Investigating Nutrient-Sensing Pathways in Ageing Human Neural Stem Cells and Age-Related Cognitive Decline

Student thesis: Doctoral ThesisDoctor of Philosophy


Ageing is associated with changes in cellular and molecular processes including the alteration of stem cell pools. In particular, biological and functional changes observed in ageing neural stem cells (NSCs), are linked to age-related cognitive decline. Recently, the systemic environment has been shown to alter both NSC regulation and age-related cognitive decline. Interestingly, a well-documented and naturally occurring way of altering the composition of the systemic environment is through diet and nutrition. Studies have found an overabundance of nutrients to be detrimental for human and animal health; the presence of specific nutrients as well as the overall increase in calorie or protein intake was shown to overstimulate conserved molecular pathways and to reduce lifespan. Conversely, dietary restriction was found to be the most efficient way of extending an organism’s lifespan. In this study, we examined nutrient sensing pathways in relation to their function in NSCs, ageing and cognition. We focus on the Sirtuin, mTOR and Insulin / Insulin like growth factor- 1 pathways and employ both in vitro and epidemiological methods to assess their contribution to age-related phenotypes. Using a human hippocampal progenitor cell line (HPC) we modelled ageing through treatment with ageing human serum and via pharmacological interventions combined with increased passage number. A semiautomated imaging platform was used for the immunocytochemical quantification of NSC proliferation, differentiation, damage and apoptosis. Further to this, candidate gene selection was preformed through literature search and validated by qPCR to measure gene expression alterations within our ageing models. Results from the in vitro experiments, were used to inform the selection of 9 genes belonging to nutrient-sensing pathways as candidate genes for a role in NSC regulation. Next, we investigated the effects of lifestyle and candidate-gene genotype on cognition using 1633 participants from the adult longitudinal population-based TwinsUK cohort. We report that treatment with human serum is able to induce changes in the HPC model that relate to both the serum-donor’s hippocampal volumes and their cognitive performance. In addition, we report interesting associations between candidate-gene expression and NSC regulation. Our data also revealed increasing passage number causes significant alterations in nutrient-sensing genes and emphasised FOXO3A, NAMPT, PTEN, GRB10 and mTOR as interesting candidates for further ageing research. Finally, epidemiological analysis showed a significant effect of lifestyle on cognition and highlighted associations between SNPs in SIRT1 and ABTB1 and cognitive performance. The results outlined in this thesis support an important role for nutrient-sensing pathways in human NSCs ageing. In addition, we provide support for the use and further development of novel in vitro models to investigate NSCs ageing and to validate existing pathways, uncover new targets and test novel therapies.
Date of Award1 Apr 2019
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorSandrine Thuret (Supervisor), Richard Dobson (Supervisor), Petra Proitsi (Supervisor) & Aleksandra Maruszak (Supervisor)

Cite this