aging and disease lecture 2- metabolism and genome Flashcards
what is the most common feature of accelerated aging?
disruption in metabolism and loss of genome integrity
where does most of the research of aging come from?
model organisms such as a C. elegans mutation that doubles life expectancy by perturbing insulin signalling which is the opposite of a progeroid syndrome
what parts of the C. elegans can you take information from?
L1 –> L2d occurs when limited food, dense population and high temperature
L2d –> dauer –> L4 occurs when plentiful food, sparse population, temperate environment
What is age-1?
a mutated gene that promotes C. elegans longevity
The mutant doubles post reproductive adult life expectancy from ~2 to ~4 weeks.
Mutant is recessive to wild type and is a partial loss of function of function.
Therefore, ONE of the normal functions of WILD TYPE age-1 is to limit adult life, reducing it by ~50% (partial loss doubles lifespan!)
what is dad-23?
age-1 and daf-23 are the SAME GENE; just different alleles on the same gene
daf-23 make dauer larvae all the time (even with plenty food)
Well nourished age 1 mutants do not make dauer larvae but do live twice as long as wild type worms as adults.
This demonstrated a link between control of dauer development AND ageing.
This is a NUTRIENT SENSING defect.
so what is the summary of daf-23 and age-1
daf-23/age-1 –complete loss-of-function –make dauers constitutively.
daf-23/age-1 –partial loss-of-function –normal adults live long. They display some of the long-lived phenotype of dauerlarvae without actually becoming a dauerlarvae.
how is dauer formation regulated?
the insulin signalling pathway
what happens during the insulin signalling pathway?
1-Insulin promotes glucose uptake from blood and conversion to glycogen.
2-Increased fatty acid synthesis.
3-Increased esterification of fatty acids –adipose tissue makes fats.
High calorific intake- insulin pathway is ON
Low calorific intake- insulin pathway is OFF
what are oxidants (free radicals)?
they damage dna and cause mutations
what are chaperones?
Mole rat has elevated chaperones.
Chaperones promote proteostasis
summary of insulin signalling and longevity…
C. elegans calorific restriction early in life promotes dauer larva formation.
Partial calorific restriction promotes longevity.
Mutants that block insulin signalling promote dauer.
Mutants that partially block insulin signalling promote longevity.
what happens in mammals?
Mammals
Dogs with LOW IGF-1 levels live longer than other breeds (small vs big dogs)
Larger animals have higher resting metabolic rates
Mouse heterozygous for IGF 1 receptor 30% life extension and increased
Oxidative stress resistance.
Calorific restricted diet -~40% life extension mice and rats.
does reduced insulin signalling cause longevity in c. elegans?
The mutant alleles that cause longevity are all partial loss of-function.
Complete loss causes constitutive dauer larva formation. Thus:
DAF-16 OFF- normal development- short life.
DAF-16 ON- starved develop as dauer larvae.
DAF-16 ON a bit - normal development but long lived.
what is p53?
Cellular senescence is a terminal stress activated defence mechanism regulated by p53.
Transcription factor- regulates gene expression
50% of all human cancers have a mutation that inactivates p53, usually in it’s DNA binding domain.
what does p53 do in each circumstance?
Moderate genome damage –induce DNA repair – return to normal
Severe genome damage (e.g. telomere dysfunction) – senescence
Severe genome damage plus hyperproliferation - apoptosis
