of chromosomes that protect the end of chromosomes from decay and fusion with other chromosomes - get shorter when cells divide and signals to damaged cells to stop cell division preventing genomic instability and mutations

24
Q

What is the telomere theory of ageing? What is the evidence against this?

A

Ageing occurs as telomeres get shorter and shorter HOWEVER, neurons do not lose the length of their telomeres but they still age so there is a lack of good correlation with age

25
Q

What are epigenetic alterations?

A

Factors causing a heritable change in gene expression in the ABSENCE of change in the DNA sequence itself e.g. DNA methylation at CpG dinucleotides, histone modifications (acetylation etc.) and non-coding RNAs (ncRNA)

26
Q

What is DNA methylation at CpG dinucleotides?

A

Cytosine at 5th carbon atom next to guanine base becomes methylated via DNMT/SAM which can influence DNA-protein integrations as TF cannot bind to promoter preventing gene expression i.e. no change in DNA sequence but change in gene expression

27
Q

What epigenetic drifts occur with age?

A

DNA has its own unique methylation profile which drifts as we age changing gene functioning/regulation causing genomic instability as transposable elements start to become expressed

28
Q

What is a transposable element/transposon (TE)?

A

DNA sequence that can change its position within a genome, sometimes creating or reversing mutations and altering the cells genetic identity and genome size

29
Q

What is aging rate influenced by?

A

Environmental factors communicating with the genome via epigenetic markers AS WELL AS genetic factors - this is why monozygotic twins do not age in an identical way

30
Q

What is the Horvath clock of ageing?

A

The only available method that measure biological (not chronological) age in various tissues utilising methylation markers on CpG sites to determine the methylation profile of that tissue - significant enrichment for cell death/survival, growth/proliferation, organismal/tissue development and cancer (error rate ~3yrs) - potential in predicted success of interventions to slow ageing

31
Q

What is proteostasis?

A

Protein homeostasis: process by which cells control the abundance and folding (3D functional structure) of the proteome

32
Q

How is proteostasis lost in ageing?

A

Young/healthy cells dispose of misfolded proteins by PQC systems but in ageing cells, this load may overwhelm PQC capacity resulting in a accumulation of misfolded proteins and loss of proteostasis - appearance of non-native protein aggregates is a common feature of aged cells and certain age-associated diseases e.g. AD, PD

33
Q

What is cellular senescence?

A

Process that imposes permanent proliferative arrest on cells in response to various stressors leading to formation of senescent cells with specific phenotypic characteristics to prevent progress of damaged cells and to trigger their removal by immune system

34
Q

What happens to cellular senescence with ageing?

A

Accumulation of senescent cells can reflect increase in rate of production or decreased clearance (e.g. weakened immune response and reduced replacement by progenitor cells referred to as = exhaustive regenerative capacity) producing more SASP(proinflammatory cytokines and matrix MMPs) and immune system activation causing high-dose chronic inflammation

35
Q

If senescent cells accumulate, what can occur as a result?

A
  1. Ageing (perhaps prematurely)

2. Cancer (removal of proliferation break)

36
Q

What is stem or progenitor cell exhaustion?

A

Inability of stem cells or progenitor cells to replenish the tissue of an organism = stem cell theory of ageing - due to decline in stem cell ability to proliferate due to stem cell senescence OR excessive proliferation

37
Q

What happens to the CNS structure with ageing?

A
  1. Decline in brain mass/weight
  2. Fewer synaptic contacts and nerve cells
  3. Reduced CBF
  4. Altered neurotransmitters: decreased DA, ACh + 5-HT but increased enzyme activity of choline acetyltransferase
38
Q

What happens to the CNS function with ageing?

A
  1. Intellect maintained until at least 80 then slowing in central processing (takes longer to perform tasks)
  2. Verbal skills maintained under 70 then gradual decrease in vocab, increased semantic error and abnormal prosody
  3. Mental activity: difficulty learning (esp. languages) and forgetfulness in non-critical areas (does not impair recall of important memories or effector function
39
Q

What happens to the PNS with ageing?

A
  1. Decrease spinal MNs
  2. Axon atrophy affecting muscles 1st
  3. Nerve conduction slows
  4. Reduced vibratory sensation esp. in feet (large myelinated fibres)
  5. Reduced thermal sensitivity e.g. pain/temp (small unmyelinated fibres)
  6. Loss of myelinated/unmyelinated nerve fibres due to decreased expression of major myelin proteins
40
Q

What different types of arteries exist?

A
  1. Elastic: large e.g. aorta
  2. Muscular: medium
  3. Arterioles: small
41
Q

What happens to the CVS with ageing?

