Hormetic Response Research Articles

Overexpression of mTOR in Leukocytes from ALS8 Patients.

The mutated VAPBP56S (vesicle B associated membrane protein - P56S) protein has been described in a Brazilian family and classified as Amyotrophic Lateral Sclerosis type 8 (ALS8). We aimed to study altered biochemical and immunological parameters in cells from ALS8 patients to identify possible biomarkers or therapeutic targets. Wild-type VAPB, VAPBP56S, mTOR, proinflammatory cytokines, and oxidant/reducing levels in serum, leucocytes, and cellular lysate from ALS8 patients and health Controls were performed by ELISA, fluorimetry, and spectrophotometry. Our results showed similar levels of mutant and wild-type VAPB in serum and intracellular lysate (p > 0.05) when ALS8 patients and Controls were compared. IL-1β, IL-6, and IL-18 levels in patients and Controls showed no difference, suggesting an absence of peripheral inflammation (p > 0.05). Oxidative metabolic response, assessed by mitochondrial ROS production, and reductive response by MTT reduction, were higher in the ALS8 group compared to Controls (p < 0.05), although not characterizing typical oxidative stress in ALS8 patients. Total mTOR levels (phosphorylated or non-phosphorylated) of ALS8 patients were significantly lower in serum and higher in intracellular lysate than the mean equivalents in Controls (p < 0.05). A similar result was observed when we quantified the phosphorylated protein (p < 0.05). We demonstrate the possibility of using these biochemical and immunological parameters as potential therapeutic targets or biomarkers. Furthermore, by hypothesis, we suggest a hormetic response in which both VAPB forms could coexist in different proportions throughout life. The mutated VAPBP56S production would increase with aging and predominate over the wild-type VAPB levels, determining the onset of symptoms and aggravating the disease.

The effect of salt dosing for chytrid mitigation on tadpoles of a threatened frog, Litoria aurea

The novel fungal pathogen Batrachochytrium dendrobatidis (chytrid) is one of the greatest threats to amphibians worldwide. Small increases in water salinity (up to ca. 4 ppt) have been shown to limit chytrid transmission between frogs, potentially providing a way to create environmental refugia to reduce its impact at a landscape scale. However, the effect of increasing water salinity on tadpoles, a life stage confined to water, is highly variable. Increased water salinity can lead to reduced size and altered growth patterns in some species, with flow-on effects to vital rates such as survival and reproduction. It is thus important to assess potential trade-offs caused by increasing salinity as a tool to mitigate chytrid in susceptible frogs. We conducted laboratory experiments to examine the effects of salinity on the survival and development of tadpoles of a threatened frog (Litoria aurea), previously demonstrated as a suitable candidate for trialling landscape manipulations to mitigate chytrid. We exposed tadpoles to salinity ranging from 1 to 6 ppt and measured survival, time to metamorphosis, body mass and locomotor performance of post-metamorphic frogs as a measure of fitness. Survival and time to metamorphosis did not differ between salinity treatments or controls reared in rainwater. Body mass was positively associated with increasing salinity in the first 14 days. Juvenile frogs from three salinity treatments also showed the same or better locomotor performance compared to rainwater controls, confirming that environmental salinity may influence life history traits in the larval stage, potentially as a hormetic response. Our research suggests that salt concentrations in the range previously shown to improve survival of frogs in the presence of chytrid are unlikely to impact larval development of our candidate threatened species. Our study lends support to the idea of manipulating salinity to create environmental refugia from chytrid for at least some salt-tolerant species.

