Generation of an In Vivo Senescent Cell Atlas: Across the life-course and in pathology

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Senescence is functionally implicated in a myriad of pathophysiological settings, including ageing, wound healing and tumour development. Whilst there is a general consensus that this is in part mediated through the acquired senescence-associated secretory phenotype (SASP), much of this work has been performed in vitro, across a limited number of cell lines. We currently have a limited understanding of what constitutes senescence in vivo, in these diverse cellular and pathological settings, and whether the functional programmes underlying senescence contain tissue and context specific features. As such we intend to isolate senescent populations from a number of distinct pathophysiological states using two fluorescent reporters and acquire the transcriptional, DNA methylation status, and nucleosome accessibility information from the same single cell. Fundamentally, our study will test the hypothesis that senescence is not one functional state, but instead is a composite of multiple functional units. Furthermore, we aim to prove that different tissue and pathophysiological contexts are associated with the emergence of unique senescent sub-populations, with functionalities that reflect the biological context. In addition to the cutting-edge single cell multi-omic approaches and novel tools developed by collaborators, we have also ensured this is a community-driven project by forming an advisory board composed of prominent members of the senescence and ageing communities.

We live in an ageing society, however while average lifespans have increased the average health-span for an individual has not kept apace. As such age-associated disorders and pathologies are becoming an increasing fiscal and social burden on our society. Senescence represents a cellular state that is a key component of organismal ageing and the development of age-associated disorders. Recent evidence in mice suggests that targeting senescence may lead to improvements in age-related disorders and promote healthy ageing. Yet the bulk of our knowledge regarding this state is based on in vitro data, and is relatively poorly understood as an in vivo phenomenon.

As such we have proposed to develop a 'Senescence Atlas' to generate data and methodologies that will have instant impact across a wide-range of research areas and diseases.

Academic Impact: Firstly, basic and translational researchers will benefit from these data, this is exemplified by the wide-range of scientific backgrounds, and respective research questions, that comprise the members of our scientific advisory board. Additionally, we aim to be a highly transparent working group, providing in-depth technical descriptions of senescent cell isolation and data analysis tools for the wider community. Finally, this project will benefit tremendously the post-docs, involving personal development, research-specific training, and ensuring efficient and complete dissemination of information to all stakeholders.

Economic impact: We live in an ageing society and as such the incidence of age-related diseases (for which senescent cells are functionally implicated) are increasing. This has produced a fertile environment wherein biotechnology and pharmaceutical companies are attempting to develop intervention strategies to treat these disorders, however our current knowledge of what to target, with regards to in vivo senescence populations, and how amenable they are to current targeting agents is relatively low. Our data can not only be used to address the former, but will specifically address the latter. As such this has the potential to act as a catalyst for these sectors.

Societal: As mentioned above, our society has an increasing burden of age-related disorders which result in a high cost to society to treat and manage. The combined impact academically and economically has the potential to provide a profound shift in society, by promoting an increased health-span, or healthy aged population.