Module 6: Ageing Flashcards
1
Q
2 biological theories of ageing?
A
- Programmed Theory
- Error Theory
2
Q
What is the programmed theory of ageing?
A
Considers ageing to have an internal clock
3
Q
What is the error theory of ageing?
A
Considers ageing to be resultant of an accumulation of damage to essential macromolecules within cells, causing the demise of such cells and organs
3
Q
What is senescence?
A
An irreversible block in cell proliferation; cells cease to divide
3
Q
Maximum number of times somatic cells can divide?
A
Approximately 75-80
4
Q
Three components of programmed theory of ageing?
A
- Programmed longevity theory
- Endocrine theory
- Immunological theory
5
Q
What is programmed longevity theory?
A
Ageing is due to long-term genetic instability and changes in gene expression leading to senescence
6
Q
What is endocrine theory?
A
Ageing is hormonally regulated
7
Q
What is immunological theory?
A
Ageing is due to the immune system being programmed to decline over time thus becoming susceptible to infection and causing low-grade, chronic, persistent inflammation
8
Q
Three components of error theory of ageing?
A
- Free radical theory
- DNA damage theory
- Wear and tear theory
9
Q
What is free radical theory?
A
Ageing is the cumulative result of oxidative damage to cells/tissues, that arises primarily as a result of free radicals being a byproduct of aerobic metabolism
10
Q
What is DNA damage theory?
A
DNA damage, via DNA mutations and breaks, overrides DNA repair occurring over time, thus contributing to genomic instability and the ageing process
11
Q
What is wear and tear theory?
A
Ageing results from gradual deterioration of vital components of cells/tissues via ‘wear and tear’ over time
12
Q
8 pillars of ageing?
A
- Cellular senescence
- Telomere shortening
- DNA damage/genomic instability
- Epigenetic drift
- Stem cell exhaustion
- Inflammaging
- Mitochondrial dysfunction
- Deregulated nutrient sensing
13
Q
Why is senescence important?
A
Prevents propagation of mutated DNA to daughter cells, so acts as a natural barrier against cancer
14
Q
Widely used markers of senscence?
A
- Increased levels of senescence-associated β-galactosidase
- Activation of genes: p16 and p14
15
Q
Why does cancer still occur despite senescence?
A
Oncogenes override senescence programming and repress apoptosis, causing accumulation of mutated cells
16
Q
Benefits of senescence? (5)
A
- Embryonic development
- Tissue regeneration
- Immunity
- Tumour suppression
- Wound healing
17
Q
Negative effects of senescence? (3)
A
- Tissue regeneration
- Chronic inflammation
- Tumor promotion
18
Q
How is ageing associated with senescence?
A
Ageing = senescent cells accumulate and build in number (so, if senescent cells eliminated, ageing may be reduced)
19
Q
What are senolytics?
A
Small molecules, administered as drugs, that induce apoptosis of senescent cells by targeting their pro-survival pathways
20
Q
What are telomeres?
A
Highly repetitive DNA sequences enclosing ends of chromosomes (shelterin complex)
21
Q
Role of telomeres?
A
Highly protective against damage and fraying of DNA
22
Q
What is telomerase?
A
Enzyme that maintains telomere length, which is generally not expressed in somatic cells
23
What impacts length of telomeres?
Length decreases with each cell division; thus, shortens over time
24
What is the main reason for ageing/cellular senescence?
DNA damage
25
3 main reasons for DNA damage?
- External insults (e.g. UV, chemicals, pollutants, infections)
- Internal insults (e.g. reactive oxygen species (ROS), which are metabolic by-products)
- DNA replication/proliferation (i.e. rapid proliferation = increased DNA damage, whilst senescence/apoptosis decrease)
26
3 types of DNA damage?
- DNA mutations
- DNA breaks
- Chromosome translocations
27
4 types of DNA mutations?
- Silent mutation
- Missense mutation
- Nonsense mutation
- Frameshift mutation
28
What is a silent mutation?
A change in DNA sequence, but no effect on protein sequence
29
What is a missense mutation?
A change in DNA sequence causing amino acid substitution
30
What is a nonsense mutation?