Mechanisms for the increase in lipid production in cyanobacteria during the degradation of antibiotics

This study evaluated the responses of cell density, photosynthesis activity, dry cell weight, lipid productivity, proteome and metabolome in two non-toxic cyanobacterial species (Synechococcus sp. and Chroococcus sp.) exposed to two frequently detected antibiotics (sulfamethoxazole and ofloxacin) at test concentrations of 0.2–20.0 μg L−1 in a 4-day culture period. Upregulated antioxidant enzymes and oxidoreductases contributed to antibiotic biodegradation in Synechococcus sp.; whereas, upregulated carotenoid protein contributed to antibiotic biodegradation in Chroococcus sp. The 4-day removal efficiencies of sulfamethoxazole and ofloxacin by cyanobacteria were 35.98–66.23% and 33.01–61.92%, respectively. In cyanobacteria, each antibiotic induced hormetic responses, such as increase in cell density, dry cell weight, and photosynthetic activity; upregulation of photosynthesis-related proteins; and elevation of lipid expression by up to 2.05-fold. Under antibiotic stress, the two cyanobacterial species preferred to store energy in the form of lipids rather than ATP, with fructose-bisphosphate aldolase playing an essential role in lipid synthesis. The downregulation of lipid transporters also facilitated lipid accumulation in Synechococcus sp. In general, the two non-toxic cyanobacterial species achieved a good combination of lipid deposition and antibiotic treatment performance, especially in Chroococcus sp. exposed to sulfamethoxazole.

A critical scientific and policy opinion on reuse and reclamation of contaminated wastewater for agriculture and other purposes

Contaminants of emerging concern and other chemicals are widespread in the environment. While their effects are ambiguous, a wealth of literature now illustrates their ability to induce various effects at concentrations/doses smaller than the toxicological threshold, leading to hormetic biphasic responses. Such responses are increasingly understood, can be positive or negative, and present an issue for wastewater reuse and reclamation for agriculture and other purposes. Considerable efforts have been placed by stakeholders at multiple levels to address the issue of low-dose effects, but there is more that can be done. To effectively address the low-dose issue, treatment/remediation sites for pollutant elimination should be improved, the number and amounts of chemicals released to the environment should be better controlled/prevented, and citizen-science approach with the involvement of NGOs and other organizations should be employed to expand the coverage of assessing pollution and its effects. This Opinion paper summarizes the main challenges introduced by the continuous discovery of emerging contaminants in the environment and the low-dose effects, discusses what has been done by stakeholders to address low-dose effects, and proposes a path forward.

Low Antioxidant Glutathione Levels Lead to Longer Telomeres: A Sex-Specific Link to Longevity?

Telomeres are repetitive DNA sequences at the end of chromosomes that protect them from degradation. They have been the focus of intense research because short telomeres would predict accelerated ageing and reduced longevity in vertebrates. Oxidative stress is considered a physiological driver of the telomere shortening and, consequently, short lifespan. Among molecules fighting against oxidative stress, glutathione is involved in many antioxidant pathways. Literature supports that oxidative stress may trigger a compensatory "hormetic" response increasing glutathione levels and telomere length. Here, we tested the link between total glutathione concentration and telomere length in captive birds (zebra finches; Taeniopygia guttata). Total glutathione levels were experimentally decreased during birds' growth using a specific inhibitor of glutathione synthesis (buthionine sulfoximine; BSO). We monitored the birds' reproductive performance in an outdoor aviary during the first month of life, and their longevity for almost 9 years. Among control individuals, erythrocyte glutathione levels during development positively predicted erythrocyte telomere length in adulthood. However, BSO-treated females, but not males, showed longer telomeres than control females in adulthood. This counterintuitive finding suggests that females mounted a compensatory response. Such compensation agrees with precedent findings in the same population where the BSO treatment increased growth and adult body mass in females but not males. BSO did not influence longevity or reproductive output in any sex. However, early glutathione levels and adult telomere length interactively predicted longevity only among control females. Those females with "naturally" low (non-manipulated) glutathione levels at the nestling age but capable of producing longer telomeres in adulthood seem to live longer. The results suggest that the capability to mount a hormetic response triggered by low early glutathione levels can improve fitness via telomere length. Overall, the results may indicate a sex-specific link between glutathione and telomere values. Telomerase activity and sexual steroids (estrogens) are good candidates to explain the sex-biased mechanism underlying the early-life impact of oxidative stress on adult telomere length.

