Aging is a complex, multi-facetted process during which key parameters in an organism change gradually, resulting in an overall functional decline. This includes a reduction of the self-renewal potential of stem cells, a decline of resistance to external stressors, defective removal of senescent cells and a diminished activity of autophagic lysosomes which reduces the cells ability to remove toxic components and recycle nutrients (1, 2).
We have analysed libraries of natural chemicals for activators of the environmental cell stress response driven by the transcription factor Nrf2. This signalling pathway is upregulated in all long-lived organisms and is critical for metabolic health (3). We have analysed these compounds for their effectiveness and toxicity in a number of cell types. We now propose to further investigate these compounds for their therapeutic potential as anti-aging compounds. We plan to address three related issues:
 The effects of natural chemicals on age-relevant signalling pathways
 Assessment of bioavailability of anti-aging natural chemicals
 Development of multifactorial bioassays
Phytochemicals (like conventional drugs) have numerous activities in the cell as they can interact with many target proteins. Some of these activities may be linked at a molecular level, while others are not. Our analysis of gene and protein expression changes in response to several phytochemicals have shown that the overall changes induced by the treatments are limited (i.e. not a wholesale change of cell function) and are specific for different phytochemicals. Nevertheless, some of the activated pathways overlap between different phytochemicals.
In silico pathway analysis has demonstrated that some of the phytochemicals we have identified not only activate genes associated with the oxidative stress response (phase II enzymes regulated by Nrf2) and the Aryl hydrocarbon receptor pathway (phase I enzymes regulated by ARH), but also the mTOR pathway implicated in aging relevant energy metabolism.
There are several physiological pathways other than the environmental cell stress response which are highly relevant to the aging process. The most prominent of which are the cellular energy sensing mechanisms around the mTOR protein, the cell senescence pathway and autophagy. As a first step we will study the effects of the natural chemicals we have already identified on these major aging pathways using established markers (e.g. S6K phosphorylation, senescence associated b-galactosidase, LC3 recruitment to lysosomes) (4–6) to obtain a more comprehensive picture of potential pleiotropic effects.
Bioavailability is a key issue for the nutritional or pharmaceutical application of natural chemicals in vivo. We will assess the metabolism of the phytochemicals we have identified in our current screens using in vitro enzymatic and bacterial transformation approaches and transwell co-cultivation systems modelling cross-gut epithelium transport.
A longer-term ambition is the generation of cell analysis systems which allow the concomitant quantification of several aging relevant pathways in a single cell. This would allow the identification of anti-aging compounds with superior activity profiles.
This project is advertised in relation to the research areas of HUMAN NUTRITION. Formal applications can be completed online: https://www.abdn.ac.uk/pgap/login.php
. You should apply for Degree of Doctor of Philosophy in Human Nutrition, to ensure that your application is passed to the correct person for processing.
NOTE CLEARLY THE NAME OF THE SUPERVISOR AND EXACT PROJECT TITLE ON THE APPLICATION FORM. Applicants are limited to applying for a maximum of 3 applications for funded projects. Any further applications received will be automatically withdrawn.
1. T. Finkel (2015) The metabolic regulation of aging, Nature Medicine. 21, 1416–1423.
2. C.E. Riera and A. Dillin (2015) Can aging be “drugged”?, Nat Med. 21, 1400–1405.
3. M.J. Steinbaugh, L.Y. Sun, A. Bartke, et al. (2012) Activation of genes involved in xenobiotic metabolism is a shared signature of mouse models with extended lifespan, American Journal of Physiology - Endocrinology and Metabolism. 303, E488–E495.
4. S. Kume, M.C. Thomas, and D. Koya (2012) Nutrient sensing, autophagy, and diabetic nephropathy., Diabetes. 61, 23–9.
5. B.G. Childs, M. Gluscevic, D.J. Baker, et al. (2017) Senescent cells: an emerging target for diseases of ageing, Nat Rev Drug Discov. 16, 718–735.
6. I. Tanida and S. Waguri (2010) Measurement of Autophagy in Cells and Tissues, In: Methods in molecular biology (Clifton, N.J.), pp. 193–214.