Muscle loss with ageing (sarcopenia) is a major contributor to frailty and loss of independency in older people. Exercise intervention can improve muscle function, but is not able to prevent age-associated muscle loss. With ageing, muscles fail to adapt to exercise, which is thought to be caused by a high inflammatory state in aged cells and tissues.
Cells in senescent state are highly pro-inflammatory and are under oxidative stress. They accumulate with age across the body, and muscle senescent cells may play a causal role in the development of sarcopenia. Remarkably, selective deletion of senescent cells (by drugs called senolytics) is able to improve a wide range of age-associated deteriorative conditions in mice including neuromuscular function. These therapies were first introduced in 2011 and have since become one of the ‘hottest’ topics in anti-ageing interventions, and first clinical trials are ongoing. We have significantly contributed to this development.
We propose that the pro-inflammatory and pro-oxidant features of senescent cells in aged muscles blunt the ability of muscles to adapt to exercise. Therefore, we hypothesise that senolytics will maintain the adaptability of muscles to exercise, thus enhancing its beneficial effects on muscle function and mass. The project is novel: potential additive or synergistic effects of senolytics combined with other anti-ageing treatments have never been assessed yet. Proving the hypothesis as true would have important implications for strategies to maintain people’s health for long-term.
The project will use mouse models to provide pre-clinical data. We have validated premature aging mouse models that show sarcopenia and loss of muscle function. You will examine the effects of solo and combination therapies of senolytics and exercise by testing muscle contraction capacity ex-vivo and by studying muscle tissues (assessing for instance myofibre size, markers of senescence and inflammation). You will further investigate underlying mechanisms at molecular level using cell culture models, focusing on the interplay between cell senescence, mitochondrial function and inflammation pathways. You will benefit from the access to cutting-edge technologies, such as imaging cytometry, Seahorse analyser, and in vivo CT imaging, as well as from a network of intense collaborations with leading labs in ageing research in the US and in Europe and with our industrial partners.
Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme can be found on our website: http://www.dimen.org.uk/
iCASE Award: Industrial partnership project
Fully funded by the MRC for 3.5yrs, including a minimum of 3 months working within the industry partner. Enhanced stipend, tuition fees and budget for consumables, travel and subsistence.
Studentships commence: 1st October 2020.
To qualify, you must be a UK or EU citizen who has been resident in the UK/EU for 3 years prior to commencement. Applicants must have obtained, or be about to obtain, at least a 2.1 honours degree (or equivalent) in a relevant subject. All applications are scored blindly based on merit. Please read additional guidance here: View Website
McArdle A, Jackson MJ. The role of attenuated redox and heat shock protein responses in the age-related decline in skeletal muscle mass and function. Essays Biochem. 2017 61(3):339-348.
Korolchuk VI, Miwa S, Carroll B, von Zglinicki T. Mitochondria in Cell Senescence: Is Mitophagy the Weakest Link? EBioMedicine. 2017 21:7-13
Short S, Fielder E, Miwa S, von Zglinicki T. Senolytics and senostatics as adjuvant tumour therapy. EBioMedicine. 2019 41:683-692.