Gene co-expression analyses of health(span) across multiple species.

Health(span)-related gene clusters/modules were recently identified based on knowledge about the cross-species genetic basis of health, to interpret transcriptomic datasets describing health-related interventions. However, the cross-species comparison of health-related observations reveals a lot of heterogeneity, not least due to widely varying health(span) definitions and study designs, posing a challenge for the exploration of conserved healthspan modules and, specifically, their transfer across species. To improve the identification and exploration of conserved/transferable healthspan modules, here we apply an established workflow based on gene co-expression network analyses employing GEO/ArrayExpress data for human and animal models, and perform a comprehensive meta-study of the resulting modules related to health(span), yielding a small set of literature backed health(span) candidate genes. For each experiment, WGCNA (weighted gene correlation network analysis) was used to infer modules of genes which correlate in their expression with a 'health phenotype score' and to determine the most-connected (hub) genes (and their interactions) for each such module. After mapping these hub genes to their human orthologs, 12 health(span) genes were identified in at least two species (ACTN3, ANK1, MRPL18, MYL1, PAXIP1, PPP1CA, SCN3B, SDCBP, SKIV2L, TUBG1, TYROBP, WIPF1), for which enrichment analysis by g:profiler found an association with actin filament-based movement and associated organelles, as well as muscular structures. We conclude that a meta-study of hub genes from co-expression network analyses for the complex phenotype health(span), across multiple species, can yield molecular-mechanistic insights and can direct experimentalists to further investigate the contribution of individual genes and their interactions to health(span).

Phenotypic and molecular responses of copepods to UV radiation stress in a clear versus a glacially turbid lake.

Zooplankton are exposed to multiple environmental stressors in alpine lakes. However, phenotypic and molecular responses of copepods to different environmental conditions, including ultraviolet radiation (UVR), are still not fully understood. Here, we tested whether gene expression patterns vary within the same species, Cyclops abyssorum tatricus, but in populations from different environments (a clear vs. a glacially turbid lake) when exposed to UVR. Moreover, we wanted to examine potential seasonal variation (summer vs. autumn) in copepod gene expression.We measured photoprotective compounds (mycosporine-like amino acids and carotenoids) and antioxidant capacities in two copepod populations and studied gene expression of heat shock proteins (hsps) as indicator of stress after UVR exposure in the laboratory.Compared with the copepod population from the clear lake, the population from the turbid lake showed lower mycosporine-like amino acid, but higher carotenoid concentrations that decreased over the season. Antioxidant capacities (both lipophilic and hydrophilic) were higher in autumn than in summer. The hsp60 and hsp90 genes were constitutively expressed, regardless of habitat origin and season, while hsp70 was upregulated after exposure to UVR (up to 2.8-fold change). We observed stronger upregulation of hsp70 gene expression in autumn for the turbid and summer for the clear lake, with highest gene expression 24 hr post-UVR exposure (up to 10.2-fold change in the turbid and 3.9-fold in the clear lake).We show how variation in phenotypic traits modulates hsp gene expression patterns, specifically hsp70 gene expression. Rapidly induced defences against cellular stress may improve survival in harsh environments such as alpine lakes, especially since these sensitive ecosystems may experience further changes in the future.

Identification of a Hydroxygallic Acid Derivative, Zingibroside R1 and a Sterol Lipid as Potential Active Ingredients of Cuscuta chinensis Extract That Has Neuroprotective and Antioxidant Effects in Aged Caenorhabditis elegans.

We examined the effects of the extracts from two traditional Chinese medicine plants, Cuscuta chinensis and Eucommia ulmoides, on the healthspan of the model organism Caenorhabditis elegans. C. chinensis increased the short-term memory and the mechanosensory response of aged C. elegans. Furthermore, both extracts improved the resistance towards oxidative stress, and decreased the intracellular level of reactive oxygen species. Chemical analyses of the extracts revealed the presence of several bioactive compounds such as chlorogenic acid, cinnamic acid, and quercetin. A fraction from the C. chinensis extract enriched in zingibroside R1 improved the lifespan, the survival after heat stress, and the locomotion in a manner similar to the full C. chinensis extract. Thus, zingibroside R1 could be (partly) responsible for the observed health benefits of C. chinensis. Furthermore, a hydroxygallic acid derivative and the sterol lipid 4-alpha-formyl-stigmasta-7,24(241)-dien-3-beta-ol are abundantly present in the C. chinensis extract and its most bioactive fraction, but hardly in E. ulmoides, making them good candidates to explain the overall healthspan benefits of C. chinensis compared to the specific positive effects on stress resistance by E. ulmoides. Our findings highlight the overall anti-aging effects of C. chinensis in C. elegans and provide first hints about the components responsible for these effects.