Substitutes a stop codon for an amino acid, causing premature termination
31
What is a frameshift mutation?
Insertion/deletion of a nucleotide, changing all amino acids downstream from that sequence
32
6 types of DNA breaks?
- Single-stranded break
- Mis-match (wrong nucleotide, doesn't connect)
- Damaged base
- Double-stranded break
- Intra-strand crosslink (nucleotide connects twice to one strand; loop)
- Inter-strand crosslink (one nucleotide connects to both strands)
33
What are chromosome translocations?
When regions of chromosomes break apart, then translocate and fuse with other chromosomes
34
How are chromosome translocations detected?
Karyotyping or FISH (fluorescence in situ hybridisation -> fluorescent DNA probes)
35
Impact of senolytic agents upon idiopathic pulmonary fibrosis?
Improved walking
36
Impact of senolytic agents upon osteoarthritis?
Reduced cartilage destruction inflammation
37
Impact of senolytic agents upon diabetes?
Reduced organ dysfunction
38
What does increased DNA repair cause?
Increased longevity
39
Characteristic of people who live >100 years?
Higher levels of DNA repair enzymes
40
What are reactive oxygen species (ROS)?
Chemical reactive species; molecules comprising an oxygen atom and an unpaired electron
41
How are ROS produced?
Natural by-product of aerobic metabolism and formation of ATP
42
What factors increase ROS production?
Ionising radiation, UV, heat, pollutants, smoke, diet (fatty foods)
43
What detrimental effects do ROS have?
Responsible for >100 human diseases; induce ageing
44
Roles of ROS? (2)
Cell signalling and immunity
45
How do ROS cause ageing?
Attack and oxidise DNA, lipids, carbohydrates, and proteins
46
What is oxidative stress?
Imbalance between ROS and body's ability to detoxify/counteract their damaging effects via antioxidants (e.g. glutathione)
47
What are progeroid syndromes?
Group of rare monogenic disorders that mimic physiological ageing
48
What are monogenic diseases?
Arise from a single gene mutation that affects DNA repair/nuclear structure
49
Symptoms of Hutchinson Gilford Progeria Syndrome?
- Rapid onset of ageing from childhood
- Disproportionately large head, eyes, and ears, wrinkled skin
- Growth retardation and sparse hair
- increased incidence of cardiovascular pathology (e.g. heart attack/stroke)
50
Cause of Hutchinson Gilford Progeria Syndrome?
Genetic mutation in LMNA gene causes abnormal variant of lamin A, instigating an unstable/damaged nuclear envelope and premature cell death
51
What is epigenetics?
Change in gene expression; not dependent upon DNA sequence, but dependent on chemical modifications
52
What is heterchromatin?
Highly compacted DNA, transcriptionally inactive ('h'=on 'h'old)
53
What is euchromatin?
Loosely packed DNA, transcriptionally active ('e'='e'nergetic)
54
What is epigenetic drift?
Divergence of epigenome due to age, which is influenced by environmental exposures
55
What impacts epigenetics?
Environmental exposures: e.g. diet, chemical exposure, exercise, social activities, moods, mental states, ancestors, and parents
56
2 main forms of epigenetic drift that instigate ageing?
- Global DNA hypomethylation
- Histone modifications
57
Correlation between heterochromatin/euchromatin and ageing?
Decrease in heterochromatin and increase in euchromatin
58
What is global DNA hypomethylation, and its correlation with ageing?
- DNA methylation associated with gene silencing and heterochromatin
- Low methylation ('hypo'methylation) causes an open chromatin structure, increasing formation of euchromatin, leading to genetic instability via DNA damage
- Aged cells lose cell type and gene expression due to hypomethylation
59
What are histone modifications, and their correlation with ageing?
- More than 30 types of histone modifications
- As we age, incorporation of different histone variants into DNA leads to opening of chromatin structure (increased formation of euchromatin), meaning cells are exposed to DNA damage
60
Role of stem cells?
Differentiate and produce specialised cells, thus generating new tissue by replacing often damaged cells
61
Unique properties of stem cells? (4)
Uncommitted, immature, high degree of plasticity, and self-renew
62
Single major driver of ageing?
