Aging Flashcards
Aging can be a result of what two things - give examples in organisms
‘wear and tear’ - decline in muscle function in drosophila or teeth worn down in elephants
Genetic - eg salmon die after they lay their eggs
What are the differences in aging between elephants and mice?
Mice live for only 41 months
By the time an elephant is born (gestation = 21 months) a mouse is half way through their life
What is the disposable soma theory?
Natural selection tunes life history of the organism so that sufficient resources are invested in maintaining the repair mechanisms that prevent aging at least until the organism has reproduced and cared for its young
List three senescence factors
DNA damage
Reactive oxygen species
Metabolism
Give three factors which increase life span
Dietry restriction
Enviromental stress
Signals from the somatic gonad
What is the rate of living theory?
Higher metabolism means organisms have a shorter life span
ie larger animals will live longer
whales = 200 years
flies = 150 days
How can drosophila show that a slower metabolism means organisms live longer?
Flies kept at 18 degress will live longer than those living at 29 degrees
18 = 120 days
29 = 40 days
Metabolism is a source of what?
Reactive oxygen species
What happens in worms treated with paraquol or juglone?
They have a longer life span showing they could be superoxide dependent
Contradicts the theory
How does glucose restriction increase lifespan?
It induces mitochondrial respiration increasing oxidative stress
Resistance to oxidative stress is induced by what?
Longevity genes
List some types of progeria syndromes
Hutchinson Guilford Nestor Guillermo Ehlers Danos Cokayne Werner
What is progeria?
Premature aging
What is hutchinson guilford disease?
A lamina mutation = nuclear architecture DNA repair
What is nestor Guillermo?
BANF1 mutation = lamina/mitosis
What is Ehlers Danos a mutation in?
Xylosylprotein 4-beta-galactosyltransferase
What is cockayne?
Group 8 excision repair cross complementing protein = DNA repair
In a non replicating cell DNA damage will cause what?
Aging = senescence
Do mice with higher mutations age quicker?
No
This suggests that damage causes aging in cells
What is PARP?
An enzyme essential for certain DNA repair processes
What happens in mice which are genetically reprogrammed to destroy senescent cells?
They live longer
What is hormesis?
When an enviromental stress activates protective mechanisms
A small insult can unleash a disproportionate protective response
When using forward genetics to identify genes involved in ages what phenotype is looked for and why?
Animals that live longer
Those that live shorter could be due to a variety of mechanisms and so may not be directly linked to aginf
The use of genetics identified which three pathways involved in aging?
IGF
TOR
Sirtuins
If L1 C.elegans are put in adverse conditions what happens?
They enter the dauer state which increases their life span from 25 to 60 days
This is under IGF1 control
Genetic screens have identified mutants which promoting longevity. What is their effect on the IGF pathway?
They were found to block insulin signalling
In drosophila the loss of IGF has been linked to what?
Resistace to oxidative stress
Female mice with mutations in IGF receptors 1 and 2 can live for how long?
Up to 33% longer than a normal mouse
Which receptor variants have been linked to human longevity in multiple cohort studies?
FOXO1, FOXO3A, AKT and IGF1
Lifespan extension by dietry restricton is mediated by what?
IGF signalling
Which genes are downstream of DAF16/FOXO in c.elegans?
Antiooxidant genes
Metabolic genes
Chaperones
Antibacterial genes
What is TOR kinase?
A major amino acid and nurtrient sensor
Stimulates growth and blocks salvage pathways such as autophagy when food is plentiful
How is the salvage pathway activated?
In times of stress
Activates TSC which blocks TOR so 4E-BP4 is activates and S6KI is blocked so no cell growth or protein synthesis occurs
What is the effect of growth factors on the TOR pathway?
They block TSC1 -TSC2 so TOR is active
4E-BP4 is blocked
S6KI is active so the wasteful pathway is active
Insulin talks to the TOR pathway via what?
PI3K and Akt
What is rapamycin?
Extends the life span of old mice
May be due to general reduction in aging phenotypes eg cancer rather than a reduction of a subset of important life limiting factors
Sirtuins are the target of what in red wine?
Resveratrol
Overexpression of sirtuins leads to what?
Extended lifespan in yeast, worms and flies
What is the effect of sirtuins which leads to longevity?
DAF16/FOXO are activated
Mitochondrial unfolded protein response
What happens in c.elegans when you remove the reproductive system vs the germ cells
Removal of reproductive system does not extend the lifespan
Removal of the germ line extends the life span up to 60%
