# Natural variation underlying extraordinary lifespan

> **NIH NIH R01** · UNIVERSITY OF OREGON · 2024 · $312,900

## Abstract

Project Summary
Aging, particularly the rapid increase in disease prevalence with age, has emerged as one of the top health
challenges in the world today. Life expectancy in the United States has increased by nearly a decade over the
last 50 years, but so too has the incidence of musculoskeletal problems, heart disease, cancer, and especially
dementia late in life. Discoveries of conserved genetic pathways in animals that increase both longevity and
healthspan have raised the hope that we can build upon on growing understanding of the biology of aging to
find interventions that allow us to live longer, healthier lives. Most of these genetic studies have been
conducted within a few laboratory-adapted model organisms. Using natural variation to investigate the genetics
of aging provides the opportunity to discover new pathways that enhance aging, particularly in ways that do not
create negative pleiotropic effects across the organism as a whole. Here, we propose to use our recent
discovery of an exceptionally long-lived natural isolate of the model nematode Caenorhabditis elegans as a
discovery platform to better understand the biology aging and to discover novel genetic targets for aging
interventions. We have implemented unique approaches to genetic mapping that capitalize upon the rapid
generation time and very large population sizes of C. elegans to select for highly recombinant individuals with
extreme phenotypes. Further, we will use a novel genomic engineering approach to generate targeted
recombination events within regions of interest. Analyzing these natural isolates, as well as targeted knockouts
of known aging related pathways, using a transcriptional “aging clock” will allow us both to isolate the genes of
interest and to assess their physiological impacts at single-cell resolution. And most importantly from a
translational point of view, we will investigate how genetic background influences the response to longevity
extending compound interventions. Specifically, we aim to (1) Identify the genetic basis of longevity extension
in an extraordinarily long-lived natural isolate of C. elegans, (2) Analyze the functional landscape of natural
variation in longevity and develop tissue-specific aging clocks using allelic substitution lines and genetic
knockouts of well-characterized stress-response pathways, (3) Determine the genetic basis of natural variation
in the response to life-extending compound interventions. Success of these aims will provide novel insights into
the fundamental biology of aging and provide new genetic targets for researchers seeking to enhance healthy
aging in humans.

## Key facts

- **NIH application ID:** 10945220
- **Project number:** 1R01AG088629-01
- **Recipient organization:** UNIVERSITY OF OREGON
- **Principal Investigator:** Patrick C. Phillips
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $312,900
- **Award type:** 1
- **Project period:** 2024-08-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10945220

## Citation

> US National Institutes of Health, RePORTER application 10945220, Natural variation underlying extraordinary lifespan (1R01AG088629-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10945220. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*