WEEK 2: cell ageing and cell death Flashcards
what are the two biological theories of ageing?
- the programmed theory: ageing has an internal clock
- error theory (damage) : ageing is a result of internal/external assaults that damage cells and organs
what is cellular senescence (pillar of ageing)
the irreversible block in proliferation (the process in which cells cease to divide)
‘zombie cells’
What is the importance of cellular senescence?
- it ensures the cell corrects DNA mutations by stopping it from dividing
-hence prevents the accumulation of cells with damaged DNA that can be cancerous
What are the benefits of senescent cells?
- used in wound healing and tissue regeneration by expressing cytokines that aid in tissue remodelling
-when cells become infected, senescence stops the division of the cell and the virus cannot survive
-they activate the innate immune system and aid in clearance of infected cells - they are essential for tumor suppression
why are senescent cells harmful later in life?
- the accumulation of senescent cells can stimulate angiogenesis - the formation of new blood vessels
-it can stimulate tumour growth by the secretion of senescence associated inflammatory factors
-ends up causing tissue degeneration and lead to various diseases due to senescence of immune cells
what is the second pillar of ageing
telomere shortening
what are telomeres?
protective caps at the end of chromosomes that serve to protect genetic material from degradation and prevent chromosomes from sticking to each other -
what role to telomeres play in cell ageing?
each time a cell divides, telomeres shorten - this limits cell division as the cell can no longer divide properly
how do telomeres protect the end of chromosomes?
they form a protective structure together with the protein complex shelterin
What is the name of the enzyme that ensures repetitive DNA sequences of the end of chromosomes are maintained?
telomerase
Where is telomerase not present and what effect does this have?
It is not present in adult somatic cells, hence as with each cell division, the telomeres start to decrease in length
What is the 3rd hallmark of ageing?
DNA damage
What is DNA damage caused by?
External insults: UV, chemicals, pollutants
Internal insults: metabolic bi-products, ROS
DNA replicatin/proliferation: rapid prolif. promoting DNA damage causing senescence
Why can DNA repair enzymes sometimes fail at repairing mutations?
If the error rate is too high, some mutations are not corrected and copied into daughter cells
What does the DNA damage theory state?
biological ageing is a result of accumulated DNA damage that is unrepaired and can alter the function/become detrimental to a cell
What 3 choices does a cell have once in undergoes extensive damage?
apoptosis, alter the function of the cell so that the cell cannot function properly, or undergo senescence
what diseases have allowed us to learn more about the mechanisms of aging?
- progeroid syndrome- when individuals age prematurely- the integrity of DNA is compromised, affecting multitudinous features in the cell leading to premature aging
- Hutchinson Gilford Progeria Syndrome
What is DNA wrapped around inside out cells?
proteins called histones
What is it called when 146 base pairs of DNA wrap around these histones?
Nucleosome
How is DNA affected in low density nucleosome structures?
DNA is more exposed and prone to becoming damaged
How is DNA affected in high density nucleosome strcutures
DNA is more protected
What does DNA methylation do?
it is epigenetic modification that leads to chromatin compation and protection of the DNA.
What is epigenetics?
heritable changes in gene expression that do not involve changes to the DNA sequence itself- instead it’s dependent on DNA modifications/histone modifications
What is epigenetic drift?
As cells age, they undergo epigenetic drift, this is the divergence of the epigenome due to age.
There is a decrease in DNA methylation which leads to open chromatin, leading to genetic instability because DNA is more prone to becoming damaged. this leads to cellular senescence, apoptosis, cellular dysfunction, and is caused by lots of factors, including diet, stress, chemical exposure, etc.
What is the 5th hallmark of ageing?
Stem cell exhaustion
Primary function of a stem cell?
To serve as a grow/repair system for the body
Stem cells are?
Uncommited immature cells with a unique capacity to self renew (identical copy of itself), reconstitute an entire tissue and produce multiple specialised cells
What role does a change in stem cell function play in ageing?
Increases ageing, reduces potential to differeniate the stem cell in some tissues, less specialised cells, reduced ability to proliferate,
Causes of a loss of stem cell number/function include?
DNA damage,
telomere shortening
senescence
abnormal cellular signaling/metabolism or epigenetic changes
What is the 6th Hallmark of ageing?
Nutrient sensing
What hormones regulate metabolism?
Growth hormone which stimulates production of
Insulin like growth factor-1 -> allows cell to uptake glucose which enhances cell growth/division
What does an increase in cell division increase?
the amount of DNA damage and cellular wear/tear
So what negative effect does an excess in food supply and fatty foods have?
an increased amount of IGF-1 hormones hence a greater rate of cell proliferation- putting stress on DNA hence inducing DNA damage and cellular ageing.
What is the 7th Hallmark of ageing?
inflammaging
What is inflammation?
A natural defense mechanism that can be detrimental if prolonged - high amounts of circulating inflammation markers in blood are referred to as inflammaging
What occurs to innate immunity as we age?
It increases while adaptive immunity decreases
an increase in innate immunity leads to?
an increase in inflammatory cytokines, which lead to increase in natural killer cells and lymphocytes, leading to persistent low grade inflammation -> DISEASES (diabetes, cancer, CVD)
what is the final hallmark of ageing?
mitochondrial dysfunction
What does mitochondria do?
They are energy factories, they make ATP from the process of respiration, it also is a platform of intracellular signalling, regulators of innate immunity (influence survival of immune cells) , regulators of apoptosis
As we get older what happens to mitochondrial function?
It declines
What does a decline in mitochondrial function lead to?
decrease in respiration increase in ROS (damages dna), increased apoptosis, activation of innate immune system
what are the 2 forms of cell death?
apoptosis & necrosis
apoptosis is?
- programmed cell death
- coordinated intracellular process
-no inflammation
necrosis is?
- unplanned cell death
- homicide by external stressors
- acute inflammation
-accidental injury
causes of apoptosis include?
cell turnover
infection -> to get rid of invading pathogens
hormone dependent atrophy
development
sculpturing tool of body (eg. preventing webbed feet)
seen in nervous system
cell death balances cell division via apoptosis
when things go wrong in apoptosis what happens?
CANCER
Two pathways for apoptosis-> Describe the first one?
intrinsic pathway: initiated inside the cell, involves DNA damage detected internally, which triggers the disruption of the mitochondrial membrane, which results in the release of apoptotic inducing molecules, which then go into the cytoplasm, bind and adapt the proteins, forming a complex called the apoptotic complex
What does the apoptotic complex activate?
Caspases
What do caspases do
They cleave more than 600 proteins in the cell inducing cell death!
Describe the second pathway for cell death
Extrinsic pathway-> involves death receptors that sit on the surface of the cell -> bind a ligand which triggers clustering of the death receptors -> activated adaptor molecules -> activate the apoptotic complex -> activate caspases -> cleave/dismantle the cell
What are the characteristic features of apoptosis?
- rounding up of the cells/cellular shrinkage
-> cells detach from neighboring cells
-> enzymatic reactions occur
-> caspases activated - Nuclear condensation and cell membrane blebbing
-> membrane pinches off forming vesicles known as apoptotic bodies - apoptotic bodies are engulfed by neighboring phagocytes
- cleared by macrophages
what are caspases?
proteases that cleave more than 600 cellular components and DNA
How is it ensured there is no inflammation during apoptosis?
phagocytosis removes the dying cell
What are the causes of necrosis?
Injury/damage
infection
Extreme cold/heat
Trauma
Radiation
Chemicals
To what scale can necrosis occur?
A large scale, it is cell death with collateral damage
