L6, Signalling Pathways Flashcards
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
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)
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
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
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
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
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)
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
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…
10
Q
Centenarian research (Ashkenazi Jews)
Concerns IIS
A
- Increased insulin sensitivity compared with younger people
- Lower IGF-1 compared with younger people
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
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
13
Q
IIS and ageing in the worm: Cell Signalling pathway
A
- Ins (ligand) binds Daf-2 (receptor)
- Daf-2 activated I-C domain phosph. Age-1 (PI3K)
- pAge-1 phosph. AKT
- pAKT phosph. Daf-16 (FOXO)
- pDaf-16 remains cytoplasmic; no daf-16 induced gene transcription
14
Q
IIS and aging in the fly: Cell signalling pathway
A
- Dilp (ligand) binds dlnR (rec.)
- Chico (IRS) binds I-C domain of dlnR
- Phosph. of dPI3K
- pdPI3K phosph. AKT
- pAKT phosph. FOXO
- pFOXO unable to enter nucleus -> no transcription
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
