AhR-mitochondria crosstalk in diet promoted longevity

衰老是神经退行性疾病发展的最重要危险因素，它受遗传和营养因素的影响。了解老龄化过程背后的机制方面，将有助于延长健康寿命，减轻社会为维持不断增长的老年人口而承受的沉重经济负担。通过提供比遗传干预更具延展性和可行性的预防衰老方法，营养干预可能特别适用于这一范围。秀丽隐杆线虫是衰老研究的一种选择性模式生物，在这种生物中首次发现了大多数进化保守的衰老调节机制。其中一种机制是线粒体功能的部分减少。值得注意的是，线粒体主要参与食物代谢。AhR转录因子的表达减少也提供了进化保守的抗衰老作用。虽然大多数关于AhR的研究都集中在其在介导高亲和力配体（如外源性药物）的毒性作用中的作用，但主要来自食物的低亲和力天然化合物正在成为其活性的直接或间接调节剂。少数研究也表明AhR在调节线粒体功能中的作用。有趣的是，我们的初步数据表明，ahr-1以饮食依赖的方式调节秀丽隐杆线虫的健康寿命。因此，目前的技术状况和我们的初步工作为探索饮食成分可能通过线粒体和AhR之间的相互作用来延缓神经元衰老的可能性提供了强有力的理论依据。秀丽隐杆线虫是研究AhR -1在神经系统中的非毒理学作用的独特工具，因为秀丽隐杆线虫的AhR -1对经典的AhR配体激活剂没有反应，而且迄今为止它的主要功能是在神经元中描述的。为了实现本提案的总体目标，我们将：1)表征ahr-1缺乏对神经元衰老的影响。2)通过AhR识别促进健康老龄化的膳食成分。3)评估ahr -线粒体串扰在饮食促进长寿中的作用。基于线虫和人类基因之间的高度保守性，该项目有望为未来可能的旨在延长人类健康寿命的预防治疗策略提供见解。因此，我们的研究结果将直接影响基础研究，但最终也将对我们社会的营养医学和社会经济方面产生影响。

Aging is the most important risk factor for the development of neurodegenerative disorders and it is shaped by genetic and nutritional factors. Understanding the mechanistic aspects underlying the aging process will help extending healthy lifespan and reducing the heavy economic burden inflicted to our society to sustain the growing elderly population. Nutritional interventions may especially serve this scope by providing more malleable and feasible age-preventive approaches than genetic interventions.The nematode C. elegans is an elective model organism for aging studies and most evolutionarily conserved mechanisms regulating the aging process were first identified in this organism. One of these mechanisms is partial reduction of mitochondrial function. Of note, mitochondria are primarily involved in food metabolism. Reduced expression of the AhR transcription factor also provide evolutionarily conserved anti-aging effects. Although most research on AhR has focused on its role in mediating the toxic effects of high affinity ligands such as xenobiotics, low affinity natural compounds mainly derived from food are emerging as direct or indirect modulators of its activity. Few studies also suggested a role for AhR in modulating mitochondrial function. Interestingly, our preliminary data indicate that ahr-1 regulates C. elegans healthspan in a diet-dependent manner. Thus, the state of the art and our preliminary work provide a strong rationale for exploring the possibility that dietary components may delay neuronal aging acting through the interplay between mitochondria and the AhR. C. elegans represents a unique tool to investigate non-toxicological roles for ahr-1 in the nervous system as C. elegans AHR-1 does not respond to classic AhR ligand activators and its main function was so far described in neurons.To achieve the overall goal of this proposal we will: 1) Characterize the impact of ahr-1 deficiency on neuronal aging.2) Identify dietary components promoting healthy aging through AhR.3) Assess the role of AhR-mitochondrial crosstalk in diet promoted longevity.Based on the high conservation between nematode and human genes this project is expected to provide insight into possible future preventive therapeutic strategies aimed at extending healthy lifespan in human. Results obtained with our study will therefore directly impact on basic research, but will also eventually have repercussion on nutritional medicine and socio-economical aspects of our society.