# DISCOVER DETERMINANTS OF INDIVIDUAL LIFESPAN AND HEALTH

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $419,456

## Abstract

PROJECT SUMMARY
There is a fundamental gap in our knowledge of healthy aging: while we understand how to genetically alter the
average lifespan of many organisms, we do not understand why some individuals within every population lead
longer and/or healthier lives (or shorter / less healthy lives) than this average. This is critical knowledge: under-
standing why some humans live longer or shorter than expected for their genotype could lead to diagnostics to
identify those at risk for short life or ill health, or even interventions to induce these long-lived, healthy states.
This work will use genetically identical C. elegans to study inter-individual variability in aging. Though
this variability is often disregarded as “biological noise”, our overarching hypothesis is that inter-individual
differences in lifespan and healthspan result from regulated processes that can be understood, predicted, and
altered. To study this, we developed an innovative imaging system in which many isolated C. elegans are reared
in identical environments, permitting lifelong measurement of reporter expression and physiological function.
The specific objective of this proposal is to identify the genetic basis of two sets of intriguing observations we
made using this system. First, we found that transcriptional regulation of the microRNAs mir-71 and lin-4 causes
young adults to commit to a particular future lifespan. Aim 1 will genetically dissect this process of fate com-
mitment. Second, we found that the traditional measure of healthspan, the population average, is confounded
because it can be improved in two distinct ways: (1) by increasing the maximum possible healthspan, or (2) by
increasing the proportion of individuals within the population that attain this maximum. Aim 2 will identify the ge-
netic pathways by which each of these two aspects of healthspan can be altered.
The hypothesis of Aim 1 is that, early in adulthood, a “lifespan commitment network” of transcriptional regu-
lators drives mir-71 and lin-4 to different, stable set-points in different individuals. We have two potent assays
for the activity of the network, and we know that different set-points lead to different lifespans via the insulin/
IGF-1-like signaling pathway (IIS). We propose to use classic techniques in genetic analysis to identify the last
remaining unknown: the upstream regulators surrounding mir-71 and lin-4 that constitute this network.
Aim 2 will test the hypothesis that IIS mutants influence each of the two aspects of healthspan, which our tools
now allow us to directly measure, through distinct mechanisms. Specifically, we propose: (1) that IIS influences
maximal healthspan via the same effector pathways by which it increases lifespan; but (2) that IIS influences the
fraction of the population reaching that maximum by lifespan-independent effects on pathogen resistance.
This work is innovative, both in the techniques used to study individual animals and to score healthspan, and ...

## Key facts

- **NIH application ID:** 10072024
- **Project number:** 5R01AG057748-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Kerry Kornfeld
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $419,456
- **Award type:** 5
- **Project period:** 2019-02-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10072024

## Citation

> US National Institutes of Health, RePORTER application 10072024, DISCOVER DETERMINANTS OF INDIVIDUAL LIFESPAN AND HEALTH (5R01AG057748-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10072024. Licensed CC0.

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