The Hormetic Response of Soil P Extraction Induced by Low-Molecular-Weight Organic Acids

The hormetic effect is a toxicological phenomenon in the soil ecosystem. The influence of low-molecular-weight organic acids (LMWOAs) on the release and activation of soil phosphorus (P) has become the focus of toxicological research. To what extent LMWOAs can regulate the hormetic effect of P release and then influence soil P nutrients is worth attention. This study aimed to investigate the effects of different types and concentrations of exogenous LMWOAs on P extraction, establish the relationship between the concentration of LMWOAs and P extraction efficiency, and calculate the hormetic parameters to understand the mechanism of types and concentrations of LMWOAs in P extraction efficiency. Four organic acids, i.e., citric, oxalic, tartaric, and malic acids, induced hormetic effects on P extraction that were concentration dependent. The relationship between LMWOAs and P extraction efficiency was explained by a quadratic polynomial equation. The critical threshold of citric acid concentration was similar to that of oxalic acid, whereas that of tartaric acid was similar to that of malic acid. The critical thresholds of the P concentration extracted by malic acid and citric acid were higher than those extracted by oxalic acid and tartaric acid due to the differences in the structure and properties of LMWOAs. The critical thresholds of P extraction efficiency of oxalic acid were lower than those of the other three organic acid types. These results provide evidence for the use of citric acid and malic acid to increase soil P.

Nitric oxide, hormesis and plant biology

The present paper provides the first integrative assessment of the occurrence of nitric oxide (NO) induced hormetic effects in plant biology. Hormetic dose responses were commonly reported for NO donors on numerous plant species of agricultural and other commercial value. The NO donors were also shown to protect plants from a wide range of chemical (i.e., multiple toxic metals) and physical stressors (i.e., heat, drought) in preconditioning (aka priming) experimental protocols showing hormetic dose responses. Practical approaches for the use of NO donors to enhance plant growth using optimized dose response frameworks were also assessed. Considerable mechanistic findings indicate that NO donors have the capacity to enhance a broad range of adaptive responses, including highly integrated antioxidant activities. The integration of the hormesis concept with NO donors is likely to become a valuable practical general strategy to enhance plant productivity across a wide range of valuable plant species facing environmental pollution and climate changes.

Bioremediation of copper using indigenous fungi Aspergillus species isolated from an abandoned copper mine soil

Bioremediation of mining soils using metal tolerant fungi is widely considered as a promising cost-effective and ecofriendly approach. This study assessed the copper removal efficiency and bioaccumulation ability of the indigenous species Aspergillus hiratsukae LF1 and Aspergillus terreus LF2 isolated from the soils of an abandoned copper mine in Oman. Nutrient medium containing five different Cu (II) levels (0 – control, 100, 200, 300 and 500 mg/L) was employed for assessing both parameters. The removal efficiency from nutrient medium (100–500 mg Cu per L) ranged from 57% to 21% for A. hiratsukae LF1, and from 69% to 24% for A. terreus LF2. A. hiratsukae LF1 and A. terreus LF2 accumulated a maximum of 4.63 and 5.95 mg Cu/g,espectively, at 500 mg/L of Cu (II) concentration. The compositional analysis of extracellular polymeric substances excreted by both species revealed a hormetic response by A. hiratsukae LF1 at 100 mg/L; whereas increasing media Cu levels induced carbohydrates production in A. terreus LF2. These results hint at the involvement of carbohydrates in the Cu-tolerance mechanism of the latter. Copper accumulation in both species was further demonstrated through scanning electron microscopy and energy dispersive spectrometry. In line with the pertaining literature, our results are somewhat inconclusive concerning whether proteins or carbohydrates play a more pivotal role in copper complexation in both species; yet, FTIR analysis showed the participation of different functional groups in Cu sorption. Overall, although additional research is required to advance the knowledge about both Aspergillus species, our findings suggest that A. terreus LF2 presents greater promise for copper bioremediation due to enhanced tolerance and accumulation capacity.

Assessment of the Hormetic Effect of Arsenic on Growth and Physiology of Two Cultivars of Maize (Zea mays L.).

