Impact of hormesis to deepen our understanding of the mechanisms underlying the bioactivities of polyphenols.

Cells, organs, and the whole body are continuously exposed to various types of stressors, including oxidative stress, protein denaturation, hypoxia, energy starvation, and pathogen insults. Hormesis is an adaptive phenomenon in which a stressor induces cellular stress responses at low or moderate doses, while catastrophic damage is manifested at high doses. Polyphenols, as xenobiotic phytochemicals, exhibit stress responses in animal cells, as demonstrated in cellular and rodent models. In this review article, the author highlighted several molecular mechanisms underlying different types of stress adaptation and hormetic phenomena induced by bioactive polyphenols to substantially understand how and why those phytochemicals function in biological systems.

The hormesis principle of neuroplasticity and neuroprotection.

Animals live in habitats fraught with a range of environmental challenges to their bodies and brains. Accordingly, cells and organ systems have evolved stress-responsive signaling pathways that enable them to not only withstand environmental challenges but also to prepare for future challenges and function more efficiently. These phylogenetically conserved processes are the foundation of the hormesis principle, in which single or repeated exposures to low levels of environmental challenges improve cellular and organismal fitness and raise the probability of survival. Hormetic principles have been most intensively studied in physical exercise but apply to numerous other challenges known to improve human health (e.g., intermittent fasting, cognitive stimulation, and dietary phytochemicals). Here we review the physiological mechanisms underlying hormesis-based neuroplasticity and neuroprotection. Approaching natural resilience from the lens of hormesis may reveal novel methods for optimizing brain function and lowering the burden of neurological disorders.

Hormesis determines lifespan.

This paper addresses how long lifespan can be extended via multiple interventions, such as dietary supplements [e.g., curcumin, resveratrol, sulforaphane, complex phytochemical mixtures (e.g., Moringa, Rhodiola)], pharmaceutical agents (e.g., metformin), caloric restriction, intermittent fasting, exercise and other activities. This evaluation was framed within the context of hormesis, a biphasic dose response with specific quantitative features describing the limits of biological/phenotypic plasticity for integrative biological endpoints (e.g., cell proliferation, memory, fecundity, growth, tissue repair, stem cell population expansion/differentiation, longevity). Evaluation of several hundred lifespan extending agents using yeast, nematode (Caenorhabditis elegans), multiple insect and other invertebrate and vertebrate models (e.g., fish, rodents), revealed they responded in a manner [average (mean/median) and maximum lifespans] consistent with the quantitative features [i.e., 30-60% greater at maximum (Hormesis Rule)] of the hormetic dose response. These lifespan extension features were independent of biological model, inducing agent, endpoints measured and mechanism. These findings indicate that hormesis describes the capacity to extend life via numerous agents and activities and that the magnitude of lifespan extension is modest, in the percentage, not fold, range. These findings have important implications for human aging, genetic diseases/environmental stresses and lifespan extension, as well as public health practices and long-term societal resource planning.

Hormesis defines the limits of lifespan.

This commentary provides a novel synthesis of how biological systems adapt to a broad spectrum of environmental and age-related stresses that are underlying causes of numerous degenerative diseases and debilitating effects of aging. It proposes that the most fundamental, evolutionary-based integrative strategy to sustain and protect health is based on the concept of hormesis. This concept integrates anti-oxidant, anti-inflammatory and cellular repair responses at all levels of biological organization (i.e., cell, organ and organism) within the framework of biphasic dose responses that describe the quantitative limits of biological plasticity in all cells and organisms from bacteria and plants to humans. A major feature of the hormetic concept is that low levels of biological, chemical, physical and psychological stress upregulate adaptive responses that not only precondition, repair and restore normal functions to damaged tissues/organs but modestly overcompensate, reducing ongoing background damage, thereby enhancing health beyond that in control groups, lacking the low level "beneficial" stress. Higher doses of such stress often become counterproductive and eventually harmful. Hormesis is active throughout the life-cycle and can be diminished by aging processes affecting the onset and severity of debilitating conditions/diseases, especially in elderly subjects. The most significant feature of the hormetic dose response is that the limits of biological plasticity for adaptive processes are less than twice that of control group responses, with most, at maximum, being 30-60 % greater than control group values. Yet, these modest increases can make the difference between health or disease and living or dying. The quantitative features of these adaptive hormetic dose responses are also independent of mechanism. These features of the hormetic dose response determine the capacity to which systems can adapt/be protected, the extent to which biological performance (e.g., memory, resistance to injury/disease, wound healing, hair growth or lifespan) can be enhanced/extended and the extent to which synergistic interactions may occur. Hormesis defines the quantitative rules within which adaptive processes operate and is central to evolution and biology and should become transformational for experimental concepts and study design strategies, public health practices and a vast range of therapeutic strategies and interventions.

