Caloric restriction and lifespan Flashcards
what are the 4 nutrient sensing pathways which regulate lifespan
TOR/AMPK, SIR 2.1, Insulin like signalling pathway (ILS) and
what is mTOR
serine/threonine kinase
what is the ultimate role of the TOR/AMPK pathway
controls protein synthesis and growth in response to nutrient intake
what are the 2 complexes that TOR is found in
mTORC1 and mTORC2
what is the mTORC1 complex and its function
TOR in complex with Raptor and regulates gene expression for growth, protein synthesis and ribosome biogenesis
what is the mTORC2 complex and its function
it is TOR in complex with Rictor and is involved in proliferation and survival through inhibition of FOXO3A signalling via S6K1 and AKT leading to increased longevity
what is the result of reduced amino acid intake
reduced tor signalling and so lifespan extension
what is the evidence for reduced tor signalling leading to increased lifespan
tor inhibitor lead to extension in drosophila, tor deficiency and KO by RNAi in c elegant increases lifespan and in double KO mice, aside from being smaller they lived longer with no other abnormalities
what is AMPK
nutrient sensing switch
under what nutrient conditions is the AMPK pathway activated
low
what is the result of AMPK activation
it inhibits protein consuming activities through blocking TOR signalling. it acts in the hypothalamus to promote feeding behaviour and in the liver to promote glucose homeostasis by deactivating cAMP responsive element biding protein (CREB)
what is the result of non-functional AMPK
decreased lifespan
how is AMPK linked to ILS pathway
it interacts to know whether there is glucose present outside of cells
how is AMPK linked to the TOR pathway
either through mTORC2 or directly with AKT which acts to repress FOXO to increase longevity
what is Daf2
it is a gene which encodes the insulin like receptor
what does the insulin like receptor bind and what is the result
insulin like proteins and phosphorylates age-1 which phosphorylates AKT1//2 complex which phosphorylates DAF16, a transcription factor, inhibiting it.
what is the result of mutations which damage Daf2 gene in c.elegans
doubled lifespan as Daf16 is activated and so able to enter the nucleus inducing transcription of genes required for altered metabolism leading to increased longevity and stress resistance
why is daf2 normally switched off after maturation
it is a dater constitutive gene so is usually only required during development but in mutants the dour constitutive gene is switched on leading to longevity
why is ILS more complex in humans
we have more types of receptors leading to controversial observations e.g. mild reduction in function leading to type-2 diabetes
what evidence in mouse models suggests mutants of daf2 homologues IGF1 and IGF2 increases lifespan
a heterozygous mouse lived longer and was more resistant to oxidative stress and when the receptor was knocked out only in adipose tissue it promoted longevity
what were the effects of reducing insulin like growth factor 1 (IGF1) signalling in mouse model of AD
protected/delayed the onset in the mouse leading to reduced near-inflammation and reduced neuronal loss
what was found in a study of 122 japanese people over the age of 105
insulin signalling was reduced due to single nucleotide polymorphisms in insulin receptors
how can resveratrol prevent aging
mimics the effect of dietary restriction, up regulating AMPK and down regulating TOR signalling
how could rapamycin be used to treat aging
inhibits interaction of mTORc1 and raptor so reduces TOR signalling
