Caloric restriction and lifespan

Question 1

what are the 4 nutrient sensing pathways which regulate lifespan

Answer 1

TOR/AMPK, SIR 2.1, Insulin like signalling pathway (ILS) and

Question 2

what is mTOR

Answer 2

serine/threonine kinase

Question 3

what is the ultimate role of the TOR/AMPK pathway

Answer 3

controls protein synthesis and growth in response to nutrient intake

Question 4

what are the 2 complexes that TOR is found in

Answer 4

mTORC1 and mTORC2

Question 5

what is the mTORC1 complex and its function

Answer 5

TOR in complex with Raptor and regulates gene expression for growth, protein synthesis and ribosome biogenesis

Question 6

what is the mTORC2 complex and its function

Answer 6

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

Question 7

what is the result of reduced amino acid intake

Answer 7

reduced tor signalling and so lifespan extension

Question 8

what is the evidence for reduced tor signalling leading to increased lifespan

Answer 8

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

Question 9

what is AMPK

Answer 9

nutrient sensing switch

Question 10

under what nutrient conditions is the AMPK pathway activated

Answer 10

low

Question 11

what is the result of AMPK activation

Answer 11

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)

Question 12

what is the result of non-functional AMPK

Answer 12

decreased lifespan

Question 13

how is AMPK linked to ILS pathway

Answer 13

it interacts to know whether there is glucose present outside of cells

Question 14

how is AMPK linked to the TOR pathway

Answer 14

either through mTORC2 or directly with AKT which acts to repress FOXO to increase longevity

Question 15

what is Daf2

Answer 15

it is a gene which encodes the insulin like receptor

Question 16

what does the insulin like receptor bind and what is the result

Answer 16

insulin like proteins and phosphorylates age-1 which phosphorylates AKT1//2 complex which phosphorylates DAF16, a transcription factor, inhibiting it.

Question 17

what is the result of mutations which damage Daf2 gene in c.elegans

Answer 17

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

Question 18

why is daf2 normally switched off after maturation

Answer 18

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

Question 19

why is ILS more complex in humans

Answer 19

we have more types of receptors leading to controversial observations e.g. mild reduction in function leading to type-2 diabetes

Question 20

what evidence in mouse models suggests mutants of daf2 homologues IGF1 and IGF2 increases lifespan

Answer 20

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

Question 21

what were the effects of reducing insulin like growth factor 1 (IGF1) signalling in mouse model of AD

Answer 21

protected/delayed the onset in the mouse leading to reduced near-inflammation and reduced neuronal loss

Question 22

what was found in a study of 122 japanese people over the age of 105

Answer 22

insulin signalling was reduced due to single nucleotide polymorphisms in insulin receptors

Question 23

how can resveratrol prevent aging

Answer 23

mimics the effect of dietary restriction, up regulating AMPK and down regulating TOR signalling

Question 24

how could rapamycin be used to treat aging

Answer 24

inhibits interaction of mTORc1 and raptor so reduces TOR signalling