Reprogramming of the transcriptome after heat stress mediates heat hormesis in Caenorhabditis elegans.

Transient stress experiences not only trigger acute stress responses, but can also have long-lasting effects on cellular functions. In Caenorhabditis elegans, a brief exposure to heat shock during early adulthood extends lifespan and improves stress resistance, a phenomenon known as heat hormesis. Here, we investigated the prolonged effect of hormetic heat stress on the transcriptome of worms and found that the canonical heat shock response is followed by a profound transcriptional reprogramming in the post-stress period. This reprogramming relies on the endoribonuclease ENDU-2 but not the heat shock factor 1. ENDU-2 co-localizes with chromatin and interacts with RNA polymerase II, enabling specific regulation of transcription after the stress period. Failure to activate the post-stress response does not affect the resistance of animals to heat shock but eliminates the beneficial effects of hormetic heat stress. In summary, our work discovers that the RNA-binding protein ENDU-2 mediates the long-term impacts of transient heat stress via reprogramming transcriptome after stress exposure.

Boron enhances adaptive responses and biological performance via hormetic mechanisms.

Boron is shown in the present review to induce hormetic dose responses in a broad range of biological models, organ systems and endpoints. Of particular importance is that numerous hormetic findings have been reported with whole animal studies, with extensive dose response evaluations with the optimal dosing being similar across multiple organ systems. These findings appear to be underappreciated and suggest that boron may have clinically significant systemic effects beyond that of its putative and more subtle essentiality functions. The re-exploration of boron's bioactivity as seen through hormetic mechanisms may also underscore the value of this approach to the assessment of micronutrient effects in human health and disease.

Lithium and hormesis: Enhancement of adaptive responses and biological performance via hormetic mechanisms.

Biomedical and consumer interest in the health-promoting properties of pure single entities of known or unknown chemical constituents and mixtures has never been greater. Since its "rediscovery" in the 1950s, lithium is an example of such a constituent that represents an array of scientific and public health challenges and medical potentials that may now be understood best when seen through the lens of the dose-response paradigm known as hormesis. The present paper represents the first review of the capacity of lithium to induce hormetic dose responses in a broad range of biological models, organ systems, and endpoints. Of significance is that the numerous hormetic findings occur with extensive concentration/dose response evaluations with the optimal dosing being similar across multiple organ systems. The particular focus of these hormetic dose-response findings was targeted to research with a broad spectrum of stem cell types and neuroprotective effects. These findings suggest that lithium may have critically valuable systemic effects with respect to those therapeutically treated with lithium as well as for exposures that may be achieved via dietary intervention.

Nitric oxide and hormesis.

This present paper provides an assessment of the occurrence of nitric oxide (NO)-induced hormetic-biphasic dose/concentration relationships in biomedical research. A substantial reporting of such NO-induced hormetic effects was identified with particular focus on wound healing, tumor promotion, and sperm biology, including mechanistic assessment and potential for translational applications. Numerous other NO-induced hormetic effects have been reported, but require more development prior to translational applications. The extensive documentation of NO-induced biphasic responses, across numerous organs (e.g., bone, cardiovascular, immune, intestine, and neuronal) and cell types, suggests that NO-induced biological activities are substantially mediated via hormetic processes. These observations are particularly important because broad areas of NO biology are constrained by the quantitative features of the hormetic response. This determines the amplitude and width of the low dose stimulation, affecting numerous biomedical implications, study design features (e.g., number of doses, dose spacing, sample sizes, statistical power), and the potential success of clinical trials.