Although growth stimulation at low arsenic doses was observed in several plants, few studies have focused on this phenomenon in more detail. The effects of different concentrations of arsenic (0-50 mg kg-1 of soil: As0-As50) on the growth and selected physiological parameters of two maize cultivars (Zea mays L. cvs. Chapalu and MvNK 333) were tested. Cultivar MvNK 333 manifested a generally higher tolerance to As than cv. Chapalu, which may be related to the lower content of As in the tissues. The highest stimulatory effect of As was recorded at doses of As1 and As2 (cv. Chapalu), and at the As5 dose (MvNK 333), there was an increase in shoot elongation, biomass, and relative water content (RWC), as well as the content of photosynthetic pigments. The stimulatory effect of lower doses of As apparently represents an adaptation mechanism that is associated with water content regulation in the given conditions. The stomata of the studied cultivars were involved in this regulation in different ways. While cv. Chapalu exhibited increased numbers of stomata on both sides of leaves, cv. MvNK 333 instead responded to the given conditions with decreased stomata size. Although hormetic manifestations closely related to changes in stomatal number and size were observed, a typical stomatal hormetic response was not observed in the given range of As doses.

A Study of Anxiety-Related Behavior under Conditions of Oxidative Stress Caused by Hydrogen Peroxide

Any stressful situation in the body can become the cause of intense formation of free radicals. Free radicals are molecules or individual atoms that have unpaired valence electrons in their outer orbit, which are characterized by high reactivity and damage cell proteins, nucleic acids, membrane lipids, and can lead to the development of many types of pathological processes. All possible triggering mechanisms of this process have not been fully explored. It is known that under certain conditions, in response to stressogenic factors, a biologically positive reaction _ adaptive stress response develops in the body which ensures the resistance of cells to stronger (lethal) doses of the stimulating agent of this reaction. The aim of the study was to explore the influence of the hormetic phenomenon on the psycho-emotional state of anxiety which arose from the dose-response of the oxidative stress caused by hydrogen peroxide in an experiment on rats. The experiment was conducted on white male lab rats. As an experimental model of oxidative stress caused by hydrogen peroxide, we used its 0.1% and 0.2% aqueous solutions and administered them orally to animals for different durations (10 and 25 days). The psycho-emotional state of anxiety was assayed by means of the elevated plus maze. The analysis of the obtained results was conducted using the student's t-criterion.The analysis of our results allows us to note that in the experiment under the conditions of chronic action of a low dose of stressogenic factor (hydrogen peroxide H2O2 &nbsp;0.1%), an improvement in the psycho-emotional state of anxiety and its stable maintenance within the maximum limits of the norm can be observed, which must be caused by the influence of the hormetic response. A further increase (doubling of the "dose") of the stressogenic factor (chronic administration of 0.2% aqueous solution of hydrogen peroxide) resulted in suppression of the hormesis. It was found that in this experimental model, oxidative stress can play a positive role in the regulation of neuroplasticity and psycho-physiological adaptation.

Melatonin and redox homeostasis

Redox homeostasis and redox signaling are constituents of preservation of a normal physiological state. Whereas the equilibrium between oxidants and nucleophiles is conserved in redox homeostasis, oxidative stress promotes the formation of a radically altered redox state. It is known that modification of circadian clock may lead to severe alteration in redox balance. Melatonin [N-acetyl-5-methoxytryptamine, (MLT)] regulates numerous physiological functions including circadian rhythm, sleep-wake cycle, gonadal activity, redox homeostasis, neuroprotection, immune-modulation, and anticancer activity in organisms. Insufficient MLT production is closely related to development of aging process, tumorigenesis, visceral adiposity, neurodegenerative disorders, etc. Reactive oxygen species (ROS) are not intrinsically harmful or beneficial in cellular redox metabolism. Redox homeostasis is an integrative status for both of the hormetic response to ROS overproduction and subsequent redox signaling. MLT and its derivatives are traditionally classified as hormone-like substances. Their redox sensitive regulatory activity and direct interaction with intracellular ROS serve as second messenger in cell signaling. This review involves the role of redox homeostasis in the pathogenesis of age-related disorders and its relationship with MLT, therefore, targeting the circadian rhythm may propose new therapeutic approach for these disorders.

