Shared Transcriptional Signature in Caenorhabditis elegans Dauer Larvae and Long-lived daf-2 Mutants Implicates Detoxification System in Longevity Assurance

Abstract

In the nematode Caenorhabditis elegans, formation of the long-lived dauer larva and adult aging are both controlled by insulin/insulin-like growth factor-1 signaling. Potentially, increased adult life span in daf-2 insulin/ insulin-like growth factor-1 receptor mutants results from mis-expression in the adult of a dauer larva longevity program. By using oligonucleotide microarray analysis, we identified a dauer transcriptional signature in daf-2 mutant adults. By means of a nonbiased statistical approach, we identified gene classes whose expression is altered similarly in dauers and daf-2 mutants, which represent potential determinants of life span. These include known determinants of longevity; the small heat shock protein/␣-crystallins are up-regulated in both milieus. The cytochrome P450, short-chain dehydrogenase/reductase, UDP-glucuronosyltransferase, and glutathione S-transferase (in daf-2 mutants) gene classes were also up-regulated. These four gene classes act together in metabolism and excretion of toxic endobiotic and xenobiotic metabolites. This suggests that diverse toxic lipophilic and electrophilic metabolites, disposed of by phase 1 and phase 2 drug metabolism, may be the major determinants of the molecular damage that causes aging. In addition, we observed downregulation of genes linked to nutrient uptake, including nhx-2 and pep-2. These work together in the uptake of dipeptides in the intestine, implying dietary restriction in daf-2 mutants. Some gene groups up-regulated in dauers and/or daf-2 were enriched for certain promoter elements as follows: the daf-16-binding element, the heat shock-response element, the heat shock-associated sequence, or the hif-1-response element. By contrast, the daf-16-associated element was enriched in genes downregulated in dauers and daf-2 mutants. Thus, particular promoter elements appear longevity-associated or aging associated.

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

“…We have demonstrated heterogeneity much earlier in the lifespan. This heterogeneity potentially complicates the interpretation of microarray studies of aging that incorporate many individuals at sampled timepoints (Lund et al 2002;Budovskaya et al 2008;McElwee et al 2004). Our ability to detect these discrete sub-populations allowed us to isolate them and compare their transcriptional profiles, where hierarchical clustering and PCA showed that the two sub-populations were indeed (Durieux et al 2011) showed that mitochondrial signals from neurons can affect the organism's lifespan through their action in the intestine.…”

“…Interestingly, some of the genes in these clusters had been identified previously in other microarray analyses (Table 3). Other clusters included four broad functional categories known to be involved in the aging process: heat-shock proteins (HSPs), cytochrome P450 family oxidases (P450 and sterol oxidases), insulin/IGF-1 signaling pathway components (Lund et al 2002;Murphy et al 2003;McElwee et al 2004, and genes broadly affecting mitochondrial function (Feng et al 2001;Lee et al 2003;Dillin et al 2002). In each functional cluster, our gene list included a number of genes not previously identified in other microarray studies of aging.…”

Alternate metabolism during the dauer stage of the nematode Caenorhabditis elegans

“…These include cytochrome P450-dependent monoxygenases (CYPs), and UDP-glucuronosyltransferases (UGTs) (Wang and Kim, 2003) as well as short-chain dehydrogenases/reductases (SDRs) (McElwee et al, 2004) and glutathione S-transferases (GSTs) (Jones et al, 2001). CYPs are involved in the biosynthesis or biodegradation of a range of endogenous lipophilic substrates such as steroids, fatty acids and aromatic compounds and also in the biodegradation of xenobiotics.…”

“…Some dauer-specific processes are reiterated in long lived daf-2 adult nematodes Genome-wide surveys of transcriptional changes resulting from reduced signalling through the DAF-2 insulin/IGF-1 receptor in long-lived daf-2 adult nematodes have been carried out using microarray (McElwee et al, 2003(McElwee et al, , 2004Murphy et al, 2003) and SAGE (Halaschek-Weiner et al, 2005) analyses. Although there is some overlap between the gene sets identified in the different experiments, a high proportion of genes is uniquely identified in each study.…”

“…Although there is some overlap between the gene sets identified in the different experiments, a high proportion of genes is uniquely identified in each study. McElwee et al (2004) identified a number of gene categories that significantly enriched in both dauer larvae and daf-2 adult nematodes. These include the HSP20/a-crystallin gene family; detoxification genes encoding CYPs, SDRs and UGTs; genes encoding transthyretin-related proteins (TRP), as well as other gene classes involved in metabolism, oxidoreductase activity and electron transport.…”