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.

项目摘要/摘要 极端粒子 - 生活在极端环境中的原则 - 为生存提供了独特的适应。极端 与等级表型相比，适应更容易衡量和表征。了解调节 极端表型可以揭示新的基因和策略，并有可能带来重大健康益处 给人类。非洲绿松石小杀，Nothobranchius Furzeri，是生存的极端诱因。这个物种 住在短暂的池塘中，每年最多可完全干燥8个月。他们进化了两个 在这种危险栖息地中生存的显着适应：压缩的成人寿命仅为4.5个月，一个 “暂停动画”的形式，胚胎可以进入滞育并在泥浆中固定直到下一个 雨季。二骨胚胎已经具有复杂的器官和组织，包括肌肉 大脑，心脏和许多复杂的细胞类型。它们可以在隔二一个年中生存3年（长约5倍） 比他们的成人寿命）没有任何可检测到的未来生活权衡。那是一个迷人的状态 暂停衰老时钟的地方，它为复杂的建立提供了长期保护的独特机制 生物。除了二共二，我们还表征了几种杀伤物种，具有显着变化 他们的救生衣。长期长寿的杀戮物种也具有受保护的机制来减缓衰老 时钟，提供了一个独特的框架，可以使用比较基因组学了解天然寿命的调节剂。 压缩的寿命和高吞吐量的绿松石杀伤模型使其非常适合 在功能上验证这些调节器并支持快速转化为衰老。这个项目将使用 配备了尖端单细胞多词以及高级实验和统计的进化镜头 在滞育过程中解码基因调节网络的方法和多个杀伤力的天然寿命 物种。我们将首先在隔离中以单细胞分辨率构建转录调节网络 识别特定器官的肿瘤保护器。接下来，我们将开发一个新颖的范式来探索 通过从大自然的寿命实验中学习而衰老，这将使我们能够解码多长时间的物种 长期保持健康，并确定其寿命的监管者。最后，我们将发展小说 将这些自然保护机制转化为反老化的方法。基于独特的生物学 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 在脊椎动物衰老期间，为新的干预措施铺平了道路，这些干预措施可能会减慢人类的衰老。