B364 > L6, Signalling Pathways > Flashcards

L6, Signalling Pathways Flashcards

(19 cards)

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1
Q

Key model organisms in aging research:

A
  • Drosophila melanogaster (Fruit flies)
  • Musculus (Mice)
  • C. elegans (Nematode worm)
  • In these models, key conserved genes and functions have been identified despite the vast differences in ecology between them -> similar effects on lifespan of DR etc
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2
Q

Key modulatory mechanisms of aging in model organisms (evolutionarily conserved genetic interventions which extend lifespan):

A
  • Reduced insulin/IGF-like signalling
  • Reduced TOR signalling
  • Dietary restriction (DR)
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3
Q

Insulin and IGF1-signalling in mammals:

A
  • IGF-1 to IGF-1R -> IRS1 to 4 phosphorylation -> PI3K converts PIP2 to PIP3 -> protein kinase activation -> FOXO phosph. -> gene transcription (including those relevant to aging)
  • Vast network with diverse effects
  • Also relevant is the TOR branch
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4
Q

C.elegans as a model organism:

A
  • Natural lifespan of 20 days
  • Small
  • Easy to keep
  • Death fluorescence signal?
  • Dauer = quiescent state where they don’t age in times of food deprivation etc
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5
Q

Key C.elegans mutants:

A
  • Many findings are the result of 1983 systemic mutagenesis screen for lifespan extending mutations
  • Age-1 (p110 subunit of PI3K) -> mutate, Dauer; first identified
  • Daf-2 (IGFR/IR homologue) -> mutate, Dauer
  • Daf-16 (FOXO homologue) -> mutate, reduce lifespan
  • -> lifespan extending effect of previous examples is contingent on daf-16 being functional and translocated into nucleus; key hub of signalling network
  • Daf-18 (PTEN homologue) -> mutate, reduce lifespan
  • Ins-7 (ligand) -> mutate, Dauer
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6
Q

Key mutants in fruit flies:

receptor, IRS, ligand, forkhead protein

A
  • InR: IGFR homologue; only one type so partial reduction increases lifespan whereas knockout is lethal
  • Chico: IRS homologue -> mutation increases lifespan by 48%
  • dFOXO: homoloque of FOXO; only one so overexpression increases lifespan
  • Ablation of dilp-producing neurosecretory cells - reduced circulating insulin-like peptides -> extension of lifespan
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7
Q

Pleiotropic effects of reduced IIS in the fly:

Metabolism, development, reproduction

A
  • Strong reductions in IIS can be lethal
  • Reducing IIS through development reduces growth (e.g. long-lived chico mutant flies)
  • Late development or adult reductions in IIS decrease reproduction and alter metabolism
  • Metabolic effects include increased hemolyph glucose levels (similar to diabetes)
  • Crucial point: Tissue specific interactions often in play (point for further research)
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8
Q

IIS and aging in the mouse: (Dwarf mice; benefits, downfalls, comparison to human condition)

Consider extrinsic vs intrinsic mortality

A
  • Snell dwarf mice have no growth hormone
  • They exhibit a reduced metabolism and a lower metabolic rate, are infertile
  • They have reduced levels of IGF-1/insulin and blood glucose -> these cascades are downregulated
  • Cold sensitive
  • Despite an increased longevity in lab conditions, they typically are not equipped to compete well for resources or evade predation as well as wild type individuals (AP!)
  • Human dwarf-syndromes related to similar genes don’t have the same lifespan extension
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9
Q

Evidence for role of IIS in aging in mice:

KO vs partial

A
  • IGF1 knockout not viable
  • IGF1-R knockouts die within 8 days of birth
  • IGF1R heterozygotes: increased lifespan, PI3K and MAPK pathways downregulated, enhanced resistance to oxidative stress
  • Further: GH resistant mice, IGF1R hyperactivation, Klotho, IRS1 null…
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10
Q

Centenarian research (Ashkenazi Jews)

Concerns IIS

A
  • Increased insulin sensitivity compared with younger people
  • Lower IGF-1 compared with younger people
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11
Q

TOR pathway and its interactions:

A
  • Regulates cellular and organismal growth..
  • Protein translation
  • Metabolism
  • Autophagy
  • Cytoskeleton organisation
  • Lipogenesis
  • Ribosomal biogenesis
  • Aging
  • -> The role of TOR on lifespan is evolutionarily conserved
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12
Q

TOR signalling and aging:

A
  • Inhibition of components of the TOR pathway extends lifespan in worms, flies and mice
  • The role of TOR in the determination of lifespan is thus evolutionarily conserved
  • Examples: let-363 (TOR homologue) mutation in worms -> lifespan extension
  • TOR mutant flies -> long lived
  • Mice with an genetic deletion in S6K1> long lived
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13
Q

IIS and ageing in the worm: Cell Signalling pathway

A
  1. Ins (ligand) binds Daf-2 (receptor)
  2. Daf-2 activated I-C domain phosph. Age-1 (PI3K)
  3. pAge-1 phosph. AKT
  4. pAKT phosph. Daf-16 (FOXO)
  5. pDaf-16 remains cytoplasmic; no daf-16 induced gene transcription
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14
Q

IIS and aging in the fly: Cell signalling pathway

A
  1. Dilp (ligand) binds dlnR (rec.)
  2. Chico (IRS) binds I-C domain of dlnR
  3. Phosph. of dPI3K
  4. pdPI3K phosph. AKT
  5. pAKT phosph. FOXO
  6. pFOXO unable to enter nucleus -> no transcription
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15
Q

Growth hormone pathway:

A
  • In mammals, IGFs and insulin pathways are separate; more complex interaction
  • Anterior pituitary makes GH -> binds to GHR on liver -> IGF-1
  • In other tissues, GH binds to GH-r -> IGF-1
  • IGF-1 in both of these sources binds IGF-1R in cells
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16
Q

Klotho mice:

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A
  • Klotho represses insulin-like I-C signalling
  • Pleiotropic roles
  • Overexpression of Klotho increases longevity
  • Mutated klotho mice die young (2 mths), premature aging
17
Q

Akt research in human cells:

Study These Flashcards
A
  • in vitro research involving inhibition of Akt in culture cells
  • Found extension of life
  • Constitutive activation promotes senescence (cells stop dividing, altered cell morphology and function -> aging)
18
Q

Rapamycin effect in lifespan and pathologies:

Study These Flashcards
A
  • Inhibits TORC1 branch of TOR pathway -> mimics lifespan extension of TOR componenet knockout
  • Antifungal and immunosupressant agent; also used in advanced renal carcinoma
  • Also effective in reducing pathology in fly and mouse models of neurodegenerative diseases (PD, HD, AD)
19
Q

Rapamycin side effects:

Study These Flashcards
A
  • Include hyperlipidaemia
  • Immunosuppressant effect detrimental in healthy individuals
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