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.

项目概要/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能力。极端 适应比渐进表型更容易测量和表征。了解监管 极端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）是一种为了生存而生存的极端微生物。这个品种 生活在每年有长达 8 个月完全干涸的短暂池塘中。他们进化出了两种 为了在这个恶劣的栖息地生存，它们做出了非凡的适应：成虫的寿命被压缩为只有 4.5 个月， “假死”的形式，胚胎可以进入滞育并在泥中生存，直到下一次 雨季。滞育胚胎已经具有复杂的器官和组织，包括肌肉，这是一种正在发育的 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（约长 5 倍） 比他们的成年寿命）没有任何可检测到的对未来生活的权衡。因此，滞育是一种令人着迷的状态 老化时钟暂停，它为复杂的系统提供了一种独特的长期保护机制 生物。除了滞育之外，我们还对几种具有显着变异的鳉鱼物种进行了表征。 他们的寿命。长寿的鳉鱼物种也具有减缓衰老的保护机制 时钟，提供了一个独特的框架来使用比较基因组学来了解自然长寿的调节因素。 绿松石鳉鱼模型的压缩寿命和高通量特性使其成为理想的选择 功能验证这些调节剂并促进快速转化为衰老。该项目将使用一个 配备尖端单细胞多组学和先进实验和统计的进化镜头 解码多种鳉鱼滞育和自然寿命期间基因调控网络的方法 物种。我们将首先在滞育中以单细胞分辨率构建转录调控网络 确定滞育保护的器官特异性调节因子。接下来，我们将开发一种新颖的范式来探索 通过从大自然的长寿实验中学习来实现衰老，这将使我们能够解码长寿物种的寿命 长期保持健康并找出长寿的调节因素。最后，我们将开发新颖的 将这些自然保护机制转化为抗衰老的方法。基于独特的生物学特性 对于这些嗜极脊椎动物，该项目将确定可以延长器官健康的全新机制 脊椎动物衰老过程中的研究，并为可能减缓人类衰老的新干预措施铺平道路。