Riboflavin depletion promotes longevity and metabolic hormesis in Caenorhabditis elegans.

Riboflavin is an essential cofactor in many enzymatic processes and in the production of flavin adenine dinucleotide (FAD). Here, we report that the partial depletion of riboflavin through knockdown of the C.elegans riboflavin transporter 1 (rft-1) promotes metabolic health by reducing intracellular flavin concentrations. Knockdown of rft-1 significantly increases lifespan in a manner dependent upon AMP-activated protein kinase (AMPK)/aak-2, the mitochondrial unfolded protein response, and FOXO/daf-16. Riboflavin depletion promotes altered energetic and redox states and increases adiposity, independent of lifespan genetic dependencies. Riboflavin-depleted animals also exhibit the activation of caloric restriction reporters without any reduction in caloric intake. Our findings indicate that riboflavin depletion activates an integrated hormetic response that promotes lifespan and healthspan in C.elegans.

A Hormetic Spatiotemporal Photosystem II Response Mechanism of Salvia to Excess Zinc Exposure.

Exposure of Salvia sclarea plants to excess Zn for 8 days resulted in increased Ca, Fe, Mn, and Zn concentrations, but decreased Mg, in the aboveground tissues. The significant increase in the aboveground tissues of Mn, which is vital in the oxygen-evolving complex (OEC) of photosystem II (PSII), contributed to the higher efficiency of the OEC, and together with the increased Fe, which has a fundamental role as a component of the enzymes involved in the electron transport process, resulted in an increased electron transport rate (ETR). The decreased Mg content in the aboveground tissues contributed to decreased chlorophyll content that reduced excess absorption of sunlight and operated to improve PSII photochemistry (ΦPSII), decreasing excess energy at PSII and lowering the degree of photoinhibition, as judged from the increased maximum efficiency of PSII photochemistry (Fv/Fm). The molecular mechanism by which Zn-treated leaves displayed an improved PSII photochemistry was the increased fraction of open PSII reaction centers (qp) and, mainly, the increased efficiency of the reaction centers (Fv′/Fm′) that enhanced ETR. Elemental bioimaging of Zn and Ca by laser ablation–inductively coupled plasma–mass spectrometry (LA–ICP–MS) revealed their co-localization in the mid-leaf veins. The high Zn concentration was located in the mid-leaf-vein area, while mesophyll cells accumulated small amounts of Zn, thus resembling a spatiotemporal heterogenous response and suggesting an adaptive strategy. These findings contribute to our understanding of how exposure to excess Zn triggered a hormetic response of PSII photochemistry. Exposure of aromatic and medicinal plants to excess Zn in hydroponics can be regarded as an economical approach to ameliorate the deficiency of Fe and Zn, which are essential micronutrients for human health.

Hormetic response to B-type procyanidin ingestion involves stress-related neuromodulation via the gut-brain axis: Preclinical and clinical observations.

B-type procyanidins, a series of catechin oligomers, are among the most ingested polyphenols in the human diet. Results of meta-analyses have suggested that intake of B-type procyanidins reduces cardiovascular disease risk. Another recent focus has been on the effects of B-type procyanidins on central nervous system (CNS) function. Although long-term B-type procyanidin ingestion is linked to health benefits, a single oral intake has been reported to cause physiological alterations in circulation, metabolism, and the CNS. Comprehensive analyses of previous reports indicate an optimal mid-range dose for the hemodynamic effects of B-type procyanidins, with null responses at lower or higher doses, suggesting hormesis. Indeed, polyphenols, including B-type procyanidins, elicit hormetic responses in vitro, but animal and clinical studies are limited. Hormesis of hemodynamic and metabolic responses to B-type procyanidins was recently confirmed in animal studies, however, and our work has linked these effects to the CNS. Here, we evaluate the hormetic response elicited by B-type procyanidins, recontextualizing the results of intervention trials. In addition, we discuss the possibility that this hormetic response to B-type procyanidins arises via CNS neurotransmitter receptors. We have verified the direction of future research for B-type procyanidins in this review.

