Ageing Flashcards
What theories of ageing are there?
Genetic - age is predetermined by genotype
Wear and tear - some energy must be used for reproduction so not all energy can be used for maintenance so wear and tear is inevitable
Environmental - damage caused by adverse environmental factors leads to progressive ageing.
Disposable soma - once natural selection is less of a pressure (later in life) genes that may have originally conveyed an adaptive advantage may be detrimental to health.
Stochastic - random cellular/molecular events eventually accumulate leading to ageing and death.
What evidence is there for the genetic theory of ageing?
Bigger animals live longer than small ones
Familial longevity
Werner syndrom
What environmental influences are there on ageing?
Most just seem to predispose to diseases of old age rather than actually causing ageing. Calorie restriction does seem to promote longevity in some studies.
What is the Hayflick limit?
The number of times a cell can replicate itself before becoming senescent. This coincides with the point where telomeres become too short.
What else did Hayflick notice with dividing cells?
There are gradual changes to the S&F of cells even before they reach there limit to divide.
How could caloric restriction prevent ageing?
Resources may be diverted towards maintenance and cellular metabolism may slow reducing damage caused by ROS.
What is the relationship between CR and insulin levels?
CR would allow glucose homeostasis with lower levels of plasma insulin. This implies insulin may play a role in ageing.
What is a dauer worm and what is its relationship to insulin signalling?
Dauer worms are long lived larval forms of a worm that are highly stress resistant. Mutations in daf-2 (worm insulin receptor) leads to prolonged time in this larval stage. Daf 2 activation leads to AKT1/2(protein kinases) phosphorylation of Daf 16 (FOXO transcription factors) which normally promotes longevity genes. Phosphorylation prevents it from entering the nucleus.
How is this similar in drosophila models?
Mutations to the drosophila insulin receptor and IR substrate protein (chico) lead to long lived mutants. This is due to increased FOXO. When mutations are localised to the fat body the anti ageing effect is still seen indicating FOXO may result in the production of humoral (endocrine) factors that either promote anti ageing or suppress ageing.
How does mice evidence link with some of the theories of ageing that link reproduction and maintenance?
Mice with small body size are longer lived and have greater stress resistance but are unable to reproduce!
What are the roles of SIRT1 and SIRT2?
1 - may increase FOXO activation
2 - blocks inhibitory effects of insulin, possibly by deacylation of FOXO.
What is klotho?
A transmembrane protein that seems to have some determination on the sensitivity of cells to insulin signalling by preventing autophosphorylation of the insulin receptor and phosphorylation of insulin receptor substrates.
What evidence is there for its role in ageing?
non-function mutations accelerate ageing
over expression seems to extend lifespan
How does delaying growth or reproduction affect lifespan?
This seems to increase the lifespan of some species
What is the theory of developmental programming in respect to ageing?
In utero environmental factors induce permanent changes to metabolism, hormone production and sensitivity to hormones that can have a long term impact on physiology and metabolism.
What are Ames and Snell dwarf mice?
Ames - Prop 1 TF k/o
Snell - Pit 1 TF k/o
Are these mice long lived?
Yes, as both of these genes lead to reduced GH and therefore reduced IGF-1 production which can also act via the insulin receptor.
Prop 1 - transcription factor involved in pituitary cell ontogenesis
Pit 1 is a GH transcription factor.
What are firko mice?
Fat specific insulin receptor k/o mice.
Do they age?
The have increased longevity. n.b the k/o is specific to fat cells!
What is the relationship between FOXO and insulin?
FOXOs downstream effects seem to convey insulin resistance and insulin prevents the translocation of FOXO to the nucleus.
How is FOXO prevented from entering the nucleus?
Phosphorylation downstream of insulin signalling prevents this.