Hormesis-tempting stressors driven by evolutionary factors for mitigating negative impacts instigated over extended exposure to chemical elements.

The adaptive responses to moderate environmental challenges by the biological systems have usually been credited to hormesis. Since the hormetic biphasic dose-response illustrates a prominent pattern towards biological responsiveness, the studies concerning such aspects will get much more significance in risk assessment practices and toxicological evaluation research. From this point of view, the past few epochs have witnessed the extending recognition of the notion concerning hormesis. The extraction of its basic foundations of evolutionary perspectives-along with the probable underlying molecular and cellular mechanisms followed by the practical implications to enhance the quality of life. To get better and more effective output in this regard, the present article has evaluated the various observations of previous investigations. The intent of integrating the novel inferences concerning the hormesis-tempting stressors driven by predominant evolutionary factors for mitigating the adverse impacts that were prompted over frequent and continuous exposure to the various chemical elements. Such inferences can offer extensive insight into the implications concerning the risk assessment of hormesis.

Hormesis effects in tomato plant growth and photosynthesis due to acephate exposure based on physiology and transcriptomic analysis.

BACKGROUND: Hormesis is a common phenomenon in toxicology described as low-dose stimulation due to a toxin which causes inhibition at a high dose. Pesticide hormesis in plants has attracted considerable research interest in recent years; however, the specific mechanism has not yet been clarified. Acephate is an organophosphorus insecticide that is used worldwide. Here, hormesis in tomato (Solanum lycopersicum L.) plant growth and photosynthesis after acephate exposure is confirmed, as stimulation occurred at low stress levels, whereas inhibition occurred after exposure to high concentrations. RESULTS: We found that low acephate concentration (5-fold lower than recommended application dosage) could enhance chlorophyll biosynthesis and stimulate photosynthesis effects, and thus improve S. lycopersicum growth. A high level of acephate (5-fold higher than recommended application dosage) stress inhibited chlorophyll accumulation, decreased photosystem II efficiency and blocked antioxidant reactions in leaves, increasing reactive oxygen species levels and damaging plant growth. Transcriptomic analysis and quantitative real-time PCR results revealed that the photosynthesis - antenna proteins pathway played a crucial role in the hormesis effect, and that LHCB7 as well as LHCP from the pathway were the most sensitive to acephate hormesis. CONCLUSION: Our results showed that acephate could induce hormesis in tomato plant growth and photosynthesis, and that photosystem II and the photosynthesis - antenna proteins pathway played important roles in hormesis. These results provide novel insights into the scientific and safe application of chemical pesticides, and new guidance for investigation into utilizing pesticide hormesis in agriculture. © 2023 Society of Chemical Industry.

Mitoresilience: Hormesis, Psycho-physical Resilience, Mitochondria and Heart Rate Variability as Relevant Interplaying Elements in Longevity Medicine.

Psycho-biological resilience is considered one of the most important factors in the epigenetics of aging. Cell senescence exhibits a series of possible biochemical derangements concerning mitochondria, proteasome, genome and membranes. Research has shown that resilience can be acquired through hormesis, a set of conservative and adaptive processes based on biphasic doseresponse to specific mild stressors, such as fasting, intake of polyphenols, exercising, physical and chemical stress and mental engagement. These stimuli were shown to elicit beneficial cellular metabolic pathways, such as sirtuin activation, mechanistic target of rapamycin and insulin growth factor- 1 downregulation, nuclear related factor 2 upregulation and autophagy. The complex of these resilience-building processes plays a documented role in longevity. Mitochondria are regarded as one of the core actors of aging processes and represent the main target of hormetic approaches [mitohormesis]; furthermore, the influence of the mind on mitochondria, and thus on the balance of health and disease has been recently established, leading to the so-called mitochondria psychobiology. Hence, psychologic and physical stress that reflects on these organelles may be regarded as a relevant factor in cell senescence, and thus the proposed "mitoresilience" denomination may be pertinent within the biomedical science of aging. Finally, the quantification of individual resilience is becoming increasingly important in aging science, and the investigation of the autonomic nervous system through heart rate variability (HRV) proved to be a valid method to quantify this parameter. In conclusion, an integrated approach targeting hormetic pathways to improve psychophysical resilience (namely mitoresilience), supported by the monitoring of HRV, may represent a valuable option in longevity medicine.

