Aging and senescence Flashcards
What is senescence?
What could this be due to?
Age related decline in function
Could be due the decline in stem cells during aging
How is senescence seen in drosophila?
What does this show?
Drosophila survival at 100% but rate of death rapidly increases with aging
Shows there is something limiting the lifespan
Is senescence due to wear and tear or genetics?
There is evidence for BOTH
What is the evidence of wear and tear for senscence?
1) Decline in muscle function in C.elegans
- Muscles for feeding degenerate over time as a result of their use –> unable to move/feed
2) Teeth worn off in elephants as they age –> die of starvation
What is the evidence of genetics for senscence?
1) Salmon
- Die soon after laying their eggs
2) Species differences in aging:
- Gestation period of elephant is 21 months
- Life span of mouse is 42months (within 21 months –> already shows clear signs of aging)
- Genetic programme in how different animals age
What theory explains aging?
The disposable soma theory:
- Natural selection tunes the life history of the organism so that sufficient resources are invested in maintaining the repair mechanisms that prevents aging
- At least until the organism has reproduced and cared for its young
- As soon as an individual cannot increase the number, or chance of survival of its offspring any further - there is no natural selection against decline/aging
If there are genes/mechanisms that increase the chance of reproductive success, what happens to them over life?
These genes are present in early life but contribute to killing the organism when the progeny is independant
Act to kill off animals that can’t help their offspring any further
What are 3 senescence factors?
1) Metabolism
2) Reactive oxygen species
3) DNA damage
What is the rate of living theory?
Examples
States that HIGH METABOLISM –> SHORT LIFESPAN
- Low metabolism in larger animals –> live longer
- Cold blooded animals live longer at LOWER temperatures
What happens in species with a high metabolism?
What does this cause?
Generate a reactive oxygen species (ROS):
- Superoxide which has a free electron, which is very reactive and unstable
- -> Causes OXIDATIVE DAMAGE to many molecules in the animal
What is the superoxide radical produced in an animal with a high metabolism central to?
Central to the ROS theory of aging
What are the contradictory results when manipulating ROS?
1) When treat WORMS with known oxygen species generators –> INCREASE lifespan
- If take out the superoxide anion –> shorten lifespan
2) Glucose restriction extends the life of C.elegans by inducing mitochondiral respiration and INCREASING oxidative stress
3) Some genes increase the RESISTANCE to oxidative stress and give longevity to animals
What are some of the ideas about how ROS works to increase/decrease lifespan?
1) May be another form of molecular damage related to oxygen that causes damage
2) May be due to the LEVELS of ROS - able to cope with levels in the body but if increase –> alarm system
What are progeria sydromes?
What is the cause?
Premature aging
Genetic cause - likely to be driving aging or preventing aging under normal conditions
What are examples of progeria sydromes?
1) Hutchinson Guilford
2) Nestor Guillermo
3) Ehlers Danos
4) Cockayne
5) Werner
What is aging to do with?
Nuclei/DNA/DNA repair
What is the DNA damage theory of aging?
States that DNA damage is the reason for aging:
- In non-replicating cells, unrepaired/unrepairable DNA damage may ACCUMULATE and cause aging
What happens to unrepaired DNA in dividing cells?
Will lead to mutations
Why do mice with a high mutation rate NOT age quicker?
It is the UNREPAIRED DNA damage that causes aging
NOT the mutation itself
Why is it likely that unrepaired DNA damage is likely to cause aging?
NAD depletion? PARP activation?
- Un repaired DNA leads to the activation of an enzyme PARP
- PARP normally uses NAD and responds to DNA damage –> depleting NAD
- Lots of un repaired DNA damage –> lots of PARP and lack of NAD
–> may cause senescence (age related decline in function)
What is PARP?
Poly ADP-ribose polymerase
How may senescent cell drive the important aspects of aging?
- Lots of DNA damage but don’t die
1) Have a senescence-associated secretory phenotype (SASP):
- Secrete molecules that ATTRACT and ACTIVATE IMMUNE cells –> leading to INFLAMMATION
2) Block stem cell mediated repair:
- Sit in the stem cell niche and ‘hog’ the space –> preventing GOOD stem cells from developing and doing their job
What happened in mice when removed the senescent cells?
They didn’t age as much as the mouse that still had them
What are 3 factors that increase life span?
1) Dietary restriction
2) Environmental stresses
3) Signals from the somatic gonad
In what organisms does dietary restriction increase lifespan?
In ALL model organisms
How does dietary restriction increase lifespan?
Decrease in CALORIC intake –> dramatically increases life span
Why do environmental stresses, like heat, increase lifespan?
Lead to an INCREASED amount of ROS
What are the theories behind how an increase in ROS increases lifespan?
1) Hormesis
2) A protective superoxide induced pathway
Describe the hormesis theory
If give a small insult to a cell by INCREASING ROS –> activates a PROTECTIVE RESPONSE that is bigger than the insult itself
What is the protective superoxide induced pathway?
An alarm pathway - warns that something is not ok
What genetic methods can we use to identify the factors involved in aging?
