Hormesis and bone marrow stem cells: Enhancing cell proliferation, differentiation and resilience to inflammatory stress.

This paper identifies and provides the first detailed assessment of hormetic dose responses by bone marrow stem cells (BMSCs) from a broad range of animal models and humans with particular emphasis on cell renewal (proliferation), cell differentiation and enhancing resilience to inflammatory stress. Such hormetic dose responses are commonly reported, being induced by a broad range of chemicals, including pharmaceuticals (e.g., caffeine, dexamethasone, nicotine), dietary supplements (e.g., curcumin, Ginkgo biloba, green tea extracts. resveratrol, sulforaphane), endogenous agents (e.g., hydrogen sulfide, interleukin 10), environmental contaminants (e.g., arsenic, PFOS) and physical stressor agents (e.g., EMF, shockwaves). Hormetic dose responses reported here for BMSCs are similar to those induced with other stem cell types [e.g., adipose-derived stem cells (ADSCs), dental pulp stem cells (DPSCs), periodontal ligament stem cells (PDLSCs), neuro stem cells (NSCs), embryonic stem cells (ESCs)], indicating a substantial degree of generality for hormetic responses in stem cells. The paper assesses both the underlying mechanistic foundations of BMSC hormetic responses and their potential therapeutic implications.

Hormesis of low-dose inhibition of pAkt1 (Ser473) followed by a great increase of proline-rich inositol polyphosphate 5-phosphatase (PIPP) level in oocytes.

Hormesis describes a biphasic dose-response relationship generally characterized by a low-dose excitement and a high-dose inhibition. This phenomenon has been observed in the regulation of cell, organ, and organismic level. However, hormesis has not reported in oocytes. In this study, we observed, for the first time, hormetic responses of PIPP levels in oocytes by inhibitor of Akt1 or PKCδ. The expression of PIPP was detected by qPCR, immunofluorescent (IF), and Western Blot (WB). To observe the changes of PIPP levels, we used the inhibitors against pAkt1 (Ser473) or PKCδ, SH-6 or sotrastaurin with low and/or high-dose, treated GV oocytes and cultured for 4 h, respectively. The results showed that PIPP expression was significantly enhanced when oocytes were treated with SH-6 or sotrastaurin 10 µM, but decreased with SH-6 or sotrastaurin 100 µM. We also examined the changes of PIPP levels when GV oocytes were treated with exogenous PtdIns(3,4,5)P3 or LY294002 for 4 h. Our results showed that PIPP level was enhanced much higher under the treatment of 0.1 µM PtdIns(3,4,5)P3 than that of 1 µM PtdIns(3,4,5)P3, which is consistent with the changes of PIPP when oocytes were treated with inhibitors of pAkt1 (Ser473) or PKCδ. In addition, with PIPP siRNA, we detected that down-regulated PIPP may affect distributions of Akt, Cdc25, and pCdc2 (Tyr15). Taken together, these results show that the relationships between PIPP and Akt may follow the principle of hormesis and play a key role during release of diplotene arrest in mouse oocytes.

The phytoprotective agent sulforaphane prevents inflammatory degenerative diseases and age-related pathologies via Nrf2-mediated hormesis.

In numerous experimental models, sulforaphane (SFN) is shown herein to induce hormetic dose responses that are not only common but display endpoints of biomedical and clinical relevance. These hormetic responses are mediated via the activation of nuclear factor erythroid- derived 2 (Nrf2) antioxidant response elements (AREs) and, as such, are characteristically biphasic, well integrated, concentration/dose dependent, and specific with regard to the targeted cell type and the temporal profile of response. In experimental disease models, the SFN-induced hormetic activation of Nrf2 was shown to effectively reduce the occurrence and severity of a wide range of human-related pathologies, including Parkinson's disease, Alzheimer's disease, stroke, age-related ocular damage, chemically induced brain damage, and renal nephropathy, amongst others, while also enhancing stem cell proliferation. Although SFN was broadly chemoprotective within an hormetic dose-response context, it also enhanced cell proliferation/cell viability at low concentrations in multiple tumor cell lines. Although the implications of the findings in tumor cells are largely uncertain at this time and warrant further consideration, the potential utility of SFN in cancer treatment has not been precluded. This assessment of SFN complements recent reports of similar hormesis-based chemoprotections by other widely used dietary supplements, such as curcumin, ginkgo biloba, ginseng, green tea, and resveratrol. Interestingly, the mechanistic profile of SFN is similar to that of numerous other hormetic agents, indicating that activation of the Nrf2/ARE pathway is probably a central, integrative, and underlying mechanism of hormesis itself. The Nrf2/ARE pathway provides an explanation for how large numbers of agents that both display hormetic dose responses and activate Nrf2 can function to limit age-related damage, the progression of numerous disease processes, and chemical- and radiation- induced toxicities. These findings extend the generality of the hormetic dose response to include SFN and many other chemical activators of Nrf2 that are cited in the biomedical literature and therefore have potentially important public health and clinical implications.