The Underexplored Dimensions of Nutritional Hormesis.

PURPOSE OF REVIEW: Hormesis is biphasic response wherein low and high doses of chemical and nutrient confer beneficial and toxic effects respectively, typically in a U-shaped manner. Hormesis is intricately related to bioenergetic state of a cell, and therefore, nutrition impacts it. Excessive nutrition can halt the endogenous antioxidant synthesis leading to cytotoxic effects. While low and optimum doses of the same bring about hormetic stimulation that can exalt the antioxidant response and reduce susceptibility towards degenerative diseases. The sirtuin family of proteins is triggered by mild stress of calorie restriction and exerts hormesis. Similarly, several phytochemicals and micronutrients are known to bring about health benefits at optimum dose and deleterious effects at high doses. Despite this attribute, nutritional hormesis is not very well researched upon because the magnitude of hormetic effect observed is generally quite modest. There is no precise regulation of optimal intake of certain foods to witness hormesis and no characterization of any biomarker that reports stress responses at various doses above or below optimal intakes. There is a major gap in research between nutrition and hormesis being affected by sirtuin family of proteins, phytochemicals, and micronutrients. RECENT FINDINGS: Mild stress of calorie restriction elevates sirtuin protein and effect of sirtuin protein on hormesis has been recently reported. More foods that enhance sirtuin protein, phytochemicals, and micronutrients need to be explored in relation to hormesis and associated health benefits.

Could "cellular exercise" be the missing ingredient in a healthy life? Diets, caloric restriction, and exercise-induced hormesis.

Overnutrition is a poor dietary habit that has been correlated with increased health risks, especially in the developed world. This leads to an imbalance between energy storage and energy breakdown. Many biochemical processes involving hormones are involved in conveying the excess of energy into pathologic states, mainly atherosclerosis, hypertension, cardiovascular diseases, and diabetes. Diverse modalities of regular exercise have been shown to be beneficial, to varying extents, in overcoming the overnutrition comorbidities. Cellular exercises and hormesis are triggered by dietary protocols that could underlie the cellular mechanisms involved in modulating the deleterious effects of overnutrition through activation of specific cellular signal pathways. Of interest are the oxidative stress signaling, nuclear factor erythroid-2, insulin-like growth factor-1, AMP-activated protein kinase as well as sirtuins and nuclear factor-κB. Therefore, the value of intermittent fasting diets as well as different diet regimens inducing hormesis are evaluated in terms of their beneficial effects on health and longevity. In parallel, important effects of diets on the immune system are explored as essential components that can undermine the overall health outcome. Additionally, the subtle but relevant relation between diet and sleep is investigated for its impact on the cardiovascular system and quality of life. The aim of this review is to focus on how calorie restriction triggers multiple molecular pathways that ultimately lead to hormetic effects resulting in cell longevity and resistance to cardiovascular disease, stroke, and cancer.

Hormesis: Transforming disciplines that rely on the dose response.

This article tells the story of hormesis from its conceptual and experimental origins, its dismissal by the scientific and medical communities in the first half of the 20th century, and its rediscovery over the past several decades to be a fundamental evolutionary adaptive strategy. The upregulation of hormetic adaptive mechanisms has the capacity to decelerate the onset and reduce the severity of a broad spectrum of common age-related health, behavioral, and performance decrements and debilitating diseases, thereby significantly enhancing the human health span. Incorporation of hormetic-based lifestyle options within the human population would have profoundly positive impacts on the public health, significantly reducing health care costs.

Hormesis and embryonic stem cells.