Identification of healthspan-promoting genes in Caenorhabditis elegans based on a human GWAS study.

To find drivers of healthy ageing, a genome-wide association study (GWAS) was performed in healthy and unhealthy older individuals. Healthy individuals were defined as free from cardiovascular disease, stroke, heart failure, major adverse cardiovascular event, diabetes, dementia, cancer, chronic obstructive pulmonary disease (COPD), asthma, rheumatism, Crohn's disease, malabsorption or kidney disease. Six single nucleotide polymorphisms (SNPs) with unknown function associated with ten human genes were identified as candidate healthspan markers. Thirteen homologous or closely related genes were selected in the model organism C. elegans for evaluating healthspan after targeted RNAi-mediated knockdown using pathogen resistance, muscle integrity, chemotaxis index and the activity of known longevity and stress response pathways as healthspan reporters. In addition, lifespan was monitored in the RNAi-treated nematodes. RNAi knockdown of yap-1, wwp-1, paxt-1 and several acdh genes resulted in heterogeneous phenotypes regarding muscle integrity, pathogen resistance, chemotactic behaviour, and lifespan. Based on these observations, we hypothesize that their human homologues WWC2, CDKN2AIP and ACADS may play a role in health maintenance in the elderly.

Genes implicated in Caenorhabditis elegans and human health regulate stress resistance and physical abilities in aged Caenorhabditis elegans.

Recently, nine Caenorhabditis elegans genes, grouped into two pathways/clusters, were found to be implicated in healthspan in C. elegans and their homologues in humans, based on literature curation, WormBase data mining and bioinformatics analyses. Here, we further validated these genes experimentally in C. elegans. We downregulated the nine genes via RNA interference (RNAi), and their effects on physical function (locomotion in a swim assay) and on physiological function (survival after heat stress) were analysed in aged nematodes. Swim performance was negatively affected by the downregulation of acox-1.1, pept-1, pak-2, gsk-3 and C25G6.3 in worms with advanced age (twelfth day of adulthood) and heat stress resistance was decreased by RNAi targeting of acox-1.1, daf-22, cat-4, pig-1, pak-2, gsk-3 and C25G6.3 in moderately (seventh day of adulthood) or advanced aged nematodes. Only one gene, sad-1, could not be linked to a health-related function in C. elegans with the bioassays we selected. Thus, most of the healthspan genes could be re-confirmed by health measurements in old worms.

Health and longevity studies in C. elegans: the "healthy worm database" reveals strengths, weaknesses and gaps of test compound-based studies.

Several biogerontology databases exist that focus on genetic or gene expression data linked to health as well as survival, subsequent to compound treatments or genetic manipulations in animal models. However, none of these has yet collected experimental results of compound-related health changes. Since quality of life is often regarded as more valuable than length of life, we aim to fill this gap with the "Healthy Worm Database" ( http://healthy-worm-database.eu ). Literature describing health-related compound studies in the aging model Caenorhabditis elegans was screened, and data for 440 compounds collected. The database considers 189 publications describing 89 different phenotypes measured in 2995 different conditions. Besides enabling a targeted search for promising compounds for further investigations, this database also offers insights into the research field of studies on healthy aging based on a frequently used model organism. Some weaknesses of C. elegans-based aging studies, like underrepresented phenotypes, especially concerning cognitive functions, as well as the convenience-based use of young worms as the starting point for compound treatment or phenotype measurement are discussed. In conclusion, the database provides an anchor for the search for compounds affecting health, with a link to public databases, and it further highlights some potential shortcomings in current aging research.

Enhanced Healthspan in Caenorhabditis elegans Treated With Extracts From the Traditional Chinese Medicine Plants Cuscuta chinensis Lam. and Eucommia ulmoides Oliv.