Nanoparticle treatment of maize analyzed through the metatranscriptome: compromised nitrogen cycling, possible phytopathogen selection, and plant hormesis.

BACKGROUND: The beneficial use of nanoparticle silver or nanosilver may be confounded when its potent antimicrobial properties impact non-target members of natural microbiomes such as those present in soil or the plant rhizosphere. Agricultural soils are a likely sink for nanosilver due to its presence in agrochemicals and land-applied biosolids, but a complete assessment of nanosilver's effects on this environment is lacking because the impact on the natural soil microbiome is not known. In a study assessing the use of nanosilver for phytopathogen control with maize, we analyzed the metatranscriptome of the maize rhizosphere and observed multiple unintended effects of exposure to 100 mg kg-1 nanosilver in soil during a growth period of 117 days. RESULTS: We found several unintended effects of nanosilver which could interfere with agricultural systems in the long term. Firstly, the archaea community was negatively impacted with a more than 30% decrease in relative abundance, and as such, their involvement in nitrogen cycling and specifically, nitrification, was compromised. Secondly, certain potentially phytopathogenic fungal groups showed significantly increased abundances, possibly due to the negative effects of nanosilver on bacteria exerting natural biocontrol against these fungi as indicated by negative interactions in a network analysis. Up to 5-fold increases in relative abundance have been observed for certain possibly phytopathogenic fungal genera. Lastly, nanosilver exposure also caused a direct physiological impact on maize as illustrated by increased transcript abundance of aquaporin and phytohormone genes, overall resulting in a stress level with the potential to yield hormetically stimulated plant root growth. CONCLUSIONS: This study indicates the occurrence of significant unintended effects of nanosilver use on corn, which could turn out to be negative to crop productivity and ecosystem health in the long term. We therefore highlight the need to include the microbiome when assessing the risk associated with nano-enabled agriculture. Video Abstract.

Cereal grass juice in wound healing: hormesis and cell-survival in normal fibroblasts, in contrast to toxic events in cancer cells.

Natural products and traditional medicines are of great importance. Recent studies have demonstrated, that cereal grass juice improves wound healing, however the cellular and molecular mechanisms underlying these processes have not been fully characterized. Also, the full phytochemical characteristics of freshly squeezed juices obtained from cereal grasses is still missing. Thus, in this study a multi-dimensional analysis of juice parameters like refraction value, pH, chlorophyll and flavonoids content as well as antioxidant properties was performed. The results demonstrate that the effect induced by freshly squeezed cereal juices is strictly cell type-dependent. In this study, it is shown for the first time, that in normal fibroblasts (BJ cells) low dose cereal grass juices exhibit strong adaptive response through hormetic mechanism mediated by NF-κB/HO-1 and insulin/IGF-1 anti-oxidant pathways. As consequence, the process of wound healing is significantly upregulated. In cancer cells (ES-2 cells), despite anti-oxidant defense mechanism activation, levels of ROS and RNS are elevated. This leads to enhanced O-GlcNAcylation, DNA damage and cell cycle arrest, and as a result impaired wound healing. This study provides insights into the underlying mechanisms through which cereal grass juices activate hermetic adaptation response in normal fibroblasts, and induce cytotoxic and genotoxic events in cancer cells.

Re-analysis of herbal extracts data reveals that inflammatory processes are mediated by hormetic mechanisms.

