Decoding natural protective mechanisms during diapause and longevity to counter aging

解码滞育和长寿期间的自然保护机制以对抗衰老

• 批准号: 10687588
• 负责人: Param Priya Singh
• 金额: $ 139.51万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10687588
• 关键词: Adult; African; Aging; Alzheimer' s Disease; Biology; Brain; Cells; Complex; Diapause; Disease; Dryness; Embryo; Environment; Future; Genes; Habitats; Health; Health Benefit; Heart; Heart Diseases; Human; Intervention; Killifishes; Learning; Life; Longevity; Malignant Neoplasms; Measures; Modeling; Muscle; Nature; Onset of illness; Organ; Organism; Pathway interactions; Phenotype; Regulation; Resolution; Risk Factors; Seasons; Therapeutic; Time; Tissues; Translating; Translations; Variant; Vertebrates; Work; animation; cell type; comparative genomics; experimental study; fascinate; gene regulatory network; lens; multiple omics; nervous system disorder; novel; novel strategies; slow potential; transcription regulatory network

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.

项目总结/摘要 极端微生物生活在极端环境中的生物进化出独特的生存适应性。极端 适应比渐进的表型更容易测量和表征。了解监管 极端的表型可以揭示新的基因和策略，有可能带来显着的健康益处 对人类非洲绿松石鳉鱼，Nothobranchius furzeri，是一种极端的生存。本种 生活在短暂的池塘里，每年有8个月完全干涸。他们已经进化出两个 在这种恶劣的栖息地生存的显着适应：压缩成人寿命只有4.5个月， 一种“悬浮生命”的形式，胚胎可以进入滞育，并在泥中生存，直到下一个 雨季滞育胚胎已经有了复杂的器官和组织，包括肌肉， 大脑，心脏和许多复杂的细胞类型它们可以在滞育中存活长达3年（约5倍长 比他们的成年寿命），而没有任何可检测的权衡未来的生活。因此，滞育是一种迷人的状态 其中老化时钟暂停，它提供了一种独特的长期保护机制， 有机体除了滞育，我们还描述了几种在 他们的寿命。寿命很长的鳉鱼物种也有保护机制来减缓衰老 时钟，提供了一个独特的框架，了解监管机构的自然寿命使用比较基因组学。 绿松石鳉鱼模型的压缩寿命和高吞吐量特性使其成为 在功能上验证这些调节器并促进快速转化为老化。该项目将使用一个 进化的透镜配备了尖端的单细胞多组学和先进的实验和统计 多尾鳉滞育和自然寿命期间基因调控网络的解码方法 物种我们将首先构建滞育单细胞分辨率的转录调控网络， 鉴定滞育保护的器官特异性调节剂。接下来，我们将开发一个新的范式来探索 通过学习自然界的长寿实验，这将使我们能够解码长寿物种是如何衰老的。 保持他们的健康很长一段时间，并确定他们的长寿的监管机构。最后，我们将开发新的 将这些自然保护机制转化为对抗衰老的方法。基于独特的生物学原理， 对于这些极端脊椎动物，该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，并为可能减缓人类衰老的新干预措施铺平道路。