To uncover potential anti-aging capacities of Traditional Chinese Medicine (TCM), the nematode Caenorhabditis elegans was used to investigate the effects of Eucommia ulmoides and Cuscuta chinensis extracts, selected by screening seven TCM extracts, on different healthspan parameters. Nematodes exposed to E. ulmoides and C. chinensis extracts, starting at the young adult stage, exhibited prolonged lifespan and increased survival after heat stress as well as upon exposure to the pathogenic bacterium Photorhabdus luminescens, whereby the survival benefits were monitored after stress initiation at different adult stages. However, only C. chinensis had the ability to enhance physical fitness: the swimming behavior and the pharyngeal pumping rate of C. elegans were improved at day 7 and especially at day 12 of adulthood. Finally, monitoring the red fluorescence of aged worms revealed that only C. chinensis extracts caused suppression of intestinal autofluorescence, a known marker of aging. The results underline the different modes of action of the tested plants extracts. E. ulmoides improved specifically the physiological fitness by increasing the survival probability of C. elegans after stress, while C. chinensis seems to be an overall healthspan enhancer, reflected in the suppressed autofluorescence, with beneficial effects on physical as well as physiological fitness. The C. chinensis effects may be hormetic: this is supported by increased gene expression of hsp-16.1 and by trend, also of hsp-12.6.

Natural products improve healthspan in aged mice and rats: A systematic review and meta-analysis.

Over the last decades a decrease in mortality has paved the way for late onset pathologies such as cardiovascular, metabolic or neurodegenerative diseases. This evidence has led many researchers to shift their focus from researching ways to extend lifespan to finding ways to increase the number of years spent in good health; "healthspan" is indeed the emerging concept of such quest for ageing without chronic or disabling diseases and dysfunctions. Regular consumption of natural products might improve healthspan, although the mechanisms of action are still poorly understood. Since preclinical studies aimed to assess the efficacy and safety of these compounds are growing, we performed a systematic review and meta-analysis on the effects of natural products on healthspan in mouse and rat models of physiological ageing. Results indicate that natural compounds show robust effects improving stress resistance and cognitive abilities. These promising data call for further studies investigating the underlying mechanisms in more depth.

Healthspan pathway maps in C. elegans and humans highlight transcription, proliferation/biosynthesis and lipids.

The molecular basis of aging and of aging-associated diseases is being unraveled at an increasing pace. An extended healthspan, and not merely an extension of lifespan, has become the aim of medical practice. Here, we define health based on the absence of diseases and dysfunctions. Based on an extensive review of the literature, in particular for humans and C. elegans, we compile a list of features of health and of the genes associated with them. These genes may or may not be associated with survival/lifespan. In turn, survival/lifespan genes that are not known to be directly associated with health are not considered. Clusters of these genes based on molecular interaction data give rise to maps of healthspan pathways for humans and for C. elegans. Overlaying healthspan-related gene expression data onto the healthspan pathway maps, we observe the downregulation of (pro-inflammatory) Notch signaling in humans and of proliferation in C. elegans. We identify transcription, proliferation/biosynthesis and lipids as a common theme on the annotation level, and proliferation-related kinases on the gene/protein level. Our literature-based data corpus, including visualization, should be seen as a pilot investigation of the molecular underpinnings of health in two different species. Web address: http://pathways.h2020awe.eu.

Healthspan Enhancement by Olive Polyphenols in C. elegans Wild Type and Parkinson's Models.

Parkinson's disease (PD) is the second most prevalent late-age onset neurodegenerative disorder, affecting 1% of the population after the age of about 60 years old and 4% of those over 80 years old, causing motor impairments and cognitive dysfunction. Increasing evidence indicates that Mediterranean diet (MD) exerts beneficial effects in maintaining health, especially during ageing and by the prevention of neurodegenerative disorders. In this regard, olive oil and its biophenolic constituents like hydroxytyrosol (HT) have received growing attention in the past years. Thus, in the current study we test the health-promoting effects of two hydroxytyrosol preparations, pure HT and Hidrox® (HD), which is hydroxytyrosol in its "natural" environment, in the established invertebrate model organism Caenorhabditis elegans. HD exposure led to much stronger beneficial locomotion effects in wild type worms compared to HT in the same concentration. Consistent to this finding, in OW13 worms, a PD-model characterized by α-synuclein expression in muscles, HD exhibited a significant higher effect on α-synuclein accumulation and swim performance than HT, an effect partly confirmed also in swim assays with the UA44 strain, which features α-synuclein expression in DA-neurons. Interestingly, beneficial effects of HD and HT treatment with similar strength were detected in the lifespan and autofluorescence of wild-type nematodes, in the neuronal health of UA44 worms as well as in the locomotion of rotenone-induced PD-model. Thus, the hypothesis that HD features higher healthspan-promoting abilities than HT was at least partly confirmed. Our study demonstrates that HD polyphenolic extract treatment has the potential to partly prevent or even treat ageing-related neurodegenerative diseases and ageing itself. Future investigations including mammalian models and human clinical trials are needed to uncover the full potential of these olive compounds.

