Module 6: Ageing Flashcards
2 biological theories of ageing?
- Programmed Theory
- Error Theory
What is the programmed theory of ageing?
Considers ageing to have an internal clock
What is the error theory of ageing?
Considers ageing to be resultant of an accumulation of damage to essential macromolecules within cells, causing the demise of such cells and organs
What is senescence?
An irreversible block in cell proliferation; cells cease to divide
Maximum number of times somatic cells can divide?
Approximately 75-80
Three components of programmed theory of ageing?
- Programmed longevity theory
- Endocrine theory
- Immunological theory
What is programmed longevity theory?
Ageing is due to long-term genetic instability and changes in gene expression leading to senescence
What is endocrine theory?
Ageing is hormonally regulated
What is immunological theory?
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
Three components of error theory of ageing?
- Free radical theory
- DNA damage theory
- Wear and tear theory
What is free radical theory?
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
What is DNA damage theory?
DNA damage, via DNA mutations and breaks, overrides DNA repair occurring over time, thus contributing to genomic instability and the ageing process
What is wear and tear theory?
Ageing results from gradual deterioration of vital components of cells/tissues via ‘wear and tear’ over time
8 pillars of ageing?
- Cellular senescence
- Telomere shortening
- DNA damage/genomic instability
- Epigenetic drift
- Stem cell exhaustion
- Inflammaging
- Mitochondrial dysfunction
- Deregulated nutrient sensing
Why is senescence important?
Prevents propagation of mutated DNA to daughter cells, so acts as a natural barrier against cancer
Widely used markers of senscence?
- Increased levels of senescence-associated β-galactosidase
- Activation of genes: p16 and p14
Why does cancer still occur despite senescence?
Oncogenes override senescence programming and repress apoptosis, causing accumulation of mutated cells
Benefits of senescence? (5)
- Embryonic development
- Tissue regeneration
- Immunity
- Tumour suppression
- Wound healing
Negative effects of senescence? (3)
- Tissue regeneration
- Chronic inflammation
- Tumor promotion
How is ageing associated with senescence?
Ageing = senescent cells accumulate and build in number (so, if senescent cells eliminated, ageing may be reduced)
What are senolytics?
Small molecules, administered as drugs, that induce apoptosis of senescent cells by targeting their pro-survival pathways
What are telomeres?
Highly repetitive DNA sequences enclosing ends of chromosomes (shelterin complex)
Role of telomeres?
Highly protective against damage and fraying of DNA
What is telomerase?
Enzyme that maintains telomere length, which is generally not expressed in somatic cells
What impacts length of telomeres?
Length decreases with each cell division; thus, shortens over time
What is the main reason for ageing/cellular senescence?
DNA damage
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)
3 types of DNA damage?
- DNA mutations
- DNA breaks
- Chromosome translocations
4 types of DNA mutations?
- Silent mutation
- Missense mutation
- Nonsense mutation
- Frameshift mutation
What is a silent mutation?
A change in DNA sequence, but no effect on protein sequence
What is a missense mutation?
A change in DNA sequence causing amino acid substitution
What is a nonsense mutation?
Substitutes a stop codon for an amino acid, causing premature termination
What is a frameshift mutation?
Insertion/deletion of a nucleotide, changing all amino acids downstream from that sequence
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)
What are chromosome translocations?
When regions of chromosomes break apart, then translocate and fuse with other chromosomes
How are chromosome translocations detected?
Karyotyping or FISH (fluorescence in situ hybridisation -> fluorescent DNA probes)
Impact of senolytic agents upon idiopathic pulmonary fibrosis?
Improved walking
Impact of senolytic agents upon osteoarthritis?
Reduced cartilage destruction inflammation
Impact of senolytic agents upon diabetes?
Reduced organ dysfunction
What does increased DNA repair cause?
Increased longevity
Characteristic of people who live >100 years?
Higher levels of DNA repair enzymes
What are reactive oxygen species (ROS)?
Chemical reactive species; molecules comprising an oxygen atom and an unpaired electron
How are ROS produced?
