18S rRNA methyltransferases DIMT1 and BUD23 drive intergenerational hormesis.

Heritable non-genetic information can regulate a variety of complex phenotypes. However, what specific non-genetic cues are transmitted from parents to their descendants are poorly understood. Here, we perform metabolic methyl-labeling experiments to track the heritable transmission of methylation from ancestors to their descendants in the nematode Caenorhabditis elegans (C. elegans). We find heritable methylation in DNA, RNA, proteins, and lipids. We find that parental starvation elicits reduced fertility, increased heat stress resistance, and extended longevity in fed, naïve progeny. This intergenerational hormesis is accompanied by a heritable increase in N6'-dimethyl adenosine (m6,2A) on the 18S ribosomal RNA at adenosines 1735 and 1736. We identified DIMT-1/DIMT1 as the m6,2A and BUD-23/BUD23 as the m7G methyltransferases in C. elegans that are both required for intergenerational hormesis, while other rRNA methyltransferases are dispensable. This study labels and tracks heritable non-genetic material across generations and demonstrates the importance of rRNA methylation for regulating epigenetic inheritance.

Histone H3.3 chaperone HIRA renders stress-responsive genes poised for prospective lethal stresses in acquired tolerance.

Appropriate responses to environmental challenges are imperative for the survival of all living organisms. Exposure to low-dose stresses is recognized to yield increased cellular fitness, a phenomenon termed hormesis. However, our molecular understanding of how cells respond to low-dose stress remains profoundly limited. Here we report that histone variant H3.3-specific chaperone, HIRA, is required for acquired tolerance, where low-dose heat stress exposure confers resistance to subsequent lethal heat stress. We found that human HIRA activates stress-responsive genes, including HSP70, by depositing histone H3.3 following low-dose stresses. These genes are also marked with histone H3 Lys-4 trimethylation and H3 Lys-9 acetylation, both active chromatin markers. Moreover, depletion of HIRA greatly diminished acquired tolerance, both in normal diploid fibroblasts and in HeLa cells. Collectively, our study revealed that HIRA is required for eliciting adaptive stress responses under environmental fluctuations and is a master regulator of stress tolerance.

Redox regulation of UPR signalling and mitochondrial ER contact sites.

Mitochondria and the endoplasmic reticulum (ER) have a synergistic relationship and are key regulatory hubs in maintaining cell homeostasis. Communication between these organelles is mediated by mitochondria ER contact sites (MERCS), allowing the exchange of material and information, modulating calcium homeostasis, redox signalling, lipid transfer and the regulation of mitochondrial dynamics. MERCS are dynamic structures that allow cells to respond to changes in the intracellular environment under normal homeostatic conditions, while their assembly/disassembly are affected by pathophysiological conditions such as ageing and disease. Disruption of protein folding in the ER lumen can activate the Unfolded Protein Response (UPR), promoting the remodelling of ER membranes and MERCS formation. The UPR stress receptor kinases PERK and IRE1, are located at or close to MERCS. UPR signalling can be adaptive or maladaptive, depending on whether the disruption in protein folding or ER stress is transient or sustained. Adaptive UPR signalling via MERCS can increase mitochondrial calcium import, metabolism and dynamics, while maladaptive UPR signalling can result in excessive calcium import and activation of apoptotic pathways. Targeting UPR signalling and the assembly of MERCS is an attractive therapeutic approach for a range of age-related conditions such as neurodegeneration and sarcopenia. This review highlights the emerging evidence related to the role of redox mediated UPR activation in orchestrating inter-organelle communication between the ER and mitochondria, and ultimately the determination of cell function and fate.

Sestrins in Physiological Stress Responses.

Sestrins are a family of proteins that respond to a variety of environmental stresses, including genotoxic, oxidative, and nutritional stresses. Sestrins affect multiple signaling pathways: AMP-activated protein kinase, mammalian target of rapamycin complexes, insulin-AKT, and redox signaling pathways. By regulating these pathways, Sestrins are thought to help adapt to stressful environments and subsequently restore cell and tissue homeostasis. In this review, we describe how Sestrins mediate physiological stress responses in the context of nutritional and chemical stresses (liver), physical movement and exercise (skeletal muscle), and chemical, physical, and inflammatory injuries (heart). These findings also support the idea that Sestrins are a molecular mediator of hormesis, a paradoxical beneficial effect of low- or moderate-level stresses in living organisms.

Phytochemicals as Prebiotics and Biological Stress Inducers.