Healthspan Maintenance and Prevention of Parkinson's-like Phenotypes with Hydroxytyrosol and Oleuropein Aglycone in C. elegans.

Numerous studies highlighted the beneficial effects of the Mediterranean diet (MD) in maintaining health, especially during ageing. Even neurodegeneration, which is part of the natural ageing process, as well as the foundation of ageing-related neurodegenerative disorders like Alzheimer's and Parkinson's disease (PD), was successfully targeted by MD. In this regard, olive oil and its polyphenolic constituents have received increasing attention in the last years. Thus, this study focuses on two main olive oil polyphenols, hydroxytyrosol (HT) and oleuropein aglycone (OLE), and their effects on ageing symptoms with special attention to PD. In order to avoid long-lasting, expensive, and ethically controversial experiments, the established invertebrate model organism Caenorhabditis elegans was used to test HT and OLE treatments. Interestingly, both polyphenols were able to increase the survival after heat stress, but only HT could prolong the lifespan in unstressed conditions. Furthermore, in aged worms, HT and OLE caused improvements of locomotive behavior and the attenuation of autofluorescence as a marker for ageing. In addition, by using three different C. elegans PD models, HT and OLE were shown i) to enhance locomotion in worms suffering from α-synuclein-expression in muscles or rotenone exposure, ii) to reduce α-synuclein accumulation in muscles cells, and iii) to prevent neurodegeneration in α-synuclein-containing dopaminergic neurons. Hormesis, antioxidative capacities and an activity-boost of the proteasome & phase II detoxifying enzymes are discussed as potential underlying causes for these beneficial effects. Further biological and medical trials are indicated to assess the full potential of HT and OLE and to uncover their mode of action.

Health and Aging: Unifying Concepts, Scores, Biomarkers and Pathways.

Despite increasing research efforts, there is a lack of consensus on defining aging or health. To understand the underlying processes, and to foster the development of targeted interventions towards increasing one's health, there is an urgent need to find a broadly acceptable and useful definition of health, based on a list of (molecular) features; to operationalize features of health so that it can be measured; to identify predictive biomarkers and (molecular) pathways of health; and to suggest interventions, such as nutrition and exercise, targeted at putative causal pathways and processes. Based on a survey of the literature, we propose to define health as a state of an individual characterized by the core features of physiological, cognitive, physical and reproductive function, and a lack of disease. We further define aging as the aggregate of all processes in an individual that reduce its wellbeing, that is, its health or survival or both. We define biomarkers of health by their attribute of predicting future health better than chronological age. We define healthspan pathways as molecular features of health that relate to each other by belonging to the same molecular pathway. Our conceptual framework may integrate diverse operationalizations of health and guide precision prevention efforts.

Contrasting diurnal patterns in antioxidant capacities, but not in expression of stress protein genes among copepod populations from clear versus glacially fed alpine and subalpine lakes.

Short-term changes in environmental conditions largely influence planktonic organisms, but their responses will depend on the habitat characteristics. Here we studied diurnal patterns in antioxidative metabolites (lipophilic and hydrophilic antioxidant capacities) and in the expression of stress protein genes (heat shock proteins, hsp) of copepods to identify short-term stress responses in clear and turbid alpine lakes, as well as in less transparent subalpine ones. Cyclops abyssorum tatricus showed diurnal variation in antioxidant capacities with maxima around noon in clear, but not in glacially fed, turbid lakes. Low fluctuations of these metabolites were also observed in another copepod, Acanthodiaptomus denticornis. Although levels of hsp genes differed between populations living in clear or glacially fed lakes, there was no diurnal rhythmicity in gene expression. Our data show that when planktonic organisms may be at greatest risk of oxidative damage, such as during the daytime in high UV radiation environments, they activate antioxidant responses. Conversely, in less transparent lakes, the physiological response seems to be unnecessary. The difference in gene expression levels suggests an ecological, albeit not acute, role of these genes in copepods experiencing daily environmental fluctuations.

Distribution and UV protection strategies of zooplankton in clear and glacier-fed alpine lakes.

