1. Chromosomes and Gene Expression
  2. Computational and Systems Biology

Global, cell non-autonomous gene regulation drives individual lifespan among isogenic C. elegans

  1. Holly E Kinser
  2. Matthew C Mosley
  3. Isaac B Plutzer
  4. Zachary Pincus  Is a corresponding author
  1. Washington University in St Louis, United States
https://doi.org/10.7554/eLife.65026
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  1. Holly E Kinser
  2. Matthew C Mosley
  3. Isaac B Plutzer
  4. Zachary Pincus
(2021)
Global, cell non-autonomous gene regulation drives individual lifespan among isogenic C. elegans
eLife 10:e65026.
https://doi.org/10.7554/eLife.65026
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Abstract

Across species, lifespan is highly variable among individuals within a population. Even genetically identical C. elegans reared in homogeneous environments are as variable in lifespan as outbred human populations. We hypothesized that persistent inter-individual differences in expression of key regulatory genes drives this lifespan variability. As a test, we examined the relationship between future lifespan and the expression of 22 microRNA promoter::GFP constructs. Surprisingly, expression of nearly half of these reporters, well before death, could effectively predict lifespan. This indicates that prospectively long- vs. short-lived individuals have highly divergent patterns of transgene expression and transcriptional regulation. The gene-regulatory processes reported on by two of the most lifespan-predictive transgenes do not require DAF-16, the FOXO transcription factor that is a principal effector of insulin/insulin-like growth factor (IGF-1) signaling. Last, we demonstrate a hierarchy of redundancy in lifespan-predictive ability among three transgenes expressed in distinct tissues, suggesting that they collectively report on an organism-wide, cell non-autonomous process that acts to set each individual's lifespan.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for all figures and tables.

Article and author information

Author details

  1. Holly E Kinser

    Depts. of Biomedical Engineering, Developmental Biology and Dept. of Genetics, Washington University in St Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Matthew C Mosley

    Program in Developmental, Regenerative, and Stem Cell Biology; Dept. of Developmental Biology; and Dept. of Genetics, Washington University in St Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Isaac B Plutzer

    Dept. of Developmental Biology and Dept. of Genetics, Washington University in St Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9370-7763

  4. Zachary Pincus

    Dept. of Developmental Biology and Dept. of Genetics, Washington University in St Louis, St Louis, United States
    For correspondence
    zpincus@wustl.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9785-5977

Funding

National Institute on Aging (R01 AG057748)

  • Holly E Kinser
  • Matthew C Mosley
  • Isaac B Plutzer
  • Zachary Pincus

National Human Genome Research Institute (T32 HG000045)

  • Holly E Kinser

Arnold and Mabel Beckman Foundation (Beckman Young Investigator)

  • Zachary Pincus

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Jan Gruber, Yale-NUS College, Singapore

Version history

  1. Received: November 19, 2020
  2. Accepted: January 13, 2021
  3. Accepted Manuscript published: February 1, 2021 (version 1)
  4. Version of Record published: February 5, 2021 (version 2)

Copyright

© 2021, Kinser et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Holly E Kinser
  2. Matthew C Mosley
  3. Isaac B Plutzer
  4. Zachary Pincus
(2021)
Global, cell non-autonomous gene regulation drives individual lifespan among isogenic C. elegans
eLife 10:e65026.
https://doi.org/10.7554/eLife.65026

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