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.

Hormesis, cellular stress response and vitagenes as critical determinants in aging and longevity

“…Loss of trx-1 completely suppresses the extended lifespan caused by mutation of eat-2, a genetic surrogate of DR in the worm (Fierro-Gonzalez et al, 2011). Interestingly, loss of trx-1 almost completely suppresses the lifespan extension produced by dietary deprivation (DD), a non-genetic model of DR in the worm (Fierro-Gonzalez et al, 2011). Thioredoxins comprise a conserved family of proteins that mostly depend on their oxidoreductase activity to reduce disulfide bonds in many target proteins .…”

“…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 (Fierro-Gonzalez et al, 2011). Differently from histone acetyltransferases (HATs) which counterbalance histone deacetylases (HDACs), a counter-regulatory program to counterbalance sirtuin deacetylase function is less well established.…”

Mitohormesis: Promoting Health and Lifespan by Increased Levels of Reactive Oxygen Species (ROS)

“…An important factor regarding the effects of CR could also be thioredoxin, as it is shown to be essential for the lifespan extension in C. elegans under dietary deprivation and knockouts of eat-2, a genetic surrogate of nematodal CR (Fierro-Gonzalez et al 2011). The oxidoreductase thioredoxin is not only involved in antioxidant response and redox regulation, but also acts as electron donor for metabolic enzymes and prevents aggregation of cytosolic proteins in the cell Holmgren 2007, Berndt et al 2008).…”

Interplay between redox and protein homeostasis

“…However, only limited information is present about their function and characteristics. 12,[62][63][64][65][66][67] Thioredoxins are highly specialized in their tissue, cell and compartmental expression pattern (Fig. 1).…”

“…67 Besides their function in redox homeostasis, thioredoxins have also been described to be involved in dauer formation, life span regulation and innate immunity. 63,66,67,70 The J-protein DNJ-27 combines chaperone function with classical TRX and PDI active sites A prominent member of the thioredoxin family that combines protein and redox homeostasis functions in one protein is the J-protein DNJ-27, which is the homolog of the mammalian ERdj5. 64 Like its mammalian homolog, DNJ-27 harbors a N-terminal J-domain, 4 trx-like domains with the CXXC motif (CSHC, CPPC, trx motif CGPC, PDI motif CGHC) and 2 divergent trx-like domains without CXXC motif (Fig.…”