Atypical antidepressants extend lifespan of Caenorhabditis elegans by activation of a non‐cell‐autonomous stress response

Abstract

SummaryOxidative stress has long been associated with aging and has recently been linked to psychiatric disorders, including psychosis and depression. We identified multiple antipsychotics and antidepressants that extend Caenorhabditis elegans lifespan and protect the animal from oxidative stress. Here, we report that atypical antidepressants activate a neuronal mechanism that regulates the response to oxidative stress throughout the animal. While the activation of the oxidative stress response by atypical antidepressants depends on synaptic transmission, the activation by reactive oxygen species does not. Lifespan extension by atypical antidepressants depends on the neuronal oxidative stress response activation mechanism. Neuronal regulation of the oxidative stress response is likely to have evolved as a survival mechanism to protect the organism from oxidative stress, upon detection of adverse or dangerous conditions by the nervous system.

Global Transcriptome Changes That Accompany Alterations in Serotonin Levels inCaenorhabditis elegans

“…Our results indicate that both the deficiency of 5-HT, as well as its excess cause global changes in the transcriptome predicted to affect numerous tissue-types. While the RNA-seq datasets presented here show good agreement with published transcriptomes from animals treated with a 5-HT antagonist, mianserin (Rangaraju et al 2015a;Rangaraju et al 2015b), Gene Ontology analysis and comparison with the various published transcriptomes showed that gene expression changes in animals with excess 5-HT correlates best with gene expression changes from animals that have activated defense responses, and RNA-seq data from tph-1 (mg280) II animals was enriched for genes related to development and chromatin function. In addition, comparisons of the transcriptomes of animals with excess 5-HT or 5-HT deficiency (tph-1 (mg280) II) and published transcriptional profiles of C. elegans mutants which they phenotypically resemble, showed no significant overlap, suggesting that the similarity in the phenotypes of these animals may stem from commonalities other than gene expression changes.…”

“…The transcriptomes of both tph-1 animals and animals with excess 5-HT overlap significantly with animals treated With the atypical antidepressant, mianserin To authenticate our RNA-seq analysis we compared our RNA-seq data with the transcriptomes of animals where 5-HT levels were modulated through alternative means, namely by treatment with the 5-HT receptor antagonist, mianserin (Rangaraju et al 2015a;Rangaraju et al 2015b). Mianserin is used as an atypical antidepressant in humans, and increases lifespan and modulates transcriptional drift in C. elegans by acting through 5-HT pathways (Rangaraju et al 2015a;Rangaraju et al 2015b). In accordance with the role of mianserin as a 5-HT antagonist, the transcriptional changes in tph-1 animals significantly overlapped those animals treated with mianserin for 5 and 10 days as adults (P = 6.95 e-5, P = 1.36 e-11) ( Figure 10A,B).…”

Decision letter: Suppression of transcriptional drift extends C. elegans lifespan by postponing the onset of mortality

“…Because the expression patterns observed in many GOs were difficult to interpret in terms of functional change, we turned to investigate expression changes in the superoxide detoxification pathway, a well-defined cellular function that declines with age (Ashburner et al, 2000;Mi et al, 2005;Kumsta et al, 2011;Bansal et al, 2015;Rangaraju et al, 2015a). As expected from our previous studies (Rangaraju et al, 2015a), the expression levels of some superoxide detoxification genes were higher in mianserin-treated animals compared to age-matched controls ( Figure 1d). Exceptions were the expression levels of sod-4 and sod-5, which were lowered upon mianserin treatment ( Figure 1d).…”

“…When we excluded all genes that changed due to age and were attenuated by mianserin, we obtained a much smaller gene-set consisting of mianserin-induced changes that was enriched for GOs related to stress, xenobiotic and immune-responses, as well as genes associated with aging and the determination of lifespan (Table 1, Figure 1-source data 5). These GOs have been previously shown to be regulated by serotonin in C. elegans with the exception of the xenobiotic response (Zhang et al, 2005;Petrascheck et al, 2007;Rangaraju et al, 2015a). Thus, accounting for age-associated transcriptional changes dramatically simplified a seemingly very complex geneexpression pattern (Figure 1b,c).…”

“…In this model, slight initial deviations in gene expression levels would be compounded over time resulting in imbalanced stoichiometries between pathway components resulting in functional decline with age ( Figure 3a). Our previous studies showed that mianserin protected C. elegans from oxidative stress by a neuronal mechanism that modulated peripheral stress response genes (NEUROX) (Rangaraju et al, 2015a). We therefore constructed drift plots for redox-associated pathways that showed that mianserin indeed increased the overall expression of oxidative stress response genes (type I) relative to age-matched controls but also attenuated transcriptional drift (type II) ( Figure 3b; Table 3).…”