Meta-Analysis of Global Transcriptomics Suggests that Conserved Genetic Pathways are Responsible for Quercetin and Tannic Acid Mediated Longevity in C. elegans

Abstract

Recent research has highlighted that the polyphenols Quercetin and Tannic acid are capable of extending the lifespan of Caenorhabditis elegans. To gain a deep understanding of the underlying molecular genetics, we analyzed the global transcriptional patterns of nematodes exposed to three concentrations of Quercetin or Tannic acid, respectively. By means of an intricate meta-analysis it was possible to compare the transcriptomes of polyphenol exposure to recently published datasets derived from (i) longevity mutants or (ii) infection. This detailed comparative in silico analysis facilitated the identification of compound specific and overlapping transcriptional profiles and allowed the prediction of putative mechanistic models of Quercetin and Tannic acid mediated longevity. Lifespan extension due to Quercetin was predominantly driven by the metabolome, TGF-beta signaling, Insulin-like signaling, and the p38 MAPK pathway and Tannic acid’s impact involved, in part, the amino acid metabolism and was modulated by the TGF-beta and the p38 MAPK pathways. DAF-12, which integrates TGF-beta and Insulin-like downstream signaling, and genetic players of the p38 MAPK pathway therefore seem to be crucial regulators for both polyphenols. Taken together, this study underlines how meta-analyses can provide an insight of molecular events that go beyond the traditional categorization into gene ontology-terms and Kyoto encyclopedia of genes and genomes-pathways. It also supports the call to expand the generation of comparative and integrative databases, an effort that is currently still in its infancy.

Exploring Target Genes Involved in the Effect of Quercetin on the Response to Oxidative Stress in Caenorhabditis elegans

“…Mertenskötter et al [42] showed that in the expression of chaperone genes, protein biosynthesis and protein degradation was positively influenced by the MAPK pathway and established the importance of this pathway in heat stress responses, possibly by a PMK-1-mediated activation of the transcription factor SKN-1 in C. elegans. Other authors have also found that components of related pathways, such as UNC-43, SEK-1, and OSR-1 are involved in the molecular mechanisms of the response to quercetin and other polyphenols [11,43,44]. Thus, the MAPK pathways could also be implicated in the effects of quercetin, which might contribute to explain the role of SKN-1 and the activation of certain HSPs observed in the present study.…”

Geroprotective and Radioprotective Activity of Quercetin, (-)-Epicatechin, and Ibuprofen in Drosophila melanogaster

“…At the same time, flavonoids regulate the activity of other signaling pathways that determined their non-antioxidant activity. For example, quercetin and (-)-epicatechin are able to modulate activity of pro-aging IGF-1/insulin and phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) pathways (Pietsch et al, 2012) (Si et al, 2011). Further, IGF-1/insulin suppression leads to translocation of the FOXO transcription factor to nucleus and activation of expression of pro-longevity genes (Si et al, 2011).…”

Molecular and physiological actions of quercetin: need for clinical trials to assess its benefits in human disease

“…A gene transcriptome approach to unraveling the mechanism of quercetin's ability to extend life span revealed that metabolic energy pathways, TGF‐β signaling, insulin‐like growth factor signaling, and the p38 MAPK pathway all play a role in mediating the life‐prolonging response. Since DAF‐12 integrates TGF‐β, insulin‐like downstream signaling, and the genetic players of the p38 MAPK pathway, it is likely a crucial regulator of the biologic action of quercetin …”