Natural by-product of aerobic metabolism and formation of ATP
What factors increase ROS production?
Ionising radiation, UV, heat, pollutants, smoke, diet (fatty foods)
What detrimental effects do ROS have?
Responsible for >100 human diseases; induce ageing
Roles of ROS? (2)
Cell signalling and immunity
How do ROS cause ageing?
Attack and oxidise DNA, lipids, carbohydrates, and proteins
What is oxidative stress?
Imbalance between ROS and body’s ability to detoxify/counteract their damaging effects via antioxidants (e.g. glutathione)
What are progeroid syndromes?
Group of rare monogenic disorders that mimic physiological ageing
What are monogenic diseases?
Arise from a single gene mutation that affects DNA repair/nuclear structure
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)
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
What is epigenetics?
Change in gene expression; not dependent upon DNA sequence, but dependent on chemical modifications
What is heterchromatin?
Highly compacted DNA, transcriptionally inactive (‘h’=on ‘h’old)
What is euchromatin?
Loosely packed DNA, transcriptionally active (‘e’=’e’nergetic)
What is epigenetic drift?
Divergence of epigenome due to age, which is influenced by environmental exposures
What impacts epigenetics?
Environmental exposures: e.g. diet, chemical exposure, exercise, social activities, moods, mental states, ancestors, and parents
2 main forms of epigenetic drift that instigate ageing?
- Global DNA hypomethylation
- Histone modifications
Correlation between heterochromatin/euchromatin and ageing?
Decrease in heterochromatin and increase in euchromatin
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
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
Role of stem cells?
Differentiate and produce specialised cells, thus generating new tissue by replacing often damaged cells
Unique properties of stem cells? (4)
Uncommitted, immature, high degree of plasticity, and self-renew
Single major driver of ageing?
Loss of stem cell number and function
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
Causes of changes to stem cells due to ageing?
DNA damage, telomere shortening, senescence, abnormal cellular signalling/metabolism, epigenetic changes
Where do neural stem cells generally reside?
Subventricular zone and hippocampus
What neural cells can stem cells differentiate into?
Neurons, astrocytes, oligodendrocytes
What blood cells can haematopoietic stem cells differentiate into?
Platelets, erythrocytes, myeloid cells, lymphoid cells
Where do haematopoietic stem cells generally reside?
Red bone marrow
What occurs to haematopoietic stem cells with age, and what effects does this have?
- Increased haematopoietic stem cells and myeloid cells
- Decreased lymphoid cells
Where do mesenchymal stem cells generally reside?
Bone/bone marrow
What bone cells can mesenchymal stem cells differentiate into?
Adipocytes, osteoblasts, chondrocytes
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
Where do muscle stem cells generally reside?
Skeletal muscle; surrounding muscle fibres
What occurs to muscle stem cells with age, and what effects does this have?
Decreased differentiation = reduction in muscle repair/mass
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
What stimulates growth hormone secretion?
When food is ingested and broken down, dietary factors stimulate release of GH into anterior pituitary
Role of growth hormone?
Stimulates production of IGF-1
Role of IGF-1 (insulin-like growth factor 1)?
Informs cells glucose is present, causing them to take up said glucose = growth
What occurs with excessive IGF-1 stimulation?
Causes more metabolism and proliferation, promoting DNA damage and hence ageing
Impact of cutting calories (diets) upon ageing?
Increase longevity
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
What are sirtuins?
Enzymes that repair/modify DNA and proteins, causing genetic stability and increasing metabolic efficiency
What is autophagy?
- ‘Self-eating’
- Homeostatic pathway in which cellular components that have worn out are degraded and recycled, stimulating development of new organelles
Impact of ageing upon autophagy?
Autophagy declines with age, causing accumulation of dysfunctional organelles and macromolecules
What is inflammaging?
Chronic, sterile, low-grade inflammation that develops with age, leading to cell and tissue destruction
3 layers of skin?
- Epidermis (avascular; epithelial cells)
- Dermis (CT; collagen/elastin fibres)
- Hypodermis (fat cells)
What occurs to skin layers with age?
