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.

Project Narrative Aging is the primary risk factor for various diseases, including cancer, heart disease, and neurological disorders such as Alzheimer’s. Strategies to slow or pause aging have immense potential to delay the onset of diseases and extend the healthy periods of our lives. In this work, we will study naturally evolved strategies to slow or pause aging in killifish, identify new genes and pathways for healthy lifespan extension, and pave the way for future therapeutics to extend human health.