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

理解我们为什么衰老以及如何逆转这一过程是迫在眉睫的科学挑战。衰老是一种复杂的现象，在包括人类在内的大多数生物体中，与组织功能和/或维持的进行性下降、与年龄相关的病理和再生潜力的衰退有关。相比之下，有少数物种，如Axolotl，表现出极长的寿命，缺乏与年龄相关的病理和无限的再生能力，构成了可忽略不计的衰老物种。这些特性提出了两个关键问题：这些生物体衰老的基础是什么？缺乏与年龄相关的衰老是否与他们特殊的再生能力有因果关系？回答这些问题将需要为axolotl建立可靠的老化生物标记物，并利用系统方法来确定从分子到单个细胞再到整个组织随时间发生的变化，以及这些变化如何受到再生过程的影响。在这里，我们建议利用独特的Axolotl模型，通过结合机器学习、生物物理建模和假说驱动的功能实验的跨学科方法来剖析再生和衰老之间的相互作用。我们方法的核心是检查细胞和组织的生物年龄以及再生对这一关键参数的影响。为了实现这一点，我们将分析转录组和染色质在紫杉醇老化过程中的可及性及其对再生挑战的反应。这将使我们能够a)通过开发衰老时钟，在大宗和单细胞水平上识别生物年龄的预测签名和衰老的生物标记物，揭示这种具有极端再生能力和可忽略不计的衰老的物种中随年龄发生的分子变化的性质和动力学；以及b)通过测试再生导致生物年龄逆转的假设，并评估祖先或其利基对再生适应性的影响，探索极端再生能力和可忽略不计的衰老之间的联系。从这项研究方案中得出的见解将有助于回答有关老龄化的性质及其与再生的相互作用的关键悬而未决的问题。此外，它们将为制定旨在促进健康老龄化和长寿的年轻化战略提供蓝图。因此，该项目将为理解老龄化提供一个新的范式，具有基本的和翻译的意义。

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.