- Lose layer of fat cells in hypodermis
- Lose collagen and elastin fibres in dermis
- Decrease in vascularity
What does age-related degrade in epidermis/dermis/hypodermis cause?
Loss of skin elasticity (sagging and wrinkling)
What does age-related lack of vascularity in skin cause?
- Accumulation of waste products
- Less nutrients/O2 going to skin cells
- Less effective thermoregulation
What does age cause to hair?
Melanocytes lost in hair follicles due to undergoing cell cycle arrest, thus leading to grey, dry, thinning hair
What is photoageing?
Degeneration of skin in proportion to UV exposure (skin spots, skin cancer, wrinkling)
What body system degenerates the least with age?
Endocrine system
Effects of ageing upon endocrine system?
- Reproductive/growth/thyroid hormones decline; release and secretion rates slow
- Target cell sensitivity decline
Why is Type II diabetes more common with age?
Decreased insulin sensitivity = accumulation of glucose in blood
Difference in brain mass with age?
Brain weighs 50% less by age 75
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
What aspect of intellectual function suffers the most with age?
Short-term memory
Effect of ageing upon bones?
Decrease in bone mass/bone mineral density (osteopenia)
Effect of ageing upon bone cells?
Osteoblasts less active than osteoclasts
Why is there less bone growth/formation with age?
- OBs < OCs
- Sex hormones (estrogen (F) and testosterone (M)) trigger less bone growth
Why are joint diseases more commonplace with age?
Less abundant synovial fluid, thin/absent articular cartilage, narrowed joint space, formation of bone spurs
What is muscle atrophy?
Replacement of muscle with adipose tissue (fat)
Impact of ageing upon composition of muscle cells?
Have fewer myofibrils and mitrochondria
Impact of ageing upon production of blood cells?
Dramatic reduction in erythropoiesis and leukopoiesis
What is anaemia?
Lack of or dysfunctional RBCs, leading to less O2 to tissues
What is coronary atherosclerosis?
Plaque build-up in heart blood vessels, potentially leading to angina, infarction, heart block
What are varicose veins?
Bulging, enlarged veins, that occur due to vessels stiffening and not expanding effectively, because of weaker valves; can increase BP
Impact of ageing on heart structure, SV, CO?
- Thinner heart walls
- Decreased SV and CO
Main effect of ageing upon respiratory system? Why?
Declining pulmonary ventilation, because costal cartilage is less flexible and there is reduced capacity for expansion
Effect of ageing upon mucociliary escalator?
Mucociliary clearance compromised, so less able to clear lungs of irritants/pathogens, rendering more susceptible to respiratory infection
Why does ageing cause reduced gas exchange?
Lungs have less elastic tissue and fewer alveoli, so less surface area
Extent of renal atrophy that occurs with age?
Kidneys 40% smaller by age 90 due to a loss of nephrons; impaired filtration rate
Effect of ageing upon fluid balance?
Less effective fluid balance -> less responsive to ADH -> sense of thirst reduced, dehydration commonplace
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
Effect of ageing upon females systems of elderly women?
Sphincters weakened, causing incontinence; nervous system can impact micturition reflex
Effect of ageing upon saliva?
Saliva reduced, so dental health negatively affected because saliva contains enzymes that kill pathogens in the oral cavity
Effects of ageing upon nose and mouth?
Reduced sense of smell/taste, gum recession
Effects of ageing upon esophagus?
Decrease in peristalsis and sphincters lose tension, causing acid reflux
Effects of ageing upon liver?
Shrinkage of liver -> less hepatocytes -> less able to detoxify substances
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
Effect of ageing upon pancreas?
Decreased secretion of pancreatic protease and lipase, meaning less nutrients
Effect of ageing upon small intestine?
Gut-associated lymphoid tissue capacity compromised, decreasing peristalsis
Effect of ageing upon large intestine?
Slowed peristalsis, causing constipation
What is lifespan?
Maximum attainable age
What is life expectancy?
Average length of life in a given population
