Ageing is the largest risk factor for the developed world’s biggest killers, and the impact of age-related disease is one of society’s foremost challenges. Men and women do not age in the same way: women live longer than men, and the sexes suffer from age-related diseases at a different rate (1). Defective immunity is implicated as both cause and effect of ageing. For example, inflammation is an essential response to wounding and infection, but when inflammation is misdirected, or chronic, tissues damage ensues and development of age-related disease is accelerated.
It has long been known that men and women have a different propensity toward infectious and auto-inflammatory diseases. In part, this is due to sex dimorphisms in the function of innate immune cells such as macrophages and their interaction with other tissues over ageing. However, the molecular regulation and cell behaviour underlying these dimorphisms is not well-understood. In addition, it is not known how pharmacological interventions that extend lifespan to different extents in males and females in the lab impact the innate immune system.
We use a Drosophila model to tackle complex and key issues of the reciprocal interactions of sex, innate immunity and ageing. To do this we use several methodological approaches, including confocal and light sheet in vivo microscopy, infection and lifespan analyses, genetics, and transcriptomics. This PhD will build on previous work describing sexually dimorphic inflammatory pathologies (2,3), and on new data on dimorphisms in macrophage function, to uncover the role for innate immunity in driving sex differences in ageing. Project aims include;
(i) identify conserved molecular regulators of sex-specific macrophage function by analysing next-generation transcriptomic data from Drosophila and mouse models;
(ii) uncover the role for macrophage sex in sexually dimorphic, age-related inflammatory pathologies and ageing through imaging and lifespan analysis techniques;
(iii) test the impact of lifespan-extending pharmacology on dimorphic innate immune tissues. https://www.ed.ac.uk/profile/dr-jennifer-regan
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Regan, J. C., & Partridge, L. (2013). Gender and longevity: why do men die earlier than women? Comparative and experimental evidence. Best practice & research Clinical endocrinology & metabolism, 27(4), 467-479.
Regan, J. C., et al (2016). Sex difference in pathology of the ageing gut mediates the greater response of female lifespan to dietary restriction. Elife, 5, e10956.
Regan JC, et al (2018) Ras inhibition by trametinib treatment in Drosophila attenuates gut pathology in females and extends lifespan in both sexes. bioRxiv 356295; doi: https://doi.org/10.1101/356295