Ageing Flashcards
Senescence
Age related decline in function due to wear and tear and genetics
Disposable soma theory
as soon as the individual cannot increase the number or chance of survival of its offspring any further, there is no natural selection against decline/ageing in that individual
Senescence factors
metabolism
reactive oxygen species
DNA damage
Factors increasing life span
dietary restriction
environmental stresses
signals from the somatic gland
Rate of living theory
animals that have a higher metabolism have a shorter life span
large animals live longer and cold blood animals live longer at low temps
What are reactive oxygen species?
oxygen molecules that have an extra electron and are very reactive so will cause oxidative damage
superoxide radical is central to this
How is experimental data contradictory to the ROS theory?
in worms treatments that are superoxide dependent increased life span
glucose restriction increases life span in c’elegans by inducing mitochondrial repsiration and oxidative stress
resistance to oxidative stress is induced by longevity genes
How is DNA damage linked to ageing?
NAD depletion via excessive PARP activation
PARP is an enzyme that responds to damaged DNA
Hormesis
low level insults that may activate protective mechanisms
How do ROS levels contribute to ageing?
not an issue, they alert a cell to a problem to all activation of counter measures
high level of anti-oxidants means that ROS is suppressed and the alert is turned off
How can we use forward genetics to understand ageing?
find mutants that affect ageing and clone the gene to see what it does
search for short lived mutants
search for long lived mutants
IGF and TOR pathways
negative regulators of ageing, so when they are blocked life span is longer
Sirtuins
positive regulators of ageing so if over-active life span is longer
NAD+ dependent protein deacetylases
act as insulin dependent activators of daf16/foxo
What does insulin signalling block?
FOXO which is a TF that when in the nucleus, promotes anti-ageing functions and linked to resistance to oxidative stress
Antioxidant genes
superoxide dismutase
metakothionine
catalase
glutathionine
s-transferase
How are antibacterial genes implicated in ageing?
blockage of autophagy limits lifespan of long lived DAF2 and IGFR mutants
How are metabolic genes implicated in ageing?
apolipoprotein genes downregulated
glycoxylate-cycle genes
genes involved in amino acid turnover
TOR kinase
major amino acid and nutrient sensor that stimulates growth and blocks salvage pathways like autophagy when food is plentiful
Reseratol
proposed anti-ageing component in red wine and japanese knot weed
activates sir proteins
NAD depletion theory of ageing
NAD is an essential cofactor for sirtuines and this declines with age
could be from unrepaired DNA damage from poly ADP ribose polymerase
Patterning vs growth of final shape
small scale growth using the diffusion of morphogens usually not more than 10 cell diameters
growth factors are what decide final shape
What are the three ways growth can occur?
proliferation
cell enlargement
accretion
Drosophila early cell cycle control
initial rapid divisions with no G1 or G2 phases
slows at cycle 14 when cellularisation occurs
What is cellularisation in drosophila development?
when nuclei migrate to periphery of the syncytium and become surrounded by a cell membrane
Why is the mesoderm one of the first domains to express string but doesn’t divide until later on?
protein tibble is induced
prevents cell divisions so invagination to form ventral furrow can take place at the right time
What is organ size controlled by?
determined by morphogens and the steepness of their gradient, not cell size/number
growth programs are flexible and can be changed depending on need
What pathways are involved in organ size?
TOR pathway promotes cell size growth
hippo pathway limits organ size
Hippo pathway
when activated acts as a kinase and leads to yap/taz exclusionfrom the nucleus
integrates various signals to create a stop growing signal
What is hippo in vertebrates?
Mst1
How is hippo activated?
via merlin/expanded/kibra
cell cell contact and polarisation due to crowding and differentiation
What is the size of adult drosophila determined by?
size of larva
determined by insulin signalling which effects both duration and rate of larval growth
Growth in mammals
occurs in a specific pattern and is under hormonal control
GF 1/2, GH, IGF1/2
How are GH levels controlled?
production of GH in the pituitary is stimulated by GHRH and inhibited by somatostatin
GH feeds back on its own production and inhibits it
How is growth influenced by the mother?
inadequate growth in utero due to famine or bad diet can lead to lifelong consequences
heart disease, obesity, diabetes
Ecdysis
molting of the larvae of insects in order to grow as the cuticle is rigid and won’t allow it
Instars
intermold stages of ecdysis
What is molting in drosphila initiated by?
activation of stretch receptors in the cuticle
leads to the release of protothoracictropic hormone from the corpus alatum
How does molting occur?
ecydyson is released from protothoracic gland in repsonse to protothoracictropic hormone
leads to cuticle seperating from epidermis, cells from this proliferate secreting a fluid that forms a barrier
starts secreting new cuticle and the old one is shed
What environmental cues can initiate metamorphosis?
nutrition
temperature
light
What signals start the process of metamorphosis in drosophila?
relative levels of juvenile hormone and ecdysone that are released from the corpus alatum
What signals control metamorphosis initiation in frogs?
balance of prolactin and thyroxine
can be changed by environmental cues that act via the hypothalamus secreting CRH
What does CRH do?
acts on pituitary and causes secretion of TSH
acts on thyroid to release thyroxin
What does thyroxin do?
positively feeds back on itself so the process is irreversible
different effects on different tissues- growth of limbs but degeneration of tail
Negative regulators of developmental signal transduction
patched regulating hedgehog
APC regulating Wnt
What are sirtuins?
NAD+ dependent protein deacetylases
overexpression extends lifespan is yeast, worms, flies
act as insulin independent activators of daf16/foxo
What may lead to NAD depletion?
unrepaired DNA damage via poly ADP ribose polymerase
What is the effect of the germline on longevity?
somatic gonads extend lifespan and germline counteracts this