FORWARD GENETICS:
- Find mutations that affect aging in model organisms –> clone the gene and find out what it does
What different mutations COULD affect aging?
1) Short lived mutants
2) Long lived mutants
What is the problem with assuming that short lived mutants die because of aging?
There are MANY mutants that can kill an animal - not necessarily aging
What is the problem with long lived mutants in mouse and zebrafish?
EXPENSIVE
Take a long time to age
What have forward screens identified in aging?
A number of pathways that have a CLEAR ROLE in aging:
1) IGF
2) TOR pathway
3) Sirtuins
What do c.elegans do if the circumstances aren’t good enough when they hatch?
Extend lifespan:
Go into a DAUER stage that lasts several months
And then go on to form normal adult
What is the IGF pathway identified in mutants that live longer?
1) Signalling through DAF2 (IGF receptor)
2) Activation of age1 (PI-3 kinase)
3) Activation of AKT-1 –> represses DAF16 (FOXO-type transcription factor)
What happens if KO IGF pathway?
What does this show?
- Activation of the FOXO-like transcription factor that is usually inhibited
- -> Live longer
Shows that the IGF pathway acts to REDUCE lifespan
What do mutations in insulin/IGF1 pathway result in?
How?
What is this linked to?
DOUBLING of the lifespan:
- Flies go into a reproductive diapause (don’t produce any more eggs)
Linked to RESISTANCE to oxidative stress (contradictory)
What genes have been linked to human longevity?
- FOXO1
- FOXO3A
- AKT
- IGF1 receptor varients
What mediates lifespan extension by dietary restriction?
MOSTLY IGF signalling (mice)
PARTLY IGF signalling (worms/fly)
What happens to mice under caloric restriction when there is a mutation in GH receptor?
DOES NOT extend life
What happens when down regulate IGF signalling?
Activation of a nuclear factor DAF16 (FOXO)
Which DOWN REGULATES insulin-like genes and UP-REGULATES other genes
What are the genes that UP-regulated by FOXO?
1) Antioxidant genes (such as superoxide)
2) Metabolic genes
3) Chaperones
4) Antibacterial
What does the blockage of autophagy in long lived DAF2/IGR mutants cause?
Limits the lifespan
What is TOR kinase?
What happens when it is activated?
A major amino acid and nutrient-sensor
When activated:
- Stimulates GROWTH
- Blocks SALVAGE PATHWAYS, such as autophagy
When is the TOR pathway activated?
When food is plentiful and insulin signalling is present
How is TOR normally activated?
By INSULIN through:
- PI3K and Akt –> INACTIVATION of TSC1/TSC2 (which normally INHIBIT TOR)
–> Activation of TOR
Why do mutations in insulin signalling cause the drosophila to increase life span?
Insulin signalling is normally required for CELL GROWTH and METABOLISM
SO, when mutated –> drosophila goes into reproductive diapause
Reproductive diapause prolongs life as no more eggs are made in this period —> theory states that age when no longer able to produce/support eggs
What is the ROS theory of aging?
What is the problem with this theory?
Aging is caused by the accumulation of free radicals in the tissue that cause damage
There is lots of contradictory evidence against this that actually ROS increases aging (due to organism going into a quiet state??)
What happens to TOR when insulin signalling is inhibited?
What does this cause?
TOR signalling is also inhibited
- Causes the activation of longevity pathways
- Reducing protein synthesis and cell growth
What is an example of a longevity pathway?
Pathway driven by 4E-BP1
What is a known inhibitor of the TOR pathway?
What does this drug do?
Rapamycin
Extends lifespan
What are Sirtuins?
What can they activate?
NAD-DEPENDANT protein DEACETYLASES
Sir proteins are INSULIN INDEPENDANT activator of Daf16 (FOXO)
What happens if over express Sirtuins in yeast, worms and flies?
How?
EXTENDS lifespan
Activates Daf16 (FOXO)
How are sirtuins present in mammals?
In MANY ISOFORMS
What is SIRT6 linked to?
How?
Longevity in mice
Due to IGF down regulation
How do Sirtuins lead to longevity?
1) Use NAD to activated Daf16 (FOXO)
2) Activation of the mitochondria
3) Unfolding of protein response in the mitochondria
What is the NAD depletion theory of aging?
- NAD levels decline with age
- Unpaired DNA damage may lead to NAD depletion (DNA damage theory of aging)
- Prevents sirtuins from working properly
–> aging
Describe the ‘cost of reproduction’
Expect a fair trade-off between REPRODUCTION and LONGEVITY
What happens if remove the entire reproductive system in c.elegans?
How is this different to if just remove the germ cells?
What does this show?
Remove entire system - no extension of lifespan
Remove just the germ cells - animals live 60% longer
Shows that the SOMATIC GONAD extends lifespan, but their effects are COUNTERACTED by the germline
What is the effect of the somatic gonads when the germ line is removed?
Somatic gonads can extend the lifespan of the IGFR (DAF2) mutants even further
What genes are important in driving the protective response?
- Activation of FOXO
- Inhibition of TOR
- Dafachoric acid
- DAF12
What do Dafachoric acid and DAF12 do?
Converge on FOXO and activate FOXO