Zooplankton, a group of aquatic animals important as trophic link in the food web, are exposed to high levels of UV radiation (UVR) in clear alpine lakes, while in turbid glacier-fed lakes they are more protected. To study the interplay between behavioral and physiological protection responses in zooplankton from those lakes, we sampled six lakes of different UVR transparency and glacial turbidity. Copepods were absent in the upper water layers of the clearest lake, while in glacier-fed lakes they were more evenly distributed in the water column. Across all lakes, the weighted copepod mean depth was strongly related to food resources (chlorophyll a and rotifers), whereas in the fishless lakes, glacial turbidity largely explained the vertical daytime distribution of these organisms. Up to ~11-times (mean 3.5) higher concentrations of photo-protective compounds (mycosporine-like amino acids, MAAs) were found in the copepods from the clear than from the glacier-fed lakes. In contrast to carotenoid concentrations and antioxidant capacities, MAA levels were strongly related to the lake transparency. Copepods from alpine lakes rely on a combination of behavioral and physiological strategies adapted to the change in environmental conditions taking place when lakes shift from glacially turbid to clear conditions, as glacier retreat proceeds.

Ageing with elegans: a research proposal to map healthspan pathways.

Human longevity continues to increase world-wide, often accompanied by decreasing birth rates. As a larger fraction of the population thus gets older, the number of people suffering from disease or disability increases dramatically, presenting a major societal challenge. Healthy ageing has therefore been selected by EU policy makers as an important priority ( http://www.healthyageing.eu/european-policies-and-initiatives ); it benefits not only the elderly but also their direct environment and broader society, as well as the economy. The theme of healthy ageing figures prominently in the Horizon 2020 programme ( https://ec.europa.eu/programmes/horizon2020/en/h2020-section/health-demographic-change-and-wellbeing ), which has launched several research and innovation actions (RIA), like "Understanding health, ageing and disease: determinants, risk factors and pathways" in the work programme on "Personalising healthcare" ( https://ec.europa.eu/research/participants/portal/desktop/en/opportunities/h2020/topics/693-phc-01-2014.html ). Here we present our research proposal entitled "ageing with elegans" (AwE) ( http://www.h2020awe.eu/ ), funded by this RIA, which aims for better understanding of the factors causing health and disease in ageing, and to develop evidence-based prevention, diagnostic, therapeutic and other strategies. The aim of this article, authored by the principal investigators of the 17 collaborating teams, is to describe briefly the rationale, aims, strategies and work packages of AwE for the purposes of sharing our ideas and plans with the biogerontological community in order to invite scientific feedback, suggestions, and criticism.

Adsorbable organic bromine compounds (AOBr) in aquatic samples: a nematode-based toxicogenomic assessment of the exposure hazard.

Elevated levels of adsorbable organic bromine compounds (AOBr) have been detected in German lakes, and cyanobacteria like Microcystis, which are known for the synthesis of microcystins, are one of the main producers of natural organobromines. However, very little is known about how environmental realistic concentrations of organobromines impact invertebrates. Here, the nematode Caenorhabditis elegans was exposed to AOBr-containing surface water samples and to a Microcystis aeruginosa-enriched batch culture (MC-BA) and compared to single organobromines and microcystin-LR exposures. Stimulatory effects were observed in certain life trait variables, which were particularly pronounced in nematodes exposed to MC-BA. A whole genome DNA-microarray revealed that MC-BA led to the differential expression of more than 2000 genes, many of which are known to be involved in metabolic, neurologic, and morphologic processes. Moreover, the upregulation of cyp- and the downregulation of abu-genes suggested the presence of chronic stress. However, the nematodes were not marked by negative phenotypic responses. The observed difference in MC-BA and microcystin-LR (which impacted lifespan, growth, and reproduction) exposed nematodes was hypothesized to be likely due to other compounds within the batch culture. Most likely, the exposure to low concentrations of organobromines appears to buffer the effects of toxic substances, like microcystin-LR.

Natural Marine and Synthetic Xenobiotics Get on Nematode's Nerves: Neuro-Stimulating and Neurotoxic Findings in Caenorhabditis elegans.