Using data from Schink et al. (2018), a large number of herbal extracts were assessed for their capacity to induce pro- and anti-inflammatory effects based on TLR4 expression normalized for cell viability in two immune cell models (i.e., HeLa-TLR4 transfected reporter cell line, and THP-1 monocytes) applying seven concentrations (0.01-3.0%). The analysis revealed that 70-80% of the extracts satisfying the a priori entry criteria also satisfied a priori evaluative criteria for hormetic concentration responses. These findings demonstrate that a large proportion of herbal extracts display hormetic dose responses in immune cells, indicating that hormetic mechanisms mediate pro- and anti-inflammatory processes and may provide a means to guide optimal dosing strategies. The identification of doses eliciting only anti-inflammatory therapeutic activity as well as the use of dose-variable herbal extracts in the treatment of inflammatory diseases will be challenging.

Aging circadian rhythms and cannabinoids.

Numerous aspects of mammalian physiology exhibit cyclic daily patterns known as circadian rhythms. However, studies in aged humans and animals indicate that these physiological rhythms are not consistent throughout the life span. The simultaneous development of disrupted circadian rhythms and age-related impairments suggests a shared mechanism, which may be amenable to therapeutic intervention. Recently, the endocannabinoid system has emerged as a complex signaling network, which regulates numerous aspects of circadian physiology relevant to the neurobiology of aging. Agonists of cannabinoid receptor-1 (CB1) have consistently been shown to decrease neuronal activity, core body temperature, locomotion, and cognitive function. Paradoxically, several lines of evidence now suggest that very low doses of cannabinoids are beneficial in advanced age. One potential explanation for this phenomenon is that these drugs exhibit hormesis-a biphasic dose-response wherein low doses produce the opposite effects of higher doses. Therefore, it is important to determine the dose-, age-, and time-dependent effects of these substances on the regulation of circadian rhythms and other processes dysregulated in aging. This review highlights 3 fields-biological aging, circadian rhythms, and endocannabinoid signaling-to critically assess the therapeutic potential of endocannabinoid modulation in aged individuals. If the hormetic properties of exogenous cannabinoids are confirmed, we conclude that precise administration of these compounds may bidirectionally entrain central and peripheral circadian clocks and benefit multiple aspects of aging physiology.

Hormetic dose response to L-ascorbic acid as an anti-cancer drug in colorectal cancer cell lines according to SVCT-2 expression.

L-Ascorbic acid (vitamin C, AA) exhibits anti-cancer effects with high-dose treatment through the generation of reactive oxygen species (ROS) and selective damage to cancer cells. The anti-cancer effects of L-ascorbic acid are determined by sodium-dependent vitamin C transporter 2 (SVCT-2), a transporter of L-ascorbic acid. In this study, we demonstrate that L-ascorbic acid treatment showed efficient anti-cancer activity in cell lines with high expression levels of SVCT-2 for a gradient concentration of L-ascorbic acid from 10 µM -2 mM. However, in low SVCT-2 expressing cell lines, high-dose L-ascorbic acid (>1 mM) showed anti-cancer effects but low-dose (<10 µM) treatment induced cell proliferation. Such conflicting results that depend on the concentration are called a hormetic dose response. A hormetic dose response to low-dose L-ascorbic acid was also observed in high SVCT-2 expressing cell lines in the presence of a SVCT family inhibitor. Insufficient uptake of L-ascorbic acid in low SVCT-2 expressing cancer cell lines cannot generate sufficient ROS to kill cancer cells, resulting in the hormetic response. Molecular analysis confirmed the increased expression of cancer proliferation markers in the hormetic dose response. These results suggest that L-ascorbic exhibits a biphasic effect in cancer cells depending on SVCT-2 expression.

Phytochemicals-induced hormesis protects Caenorhabditis elegans against α-synuclein protein aggregation and stress through modulating HSF-1 and SKN-1/Nrf2 signaling pathways.

Mild stress activates the adaptive cellular response for the subsequent severe stress called hormesis. Hormetic stress plays a vital role to activate multiple stress-responsive genes for the benefit of an organism. In tropical regions of world, tubers of Dioscorea spp. has been extensively used in folk medicine and also consumed as food. In this study, we report that the phytochemicals of Dioscorea alata L., tubers extends the lifespan of nematode model Caenorhabditis elegans by hormetic mechanism. We showed that the low dose of tubers extract at 200 and 300 µg/mL extends the mean lifespan of wild-type worms, whereas higher doses are found to be toxic. Supplementation of tubers extract slightly increased the intracellular ROS in second-day adult worms and it might activate the adaptive stress response, which protects the worms from oxidative and thermal stress. Transgenic reporter gene expression assay showed that extract treatment enhanced the expression of stress protective genes such as hsp-16.2, hsp-6, hsp-60 and gst-4. Further studies proved that the transcription factors HSF-1 and SKN-1/Nrf2 were implicated in hormetic stress response of the worms. Moreover, pretreatment of extract reduced the high glucose-mediated lipid accumulation by enhancing the expression of glyoxalase-1. It was also found that the aggregation of Parkinson's related protein α-synuclein reduced in the transgenic strain NL5901 and extended its lifespan. Finally, our results concluded that the presences of hormetic dietary phytochemicals in tubers might drive the stress response in C. elegans via HSF-1 and SKN-1/Nrf2 signaling pathways.

