The thioredoxin TRX-1 regulates adult lifespan extension induced by dietary restriction in Caenorhabditis elegans

Abstract

Dietary restriction (DR) is the only environmental intervention known to extend adult lifespan in a wide variety of animal models. However, the genetic and cellular events that mediate the anti-aging programs induced by DR remain elusive. Here, we used the nematode Caenorhabditis elegans to provide the first in vivo evidence that a thioredoxin (TRX-1) regulates adult lifespan extension induced by DR. We found that deletion of the gene trx-1 completely suppressed the lifespan extension caused by mutation of eat-2, a genetic surrogate of DR in the worm. However, trx-1 deletion only partially suppressed the long lifespan caused by mutation of the insulin-like receptor gene daf-2 or by mutation of the sensory cilia gene osm-5. A trx-1::GFP translational fusion expressed from its own promoter in ASJ neurons (Ptrx-1::trx-1::GFP) rescued the trx-1 deletion-mediated suppression of the lifespan extension caused by mutation of eat-2. This rescue was not observed when trx-1::GFP was expressed from the ges-1 promoter in the intestine. In addition, overexpression of Ptrx-1::trx-1::GFP extended lifespan in wild type, but not in eat-2 mutants. trx-1 deletion almost completely suppressed the lifespan extension induced by dietary deprivation (DD), a non-genetic, nutrient-based model of DR in the worm. Moreover, DD upregulated the expression of a trx-1 promoter-driven GFP reporter gene (Ptrx-1::GFP) in ASJ neurons of aging adults, but not that of control Pgpa-9::GFP (which is also expressed in ASJ neurons). We propose that DR activates TRX-1 in ASJ neurons during aging, which in turn triggers TRX-1-dependent mechanisms to extend adult lifespan in the worm.

Introduction

Dietary restriction (DR) has been shown to extend adult lifespan in a wide range of organisms (reviewed in [1]). The anti-aging action of DR has been proposed to operate through activation of signaling cascades that subsequently increase stress resistance mechanisms to counteract organismal deterioration inflicted by long-term stress (reviewed in [2]). However, the signaling molecules that trigger the DR-induced pro-longevity machinery at the organismal level are still far from known.

Thioredoxins comprise a conserved family of proteins that mostly depend on their oxidoreductase activity to reduce disulfide bonds in many target proteins (reviewed in [3], [4]). In addition to their role as antioxidants against oxidative stress, as electron donors for metabolic enzymes or as redox regulators of signaling molecules and transcription factors, thioredoxins have also been shown to prevent cytosolic proteins from aggregating in the cell (reviewed in [3], [5]). Furthermore, thioredoxins have also been implicated in the regulation of aging. The first in vivo studies reporting the effects of mammalian Trx1 during aging showed that overexpression of human Trx1 in mice extends lifespan [6].

However, to date, it has not been studied in vivo whether thioredoxins regulate adult lifespan extension induced by DR. To our knowledge, the only studies designed to understand the relationship between thioredoxins and DR during aging have been performed in vitro using rat kidney [7], [8] or combining in vitro and ex vivo methods using rat muscle and mouse myoblast cell lines, respectively [9]. Therefore, the in vivo mechanisms by which thioredoxins regulate lifespan extension induced by DR still remain unknown.

For that purpose, we used Caenorhabditis elegans, an excellent animal model that provides valuable in vivo genetic and cell biological tools. The C. elegans gene trx-1 encodes a thioredoxin that is expressed in one pair of neurons in the nervous system: the ASJ sensory neurons. Previously we and others have shown that trx-1 deletion shortens adult lifespan and increases the sensitivity to paraquat-induced oxidative stress [10], [11]. In addition, transgenic C. elegans overexpressing trx-1 in ASJ neurons of wild-type animals was shown to have extended adult lifespan [11].

Since trx-1 regulates aging and stress resistance in the worm, we investigated whether it also regulates adult lifespan extension induced by DR. In our present study, we used genetic and cell biological tools to understand in vivo the relationship between the thioredoxin TRX-1 and adult lifespan extension through DR in C. elegans.