On the meta-analysis of hormetic effects

The evidence for hormetic responses with chemical effects at doses lower than the no-observed-adverse-effect-level (sub-NOAEL) is increasing, creating a need for meta-analyses of sub-NOAEL effects across studies. However, the distinct features of hormetic responses complicate the procedures of meta-analyses aiming to study sub-NOAEL, hormetic effects, and there is no standardized methodology to serve as a guideline. In this piece, a protocol is proposed, which covers the selection of more holistic keywords to be integrated into the literature search queries, the designation of control, and the identification of NOAEL (and thus sub-NOAEL dose responses). It also considers the selection of the response indicators and the incorporation of time and dose as sources of variation. This protocol can serve as a reference point for a harmonized and more robust methodology to meta-analyze sub-NOAEL effects of chemicals on living organisms.

The Potential Implications of Hydrogen Sulfide in Aging and Age-Related Diseases through the Lens of Mitohormesis.

The growing increases in the global life expectancy and the incidence of chronic diseases as a direct consequence have highlighted a demand to develop effective strategies for promoting the health of the aging population. Understanding conserved mechanisms of aging across species is believed helpful for the development of approaches to delay the progression of aging and the onset of age-related diseases. Mitochondrial hormesis (or mitohormesis), which can be defined as an evolutionary-based adaptive response to low-level stress, is emerging as a promising paradigm in the field of anti-aging. Depending on the severity of the perceived stress, there are varying levels of hormetic response existing in the mitochondria called mitochondrial stress response. Hydrogen sulfide (H2S) is a volatile, flammable, and toxic gas, with a characteristic odor of rotten eggs. However, H2S is now recognized an important gaseous signaling molecule to both physiology and pathophysiology in biological systems. Recent studies that elucidate the importance of H2S as a therapeutic molecule has suggested its protective effects beyond the traditional understanding of its antioxidant properties. H2S can also be crucial for the activation of mitochondrial stress response, postulating a potential mechanism for combating aging and age-related diseases. Therefore, this review focuses on highlighting the involvement of H2S and its sulfur-containing derivatives in the induction of mitochondrial stress response, suggesting a novel possibility of mitohormesis through which this gaseous signaling molecule may promote the healthspan and lifespan of an organism.

Unique Features of the Tissue Structure in the Naked Mole Rat (Heterocephalus glaber): Hypertrophy of the Endoplasmic Reticulum and Spatial Mitochondrial Rearrangements in Hepatocytes.

The reason for the exceptional longevity of the naked mole rat (Heterocephalus glaber) remains a mystery to researchers. We assumed that evolutionarily, H. glaber acquired the ability to quickly stabilize the functioning of mitochondria and endoplasmic reticulum (ER) to adjust metabolism to external challenges. To test this, a comparison of the hepatic mitochondria and ER of H. glaber and C57BL/6 mice was done. Electron microscopy showed that 2-months-old mice have more developed rough ER (RER) than smooth ER (SER), occupying ~17 and 2.5% of the hepatocytic area correspondingly, and these values do not change with age. On the other hand, in 1-week-old H. glaber, RER occupies only 13% constantly decreasing with age, while SER occupies 35% in a 1-week-old animal, constantly rising with age. The different localization of mitochondria in H. glaber and mouse hepatocytes was confirmed by confocal and electron microscopy: while in H. glaber, mitochondria were mainly clustered around the nucleus and on the periphery of the cell, in mouse hepatocytes they were evenly distributed throughout the cell. We suggest that the noted structural and spatial features of ER and mitochondria in H. glaber reflect adaptive rearrangements aimed at greater tolerance of the cellular system to challenges, primarily hypoxia and endogenous and exogenous toxins. Different mechanisms of adaptive changes including an activated hepatic detoxification system as a hormetic response, are discussed considering the specific metabolic features of the naked mole rat.