Drosophila larvae fed palm fruit juice (PFJ) delay pupation via expression regulation of hormetic stress response genes linked to ageing and longevity.

Palm fruit juice (PFJ) containing oil palm phenolics is obtained as a by-product from oil palm (Elaeis guineensis) fruit milling. It contains shikimic acid, soluble fibre and various phenolic acids including p-hydroxybenzoic acid and three caffeoylshikimic acid isomers. PFJ has also demonstrated beneficial health properties in various biological models. Increasing concentrations of PFJ and different PFJ fractions were used to assess growth dynamics and possible anti-ageing properties in fruit flies (Drosophila melanogaster) genotype w1118. Microarray gene expression analysis was performed on whole fruit fly larvae and their fat bodies, after the larvae were fed a control Standard Brandeis Diet (SBD) with or without PFJ. Transcripts from Affymetrix GeneChips were utilised to identify the possible mechanisms involved, with genes having fold changes > |1.30| and p < 0.05 considered differentially expressed. PFJ dose-dependently delayed larval growth and pupation, but not percent eclosion from pupae. Eclosed male fruit flies fed PFJ or its fractions during the larval stage tended to have 20-40% improved survival ratings over controls when allowed to age on the control diet (SBD). Microarray analysis of whole fruit fly larvae revealed that 127 genes were up-regulated, while 67 were down-regulated by PFJ. Functional analysis revealed transport and metabolic processes were up-regulated, while development and morphogenesis processes, including the nutrient-sensing Tor gene, were down-regulated by PFJ, whereas microarray analysis of larval fat bodies found 161 genes were up-regulated, while 84 genes were down-regulated. Genes involved in defence response and determination of adult lifespan, including those encoding various heat shock proteins and the antioxidant enzyme Sod2, were up-regulated, while cell cycle and growth genes were down-regulated. Thus, PFJ supplementation lengthened the growth stages in fruit fly larvae that was reflected in extended ageing of adult flies, suggesting that larval expression of hormetic stress response genes was linked to subsequent ageing and longevity.

Hormesis as a mechanistic approach to understanding herbal treatments in traditional Chinese medicine.

Traditional Chinese medicine (TCM) has been long practiced and is becoming ever more widely recognized as providing curative and/or healing treatments for a number of diseases and physiological conditions. This paper posits that herbal medicines used in TCM treatments may act through hormetic dose-response mechanisms. It is proposed that the stimulatory (i.e., low dose) and inhibitory (i.e., high dose) components of the hormetic dose response correspond to respective "regulating" and "curing" aspects of TCM herbal treatments. Specifically, the "regulating" functions promote adaptive or preventive responses, while "curing" treatments alleviate the clinical symptoms. Patterns of hormetic responses are described, and the applicability of these processes to herbal medicines of TCM are explicated. It is noted that a research agenda aimed at elucidating these mechanisms and patterns would be expansive and complex. However, we argue its value, in that hormesis may afford something akin to a Rosetta Stone with which to interpret, translate, and explain TCM herbology in ways that are aligned with biomedical perspectives that could enable a more integrative approach to medicine.

Predicting biphasic responses in binary mixtures: Pelargonic acid versus glyphosate.

