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Investigating the role of insulin/IGF-like signalling in brain ageing


Project Description

Improvements in healthcare and life style in many countries have resulted in increased life expectancy, but health expectancy is not increasing at the same rate. Therefore, there is a great need for the development of therapeutic interventions to improve health and function at older ages. Encouragingly, the study of ageing in model organisms such as worms, flies and mice, has led to the discovery that evolutionarily conserved genes and signalling pathways modulate ageing, making it amenable to pharmaceutical or lifestyle modification. The evidence for the evolutionarily conserved role of signalling pathways in ageing is strongest for the Insulin,IGF-like/Target of Rapamycin (IIS/TOR) nutrient sensing signalling network. Mutations that alter IIS/TOR can have pleiotropic effects on growth, development, metabolic homoeostasis and reproduction. Despite the potential for severe detrimental effects, such as diabetes in mammals, reduced IIS/TOR extends lifespan in worms, flies and mice. The IIS pathway converges onto the master transcription factor DAF-16/FOXO to regulate a plethora of health assuring processes including stress resistance, energy storage, mitochondrial health, damage clearance, response to infection, recycling and repair mechanisms. DAF-16/FOXO has been found to promote both lifespan and healthspan extension from worms to flies and mice, with strong indications that it does so in humans as well. As a result, this signalling network and its downstream effectors are an important focus of ageing research in terms of identifying potential therapeutic drug targets.

However, in recent years, the health benefits of DAF-16/FOXO overactivation (ie reduced IIS) in the worm and fly has been increasingly questioned. Despite affording very significant lifespan extensions and metabolic improvements, motor and cognitive functions were found to be impaired in both models. We currently know very little about the role of IIS in the ageing and function of specific tissues, particularly the brain. We and others have discovered that lifespan and behavioural/cognitive healthspan are often disconnected and our data raise the possibility that therapeutic ageing interventions could result in deleterious effects on brain function. We have shown that lifespan extension due to reduced IIS in Drosophila can occur concurrently with normal, ameliorated or exacerbated locomotor senescence. Our data indicate that the Drosophila insulin receptor independently modulates lifespan and age-specific function of different locomotor behaviours in a sexually dimorphic fashion and reduced IIS is not beneficial to the neural circuitry underlying the behaviours in both sexes despite increasing the lifespan of females (Haji Ismail et al, 2015). We have more recently found that reduced IIS in neurons does not result in these deleterious effects on locomotor behavioural function due to exacerbating the ageing of neurons but instead results in functional deficits that may outweigh any positive effects of reduced IIS on neuronal ageing. However, it is still unclear whether neuronal ageing is slowed or delayed due to reduced IIS, in the same way as it is in the periphery, and whether other behavioural functions, in addition to locomotor behaviour, are deleteriously affected.


Primary Aims of the Project and Research Questions

Hypothesis: The disconnection between lifespan and brain healthspan in long-lived flies with reduced IIS is due to altered brain function that masks protective effects of the treatment on brain ageing.
Primary Aim: To investigate the mechanisms underlying the age-related behavioural dysfunction due to reduced neuronal IIS in Drosophila melanogaster.

Research Questions:
(1) Does reduced IIS delay or slow neuronal ageing?
(2) How does reduced neuronal IIS affect cognitive (learning and memory) senescence?
(3) Are the observed lifespan effects and the deleterious effects of reduced neuronal IIS on behavioural/cognitive senescence dependent on FOXO?
(4) Does reduced neuronal IIS affect synapse number and/or neurodegeneration in the fly brain with age?
(5) How does reduced neuronal IIS affect the normal age-related decline of neurotransmitter levels in the brain?

These questions will be tackled using genetic manipulation of IIS in the fly with behavioural, molecular and anatomical analyses. The long term goal of the research is to understand how IIS modulates neuronal function and ageing to enable us in the future to identify specific genes downstream of IIS that can be safely targeted to promote healthy brain ageing with no detrimental side effects on neuronal function.




Funding Notes

Applications should be made directly to Dr Sue Broughton and should include:

CV (max 2 A4 sides), including details of two academic references
A cover letter outlining your qualifications and interest in the studentship (max 2 A4 sides)

References

Haji Ismail M.Z.B., Hodges M.D., Boylan M., Achall R., Shirras A.D. & Broughton S.J. (2015). The Drosophila Insulin Receptor Independently Modulates Lifespan and Locomotor Senescence. PLoS ONE 10(5): e0125312. doi:10.1371/journal.pone.0125312

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