Ageing Flashcards
Why is it difficult to study ageing?
it’s difficult to study aging in people as old people usually have multiple health cconditions and therefore are a source of wide variability in research
How to define aging?
- mmune system not reaccting as well to disease or an overreactive system causing chronic inlammation
- young cells are better at maintaining and repairing their genomes than older cells
- shortening of telomeres as you age in somatic cells
- oxidative stress in some tissues plays an important role in aging
- senescence ; we used to think that the cells just sit there and fdo nothing but they can release pro inflamatory cytokines and stuff which can damage cells and contribute to aging
- you tend to have more fibrous tissue in your muscles → you fall over and break stuff → you get in hospital and you decline and die 🙂
- young cells and tissues can maintain homeostasis much better → as you age the balance in your cells is disturbed and your functions decline
What is the role of fat in ageing?
we used to think that fat was neutral but it turns out that fat can induce damage to other cells (especially around the vital organs)
What are some challenges for studying ageing in humans?
- gradual and therefore expensive (it’s quite difficult to follow somebody from their birth to their 80s
- dynamics can change (sudden decline in health)
- people age in different ways
- external and internal influences
- lack of biomarkers
- humans are complex and long lived
- model organisms
- old mouse is not the same as old human (18 months vs 95 years) so working with model organisms may be difficult
How do your muscles change as you age?
- if you’re over 50 you will start losing muscle even if you lift (but still lift!)
- increased fibre size variability
- fibres are more disorganised
- larger extracellular spaces
- protein aggregates within the interstitial matrix
- inccreased infiltration of noncontracctile material
- function declines
How do mitochondria change as the muscles age?
- changes in mitochondria:
- fewer and larger
- vaccuolization of the matrix
- shortened cristae
- muscle ATP production by mitochondria declines about 5% per decade
- less mtDNA and more damage
- energy for basal activity and not stress or exercise
How can you identify satelite cells?
satelite cells are Pax7+ and therefore can be easily identified
What happens to the satellite stem cell niche as you age?
- old satelite cells
- rodents/humans: fewer satelite cells and they can divide less
- in vitro: old rodent satellite cells produce less organized/more fragile myotubules
- more fibrogenic than myogenic
- apoptose more often
What factor do ageing muscle fibres express and what does it do?
- aged muscle fibres express more Fgf2 (fibroblast growth factor)
- takes satelite cells out of quiescence and depletes them
What other factor falls in the muscle as you age and what’s the effect of that?
in the old system you will get less of the Wisp and you will get disfunctional repair of the muscle
What is parabiosis?
parabiosis (you take the vascular system of the old organism and connect it to the young organism and you look at what the young blood can do to the older organism
What happened in the rejuvenated muscle niche?
- rejuvenate muscle satellite niche
- decrease cannonical Wnt signalling
- can prevent aged satellite cells switching from myogenic tofibrogenic lineage as proliferate
- injecting Wnt3a into repairing muscle lef to more fibrosis
What happens to Notch signalling as you age?
Notch/Delta signaling down with age (controls cell proliferation, cell differentiation and binary cell fate decisions)
Why is studying signalling pathways in ageing difficult?
lots of the singalling pathways that were identified to be connected to aging are difficult to play with therapeutically because they may increase the risk of cancer as they are quite often mitogenic or intefere with the immune response of the organism
What happens to HSCs as you age?
- young organisms tend to make the right proportions of the hematopoeticc cells
- as you age you tend to make more of a specific lineage → aging doesn’t affect all stem cells in the same way
What is sarcopenia?
- loss of muscle mass/cells
- causes frailty : exhsaution, reduced physical activity, slow walking, reduced grip strength
What are some causes of sarcopenia?
- endoccrine eg lose anabolic testosterone
- nutritional
- inactivity (exercise can help e.g. to increase ROS scavengers
- inflamatory processes eg IL-6 increases
- reduced anabolism
- reduced activity of satellite cells
- diseases can also contribute to sacropenia
can we prevent frailty?
- exercise doesn’t really help
- reducing inflamation
- hormonal treatment
- nutritional intervention
What are two main factors that affect the declining CV heart as we age?
- two changes as we age
- heart has reduced function
- the rest of the body is ageing and stressing the CV system
What happens to the heart as we age?