Predicting hormesis in mixtures is challenging, but essential considering that chemical exposures often occur in mixtures and at low doses. This study investigated mixture effects with two herbicides prone to induce hormesis and to interact, namely pelargonic acid versus glyphosate. Five independent mixture experiments were conducted in vitro to assess effects on root growth of lettuce. Mixture effects on the dose were analyzed using classical joint-action models in terms of deviation from the reference model of concentration addition. For effects on the hormetic magnitude (ymax), a linear reference model was utilized. Hormesis was inconsistent across rays, so that effects on inhibitory doses and ymax could be evaluated, but not effects on hormetic doses. Mixture effects on the dose were additive at lower doses changing to strong high-dose synergism. Mixture effects on ymax followed a linear change with mixture ratio or significantly deviated from linearity with a one-sided trend across rays in two experiments. The trend was antipodal between experiments, but well described by a curved ymax model based on single dose-response relationships. Atypical ymax deviations were associated with strong synergism at ED50, suggesting that the linearity model applies for chemicals showing no/minor interaction at ED50, while for strongly interacting chemicals ymax predictions seem more critical. The study unambiguously proved synergism on the dose for pelargonic acid versus glyphosate and indicated an impact of these joint effects on ymax. The study confirms the predictability of hormesis in mixtures and provides a further methodological step towards an incorporation of hormesis into mixture-toxicity evaluations.

Hormetic effect of panaxatriol saponins confers neuroprotection in PC12 cells and zebrafish through PI3K/AKT/mTOR and AMPK/SIRT1/FOXO3 pathways.

Hormesis is an adaptive response of living organisms to a moderate stress. However, its biomedical implication and molecular mechanisms remain to be intensively investigated. Panaxatriol saponins (PTS) is the major bioactive components extracted from Panax notoginseng, a widely used herbal medicine for cerebrovascular diseases. This study aims to examine the hormetic and neuroprotective effects of PTS in PC12 cells and zebrafish Parkinson's disease (PD) models. Our results demonstrated that PTS stimulated PC12 cell growth by about 30% at low doses, while PTS at high doses inhibited cell growth, which is a typical hormetic effect. Moreover, we found that low dose PTS pretreatment significantly attenuated 6-OHDA-induced cytotoxicity and up-regulated PI3K/AKT/mTOR cell proliferation pathway and AMPK/SIRT1/FOXO3 cell survival pathway in PC12 cells. These results strongly suggested that neuroprotective effects of PTS may be attributable to the hormetic effect induced by PTS through activating adaptive response-related signaling pathways. Notably, low dose PTS could significantly prevent the 6-OHDA-induced dopaminergic neuron loss and improve the behavior movement deficiency in zebrafish, whereas relative high dose PTS exhibited neural toxicity, further supporting the hormetic and neuroprotective effects of PTS. This study indicates that PTS may have the potential in the development of future therapeutic medicines for PD.

Hormetic effect induced by depleted uranium in zebrafish embryos.

The present work studied the hormetic effect induced by uranium (U) in embryos of zebrafish (Danio rerio) using apoptosis as the biological endpoint. Hormetic effect is characterized by biphasic dose-response relationships showing a low-dose stimulation and a high-dose inhibition. Embryos were dechorionated at 4h post fertilization (hpf), and were then exposed to 10 or 100µg/l depleted uranium (DU) in uranyl acetate solutions from 5 to 6 hpf. For exposures to 10µg/l DU, the amounts of apoptotic signals in the embryos were significantly increased at 20 hpf but were significantly decreased at 24 hpf, which demonstrated the presence of U-induced hormesis. For exposures to 100µg/l DU, the amounts of apoptotic signals in the embryos were significantly increased at 20, 24 and 30 hpf. Hormetic effect was not shown but its occurrence between 30 and 48 hpf could not be ruled out. In conclusion, hormetic effect could be induced in zebrafish embryos in a concentration- and time-dependent manner.

Hormesis: principles and applications.

Hormesis has emerged as a central concept in biological and biomedical sciences with significant implications for clinical medicine and environmental risk assessment. This paper assesses the historical foundations of the dose-response including the threshold, linear and hormetic models, the occurrence and frequency of the hormetic dose response in the pharmacological and toxicological literature, its quantitative and temporal features, and underlying mechanistic bases. Based upon this integrative foundation the application of hormesis to the process of risk assessment for non-carcinogens and carcinogens is explored.

Hormesis within a mechanistic context.

This paper provides an assessment of the mechanistic foundations of hormesis and how such understandings evolved over the course of the past century. Particular emphasis is placed on recent developments particularly with respect to receptor-based and cell signaling-based pathways. Of particular importance is that the quantitative feature of the hormetic dose response are independent of mechanism.

Unequal brothers : are homeopathy and hormesis linked?

