Testing classical and emerging evolutionary theories of ageing in ecologically relevant environments

衰老是生物体随着年龄的增长而发生的生理退化，导致生殖能力降低和/或死亡的可能性增加。老龄化降低了适应性，在人口动态中起着关键作用，但我们对老龄化生物学的理解仍然不完整。衰老的进化理论认为，衰老的进化是因为随着年龄的增长，对特征的选择强度下降。然而，这一理论并没有解释哪些生理过程导致衰老。衰老的最主要的生理学理论是一次性索马理论（DST），该理论认为，生长、繁殖和寿命之间的竞争性能量分配导致不完善的躯体维持和修复，因此衰老是由未修复的细胞损伤的缓慢积累引起的。DST受到越来越多的挑战，研究表明，寿命的增加并不一定会导致健康的减少，从而质疑在衰老的演变中，生长，繁殖和寿命之间的能量权衡的中心地位。正在兴起的新理论--衰老发展理论（DTA）认为，衰老是由生物过程引起的，这些生物过程对发育、生长和早期生殖进行了优化，随着年龄的增长，衰老变得有害，因为作用于年龄特异性基因表达的自然选择太弱，无法优化它。进化上保守的营养传感分子信号通路被预测在衰老中起着重要作用，因为这些“生活史联系”途径调节生物体对环境变化的反应。至关重要的是，这两种衰老理论提供了关于实验性寿命延长对其他关键生命史特征以及最终对达尔文适应性的影响的独特预测。DST通过对发育、生长或繁殖的负面影响来预测寿命延长的健身成本。DTA预测，成年期基因表达的优化可以改善生物体的生理机能，同时增加寿命和健康。这是因为DTA认为衰老是晚年基因表达选择不足的结果，而不是身体维护和修复的资源不足。这两个理论的预测从未在复杂的生态相关环境中进行过实验验证。我们实验室最近的工作为以下想法提供了原理证明：使用摄食RNA干扰（RNAi）方法敲低daf-2（在秀丽隐杆线虫线虫中编码胰岛素受体样蛋白的“死神基因”）仅成年期IIS下调可以在简单和良性的实验室环境中提高寿命和适应性。在这里，我们提出了一种新的方法，建立在我们以前的工作，联合收割机的遗传“工具”可用于C。在复杂的生态相关环境中进行适应性测定。我们将首先测试daf-2 RNAi线虫在三代广泛的生态相关压力环境下是否优于对照蠕虫。然后，我们将测试daf-2 RNAi动物是否会在模拟其自然环境的复杂受控微观世界中表现得更好。最后，我们将进行首次实验，我们将测试成年蠕虫中的IIS下调是否会改善自然界中的种群增长和生存能力。这个三管齐下的研究计划将通过提供第一组实验来弥合知识鸿沟，这些实验将使我们能够测试在自然环境中是否可以同时改善衰老和健康。elegans模型系统的遗传和表观遗传研究以独特和前所未有的方式，该项目将提供一个步骤的变化，我们的理解如何老化演变。

Ageing, a physiological deterioration of an organism with advancing age, results in reduced reproductive performance and/or increased likelihood of death. Ageing reduces fitness and plays a pivotal role in population dynamics, but our understanding of the biology of ageing is still incomplete. Evolutionary theory of ageing posits that ageing evolves because the strength of selection on traits decline with age. However, this theory does not explain which physiological processes cause senescence. The most dominant physiological theory of ageing is the Disposable Soma Theory (DST) which maintains that competitive energy allocation between growth, reproduction and longevity results in imperfect somatic maintenance and repair, so that ageing is caused by slow accumulation of unrepaired cellular damage. The DST has been increasingly challenged by studies showing that increased longevity does not necessarily result in reduced fitness thereby questioning the centrality of the energy trade-off between growth, reproduction and longevity in the evolution of ageing. The emerging new theory, the Developmental Theory of Ageing (DTA), argues that ageing is caused by biological processes that are optimised for development, growth and early-life reproduction and become harmful with advancing age because natural selection acting on age-specific gene expression is too weak to optimise it. Specifically, evolutionarily conserved nutrient-sensing molecular signalling pathways are predicted to play a fundamental role in ageing because these "life-history nexus" pathways regulate the response of the organisms to environmental change. Crucially, these two theories of ageing provide distinct and unique predictions regarding the effect of the experimental lifespan extension on other key life-history traits and, ultimately, on Darwinian fitness. The DST predicts the fitness cost of increased longevity through negative effects on either development, growth or reproduction. The DTA predicts that optimisation of gene expression in adulthood can improve the organismal physiology and concurrently increase longevity and fitness. This is because the DTA considers ageing to be a result of insufficient selection on late-life gene expression rather than insufficient resources for somatic maintenance and repair.The predictions of these two theories have never been tested experimentally against each other in complex ecologically relevant environments. Recent work from our laboratory provides the proof-of-principle for the idea that adulthood-only IIS downregulation using feeding RNA interference (RNAi) approach to knockdown daf-2, the "grim reaper gene" that encodes an insulin receptor-like protein in Caenorhabditis elegans nematodes can improve longevity and fitness in simple and benign laboratory environment. Here we propose a novel approach that builds on our previous work to combine the genetic "tools" available for C. elegans with fitness assays in complex ecologically relevant environments. We will first test whether daf-2 RNAi nematodes outperform the control worms under a broad range of ecologically relevant stressful environments across three generations. We then will test whether daf-2 RNAi animals will perform better in complex controlled microcosms that will mimic their natural environments. Finally, we will perform the first-of-a-kind experiment where we will test whether IIS downregulation in adult worms improves population growth and viability in nature. This three-pronged research program will bridge the knowledge gap by providing the very first set of experiments that will allow us to test whether ageing and fitness can be concurrently improved in natural environments.By combining ecological relevance and complexity with the immense power of C. elegans model system for genetic and epigenetic research in a unique and unprecedented way, this project will provide a step-change in our understanding of how ageing evolves.