Phytochemicals in fruits and vegetables produce health benefits, but questions remain regarding their bioavailability, molecular targets, and mechanism of action. Here, we address these issues by considering the prebiotic and biological properties of phytochemicals. A fraction of phytochemicals consumed orally passes through the gut lumen, where it modulates the composition of the gut microbiota and maintains intestinal integrity. Phytochemicals and microbiota-derived metabolites that are absorbed by the organism comprise compounds that, at low doses, induce stress resistance mechanisms, including autophagy, DNA repair, and expression of detoxifying and antioxidant enzymes. We propose that these mechanisms improve cellular and organ function and can account for the promiscuous bioactivities of phytochemicals, despite their limited bioavailability and extremely varied chemical structures.

Mitragynine and Morphine Produce Dose-dependent Bimodal Action on Food but not Water Intake in Rats.

Novel compounds such as mitragynine, the primary alkaloid in kratom (Mitragyna Speciosa), have emerged as alternative self-treatments for opioid use disorder. Mitragynine binds numerous receptor types, including opioid receptors, which are known to modulate food consumption. However, the ability of acute mitragynine to modulate food consumption remains unknown. The current study assessed the effects of acute mitragynine or morphine administration on unconditioned food and water intake in 16 Sprague Dawley rats. Food and water intake changes were monitored in response to morphine, mitragynine (1.78-56 mg/kg, intraperitoneal), saline, or vehicle controls for 12 hours starting at the onset of the dark cycle. Naltrexone pretreatment was utilized to examine pharmacological specificity. Both morphine and mitragynine demonstrated a biphasic food intake dose-effect, with low doses (5.6 mg/kg) increasing and high doses (56 mg/kg) decreasing food intake. All morphine doses reduced water intake; however, only the highest dose of mitragynine (56 mg/kg) reduced water intake. Naltrexone attenuated both stimulatory and inhibitory effects of morphine on food intake, but only the stimulatory effect of mitragynine. In conclusion, low doses of mitragynine stimulate food intake via opioid-related pathways, while high doses likely recruit other targets.

Agricultural insect pests as models for studying stress-induced evolutionary processes.

Agricultural insect pests (AIPs) are widely successful in adapting to natural and anthropogenic stressors, repeatedly overcoming population bottlenecks and acquiring resistance to intensive management practices. Although they have been largely overlooked in evolutionary studies, AIPs are ideal systems for understanding rapid adaptation under novel environmental conditions. Researchers have identified several genomic mechanisms that likely contribute to adaptive stress responses, including positive selection on de novo mutations, polygenic selection on standing allelic variation and phenotypic plasticity (e.g., hormesis). However, new theory suggests that stress itself may induce epigenetic modifications, which may confer heritable physiological changes (i.e., stress-resistant phenotypes). In this perspective, we discuss how environmental stress from agricultural management generates the epigenetic and genetic modifications that are associated with rapid adaptation in AIPs. We summarise existing evidence for stress-induced evolutionary processes in the context of insecticide resistance. Ultimately, we propose that studying AIPs offers new opportunities and resources for advancing our knowledge of stress-induced evolution.

Heat-induced hormesis in longevity is linked to heat-stress sensitivity across laboratory populations from diverse altitude of origin in Drosophila buzzatii.

Heat-induced hormesis in longevity is the increase in life span resulting from the previous exposure to a mild heat stress early in life. Here we examined heat-induced hormesis of Drosophila buzzatii in five mass-mating populations, which were derived from five wild populations along an elevation gradient from 202 to 1855 m above sea level in North-Western Argentina. Five day old flies were exposed to 37.5 °C for 90 min to induce hormesis and its possible variation across altitudinal populations. This heat treatment strongly extended longevity in lowland-derived flies from the most heat-resistant population only. Both heat-induced effects on longevity and heat-knockdown time (heat-stress sensitivity) were negatively correlated to altitude of population of origin. Hormesis was positively correlated to heat-knockdown time across populations. These results indicate that variation in heat-induced hormesis can not be considered as independent of heat-stress sensitivity (or heat-knockdown time) in populations of insects.

The potential of flavonoids to mitigate cellular senescence in cardiovascular disease.