Marine algae release a plethora of organic halogenated compounds, many of them with unknown ecological impact if environmentally realistic concentrations are applied. One major compound is dibromoacetic acid (DBAA) which was tested for neurotoxicity in the invertebrate model organism Caenorhabditis elegans (C. elegans). This natural compound was compared with the widespread synthetic xenobiotic tetrabromobisphenol-A (TBBP-A) found in marine sediments and mussels. We found a neuro-stimulating effect for DBAA; this is contradictory to existing toxicological reports of mammals that applied comparatively high dosages. For TBBP-A, we found a hormetic concentration-effect relationship. As chemicals rarely occur isolated in the environment, a combination of both organobromines was also examined. Surprisingly, the presence of DBAA increased the toxicity of TBBP-A. Our results demonstrated that organohalogens have the potential to affect single organisms especially by altering the neurological processes, even with promoting effects on exposed organisms.

Low concentrations of dibromoacetic acid and N-nitrosodimethylamine induce several stimulatory effects in the invertebrate model Caenorhabditis elegans.

Dibromoacetic acid (DBAA) and N-nitrosodimethylamine (NDMA) have natural and anthropogenic sources and are ubiquitously distributed in the environment. They are classified as toxic and carcinogenetic and various studies have addressed their effects on vertebrates. Furthermore, there is no information about the whole-organism effects at low concentrations or about their impact on invertebrates. Therefore, these compounds were studied with the model invertebrate Caenorhabditis elegans (C. elegans) at relatively low concentrations. Biological tests (life span, reproduction, body size, thermal stress resistance) as well as biochemical (pro- and antioxidative capacity and lipid peroxidation) and biomolecular assays (transcription of stress genes) were performed. None of the applied concentrations showed a toxic potential. Instead, they extended life span and increased the body length. Both xenobiotics did not cause oxidative stress or DNA damages, or acted as endocrine disruptors. The stimulatory effects on C. elegans were most likely not a result of an induced protective stress response. Instead, an 'energy saving mode', indicated by the reduced transcription of many stress response genes, could have provided additional resources for longevity and growth. Although both substances are potentially toxic at higher doses, the present study underlines the importance of testing lower concentrations and their impact on invertebrates.

Neurotoxic action of microcystin-LR is reflected in the transcriptional stress response of Caenorhabditis elegans.

Cyanobacterial blooms in aquatic environments are frequently characterized by elevated levels of microcystins, a potent hepatotoxin. Here we exposed the nematode Caenorhabditis elegans with environmentally realistic concentrations of MC-LR to explore its non-hepatic toxicity. Lifespan, reproduction and growth assays confirmed the toxic potential of 100µg/L MC-LR even in this liver-lacking invertebrate. Whole-genome microarray analysis revealed that a neuromodulating action was the dominant response in nematodes challenged with 100µg/L MC-LR. Indeed, most of the 201 differentially expressed genes were associated with neurobehavior, neurogenesis, and signaling associated pathways. In addition, a whole-genome miRNA-microarray highlighted that, in particular, members of the let-7 family were differentially regulated. These miRNAs are involved in the developmental timing of cell fates, including neurons, and are probably also part of the stress response system. To conclude, neurological modulation is the main transcriptional stress response in C. elegans exposed to MC-LR.

Two organobromines trigger lifespan, growth, reproductive and transcriptional changes in Caenorhabditis elegans.

Organobromines of natural and artificial origin are omnipresent in aquatic and terrestrial environments. Although it is well established that exposure to high concentrations of organobromines are harmful to vertebrates, few studies have investigated the effect of environmentally realistic concentrations on invertebrates. Here, the nematode Caenorhabditis elegans was challenged with two organobromines, namely dibromoacetic acid (DBAA) and tetrabromobisphenol-A (TBBP), and monitored for changes in different life trait variables and global gene expression patterns. Fifty micromolar DBAA stimulated the growth and lifespan of the nematodes; however, the onset of reproduction was delayed. In contrast, TBBP changed the lifespan in a hormetic fashion, namely it was stimulated at 0.1 µM but impaired at 50 µM. The reproductive performance was even impaired at 2 µM TBBP. Moreover, DBAA could not reduce the toxic effect of TBBP when applied as a mixture. A whole-genome DNA microarray revealed that both organobromines curtailed signalling and neurological processes. Furthermore on the transcription level, 50 µM TBBP induced proteolysis and DBAA up-regulated biosynthesis and metabolism. To conclude, even naturally occurring concentrations of organobromines can influence the biomolecular responses and life cycle traits in C. elegans. The life extension is accompanied by negative changes in the reproductive behaviour, which is crucial for the stability of populations. Thus, this paper highlights that the effects of exposure to moderate, environmentally realistic concentrations of organobromines should not be ignored.