Interplay between regeneration and ageing in the axolotl, a species of negligible senescence

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Understanding why we age and how to revert this process are pressing scientific challenges. Ageing is a complex phenomenon that in most organisms, including humans, is associated with a progressive decline in tissue function and/or maintenance, age-related pathologies and decays in regenerative potential. In contrast, there are a handful of species such as the axolotl which exhibit extreme longevity, lack of age-related pathologies and indefinite regenerative capacity, constituting species of ‘negligible senescence’. These properties raise two critical questions: what principles underlie ageing in these organisms? Is the lack of age-related decay with time causally linked to their particular regenerative abilities? Answering them will require establishing reliable ageing biomarkers for the axolotl and leveraging systems approaches to determine the changes that occur with time from molecules to individual cells to entire tissues and how these are affected by regenerative processes. Here, we propose to leverage the unique axolotl model through an interdisciplinary approach combining machine learning, biophysical modelling and hypothesis-driven functional experimentation to dissect the interplay between regeneration and ageing. Central to our approach is the examination of the biological age of cells and tissues and the influence of regeneration on this key parameter. To achieve this, we will analyse the transcriptome and chromatin accessibility landscapes of axolotl ageing and their response to regenerative challenges. This will allow us to a) uncover the nature and dynamics of molecular changes that occur with age in this species of extreme regenerative abilities and negligible senescence through identifying predictive signatures of biological age and biomarkers of ageing at the bulk and single-cell level by developing ageing clocks; and b) probe the link between extreme regenerative abilities and negligible senescence, by testing the hypothesis that regeneration leads to the reversal of biological age and assessing the impact of biological age of progenitors or their niche on regenerative fitness. The insights derived from this research programme will contribute to answering critical outstanding questions regarding the nature of ageing and its interplay with regeneration. Further, they will provide a blueprint for the development of rejuvenation strategies aimed at the promotion of healthy ageing and longevity. Thus, this project will offer a new paradigm for the understanding of ageing, of fundamental and translational significance.