Aging is one of the most significant factors affecting cardiovascular health, with cellular senescence being a central hallmark. Senescent cells (SCs) secrete a specific set of signaling molecules known as the senescence-associated secretory phenotype (SASP). The SASP has a remarkable impact on age-associated diseases, particularly cardiovascular diseases (CVD). Targeting SCs through anti-aging therapies represents a novel strategy to effectively retard senescence and attenuate disease progression. Accumulating evidence demonstrates that the flavonoids, widely presented in fruits and vegetables worldwide, can delay or treat CVD via selectively eliminating SCs (senolytics) and modulating SASPs (senomorphics). Nevertheless, only sporadic research has illustrated the application of flavonoids in targeting SCs for CVD, which requires further exploration. This review recapitulates the hallmarks and key molecular mechanisms involved in cellular senescence, then summarizes senescence of different types of cardiac cells and describes the mechanisms by which cellular senescence affects CVD development. The discussion culminates with the potential use of flavonoids via exerting their biological effects on cellular senescence to reduce CVD incidence. This summary will provide valuable insights for cardiovascular drug design, development and clinical applications leveraging flavonoids.

Enhancing the human health and lifespan: a targeted strategy emphasizing statins.

There has been substantial research interest in finding activities/agents that slow the onset and reduce the severity of numerous age-related diseases/conditions. This assessment indicates that the most studied agent intended to promote health in human population investigations for a broad spectrum of diseases are the statins, with large-scale epidemiological studies addressing numerous health endpoints. The key findings are that statin treatment consistently reduces the occurrence and attenuates the course of numerous non-communicable and contagious pathologies and numerous types of cancer with high mortality rates by about 20-50%. That one agent could affect such a broad based and consistently positive trends in epidemiological studies is unexpected and impressive, along with consistent cell and animal model research. Underlying mechanisms have been proposed that significantly contribute to the spectrum of salutary effects of statins, especially the capacity to activate Nrf2 showing hormetic dose responses in multiple organs and cell types, due to its bioavailability and broad tissue distribution. The widespread use of statins, which has the capacity to enhance human health span, should be considered for experimental exploration as a novel public health strategy that includes practical approaches for reduction of the most common adverse effects of this class of drugs including myalgia/myopathy and transaminitis.

The potential longevity-promoting hypoxic-hypercapnic environment as a measure for radioprotection.

Many biological mechanisms of aging well converge with radiation's biological effects. We used scientific insights from the field of aging to establish a novel hypoxic-hypercapnic environment (HHE) concept for radioprotection. According to this concept, HHE which possesses an anti-aging and longevity-promoting potential, should also act as a radiomitigator and radioprotector. As such, it might contribute greatly to the safety and wellbeing of individuals exposed to high levels of radiation, whether in planned events (e.g. astronauts) or in unplanned events (e.g. first responders in nuclear accidents).

Seven knowledge gaps in modern biogerontology.

About a year ago, members of the editorial board of Biogerontology were requested to respond to a query by the editor-in-chief of the journal as to what one question within their field of ageing research still needs to be asked and answered. This editorial is inspired by the wide range and variety of questions, ideas, comments and suggestions received in response to that query. The seven knowledge gaps identified in this article are arranged into three main categories: evolutionary aspects of longevity, biological survival and death aspects, and heterogeneity in the progression and phenotype of ageing. This is not an exhaustive and exclusive list, and may be modified and expanded. Implications of these knowledge gaps, especially in the context of ongoing attempts to develop effective interventions in ageing and longevity are also discussed.

A comprehensive model for the biochemistry of ageing, senescence and longevity.

Various models for ageing, each focussing on different biochemical and/or cellular pathways have been proposed. This has resulted in a complex and non-coherent portrayal of ageing. Here, we describe a concise and comprehensive model for the biochemistry of ageing consisting of three interacting signalling hubs. These are the nuclear factor kappa B complex (NFκB), controlling the innate immune system, the mammalian target for rapamycin complex, controlling cell growth, and the integrated stress responses, controlling homeostasis. This model provides a framework for most other, more detailed, biochemical pathways involved in ageing, and explains why ageing involves chronic inflammation, cellular senescence, and vulnerability to environmental stress, while starting with the spontaneous formation of advanced glycation end products. The totality of data underlying this model suggest that the gradual inhibition of the AMPK-ISR probably determines the maximal lifespan. Based on this model, anti-ageing drugs in general, are expected to show hormetic dose response curves. This complicates the process of dose-optimization. Due to its specific mechanism of action, the anti-aging drug alkaline phosphatase is an exception to this rule, because it probably exhibits saturation kinetics.

Time Is Ripe for Targeting Per- and Polyfluoroalkyl Substances-Induced Hormesis: Global Aquatic Hotspots and Implications for Ecological Risk Assessment.

