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

了解我们为什么衰老以及如何逆转这一过程是紧迫的科学挑战。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，衰老与组织功能和/或维持的逐渐下降、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，如蝾螈，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变与时间的因果关系，他们特定的再生能力？研究人员需要为蝾螈建立可靠的衰老生物标志物，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，我们建议通过跨学科的方法结合机器学习，生物物理建模和假设驱动的功能实验来利用独特的蝾螈模型，以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学年龄以及再生对这一关键参数的影响。为了实现这一目标，我们将分析蝾螈衰老的转录组和染色质可及性景观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，在体细胞和单细胞水平上识别生物学年龄的预测特征和衰老的生物标志物，揭示这种具有极端再生能力和可忽略衰老的物种随着年龄发生的分子变化的性质和动态;和B）探索极端再生能力和可忽略的衰老之间的联系，通过测试再生导致生物年龄逆转的假设，并评估祖细胞的生物年龄或其生态位对再生适合度的影响。从这个研究计划中获得的见解将有助于回答关于衰老的性质及其与再生的相互作用的关键未决问题。此外，它们将为制定旨在促进健康老龄化和长寿的振兴战略提供蓝图。因此，该项目将为理解老龄化提供一个新的范式，具有根本和转化意义。

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.