Frailty Flashcards
frailty
‘multiple physiological systems losing reserves”
frailty
- muscle, immunity, endocrine signalling
frailty is
reversible and preventable and not inevitable in ageing
frailty and hormones
endocrine changes
frailty and msucles
weakening of the muscle
frailty and the brain
degeneration
sarcopenia
loss of muscle
cardiac muscle is striated and cardiomycoytes are connected via
intercalated discs
cardiac muscle contraction via
Gs
1) activation of adenylyl cyclase
2) increase in cAMP
3) increase in PKA
4) PKA phosphorylates calcium L type channels so they open causing an influx of calcium
5) calcium induced calcium release when calcium binds to calmodulin
6) Ca/Calmodulin complex binds to MLCK- contraction
6) MLCP removes phosphates- causing relaxation
In cardiac muscle contraction L-type Calcium channels and RyRs are
not couple- but activated by the influx of calcium
cardiac muscle and ageing
heart tissue thickens and stiffens,increasing risk of cardiovascular disease
smoot muscle
no sarcomeres- non striated
- single nucleus int he centre of the cell
- basal lamina surround cells containing extraceullualr proteins
s.muscle is activate by
stretch, nervous hormones
s. muscle contraction
via Gq
1) when activated Gq cause IP3 to be hydrolysed
2) hydrolysed to PIP2 and DAG
3) PIP2 causes the SR to release calcium, calcium binds to calmodulin and causes activation of MLCK- contraction
4) MLCP removes phosphate from MLC causing relaxation
how is s. muscle contraction different
NO TROPONIN
Gi and smooth muscle
e. g. A2contraction- due to less cAMP inhibiting MLCK
- vasoconstriction
Gs and smooth muscle
e. g B2 relaxation
- more cAMP
- increased inhibition of MLCK
- vasodilation
example of Gq GPCR in smooth muscle
ADH V1 R and angiotensin II AT1R
s. muscle and ageing
signify decrease in s.muscle function with increased age
skeletal muscle fibres
behave as a single unit, multinucleate.
Surrounded by sarcoplasmic reticulum with invaginated T-tubules
Skeletal muscle contraction
1) AP reaches sarcoma causing depolarisation
2) depolarisation is conducted down the T-tubules
3) depolarisation causes conformation change in the dihydropyridine receptors, which are mechanically coupled with RyRs
4) conformational of DHPR causes RyR to be activated and calcium to be released from the SR
5) calcium binds to troponin, which means myosin heads are now able to form cross bridges with actin - contraction
in skeletal muscle contraction..
contraction is maintained for as long as calcium is bound to troponin
as you get older skeletal muscle
decreases due to sarcopenia and we become weaker
sarcomeres and ageing
- lost with raging
- reduction in muscle fiber lengt due to a decree in sarcomere number
- sarcomere spacing becomes disorganised
- muscle nuclei become centralised along the muscle fibre
- plasma membrane becomes less excitable
how many hallmarks of ageing are there
9
there more hallmarks (aggregation)
the more accelerated ageing is
what are the 9 hallmarks of ageing
1) genomic instability
2) telomere attrition
3) epigenetic hanges
4) loss of proteostatis
5) deregulated nutrient sensing
6) mitochondrial dysfunction
7) cellular senescence
8) stem cell exhaustion
9) alter intracellular communication
only cells expressing the enzyme telomerase can
make DNA at the end of telomerases
cells which express telemorase
stem cells (can reproduce forever) and cancer cells
everytime cells of through mitosis
telomeres shorten
shortening of telomeres=
Hay flick limit
Epigenetic alterations
histone modifications and DNA methylation change gene expression
methylation =
turns off
actetylation=
turns on
loss of proteostasis
protein misfiling and aggregation e.g. parkinsons
deregulated nutrient sensing
can cause less IGF- meaning less protein synthesis as you get older
Mitochondrial dysfunction
ROS- apoptosis like excitotoxicity
cellular sensence
increase the likelihood of disease of ageing
senescent cells
stay around and don’t die due to not producing much apoptotic proteins. These cells cause damage to tissue due to pro-inflammatory cytokines causing INFLAMMAGING
senescent cells make disease like
diabetes and liver failure more common
e.g. autoimmune diseases
cure for ageing?
if we could kill off scene sent cells- e.g. mice will live 30% longer in better health
stem cell exhaustion
decline in blood cells e.g. adaptive immune cells and reduced chemotactic motility of innate neutrophils
how are neutrophils affected by ageing
reduced chemotactic motility of innate neutrophils
myostatin
Myostatin is a myokine, a protein produced and released by myocytes that acts on muscle cells’ autocrine function to inhibit myogenesis: muscle cell growth and differentiation. In humans it is encoded by the MSTN gene.
when myostatin is bound to receptor
leads to pathways which breakdown muscle- decreasing muscle mass
- not sure if levels change in ageing, but definitely increased in obesity
if myostatin gene is mutated or deleted
can increase muscle mass
catabolic state
when proteins are being broken down- muscle mass decreases- sarcopenia
as we get older and if on restricted diet IGF-1
decreases
why does IGF-1 decrease
due to epigenetic switching off and deregulation of fiet
reduced exercise and activity often occurs with age and this causes
atrophy of muscle
which pathway is associated with inflammaging
NF-kB
immunoscencence
the gradual deterioration of the immune system, brought on by ageing.
refers to the hosts capacity to response to infection as well as the development of long term immune memory
immunescence is a major contributing factor
to increased frequency of morbidity and mortality among the elderly
Hemtopoietic stem cells and immunoscence
Reach senescence
Due to DNA damage
Oxidative stress increases over time to reduce cell cycle due to mitochondrial feedback
macrophages and and immunoscenence
- phagocytic ability decreases
- number decreases
T-helper cell and and immunoscence
and immunoscence
T killer cell and immunoscence
Thymus size decreases from birth
Number of T cell produced decreases
Cytotoxicity decreases
B cell and immunoscence
Number decreases
Smaller pop. mean fewer immunoglobulins produced
Opsonisation by Ig decreases- less effective at drawing in T cells
Natural killer cells and immunoscence
cytotoxicity decreases with age
They become less effective at killing pathogens
More susceptible to viral infections
inflammaging
chronic inflammation
- skin detrioates
- joint ache
- heart disease
- cancer
- arthritis
- alzhemers
inflammaging activates
innate immunity and macrophages ar eno longer able to turn off.
- pro-inflmamtory cytokines e.g. TNF-alpha= inflammaging
causes of inflammaging
- stress
- oxidative stress
- DNA damage
- stem cell aaeing
pathways associated with inflammaging
- NF-kB
- TOR- activates NF-kB
- RAS0 activates pro-inflmmaotry cytokine production
NF-kB
regulating ageing and inflammation
TOR
regulates growth and proliferation of cells (always
Activating NF-kB)
RAS
activation leads to pro-inflammatory cytokine production
Vascular inflammation and senescence
which gene encodes myostatin
MST- member of TGF beta protein family
individuals who have mutations in both copies of myostatin gene have
significantly more muscle mass and are stronger than normal
