Project Outline

Sex is a key determinant of almost all aspects of animal physiology. Fundamental biological differences between males and females result in sexually dimorphic responses across a diverse array of phenotypes including ageing. Furthermore, sex impacts on the pathogenesis of most, if not all, diseases, including those commonly associated with ageing including obesity, diabetes, cancers and neurodegeneration. Yet despite the prevalence of sexual dimorphisms on phenotype, sex has historically been ignored in basic and preclinical research and so the underlying mechanisms that lead to many sex-specific effects are not well understood. As such, there is an urgent priority to redress this gap in the knowledge particularly where sex differences could impact on clinical outcomes.

The fruit-fly, Drosophila melanogaster, is a well-established and powerful model for the in vivo study of genes that influence ageing. As a sexually dimorphic species, we will use Drosophila to further understand how sex differences impact on lifespan and age-related physiology with a particular focus on cellular metabolism.

We have identified several key metabolic processes that differ between males and females. We will now use genetic tools to manipulate their activity and test whether these sex-specific differences in cellular metabolism are related to sexually dimorphic lifespan responses. Other techniques used in the project will include gene expression analysis by qRT-PCR, behavioural assays, immunohistochemistry & confocal microscopy. These studies will reveal fundamental new insights into how metabolic systems are co-ordinately yet differentially regulated in the two sexes helping us to better understand the complex relationship between sex, cellular metabolism and ageing.

References

Laskovs M, Partridge L, Slack C (2022). Molecular inhibition of RAS signalling to target ageing and age-related health. Disease Models & Mechanisms: 15(10): dmm049627. doi: 10.1242/dmm.049627

Slack C, Alic N, Foley A, Hoddinott M, Cabecinha M, Partidge L (2015). The Ras-Erk-ETS pathway is a drug target for longevity. Cell 62:72-83.

Slack C and Partridge L (2013) Genes, pathways and metabolism in ageing. Drug Discovery Today: Disease Models 10: e87-e93.

Techniques

• Genetic manipulations using transgenic technologies in Drosophila.
• Drosophila physiological and behavioural analyses e.g. survival assays.
• Gene expression analysis by quantitative real-time PCR.
• Molecular biology e.g. PCR, cloning, genomic engineering.
• Immunohistochemistry and confocal microscopy