Decoding natural protective mechanisms during diapause and longevity to counter aging

项目摘要/摘要 极端微生物--生活在极端环境中的有机体--进化出独特的生存适应能力。极端 适应性比渐进型更容易衡量和表征。理解规则中的 极端表型可以揭示新的基因和策略，有可能带来显著的健康益处 对人类来说。非洲绿松石龙鱼，是一种生存的极端生物。这一物种 生活在短暂的池塘里，每年有长达8个月的时间完全干涸。他们进化出了两个 在这种恶劣的栖息地生存的非凡适应：压缩的成年寿命只有4.5个月和 暂停生命的形式，胚胎可以进入滞育状态，并在泥浆中生存到下一次 雨季。滞育胚胎已经有了复杂的器官和组织，包括肌肉，一种发育中的 大脑、心脏和许多复杂的细胞类型。它们可以滞育存活长达3年(~5倍以上 比他们的成年寿命更长)，对未来的生活没有任何可察觉的权衡。因此，滞育是一种迷人的状态。 在那里老化的时钟暂停，它提供了一种独特的机制，为复杂的 有机体。除了滞育外，我们还研究了几种千层鱼的显著变化。 他们的寿命。值得注意的是，长寿的剑鱼物种也有延缓衰老的保护机制 Clock，提供了一个独特的框架，利用比较基因组学来理解自然长寿的调节因素。 绿松石千里鱼模型的压缩寿命和高吞吐量特性使它们成为 从功能上验证这些调节器，并促进快速转换到老化。此项目将使用 配备尖端单细胞多组学和先进实验和统计的进化透镜 破译多尾金枪鱼滞育和自然寿命基因调控网络的方法 物种。我们将首先在单细胞分辨率下构建转录调控网络 确定特定器官的滞育保护调节剂。接下来，我们将开发一种新的范式来探索 通过学习大自然的长寿实验来衰老，这将使我们能够破译物种的长寿 长期保持他们的健康，并找出他们长寿的调节者。最后，我们将开发小说 将这些自然保护机制转化为对抗衰老的方法。基于独一无二的生物学原理 这些极端嗜好的脊椎动物，这个项目将确定可以延长器官健康的全新机制 在脊椎动物的衰老过程中，并为潜在地减缓人类衰老的新型干预措施铺平了道路。

Project Summary/Abstract Extremophiles—organisms that live in extreme environments—evolve unique adaptations for survival. Extreme adaptations are easier to measure and characterize than gradual phenotypes. Understanding the regulation of extreme phenotypes can reveal novel genes and strategies with the potential to bring significant health benefits to humans. The African turquoise killifish, Nothobranchius furzeri, is an extremophile for survival. This species lives in ephemeral ponds that completely dry up for up to 8 months each year. They have evolved two remarkable adaptations to survive in this harsh habitat: a compressed adult lifespan of only 4.5 months and a form of ‘suspended animation’, whereby embryos can enter diapause and subsist in the mud until the next rainy season. Diapause embryos already have complex organs and tissues, including muscle, a developing brain, a heart, and many complex cell types. They can survive in diapause for up to 3 years (~5 times longer than their adult lifespan) without any detectable trade-off for future life. Thus, diapause is a fascinating state where the aging clock is paused, and it provides a unique mechanism of long-term protection to a complex organism. In addition to diapause, we have characterized several killifish species with significant variations in their lifespans. Significantly long-lived killifish species also have protective mechanisms to slow the aging clock, providing a unique framework to understand regulators of natural longevity using comparative genomics. The compressed lifespan and high throughput nature of the turquoise killifish model make them ideal for functionally validating these regulators and facilitating rapid translation to aging. This project will use an evolutionary lens equipped with cutting-edge single-cell multi-omics and advanced experimental and statistical approaches to decode gene regulatory networks during diapause and natural longevity in multiple killifish species. We will first construct transcriptional regulatory networks at single-cell resolution in diapause to identify organ-specific regulators of diapause protection. Next, we will develop a novel paradigm to explore aging by learning from nature’s longevity experiments, which will allow us to decode how long-lived species maintain their health for a long time and identify the regulators of their longevity. Finally, we will develop novel approaches to translate these natural protective mechanisms to counter aging. Based on the unique biology of these extremophile vertebrates, this project will identify entirely new mechanisms that can prolong organ health during aging in vertebrates and pave the way for novel interventions that can potentially slow aging in humans.