Globally implemented ecological risk assessment (ERA) guidelines marginalize hormesis, a biphasic dose-response relationship characterized by low-dose stimulation and high-dose inhibition. The present study illuminated the promise of hormesis as a scientific dose-response model for ERA of per- and polyfluoroalkyl substances (PFAS) represented by perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS). A total of 266 hormetic dose-response relationships were recompiled from 1237 observations, covering 30 species from nine representative taxonomic groups. The standardized hormetic amplitudes followed the log-normal probability distribution, being subject to the limits of biological plasticity but independent of stress inducers. The SHapley Additive exPlanations algorithm revealed that the target endpoint was the most important variable explaining the hormetic amplitudes. Subsequently, quantitative frameworks were established to incorporate hormesis into the predicted no-effect concentration levels, with a lower induction dose and a zero-equivalent point but a broader hormetic zone for PFOS. Realistically, 10,117 observed concentrations of PFOA and PFOS were gathered worldwide, 4% of which fell within hormetic zones, highlighting the environmental relevance of hormesis. Additionally, the hormesis induction potential was identified in other legacy and emerging PFAS as well as their alternatives and mixtures. Collectively, it is time to incorporate the hormesis concept into PFAS studies to facilitate more realistic risk characterizations.

Ecological risk threshold for chromium in Chinese soils and its prediction models.

The derivation of chromium (Cr) ecological risk thresholds in soils remains limited, despite their importance as measurement standards and indicators for enacting soil protection policies. In this study, toxicity of Cr in soil to different species was tested based on Log-Logistic dose-effect relationship. On this basis, combined with Cr toxicity measurement data in literature, the ecological risk threshold HC5 for protecting 95% species safety in soils with different properties was obtained by fitting species sensitivity distribution curve (SSD). This research collected various Cr toxicological data from Chinese cropland soils, based on 31 different endpoints covering soil fauna, functional indicators of microorganisms, terrestrial plants, etc., sourced from both our laboratory and existing literature. We applied the SSD method to estimate the hazardous concentration of Cr for HC5 and ultimately established a predictive model according to HC5 and different soil properties. As a result, the EC10 (an effective concentration of Cr resulting in 10% suppression of terminal biological activity) based on 7 different soils and 4 endpoints ranged from 16.8 to 148.0 mg kg-1, and the hormesis of Cr induction reached up to 109%. Overall, the toxicity (EC10) to microorganisms was much lower, while it was higher for graminoids. All the toxicity data were corrected through an aging factor with up to 540 days of equilibration before fitting the SSD curves. After that, a prediction model considering HC5 values and soil properties was established as LogHC5 = 3.003LogpH +0.651LogOC +0.013LogCEC - 0.476. The model was well-verified in field experiments, as the actual and predicted values fell within a 2-fold error range. This approach offers a rigorous scientific foundation for determining the Cr ecological risk threshold and could be important for the conservation of ecological species in soils.

Ozone risk assessment with free-air controlled exposure (FACE) experiments: A critical revisit.

Since risk assessments of tropospheric ozone (O3) are crucial for agricultural and forestry sectors, there is a growing body for realistic assessments by a stomatal flux-based approach in Free-Air Controlled Exposure (FACE) facilities. Ozone risks are normally described as relative risks (RRs), which are calculated by assuming the biomass or yield at zero O3 dose as "reference". However, the estimation of the reference biomass or yield is challenging due to a lack of O3-clean-air treatment at the FACEs and the extrapolation without data in a low O3 range increases the bias for estimating the reference values. Here, we reviewed a current methodology for the risk assessment at FACEs and presented a simple and effective way ("modified Paoletti's approach") of defining RRs just using biomass or yield data with a range of expected impacts under the FACE conditions hypothesizing three possible scenarios based on prediction limits using 95% credible intervals (CI) (1. Best fit using the intercept as reference, 2. Optimistic scenario using a lower CI and 3. Worst scenario using an upper CI). As a result, O3-sensitive species show a relatively narrow effect range (optimistic vs. worst scenario) whereas a wide range of response may be possibly taken in resistant species. Showing a possible effect range allows for a comprehensive understanding of the potential risks and its uncertainties related to a species sensitivity to O3. As a supporting approach, we also recommend to use scientifically relevant tools (i.e., ethylenediurea treatments; mechanistic plant models) for strengthening the obtained results for the RRs against O3. Interestingly, the moderately sensitive or resistant species showed non-linear rather than linear dose-response relationships, suggesting a need for the flexible functional form for the risk assessment to properly describe the complex plant response such as hormesis, which depends on their plasticity to O3 stress.

Tetraniliprole risk assessment: Unveiling a hidden threat for managing a generalist herbivore.

