Sirtuins

Question 1

which pathways does the sirtuin pathway interconnect

Answer 1

TOR/AMPK and ILS

Question 2

how is Sir2 involved in transcriptional repression

Answer 2

it maintains regions of DNA in a condensed form for long periods (heterochromatin)

Question 3

what is the mechanism for Sir2 transcriptional repression

Answer 3

it deacetylates histones. the reaction is coupled to cleavage of NAD+ to from NAM and O-acetyl-adp-ribose

Question 4

how does Sir2 promote longevity in Yeast

Answer 4

as yeast DNA divides its rDNA can be recombined to form ERCs which accumulate in the mother cell. expressing these in the daughter cell can induce premature senescence. Sir2 has a role in stalling appearance of ERCs through creating heterochromatin regions to prevent transcription of these regions

Question 5

what are ERCs

Answer 5

extrachromosomal rDNA circles

Question 6

what is the result of deletion of Sir2 in yeast

Answer 6

decreases lifespan

Question 7

what is the result of additional copies of Sir2 in yeast

Answer 7

increases lifespan

Question 8

are ERCs formed in all organisms

Answer 8

no just yeast

Question 9

is sir-2 conserved throughout evolution

Answer 9

yes

Question 10

how many members are there of the mammalian sirtuin family

Answer 10

7

Question 11

what is the result of overexpression of Sir2 in c.elegans

Answer 11

it increased lifespan

Question 12

what is the result of overexpression of Sir2 in c.elegans mutants which already have an increased lifespan due to mutations in daf2

Answer 12

no effect

Question 13

how does sir2 effect longevity in c.elegans

Answer 13

under acute stress daf16 becomes dephosphorylated and forms a complex with 14-3-3 which translocates into the nucleus and interacts with sir2.1 which allows transcription of genes required for longevity

Question 14

describe the 2 pathways which activate sir2 under low calorie conditions

Answer 14

one leads to increased mitochondrial respiration so an increased ratio of NAD+:NADH whils the other goes via NAD scavenging protein called PNC1 which is activated by caloric restriction and reduces NADH levels increasing the NAD:NADH ratio and activating sir2

Question 15

what is the result of moderate and extreme caloric restriction on yeast

Answer 15

increaed lifespan

Question 16

under which caloric conditions is lifespan extension independent of sir2

Answer 16

severe restriction

Question 17

which form of caloric restriction increases lifespan the most

Answer 17

moderate restriction

Question 18

in yeast, is sir2 upstream or downstream of mitochondrial respiration

Answer 18

downstream- inc. mit resp= sir2 activation

Question 19

in organisms aside from yeast, is sir2 upstream or downstream of mitochondrial respiration

Answer 19

upstream

Question 20

how do sirtuins activate mitochondrial respiration in mice

Answer 20

caloric restriction induces enothelial NO synthase which increases levels of NO, inducing sirt1 expression which leads to the deactivation of PGC1a, a transcriptional coactivator which activates mitochondrial respiration, increasing biogenesis and increased levels of ROS activating the stress response which is beneficial for lifespan extension

Question 21

how do sirtuins increase mitochondrial resp in humans

Answer 21

a 6 month caloric restriction diet activated SIRT1 in muscle tissue and expression of mit. genes including a gene involved in mitochondrial dan transcription and genes involved in mitochondrial biogenesis

Question 22

what is the function of SIRT1 in mammalian brain cells

Answer 22

linked to processes involved in weight gain on a high fat diet

Question 23

how is hSIRT1 implicated in stress management

Answer 23

it deacetylates FOXO to boost cellular capacity to repair DNA damage. FOXO targets genes required for stress resistance as well as genes implicated in longevity

Question 24

how is hSIRT1 implicated in metabolism

Answer 24

SIRT1 deacetylates PGCA1 leading to increased respiration.
In caloric restriction SIRT1 deacetylates FOXO which activates Ppar which alters gene expression leading ro less differentiation of cells in adipose tissue

Question 25

what are the 2 mechanisms for hSIRT1 involvement in AD

Answer 25

SIRT1 activates apia secretes to differently cleave precursor protein, reducing the amount of amyloid protein.
overexpression of SIRT1 deacetylates Tau which destabilises it so it can be more easily degraded by the proteasome, preventing aggregates and tangles

Question 26

how does resveratrol modulate NAD+/NADH

Answer 26

it activates AMPK stimulating NAD+ synthesis which activates sirtuins and mitochondrial respiration, mitochondrial fatty acid oxidation and gluconeogenesis

Question 27

what is the effect of increased mitochondrial respiration as a result of treatment with resveratrol

Answer 27

it has been shown to block deleterious effects of a high fat diet in mice

Question 28

how can NAD+/NADH be modulated using inhibitors

Answer 28

PARP and CD38 both consume NAD+ so inhibiting these increases levels of NAD+, activating sirtuins