A PTEN variant uncouples longevity from impaired fitness in Caenorhabditis elegans with reduced insulin/IGF-1 signaling

Hae-Eun H Park,Dongyeop Lee,Yujin Lee,Won Do Heo,Heehwa G Son,Eunah Kim,Seung-Jae V Lee,Sangsoon Park,Ozlem Altintas,Wooseon Hwang,Seokjin Ham

doi:10.1038/s41467-021-25920-w

Abstract

Insulin/IGF-1 signaling (IIS) regulates various physiological aspects in numerous species. In Caenorhabditis elegans, mutations in the daf-2/insulin/IGF-1 receptor dramatically increase lifespan and immunity, but generally impair motility, growth, and reproduction. Whether these pleiotropic effects can be dissociated at a specific step in insulin/IGF-1 signaling pathway remains unknown. Through performing a mutagenesis screen, we identified a missense mutation daf-18(yh1) that alters a cysteine to tyrosine in DAF-18/PTEN phosphatase, which maintained the long lifespan and enhanced immunity, while improving the reduced motility in adult daf-2 mutants. We showed that the daf-18(yh1) mutation decreased the lipid phosphatase activity of DAF-18/PTEN, while retaining a partial protein tyrosine phosphatase activity. We found that daf-18(yh1) maintained the partial activity of DAF-16/FOXO but restricted the detrimental upregulation of SKN-1/NRF2, contributing to beneficial physiological traits in daf-2 mutants. Our work provides important insights into how one evolutionarily conserved component, PTEN, can coordinate animal health and longevity.

Highlights

Insulin/insulin-like growth factor-1 (IGF-1) signaling (IIS) regulates various physiological aspects in numerous species
We showed that daf-18(yh1) partially retained the activity of the DAF-16/FOXO in daf-2 mutants while preventing the adverse activation of the SKN-1/nuclear factor erythroid 2-related factor 2 (NRF2) that appears to underlie the reduction in lifespan and health span
We identified a specific missense mutation in the daf-18/phosphatase and tensin homolog (PTEN) that sustained the long lifespan and enhanced immunity conferred in daf-2/insulin/IGF-1 receptor mutant C. elegans, without apparent accompanying defects in development and health span

Summary

Introduction

Insulin/IGF-1 signaling (IIS) regulates various physiological aspects in numerous species. In Caenorhabditis elegans, mutations in the daf-2/insulin/IGF-1 receptor dramatically increase lifespan and immunity, but generally impair motility, growth, and reproduction. Whether these pleiotropic effects can be dissociated at a specific step in insulin/IGF-1 signaling pathway remains unknown. Other transcription factors, including SKN-1/ nuclear factor erythroid 2-related factor 2 (NRF2) and heat shock transcription factor 1 (HSF-1), are crucial for longevity and stress resistance in daf-2 mutants[1,4,5,6,7,18] These transcription factors regulate the expression of common and distinct subsets of target genes, which appear to elicit various physiological effects. It remains unclear whether specific IIS components and/or particular targets of these key transcription factors regulate discrete physiological aspects of IIS, including longevity, health span, and development

Objectives

Methods

Results

Conclusion