The debate between those who believe homeopathy and hormesis derive from the same root and those who believe the two are different phenomena is as old as hormesis. It is an emotionally loaded discussion, with both sides fielding arguments which are far from scientific. Careful analysis of the basic paradigms of the two systems questions the claim of the homeopaths, who find similarities between them. The authors discuss these paradigms, indicating the differences between the claims of homeopathy and hormesis. It is time for thorough and serious research to lay this question to rest. One possible approach is to compare the activity of a hormetic agent, prepared in the usual way, with that of the same agent in the same concentration prepared homeopathically by serial dilution and succussion.

Hormetic effects of extremely diluted solutions on gene expression.

This paper summarizes the results of investigations showing how molecular biological tools, such as DNA-microarrays, can provide useful suggestions about the behaviour of human organisms treated with microamounts of drugs or homeopathic medicines. The results reviewed here suggest firstly that the action of drugs is not quenched by ultra-high dilution and proceeds through modulation of gene expressions. The efficacy of drug solutions seems to be maintained in ultra-highly diluted preparations, a fact which constitutes a challenge to the dogma of quantization of matter. The second and more important result is that the different gene expression profiles of cell systems treated with the same drugs at different dilutions suggest the existence of hormetic mechanisms. The gene expression profiles of cells treated with copper(II) sulfate, Gelsemium sempervirens and Apis mellifica, are characterized by the same common denominator of the concentration-dependent inversion of gene expression, which can justify at a molecular level the concept of simile adopted in homeopathy. The main conclusion we draw from these results is that these procedures provide new kinds of information and a tool for disclosing the mechanisms involved in hormetic effects. The application of these effects to modern medicine may allow researchers to conceive unprecedented therapeutic applications or to optimize the currently used ones in the framework of a low-dose pharmacology based on a reliable experimental platform.

Cell sensitivity, non-linearity and inverse effects.

It has been claimed that the homeopathic principle of 'similarity' (or 'similia') and the use of individualized remedies in extremely low doses conflicts with scientific laws, but this opinion can be disputed on the basis of recent scientific advances. Several mechanisms to explain the responsiveness of cells to ultra-low doses and the similarity as inversion of drug effects, have again been suggested in the framework of hormesis and modern paradoxical pharmacology. Low doses or high dilutions of a drug interact only with the enhanced sensitivities of regulatory systems, functioning as minute harmful stimuli to trigger specific compensatory healing reactions. Here we review hypotheses about homeopathic drug action at cellular and molecular levels, and present a new conceptual model of the principle of similarity based on allosteric drug action. While many common drugs act through orthostatic chemical interactions aimed at blocking undesired activities of enzymes or receptors, allosteric interactions are associated with dynamic conformational changes and functional transitions in target proteins, which enhance or inhibit specific cellular actions in normal or disease states. The concept of allostery and the way it controls physiological activities can be broadened to include diluted/dynamized compounds, and may constitute a working hypothesis for the study of molecular mechanisms underlying the inversion of drug effects.

A catechin-enriched green tea extract prevents glucose-induced survival reduction in Caenorhabditis elegans through sir-2.1 and uba-1 dependent hormesis.

Hyperglycemia is a hallmark of diabetes mellitus which leads to the onset of complications in the long term. Green tea through its high content of polyphenolic catechins, on the other hand, is suggested to prevent or at least delay such detrimental complications. In the present study we fed the nematode Caenorhabditis elegans on a liquid medium supplemented with 10mM glucose in the absence or presence of a catechin-enriched green tea extract (CEGTE). After exposure of young adults for 48h survival was subsequently measured under heat stress at 37°C. Whereas CEGTE at 0.01% did not affect the survival of wild type nematodes, it completely reversed the glucose-induced survival reduction. Those effects were not achieved through the monomeric catechins included in CEGTE. RNA interference (RNAi) for sir-2.1 not only prevented the survival extension by CEGTE under simultaneous glucose exposure but also caused a further reduction of survival. Likewise, the knockdown of uba-1, encoding the only E1-ubiquitin-activating enzyme in C. elegans, proved that UBA-1 is essential for the survival extension by CEGTE and that its loss of function changes CEGTE from a survival extending into a survival reducing extract. Stimulation of the proteasome by CEGTE was finally proven through measurements of the proteolytic cleavage of a fluorogenic peptide substrate. To conclude, our studies provide evidence that CEGTE reverses glucose-induced damage in C. elegans through activation of adaptive responses mediated by SIR-2.1 and proteasomal degradation. The hormetic mode of action is revealed by a reduction of survival once the adaptive processes were blocked.