A
  1. Thickening/stiffening of large arteries due to collagen/Ca2+ deposition + loss of elastic fibres in medial layer: increased SBP and decline in DBP after 6th decade
  2. L ventricle modest concentric wall thickening due to progressive myocyte loss + compensating mild hypertrophy
  3. Reduced sensitivity to sympathetic stimuli compromising myocardial contractility/pumping ability
  4. Max aerobic capacity declines due to reduction in peak HR + peripheral O2 utilisation
  5. CV performance reduced due to deficits in β-adrenergic receptor density and postsynaptic signalling efficiency
42
Q

What overall happens to the CVS as a result of ageing?

A

Reduction in physiological functional capacity which results in loss of independence as ageing increases risk of L ventricular hypertrophy, chronic HF and AF

43
Q

What GI system structural changes occur with age?

A
  1. Decreased liver size and blood flow (drug metabolism affected)
  2. Impaired response to gastric mucosal injury + reduced saliva production
  3. Reduced pancreatic mass + enzyme reserve
  4. Decrease in effective colonic contractions
  5. Decrease in GALT
44
Q

What GI system functional changes occur with age?

A
  1. Reduced stomach acid production
  2. Impaired acid clearance
  3. Slowing of gastric emptying
  4. Nutrition absorption decrease (Ca2+, vit D)
  5. Delay in colonic transit
  6. Reduced rectal wall sensitivity
  7. Reduced tensile strength in muscle of colonic wall
  8. Reduced insulin secretion
45
Q

What structural changes occur to the kidneys with ageing?

A
  1. Kidney size decreases
  2. Nephron no. and size decreases
  3. Glomerular no. and shape changes (simplification: reduced glomerular capillary loops)
  4. GBM thickening making it stiffer and more fragile
  5. Increase in GBM permeability
46
Q

What functional changes occur to the kidneys with ageing?

A
  1. Increase in GBM permeability causes increased urinary excretion of proteins inc. albumin
  2. GFR is maintained until the 4th decade where is decline per decade thereafter
  3. Reduced kidney muscle mass results in CrCl reduction so less Cr excretion daily in urine
  4. RBF maintained until 4th decade whereby it declines 10% per decade
47
Q

What happens to the bones with ageing?

A
  1. Bone (trabecular/cortical) density reduces
  2. Reduced osteoclast bone formation
  3. Reduced bone remodelling
  4. Increased adipocyte formation in bone marrow
  5. Slower fracture healing
  6. Decreased Vit absorption (Vit D needed for osteoblastic bone formation)
  7. Increased bone loss leading to loss of bone height (stooping)
  8. Reduced bone density + micro-architectural bone deterioration (osteoporosis and falls)
48
Q

What happens to joints with ageing?

A
  1. Reduced thickness of articular cartilage
  2. Reduction in no. of chondrocytes (exhibit features similar to senescent phenotypes impairing their abilities)
  3. Excessive collagen cross-linking leading to increased stiffness and brittleness of collagen disordering the cartilage matrix
49
Q

What is the most abundant matrix protein in cartilage?

A

Type II collagen

50
Q

What is the function of chondrocytes?

A

Maintain cartilage homeostasis in part through production of ECM components

51
Q

What happens to muscles with ageing?

A
  1. Skeletal muscle mass/strength/quality decline (sarcopenia)
  2. Distribution of fibre type changes
  3. Increased % of type I fibres compared to type II
  4. Type II fibres decrease BMR and there is redistribution of fat depots + infiltration into muscle bundles
52
Q

What is the difference between type I and II muscle fibres?

A

Type I: small, slow-contracting, low tension output fibres that are highly resistant to fatigue with many mitochondria and aerobic enzymes for energy production

Type II: larger, faster contracting fibres that produce large tension output but fatigue quickly

53
Q

How can healthy ageing be promoted?

A 
Stem-cell-based therapies
Anti-inflammatory drugs and blood-borne rejuvenation factors
Elimination of damaged cells
Telomerase reactivation
Epigenetic drugs
Activation of chaperones and proteolytic systems
Dietary restriction 
Mitohormetics/mitophagy
Clearance of senescent cells
54
Q

What affects the rate of epigenetic drift?

A 
Diet
Diurnal/seasonal correlations
Disease exposure
Toxic chemicals
Drugs of abuse
Financial status
Exercise
Microbiome
Therapeutic drugs
Alternative medicine
Social interactions
Psychological state
55
Q

The more regulated a person’s epigenome becomes:

A

The more prematurely they will age and the higher disease risk they will have

56
Q

How can sarcopenia be reversed?

A

If high intensity exercise is maintained

Block 3 (40 decks)

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