Oxidative stress and longevity in Caenorhabditis elegans as mediated by SKN‐1

Abstract

SummaryOxidative stress has been hypothesized to play a role in normal aging. The response to oxidative stress is regulated by the SKN-1 transcription factor, which also is necessary for intestinal development in Caenorhabditis elegans. Almost a thousand genes including the antioxidant and heat-shock responses, as well as genes responsible for xenobiotic detoxification were induced by the oxidative stress which was found using transcriptome analysis. There were also 392 down-regulated genes including many involved in metabolic homeostasis, organismal development, and reproduction. Many of these oxidative stress-induced transcriptional changes are dependent on SKN-1 action; the induction of the heat-shock response is not. When RNAi to inhibit genes was used, most had no effect on either resistance to oxidative stress or longevity; however two SKN-1-dependent genes, nlp-7 and cup-4, that were up-regulated by oxidative stress were found to be required for resistance to oxidative stress and for normal lifespan. nlp-7 encodes a neuropeptide-like protein, expressed in neurons, while cup-4 encodes a coelomocyte-specific, ligand-gated ion channel. RNAi of nlp-7 or cup-4 increased sensitivity to oxidative stress and reduced lifespan. Among down-regulated genes, only inhibition of ent-1, a nucleoside transporter, led to increased resistance to oxidative stress; inhibition had no effect on lifespan. In contrast, RNAi of nhx-2, a Na + ⁄ H + exchanger, extended lifespan significantly without affecting sensitivity to oxidative stress. These findings showed that a transcriptional shift from growth and maintenance towards the activation of cellular defense mechanisms was caused by the oxidative stress; many of these transcriptional alterations are SKN-1 dependent.

Molecular characterization of the transition to mid-life in Caenorhabditis elegans

“…A Venn diagram shows the degree of overlap between the gene lists from three previous studies of aging in C. elegans, similar to a figure presented in Park et al (2009), Murphy et al (2003, and Budovskaya et al (2008). This overlap reflects real differences in the response of animals to experimental regimes, but also the differences in the microarray platforms.…”

“…These three studies defined differentially expressed genes found in daf-2 mutant animals compared with daf-2; daf-16 animals (Murphy et al 2003), over an aging time course (Budovskaya et al 2008) and after treatment with hyperbaric oxygen (Park et al 2009). After converting the reported WormBase transcript IDs to official gene names, we had lists of 496 genes within the daf-2 transcriptome ("daf2"), 1,175 genes from the aging time course ("Aging"), 1,206 genes from the oxidative stress study ("Stress"), and 635 significantly regulated genes in state II worms ("State").…”

“…4). The three- set comparison was previously published, and it has been discussed (Park et al 2009). Nearly a quarter (11/ 48) of the genes found in all of the three previous studies is also found in our list (compare centermost region of overlap in Fig.…”

“…To examine the aging process in genetic detail, several microarray analyses comparing transcript levels at differing chronological ages have been performed. These studies used isolated individual animals (Golden and Melov 2004), populations with similar body muscle function phenotypes (Golden et al 2008), or pools of worms (Lund et al 2002;Murphy et al 2003;Budovskaya et al 2008;Park et al 2009). The identification of a transcription factor "circuit" (Budovskaya et al 2008) provided the first genetic evidence supporting antagonistic pleiotropy (Pincus and Slack 2008), a theory that suggests that some traits that are beneficial in early development may be deleterious when they are expressed later in life (Walker 2011).…”

Effects and mechanisms of prolongevity induced by Lactobacillus gasseri SBT2055 in Caenorhabditis elegans

“…5a). Expression of sod‐1 and the genes encoding heat‐shock proteins is induced in the presence of oxidative stress (Park et al ., 2009), with SOD‐1 contributing to 80% of the total SOD activity in C. elegans (Doonan et al ., 2008). We observed that SOD activity was increased in LG2055‐fed worms compared with that in OP50‐fed worms (Fig.…”