Loss of stem cell number and function
63
3 main possible changes to stem cells due to ageing?
- Reduced potential to differentiate -> less specialised cells
- Reduced potential to proliferated -> less stem cells -> less specialised cells
- Enhanced potential to differentiate -> less stem cells
64
Causes of changes to stem cells due to ageing?
DNA damage, telomere shortening, senescence, abnormal cellular signalling/metabolism, epigenetic changes
65
Where do neural stem cells generally reside?
Subventricular zone and hippocampus
66
What neural cells can stem cells differentiate into?
Neurons, astrocytes, oligodendrocytes
67
What blood cells can haematopoietic stem cells differentiate into?
Platelets, erythrocytes, myeloid cells, lymphoid cells
68
Where do haematopoietic stem cells generally reside?
Red bone marrow
69
What occurs to haematopoietic stem cells with age, and what effects does this have?
- Increased haematopoietic stem cells and myeloid cells
- Decreased lymphoid cells
70
Where do mesenchymal stem cells generally reside?
Bone/bone marrow
71
What bone cells can mesenchymal stem cells differentiate into?
Adipocytes, osteoblasts, chondrocytes
72
What occurs to mesenchymal stem cells with age, and what effects does this have?
- Increased adipocytes = more bone marrow fat accumulates
- Decreased osteoblasts = less trabecular/spongy bone
73
Where do muscle stem cells generally reside?
Skeletal muscle; surrounding muscle fibres
74
What occurs to muscle stem cells with age, and what effects does this have?
Decreased differentiation = reduction in muscle repair/mass
75
What is the somatotropic axis?
- One of the main hormone pathways
- Involves growth hormone (GH) and IGF-1; mutations in these genes expand lifespan
- Minimal activation of pathway promotes lifespan, maximum activation of pathway decreases lifespan
76
What stimulates growth hormone secretion?
When food is ingested and broken down, dietary factors stimulate release of GH into anterior pituitary
77
Role of growth hormone?
Stimulates production of IGF-1
78
Role of IGF-1 (insulin-like growth factor 1)?
Informs cells glucose is present, causing them to take up said glucose = growth
79
What occurs with excessive IGF-1 stimulation?
Causes more metabolism and proliferation, promoting DNA damage and hence ageing
80
Impact of cutting calories (diets) upon ageing?
Increase longevity
81
Why do diets slow ageing?
- Reduce GH/IGF-1 pathway, reducing metabolism/cell growth and hence DNA damage
- Sirtuins activated due to nutrient scarcity, increasing metabolic efficiency and thus genomic stability
- Activates autophagy
82
What are sirtuins?
Enzymes that repair/modify DNA and proteins, causing genetic stability and increasing metabolic efficiency
83
What is autophagy?
- 'Self-eating'
- Homeostatic pathway in which cellular components that have worn out are degraded and recycled, stimulating development of new organelles
84
Impact of ageing upon autophagy?
Autophagy declines with age, causing accumulation of dysfunctional organelles and macromolecules
85
What is inflammaging?
Chronic, sterile, low-grade inflammation that develops with age, leading to cell and tissue destruction
86
3 layers of skin?
1. Epidermis (avascular; epithelial cells)
2. Dermis (CT; collagen/elastin fibres)
3. Hypodermis (fat cells)
87
What occurs to skin layers with age?
- Lose layer of fat cells in hypodermis
- Lose collagen and elastin fibres in dermis
- Decrease in vascularity
88
What does age-related degrade in epidermis/dermis/hypodermis cause?
Loss of skin elasticity (sagging and wrinkling)
89
What does age-related lack of vascularity in skin cause?
- Accumulation of waste products
- Less nutrients/O2 going to skin cells
- Less effective thermoregulation
90
What does age cause to hair?
Melanocytes lost in hair follicles due to undergoing cell cycle arrest, thus leading to grey, dry, thinning hair
91
What is photoageing?
Degeneration of skin in proportion to UV exposure (skin spots, skin cancer, wrinkling)
92
What body system degenerates the least with age?
