L6 - Ageing and Sensecence Flashcards
What is sensecence
Age related decline in function
What are the posible reasons for senescence
Wear and tear
Genetics
Describe the evidence for the wear and tear model of sensence
Muscles thar are required for feeding degenerate over time because of their use
Elephants teeth wear away and they then die of starvation
What is the disposable soma thoery
Natural selection tunes life history of the organism so that sufficient rescources are invested in manitnianing repair mechanims AT LEAST UNTIL THEY HAVE TAKE CARE OF ITS YOUNG
Name three seescence factors
Metabolism
Reactive oxygen species
DNA damage
Factors which increase lifespan (3)
Dietary restriction
Environment
Signals from the somatic gonad
What is the rate of living theory
High metabolism gives a short lifespan –> larger animals live for longer
Why would cold blooded animals live for longer
Live at lower temperatures - don’t have to maintain a body temperature - lower rate of metabolism
High metabolism gives rise to
Reactive oxygen species (ROS)
What is central in the ROS theory of ageing
Superoxide radical `
What evidence is there to suggest that ROS radicals are anti-aging
In worms - paraquate of juglone treatment can act to increase the lifespan
Glucose restriction increases C.elegans lifespan by inducing mitochondrial respiration and increasing oxidative stress
Hutchinson guilford is caused by a mutation in what gene
What is the effect of this
LAMINA - affecting the nucelar architecture potentially impacting on the ability of the cell to repair DNA
Nestor Guillermo caused by mutations in what
BANF1 - affecting LAMINA and mitosis
Cockayne syndrome caused by
Muations in group 8 excision repair cross complementing proteins - affecting the ability to repair the DNA
How is Werners syndrome causes
Mutations in a RECQ helicase affecting repair/chromosomal segregation at anaphase
What is seen in mice with an increased rate of mutation
They do not age quicker
What type of DNA damage causes ageing
Unrepaired damage in non replicating cells
Why does unrepaired DNA damage in non-replicating cells cause aging
Through depletion of NDA through excessive PARP activation
What is PARP
Poly ADP ribose polyerase
What does PARP respond to
DNA damage
How many senescent cells promote the ageing phenotype
Through the secretion of pro-inflammaotry mediators
What is one factor which increases lifespan
Dietart restruction - lower nutrient metabolism (causes aging)
Describe howw the gerneration of ROS may increase lifespan
Low level of production may activate protective mechanims in a process called HORMESIS
What is hormesis
Protective measures as a result of low level insults of ROS
What else may increase lifespan
Emanation from the gonad (factors produced by the gomad)
How may forward genetics be used to understanding ageing
Find mutants where aging is affected
Clone gene
Identify function
Limitations of using short live mutants
Hard to tell which genes are required for ageing and which ones are required for life
3 pathwyas involveing in ageing
IGF
TOR
Siryuins
Normal c.elegans lifespan
25
What is the max life span of C.elegans - how does it live this lng
Entering the dauer stage can live for 60 days and upwards
What is the role of IGf
Inhibitions of DAF16 (AKA FOXO)
DAF16 AKA
FOXO
What is FOXO
A transcriptional regulator of genes which increase the resistance to various stressors
What is the effect of mutations in the IGF pathway in flies
What does this do
Double lifespan
Puts flies into reproductive diapause
What is the effect of mutating the IGF pathway in mammals
Can live for up to 3 times as long
What type of genes does FOXO downregulate
Insulin like genes
Including : Antioxidants Metabolic Chaperones Antibacterial
What is the role of FOXO on antioxidant genes
Increased resistance to ROS
What is the role of FOXO downregulating antibacterial genes
Prevention of autophagy which limits lifespan
What is TOR kinase
A major amino acid and nutrient sensor that stimulates gorwth and blocks slavage pathways such as autphagy when food is plentiful
What is the effect of stress on the TOR pathway
Activation of TSC
Inhibition of TOR
Activation of 4E-BP and inhibition of S6K1
SALAVGE PATHWAYS ACTIVE
What is the effect of growth factors and amino acids on TOR pathway
Blocking of TSC1-TSC2
Activation of Tor
Inactivation 4E-BP, activation of S6K1
WASTEFUL PATHWAYS ARE ACTIVE
How does insulin interact with the TOR pathway
Growth factor that talks to TOR via PI3K and Akt causing the inactivation of TSC1/TSC2 and the activaiton of TOR
Effect of blocking inuslin signalling
Inactivation of TOR
Activation of longevity pathways
What is rapamycin
What are its effects
Blocking TOR
extends lifespan
How is rapamycin seen to extend the life of OLD mice
Not through general reduction but through the reduction of life limitting factors (cancer)
what are sirtuins
NAD dep ptoein deaceylases
Affect of overexpression of sirtunins
Exntesion of lifespan
What is the effect of Sir2.1 in C.elegans
Activation of FOXO/DAF16
Also UPR-mt
What is UPR-mt
Mitochondrial unfolded protein response
Sir proteins act as
Insulin dependent activatiors of Daf16/FOXO
What is resveratrol
What does it activate
What is the knokc on result of this in mammals
Proposed anti-ageing agent in red win
Activation of Sir proteins
Downregulation of IGF1
Sir pathway
NAD –> Sirtuins –> DAF16/FOXO + UPR-mt –> Longevity
What is the NAD depeletion theory of aging
Certain mt mutations inc lifespan
Might cause a response of UPR-mt (like Sir)
NAD cofactor for sin - NAD levels decline with age
Unrepaired DNA damage may leaf to depletion of NAD and Poly ADP ribose polymerase (PARP) activation
Describe what is seen in C elegans when
Removal of entire repro system
Removal of only germ cells
No effect
Animals live up to 60% longer
Somatic gonad ____________ but these effects are __________ by the ______________
Extends
Counteracts
Germline
