# Decoding natural protective mechanisms during diapause and longevity to counter aging

> **NIH NIH DP2** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $1,395,075

## Abstract

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.

## Key facts

- **NIH application ID:** 10687588
- **Project number:** 1DP2AG086979-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Param Priya Singh
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $1,395,075
- **Award type:** 1
- **Project period:** 2023-09-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10687588

## Citation

> US National Institutes of Health, RePORTER application 10687588, Decoding natural protective mechanisms during diapause and longevity to counter aging (1DP2AG086979-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10687588. Licensed CC0.

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