Cellular senescence and regeneration in the epithelia: novel mechanisms and therapeutic approaches

The UK population is ageing. In 2019, 12.3 million people were aged 65 or over. By 2066 this number is estimated to reach 20.4 million (26% of all UK population). We are living longer than at any time in human history, but this victory of public health is accompanied by an unfortunate side-effect: a new epidemic of chronic, age-associated diseases for which cures remain elusive. I want to combat age-onset disease by targeting its main mechanism: cellular senescence. Senescent cells accumulate in aged skin and other epithelia, increasing inflammation and promoting tissue damage. The inevitable consequence is that old skin is not as efficient at repair and is more susceptible to damage and disease. This reality of ageing has been documented since World War I, with the observation that wounds heal more slowly in older soldiers whereas the fetus heals cutaneous wounds without a scar. My projects aim to revolutionize the current perception of senescence -as an immutable, inevitable process- and provide new tools to increase regeneration in the skin, improving the quality of life, and promoting ''healthspan'' for the next generation. In my group we will investigate: (i) The molecular mechanisms of senescence in the skin to understand in detail this phenomenon. My preliminary data suggest that senescence onset in the skin is linked to the loss of primary cilia, highly specialized antennas that are crucial for regeneration. I aim to understand where senescence starts in the skin, how it starts, and if targeted interventions towards the primary cilia can increase skin regeneration. (ii) Novel targets to prevent senescence and accelerate skin regeneration using a novel model: the spiny mouse. The african spiny mouse is able to shed up to 60% of its back's skin to avoid predation. However, unlike other mammalians, the spiny can regrow the skin, muscle, cartilage and even hair, with minimal signs of fibrosis. I aim to understand which pathways are responsible for this fibrosis-free wound healing and apply the results to improve skin regeneration in humans. (iii) Diagnostics to identify the best therapeutic window and potential clinical interventions. Defining WHEN to target a condition is as equally important as the treatment itself. As I have done with my current biosensor company (http://sensibile.co.uk/), where we detect senescence biosignatures in donor organs before transplant, I aim to determine the levels of senescence in skin. By doing so, we could determine the risk of older patients undergoing surgical treatment, or apply interesting results to cosmetic purposes, increasing the translational and entrepreneurial opportunities for the laboratory and the University of Edinburgh. Finally, I firmly believe that great science requires a great team. My priority would be to provide the best experience to my team, taking into account their diversities, to establish an inclusive group that can foster creativity and innovation. As I have been doing with all my students, especially during the COVID-19 pandemic, I aim to provide not only technical expertise, but also an opportunity to grow as scientists, and personal help should they require it. Research integrity, responsible innovation, diversity and inclusion will be the core of my lab, to deliver outstanding research and unique translational opportunities.