Ageing Flashcards
Is ageing inevitable? What is the evidence for this?
No - many organisms show very little ageing such as Hydra Oligactis. Jean Calmet is a human that lived to 122 years and 24% of her relatives lives over 80 years. compared with 2% of controls. However twin studies suggest the heritability of life expectancy is 24%.
Why does ageing occur?
Inevitable result of declining force of natural selection. There are multiple theories behind why it happens.
Antagonists pleiotropy theory - allele that is beneficial in early life is not in later life. Still selected for becasue reproduction occurs early and stops at mid age.
Disposable soma theory - the bodies resources are directed to reproduction early in life at the detriment of somatic cells later in life. This would predict greater life expectancy if reduced fecundity and this is seen in flies.
Describe the hallmarks of ageing.
Genomic instability Telomeric attrition Epigenetic alterations Loss of protein stability Deregulated nutrient sensing Mitochondrial dysfunction Cellular senescence Stem cell exhaustion
What is ageing at a DNA level?
Accumulation DNA damage that the cell is less able to repair.
Intrinsic damage - replication fork stalling, telomeric erosion, ROS
Extrinsic damage - ionising radiation
Ageing does correlate with ability to repair DNA in organisms with longer life spans. Plants???
Discuss ROS production and the damage it can cause
Intrinsically from mitochondria and immune cells (but note ROS required for intracellular signalling).
Superoxide production is not an enzymatic process so higher metabolism = more ROS. ROS also effects proteins and lipids.
Guanine particualrly susceptible to ROS - forming 8 oxo guanine. This does not block the fork and can bind C or A, these miss matches are not always repaired.
How are ROS levels repaired in the body?
Balance of antioxidants vs oxidants
Antioxidant examples are Vitamin A, C and E. Also SOD. If you over-express SOD then the fly has an increased lifespan, but mice defective is SOD don’t show rapid ageing.
What is the role of mitochondria in ageing
Dysfunctional mitochondrial increase with age and so increase ROS production. Dysfunction within the mitochondria also associated with age related diseases such as Huntington’s and Parkinson’s disease.
Polymerase G controls all of the DNA metabolism in the mitochondria. KO in mice have a mutator phenotpye and increased ageing. Mice who are -/+ have increased mutations but no change in ageing. KO mice have no increase ROS so maybe not involved? Perhaps it is energy/apoptosis that’s involved.
Swap the mtDNA in a mice and there are drastic changes in life expectancy. Suggest mtDNA and nDNA co evolved.
Summary - ROS important for inducing mutations but not necessarily ageing itself.
What did experiments in C.elegans find regarding insulin/IGF patway in relation to ageing?
Single gene mutants increase life expectancy in C.elegans by 300%. All mutants trialed always required DAF16 to be active. KO of DAF16 are short lived.
DAF16 involved in maturing worm to reproductive stage of life. If two precurosr germ cells are ablated = sterility but increased life expectancy mediated by DAF16.
Mutations in insulin/IGF1 pathway that increase lifespan also decrease fecundity - matches fecundity to nutrition.
IGF1 involved in growth in mammals, LOF mutations cause increase lifespan.
How do calories influence lifespan?
Calorific restriction extend lifespan in animals. This is because the body switched to maintaining somatic functions until there is enough nutrition to reproduce. DR increases the bodies insulin sensitivity and response to stress.
DR also slow or prevents age related diseases. Pathway mediating this was identified in C.elegans and shown to be conserved in mice and flies - regulated by TOR kinase.
Experiments in monkeys showed same results as above. One drugs - resveratrol can mimic the response without changes in diet or calories consumption. Monkeys taking this drug has increase lifespan, increased insulin sensitivity and so decreased IGF-1, increased mitochondria and decreased organ pathology.