Endocrine system
93
Effects of ageing upon endocrine system?
- Reproductive/growth/thyroid hormones decline; release and secretion rates slow
- Target cell sensitivity decline
94
Why is Type II diabetes more common with age?
Decreased insulin sensitivity = accumulation of glucose in blood
95
Difference in brain mass with age?
Brain weighs 50% less by age 75
96
Effects of ageing upon nervous system? (4)
- Cerebral and neural atrophy (loss of brain matter)
- Neurons accumulate waste product (lipofuscin)
- Degeneration of myelin, as it becomes patchy, thus slowing signals
- Reduced neurotransmitter production
97
What aspect of intellectual function suffers the most with age?
Short-term memory
98
Effect of ageing upon bones?
Decrease in bone mass/bone mineral density (osteopenia)
99
Effect of ageing upon bone cells?
Osteoblasts less active than osteoclasts
100
Why is there less bone growth/formation with age?
- OBs < OCs
- Sex hormones (estrogen (F) and testosterone (M)) trigger less bone growth
101
Why are joint diseases more commonplace with age?
Less abundant synovial fluid, thin/absent articular cartilage, narrowed joint space, formation of bone spurs
102
What is muscle atrophy?
Replacement of muscle with adipose tissue (fat)
103
Impact of ageing upon composition of muscle cells?
Have fewer myofibrils and mitrochondria
104
Impact of ageing upon production of blood cells?
Dramatic reduction in erythropoiesis and leukopoiesis
105
What is anaemia?
Lack of or dysfunctional RBCs, leading to less O2 to tissues
106
What is coronary atherosclerosis?
Plaque build-up in heart blood vessels, potentially leading to angina, infarction, heart block
107
What are varicose veins?
Bulging, enlarged veins, that occur due to vessels stiffening and not expanding effectively, because of weaker valves; can increase BP
108
Impact of ageing on heart structure, SV, CO?
- Thinner heart walls
- Decreased SV and CO
109
Main effect of ageing upon respiratory system? Why?
Declining pulmonary ventilation, because costal cartilage is less flexible and there is reduced capacity for expansion
110
Effect of ageing upon mucociliary escalator?
Mucociliary clearance compromised, so less able to clear lungs of irritants/pathogens, rendering more susceptible to respiratory infection
111
Why does ageing cause reduced gas exchange?
Lungs have less elastic tissue and fewer alveoli, so less surface area
112
Extent of renal atrophy that occurs with age?
Kidneys 40% smaller by age 90 due to a loss of nephrons; impaired filtration rate
113
Effect of ageing upon fluid balance?
Less effective fluid balance -> less responsive to ADH -> sense of thirst reduced, dehydration commonplace
114
Effect of ageing upon urinary systems of elderly males?
80% of aged men have benign prostate enlargement, making it harder to control bladder and void urine, causing urine retention
115
Effect of ageing upon females systems of elderly women?
Sphincters weakened, causing incontinence; nervous system can impact micturition reflex
116
Effect of ageing upon saliva?
Saliva reduced, so dental health negatively affected because saliva contains enzymes that kill pathogens in the oral cavity
117
Effects of ageing upon nose and mouth?
Reduced sense of smell/taste, gum recession
118
Effects of ageing upon esophagus?
Decrease in peristalsis and sphincters lose tension, causing acid reflux
119
Effects of ageing upon liver?
Shrinkage of liver -> less hepatocytes -> less able to detoxify substances
120
Effect of ageing upon stomach?
Stomach wall's elasticity reduced -> decreased bicarbonate and gastromucosal production, as well as delayed gastric emptying of chyme; also gastric mucosa atrophies -> less HCl and intrinsic factor
121
Effect of ageing upon pancreas?
Decreased secretion of pancreatic protease and lipase, meaning less nutrients
122
Effect of ageing upon small intestine?
Gut-associated lymphoid tissue capacity compromised, decreasing peristalsis
123
Effect of ageing upon large intestine?
Slowed peristalsis, causing constipation
124
What is lifespan?
Maximum attainable age
125
What is life expectancy?
Average length of life in a given population