- fibrosis
- some dead cells
- plaques
- decrease heart rate and arythmias
- scar tissue
Discuss the the role of vinculin in the ageing heart
- proteomic analysis on the heart muscle
- the cells were upregulating vinculin (Vinculinis a cytoskeletal protein associated with cell-cell and cell-matrix junctions,) and the idea was that this would improve cell to cell adhesion and help the cytoskeleton better support the heart muscle
Discuss the effects of young Sca1+ cells on the ageing heart
Long term repopulation of aged bone marrow stem cells using young Sca1 cells promotes aged heart rejuvenattion
- reconstitution of aged BM cells with young Sca1+ cells
- effective homing of functional stem cells in the aged heart
- promoted aged heart rejuvenation through activation of the Cxcl12/Cxcr4 pathway of cardiac endothelial cells
Discuss the impact of calorific restriction in the ageing heart
- indirect: reduce serum cholesterol, tryglycerides, fasting glucose and facting insulin levels = lower risk of arthosclerossi reduce blood cells
- in evolution when you have periods of stress th cells are upregulating the DNA repair systems to protect themselves so that’s what it seems to be what’s happening with calorific restrictions
What is the difference between progeroid syndromes and unimodal syndromes?
- progeroid syndromes (segmental) - affect many organs
- or one (unimodal)- affect just one organ
Name some progeroid and unimodal syndromes
- segemental progeroid syndromes:
- Werner syndrome
- ataxia telangiectasia
- dyskeratosis cognetia
- Hutchinson-Gilford
- progeria syndrome and Bloon syndrome
- unimodal progeroid
- familial Alzheimers disease
- familial Parkinsons disease
What is Werner syndrome?
- autosomal recessive
- rare (one in a million)
- develop normally until puberty , stop growing and start ageing
- from 30yrs cataracts, grey hair. osteoporosis, cancer, poor glucose regulation immune changes, skin atrophy, myocardial infarction
- median death around 47/8 usually of myocardial infarction and cancer
What is Werner syndrome?
- autosomal recessive
- rare (one in a million)
- develop normally until puberty , stop growing and start ageing
- from 30yrs cataracts, grey hair. osteoporosis, cancer, poor glucose regulation immune changes, skin atrophy, myocardial infarction
- median death around 47/8 usually of myocardial infarction and cancer
What is the cause of Werner syndrime?
- the cause of Werner syndrome is a DNa helicase
- sometimes there are issues with the nuclear localization singla and the.mutations can affect whether the protein can get inside the nucleus or not
Describe the experiment that lead to the discovery of Wrn function in human ageing
- they had a human ES cell line that lacked WRN
- they differentiated them to mesencyhhymal styem cells and looked at chromatin
- chromatin organisation and interaction with lamina can be altered
- WRN null MSCs behaved like old cells in vitro - proliferated less, shorter telomeres, upregulated ageing and senescence markers
>90% of differently methylated regions in WRN were not affected by ageing so it’s not just accelerated normal ageing - most were in genes associated with transcription factors
- suggests Werner syndrome due to incorrect control of gene expression
What is Ataxia telangiectasia?
- rare autosomal recessive
- progressive cerebellar degeneration
- skin abnormalities
- pigmentary abnormalities and hair greying
- immunodeficiency
- a wide range of malignant tumours
What is the cause of AT?
- mutation in ATM gene - a kinase which senses the double stranded breaks in the DNa and triggers the repair adn telomere maintnance
- the kinease is also involved in chekcpoint activity during cell cycle → malignant aggresive tumours
- when dividing ATM mostly in the nuclus and when not some in cytoplasm functions to activate and coordinate singalling involved in cell cycle checkpoint. response to oxidative stress mitochondrial funtion and apoptosis/senescence
- AT cells show telomere shortening, genome instability and premature sensescence
- iPS cells with AT show X-ray sensitivity chromosomal aneuploidy and death
What is Dyskeratosis Congenita?
- rare, inherited, usually male
- mucous membranes, teeth, nails, skin pigmentation affected
- can have gery hair, osteoporosis and cancer
- most die of bone marrow failure
What is Dyskeratosis Congenita?
- rare, inherited, usually male
- mucous membranes, teeth, nails, skin pigmentation affected
- can have gery hair, osteoporosis and cancer
- most die of bone marrow failure
What is the cause of DC?
- 9+ DC genes: all involved in telomere homeostasis (telomere components or telomere cap)
- reminder: Telomeres = TTAGGG repeats that can expand over 10 kb to cap ends of each chromosome
- function: protect chromosomal ends, stop chromosome instability