Sirtuins Flashcards
which pathways does the sirtuin pathway interconnect
TOR/AMPK and ILS
how is Sir2 involved in transcriptional repression
it maintains regions of DNA in a condensed form for long periods (heterochromatin)
what is the mechanism for Sir2 transcriptional repression
it deacetylates histones. the reaction is coupled to cleavage of NAD+ to from NAM and O-acetyl-adp-ribose
how does Sir2 promote longevity in Yeast
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
what are ERCs
extrachromosomal rDNA circles
what is the result of deletion of Sir2 in yeast
decreases lifespan
what is the result of additional copies of Sir2 in yeast
increases lifespan
are ERCs formed in all organisms
no just yeast
is sir-2 conserved throughout evolution
yes
how many members are there of the mammalian sirtuin family
7
what is the result of overexpression of Sir2 in c.elegans
it increased lifespan
what is the result of overexpression of Sir2 in c.elegans mutants which already have an increased lifespan due to mutations in daf2
no effect
how does sir2 effect longevity in c.elegans
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
describe the 2 pathways which activate sir2 under low calorie conditions
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
what is the result of moderate and extreme caloric restriction on yeast
increaed lifespan
under which caloric conditions is lifespan extension independent of sir2
severe restriction
which form of caloric restriction increases lifespan the most
moderate restriction
in yeast, is sir2 upstream or downstream of mitochondrial respiration
downstream- inc. mit resp= sir2 activation
in organisms aside from yeast, is sir2 upstream or downstream of mitochondrial respiration
upstream
how do sirtuins activate mitochondrial respiration in mice
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
how do sirtuins increase mitochondrial resp in humans
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
what is the function of SIRT1 in mammalian brain cells
linked to processes involved in weight gain on a high fat diet
how is hSIRT1 implicated in stress management
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
how is hSIRT1 implicated in metabolism
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
what are the 2 mechanisms for hSIRT1 involvement in AD
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
how does resveratrol modulate NAD+/NADH
it activates AMPK stimulating NAD+ synthesis which activates sirtuins and mitochondrial respiration, mitochondrial fatty acid oxidation and gluconeogenesis
what is the effect of increased mitochondrial respiration as a result of treatment with resveratrol
it has been shown to block deleterious effects of a high fat diet in mice
how can NAD+/NADH be modulated using inhibitors
PARP and CD38 both consume NAD+ so inhibiting these increases levels of NAD+, activating sirtuins