Paternal alcohol exposures program intergenerational hormetic effects on offspring fetoplacental growth

Hormesis refers to graded adaptive responses to harmful environmental stimuli where low-level toxicant exposures stimulate tissue growth and responsiveness while, in contrast, higher-level exposures induce toxicity. Although the intergenerational inheritance of programmed hormetic growth responses is described in plants and insects, researchers have yet to observe this phenomenon in mammals. Using a physiologically relevant mouse model, we demonstrate that chronic preconception paternal alcohol exposures program nonlinear, dose-dependent changes in offspring fetoplacental growth. Our studies identify an inverse j-shaped curve with a threshold of 2.4 g/Kg per day; below this threshold, paternal ethanol exposures induce programmed increases in placental growth, while doses exceeding this point yield comparative decreases in placental growth. In male offspring, higher paternal exposures induce dose-dependent increases in the placental labyrinth layer but do not impact fetal growth. In contrast, the placental hypertrophy induced by low-level paternal ethanol exposures associate with increased offspring crown-rump length, particularly in male offspring. Finally, alterations in placental physiology correlate with disruptions in both mitochondrial-encoded and imprinted gene expression. Understanding the influence of ethanol on the paternally-inherited epigenetic program and downstream hormetic responses in offspring growth may help explain the enormous variation observed in fetal alcohol spectrum disorder (FASD) phenotypes and incidence.

Cep-1 mediated the mitohormesis effect of Shengmai formula in regulating Caenorhabditis elegans lifespan

Ageing is one of the major causes of many diseases such as cardiovascular diseases, diabetes, neurodegenerative disorders, and cancer. It has been found that mitochondrion acts as a crucial regulator of healthy lifespan. In this work, traditional Chinese medicine Shengmai formula (SMH) was used to treat mitochondrial mutants of Caenorhabditis elegans. The results showed that SMH shortened the lifespan of short-lived mev-1 mutant, but lengthened the lifespan of long-lived isp-1 mutant. Acute SMH treatment has benefit effect by increasing resistance capacity and motion activity in both ETC mutants and wild type N2. Compared with N2, the genome-wide transcriptome profile of ETC mutants showed on a similar pattern after SMH treatment. GO and KEGG enrichment analysis addressed that SMH-induced genes mainly enriched in metabolic process and oxidation-reduction process. The ROS levels in ETC mutants and N2 firstly rose then fell after SMH treatment, in company with the elevation of SOD-1, SOD-3 and GST-4, the increment of HSP-16.2 combined with heat shock. SMH increased oxygen consumption and ATP content, improved the restoration of mitochondrial homeostasis. SMH-induced opposed lifespan outcomes were markedly counteracted by cep-1 RNAi, together with the mitochondrial dynamics. Western blot assay also demonstrated a SMH-induced CEP-1 expression. Collectively, SMH acts as a prooxidant to regulate mitochondrial homeostasis and causes mitohormesis to exert therapeutic effect based on the redox background of the recipients, and cep-1 was required for the mitochondrial hormetic responses. The results shed a light on the rational clinical anti-ageing applications of SMH in the future.

Mitochondrial function and nutrient sensing pathways in ageing: enhancing longevity through dietary interventions.

Ageing is accompanied by alterations in several biochemical processes, highly influenced by its environment. It is controlled by the interactions at various levels of biological hierarchy. To maintain homeostasis, a number of nutrient sensors respond to the nutritional status of the cell and control its energy metabolism. Mitochondrial physiology is influenced by the energy status of the cell. The alterations in mitochondrial physiology and the network of nutrient sensors result in mitochondrial damage leading to age related metabolic degeneration and diseases. Calorie restriction (CR) has proved to be as the most successful intervention to achieve the goal of longevity and healthspan. CR elicits a hormetic response and regulates metabolism by modulating these networks. In this review, the authors summarize the interdependent relationship between mitochondrial physiology and nutrient sensors during the ageing process and their role in regulating metabolism.