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

• Published in: eLife Vol. 10
• Main Authors: Kinser, Holly E, Mosley, Matthew C, Plutzer, Isaac B, Pincus, Zachary
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 01.02.2021; eLife Sciences Publications, Ltd
• Subjects: Aging; aging biomarker; Animals; Biomarkers; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Chromosomes and Gene Expression; Computational and Systems Biology; Divergence; Forkhead protein; Gene expression; Gene Expression Regulation; Gene regulation; Genes, Reporter - genetics; Genetic engineering; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; individual variability; Insulin; Insulin-like growth factor I; Life span; lifespan; Longevity; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Population genetics; Signal Transduction; Transgenes; computational biology; systems biology; C. elegans; individual variability; lifespan; chromosomes; aging biomarker; gene expression
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.65026

Across species, lifespan is highly variable among individuals within a population. Even genetically identical 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.