L6 - Ageing and Senescence Flashcards by Ellie R

What is senescence?

Age dependent decline in vital physiological functions

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Where is senescence seen clearly?

Seen in the survival of drosophila

After 50 days the % survival rate dramatically drops

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What are the two main causes of senescence?

Wear and tear
- Decline in muscle function in C.elegans
- Teeth worn off in elephants - can die of starvation at old age
Genetics
- Salmon – die soon after laying their eggs
- Species differences in ageing
- When elephant gestation has finished a mouse is already middle-aged and aged

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What is the disposable soma theory?

As soon as an individual cannot reproduce or increase the chance of survival of its offspring any further, there is no natural selection against aging
If genes or mechanisms exist that increase the reproductive success in early life stages but are harmful once progeny is independent, they will be selected for

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What are 3 senescence factors?

Metabolism
Reactive oxygen species
DNA damage

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What is the rate of living theory?

High metabolism (often in small animals) = shorter lifespan 
Cold blooded animals live longer at low temperatures

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Why is a high metabolism linked to a shorter lifespan?

High metabolism leads to the formation of reactive oxygen species and oxidative damage
The superoxide radical is central to the related theory of ROS in ageing

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Manipulation of ROS in worms has shown?

Paraquat/juglone treatment and glucose restriction increases lifespan
Lifespan extension is superoxide dependent
If removed the lifespan in reduced
Glucose restriction induces mitochondrial respiration and increases oxidative stress

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Resistance to oxidative stress is induced by?

Longevity genes?

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What are progeria syndromes?

Syndromes with a genetic cause where patients show premature ageing

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What mutations cause Hutchinson Guildford syndrome?

Lamina mutations –> nuclear architecture

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What mutations cause Nestor Guillermo syndrome?

BANF1 mutations –> Lamina/mitosis

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What mutations cause Ehlers Danos syndrome?

Xylosylprotein 4-beta-galactosyltransferase

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What mutations cause Cockayne syndrome?

Group 8 excision-repair cross-complementing protein –> DNA repair

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What mutations cause Werner syndrome?

RecQ DNA helicase DNA repair/replication/chromosome segregation

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What is the DNA damage theory of ageing?

In non-replicating cells unrepaired DNA damage may accumulate and cause aging
In dividing cells it will lead to mutations
Clear that it is DNA damage rather than mutations that will lead to aging
- Mouse models that have increased mutation rates but do not age more rapidly

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Why do mice with a higher mutation rate not age quicker?

Might be through NAD depletion by DNA damage induced PARP activation
Poly ADP-ribose polymerase (PARP)
- Responds to damaged DNA
- Essential for certain DNA repair processes
- May lead to cell senescent

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How do senescent cells drive important aspects of ageing?

Senescent cells get in the way of normal stem cell based repair
They prime an ageing phenotype by secreting factors like proinflammatory mediators
Sit in stem cell niches preventing stem cells from doing their job

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What 3 factors increase life span?

Dietary restriction
Environmental stresses
Signals from the somatic gonad

What is an example of how dietary restriction increases life span?

Rat - 40% life extension when calorific intake reduced from 120-40

How do environmental stresses affect life span?

Environmental stresses - heat, ROS generators
Hormesis – low levels insults (increasing ROSs) activate protective mechanisms reducing overall ROS impact
- Net benefit of having a small insult
- Protective superoxide induced pathway
ROS are not relevant for aging, but are molecular reporters for stress leading to activation of anti-ageing mechanisms

How is forward genetics used in model organisms to understand ageing?

Find mutants that affect aging, then clone the gene and see what is does
Search for short lived mutants
- Tricky - don’t know whether it is aging causing this
Search for long lived mutants
- Developmental models - C.Elegans or Drosophila
- Short life span, isogenic strains, cheap

What 3 pathways that function to extend life span have been discovered through forward screen for long-lived mutants?

IGF pathway
TOR pathway
Sirtuins

What is a dauer state?

C.elegans have a normal life span of 25 days
If crowding and lack of food they can enter a dauer state - lasts up to 60 days
Does not affect the life span

How did they discover genes that promote longevity in C.elegans?

Genetic screens led to the identification of mutants that promote longevity - Part of insulin signalling (IGF) pathway - block insulin

How does insulin signalling affect longevity?

IGF signalling inhibits the transcription factor DAF16 (FOXO) - FOXO regulates genes that increase resistance to various stressors - Signalling via DAF2/IGFR inhibits DAF16, SKN1 and HSF1 Mutations in IGF1 pathway increases lifespan - resistance to oxidative stress - Female mice with a mutation in IGF1R live 33% longer

Lifespan extension with dietary restriction is mainly seen in?

Mice | Growth hormone receptor mutants (downregulate IGF) - dietary restriction does not extend life

Lifespan extension mediated by IGF signalling is mainly seen in?

Worms | Fly

What is the insulin signalling pathway in humans?

FOXO1 and FOXO3A, AKT and IGF1 receptor variants have been linked to human longevity

Insulin signalling pathway overview

1. Down regulating IGF signalling 2. Activation of DAF16/Foxo 3. Foxo downregulates Insulin-like genes --> nonautonomous effects

What insulin-like genes does FOXO downregulate?

Antioxidant genes - Superoxide dismutase, metallothionine, catalase --> ROS theory - Foxo leads to increased resistance against ROS Metabolic genes - Apolipoprotein genes, glyoxylate-cycle genes, genes involved in amino acid turnover Chaperones - Small heat-shock protein genes Antibacterial genes - Blockage of autophagy limits lifespan of long lived DAF2/IGFR mutants

What is TOR kinase?

An amino-acid and nutrient sensor Stimulates growth Blocks salvage pathways such as autophagy when food is plentiful

How does insulin communicate with TOR?

Via PI3K and Akt Inactivating TSC1/TSC2 (normal block TOR) Activating TOR

What downstream events happen if insulin signalling is blocked?

Activates TSC TSC blocks TOR Activates 4E-BP1 Activation of salvage/longevity pathways

What is the role of Rapamycin?

Blocks TOR therefor extending lifespan | - Due to a reduction in important life limiting factors – cancer

In which animal is FOXA required for TOR dependents lifespan extension?

C.elegans

In which animal does blockage of S6 kinase extend lifespan?

Worms | Flies

In which animal does overexpression of 4E-BP extend lifespan?

Flies

What are sirtuins?

NAD+-dependent protein deacetylases | Overexpression extends lifespan

What is the role of sirtuins in C.elegans?

Sir-2.1 activates Foxo/DAF16 and mitochondrial unfolded protein response - Sir proteins act as Insulin independent activators of DAF16/Foxo - Leads to longevity Certain mitochondrial mutations extend lifespan - Similar to SIRT activation - result in a mitochondrial unfolded protein response

What is the role of Resveratrol?

Activates Sir proteins

In mammals which Sir protein is linked to longevity in males?

SirT6

What is the role of NAD in the Sirtuins pathway?

NAD is a cofactor for Sirtuins NAD levels decline with age Unrepaired DNA damage might lead to NAD depletion – lead to NAD depletion of aging

Ageing is a trade-off between?

Reproduction and longevity

How does the reproductive system of C.elegans affect their lifespan?

Removal of entire reproductive system does not extend lifespan When only germ cells are removed animals live 60% longer

How do somatic gonads and the germline effect lifespan?

Somatic gonads extend lifespan but their effects are counteracted by germline If you remove germline the effect from somatic gonads can extend the lifespan of IGFR/DAF2 mutants even further

What other two hormones are involved in ageing?

Steroidal hormones and DAF12 nuclear hormone receptor | They act on DAF16/FOXO - different manner than insulin