Ageing Flashcards by Tara Sheridan

Senescence

Age related decline in function due to wear and tear and genetics

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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

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Senescence factors

metabolism
reactive oxygen species
DNA damage

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Factors increasing life span

dietary restriction
environmental stresses
signals from the somatic gland

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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

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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

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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

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How is DNA damage linked to ageing?

NAD depletion via excessive PARP activation
PARP is an enzyme that responds to damaged DNA

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Hormesis

low level insults that may activate protective mechanisms

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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

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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

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IGF and TOR pathways

negative regulators of ageing, so when they are blocked life span is longer

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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

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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

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Antioxidant genes

superoxide dismutase
metakothionine
catalase
glutathionine
s-transferase

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How are antibacterial genes implicated in ageing?

blockage of autophagy limits lifespan of long lived DAF2 and IGFR mutants

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How are metabolic genes implicated in ageing?

apolipoprotein genes downregulated
glycoxylate-cycle genes
genes involved in amino acid turnover

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TOR kinase

major amino acid and nutrient sensor that stimulates growth and blocks salvage pathways like autophagy when food is plentiful

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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