Insecticide resistance poses a significant challenge in managing generalist herbivores such as the tobacco cutworm (TCW), Spodoptera litura. This study investigates the potential risks associated with using the novel diamide insecticide tetraniliprole to control TCW. A tetraniliprole-resistant strain was developed through twelve generations of laboratory selection, indicating an intermediate risk of resistance development. Field monitoring in China revealed a significant incidence of resistance, particularly in the Nanchang (NC) population (>100-fold). Tetraniliprole showed moderate to high cross-resistance to multiple insecticides and was autosomally inherited with incomplete dominance, controlled by multiple genes, some of which belong to the cytochrome P450 family associated with enhanced detoxification. Life table studies indicated transgenerational hormesis, stimulating TCW female fecundity and increasing population net reproduction rates (R0). These findings suggest a potential for pest resurgence under tetraniliprole use. The integrated risk assessment provides a basis for the sustainable management of TCW using tetraniliprole.

Time-dependent hormesis transfer from five high-frequency personal care product components to mixtures.

There is potential for personal care products (PCPs) components and mixtures to induce hormesis. How hormesis is related to time and transmitted from components to mixtures are not clear. In this paper, we conducted determination of components in 16 PCP products and then ran frequent itemset mining on the component data. Five high-frequency components (HFCs), betaine (BET), 1,3-butanediol (BUT), ethylenediaminetetraacetic acid disodium salt (EDTA), glycerol (GLO), and phenoxyethanol (POE), and 14 mixtures were identified. For each mixture system, one mixture ray with the actual mixture ratios in the products was selected. Time-dependent microplate toxicity analysis was used to test the luminescence inhibition toxicity of five HFCs and 14 mixture rays to Vibrio qinghaiensis sp.-Q67 at 12 concentration gradients and eight exposure times. It is showed that BET, EDTA, POE, and 13 mixture rays containing at least one J-type component showed time-dependent hormesis. Characteristic parameters used to describe hormesis revealed that the absolute value of the maximum stimulatory effect (|Emin|) generally increased with time. Notably, mixtures composed of POE and S-type components showed greater |Emin| than POE alone at the same time. Importantly, the maximum stimulatory effective concentration, NOEC/the zero effective concentration point, and EC50 remained relatively stable. Nine hormesis transmission phenomena were observed in different mixture rays. While all mixtures primarily exhibited additive action, varying degrees of synergism and antagonism were noted in binary mixtures, with no strong synergism or antagonism observed in ternary and quaternary mixtures. These findings offer valuable insights for the screening of HFCs and their mixtures, as well as the study of hormesis transmission in personal care products.

Strengthening through adversity: The hormesis model in developmental psychopathology.

BACKGROUND: Employing a developmental psychopathology framework, we tested the utility of the hormesis model in examining the strengthening of children and youth through limited levels of adversity in relation to internalizing and externalizing outcomes within a brain-by-development context. METHODS: Analyzing data from the Adolescent Brain and Cognitive Development study (N = 11,878), we formed latent factors of threat, deprivation, and unpredictability. We examined linear and nonlinear associations between adversity dimensions and youth psychopathology symptoms and how change of resting-state functional connectivity (rsFC) in the default mode network (DMN) from Time 1 to Time 5 moderates these associations. RESULTS: A cubic association was found between threat and youth internalizing problems; low-to-moderate family conflict levels reduced these problems. Deprivation also displayed a cubic relation with youth externalizing problems, with moderate deprivation levels associated with fewer problems. Unpredictability linearly increased both problem types. Change in DMN rsFC significantly moderated the cubic link between threat levels and internalizing problems, with declining DMN rsFC levels from Time 1 to Time 5 facilitating hormesis. Hormetic effects peaked earlier, emphasizing the importance of sensitive periods and developmental timing of outcomes related to earlier experiences. CONCLUSIONS: Strengthening through limited environmental adversity is crucial for developing human resilience. Understanding this process requires considering both linear and nonlinear adversity-psychopathology associations. Testing individual differences by brain and developmental context will inform preventive intervention programming.

Flavonoids commonly induce hormetic responses.

The present paper provides a new perspective of previously published findings by Siwak (Food Chem 141:1227-1241, 2013) which showed that 15 structurally diverse flavonoids reduced toxicity (i.e., enhanced cell viability) from hypochlorite using the MTT assay within a pre-conditioning experimental protocol, with each agent showing a similar biphasic concentration response relationship. We use this Commentary to point out that each of the concentration response relationships are consistent with the hormetic dose response. The paper of Siwak (Food Chem 141:1227-1241, 2013) is unique in that it provides a comparison of a relatively large number of agents using the identical experimental protocol.