This paper provides an identification and detailed assessment of hormetic dose responses of embryonic stem cells (ESCs) with particular emphasis on cell renewal (proliferation) and differentiation, underlying mechanistic foundations and potential therapeutic implications. Hormetic dose responses were commonly reported, being induced by a broad range of chemicals, including pharmaceuticals (e.g., atorvastatin, isoproterenol, lithium, nicotine, ouabain), dietary supplements (e.g., curcumin, multiple ginsenosides, resveratrol), endogenous agents (e.g., estrogen, hydrogen peroxide, melatonin), and physical stressor agents (e.g., hypoxia, ionizing radiation). ESC-hormetic dose responses are similar for other stem cell types (e.g., adipose-derived stem cells, apical papilla, bone marrow stem cells, dental pulp stem cells, endothelial stem cells, muscle stem cells, periodontal ligament stem cells, neural stem cells), indicating a high degree of generality for the hormetic-stem cells response. The widespread occurrence of hormetic dose responses shown by ESCs and other stem cells suggests that the hormetic dose response may represent a fundamental and highly conserved evolutionary strategy.

Brain health promotion: Tactics within a strategic approach based upon valid, yet evolving scientific evidence.

There is growing interest in finding ways to enhance longevity and the quality of life. This paper summarizes a vast scientific literature over the past two decades that has suggested approaches to enhancing biological resilience - and particularly neurological function - via hormetic and preconditioning processes. The employment of hormesis and preconditioning has been shown to protect biological systems from many of the effects of aging, both by sustaining structural and functional integrity, and by affording relative protection against certain types of diseases. The paper confronts the challenges - and opportunities - for society when considering possible practical use of evolving evidence about the mechanisms, processes and effects of these biological phenomena.

Healthy ageing and Mediterranean diet: A focus on hormetic phytochemicals.

Mediterranean diet (MedDiet) is rich in fruits and vegetables associated with longevity and a reduced risk of several age-related diseases. It is demonstrated that phytochemicals in these plant products enhance the positive effects of MedDiet by acting on the inflammatory state and reducing oxidative stress. Evidence support that these natural compounds act as hormetins, triggering one or more adaptive stress-response pathways at low doses. Activated stress-response pathways increase the expression of cytoprotective proteins and multiple genes that act as lifespan regulators, essential for the ageing process. In these ways, the hormetic response by phytochemicals such as resveratrol, ferulic acid, and several others in MedDiet might enhance cells' ability to cope with more severe challenges, resist diseases, and promote longevity. This review discusses the role of MedDiet phytochemicals in healthy ageing and the prevention of age-related diseases.

Luteolin and hormesis.

The present paper provides the first integrated assessment of the capacity of luteolin to induce hormetic dose responses. It was shown that luteolin induced hormetic responses in multiple biological systems, including enhancing neuroprotection in various experimental model disease systems, improving wounding healing, especially in experimental models of high-risk population subgroups, such as diabetics, as well as enhancing osteogenesis in models of osteoporosis. The mechanistic basis for the luteolin-induced hormetic dose responses has been demonstrated to commonly involve the upregulation of the nuclear factor erythroid-derived 2-like 2 (Nrf2), which mediates the extensive range of anti-inflammatory effects induced by luteolin in multiple cell types and organ systems.

Ferulic acid and hormesis: Biomedical and environmental implications.

The present paper provides the first systematic assessment of the capacity of ferulic acid to induce hormetic dose responses in biological systems. Ferulic acid induced hormetic effects in a broad range of animal models, affecting numerous biological endpoints, with particular focus on neuroprotective effects. Emerging evidence in multiple biomedical systems indicates that the hormetic effects of ferulic acid depend upon the activation of the transcription factor Nrf2. Ferulic acid was also shown to have an important role in ecological settings, being routinely released into the environment by numerous plant species, acting as an allelopathic agent affecting the growth of neighboring species via hormetic dose responses. These findings demonstrate the potential ecological and biomedical importance of ferulic acid effects and that these effects are commonly expressed via the hormetic dose response, suggesting complex multisystem evolutionary regulatory strategies.

Phenolic acid metabolites of polyphenols act as inductors for hormesis in C. elegans.

INTRODUCTION: Aging represents a major risk factors for metabolic diseases, such as diabetes, obesity, or neurodegeneration. Polyphenols and their metabolites, especially simple phenolic acids, gained growing attention as a preventive strategy against age-related, non-communicable diseases, due to their hormetic potential. Using Caenorhabditis elegans (C. elegans) we investigate the effect of protocatechuic, gallic, and vanillic acid on mitochondrial function, health parameters, and the induction of potential hormetic pathways. METHODS: Lifespan, heat-stress resistance and chemotaxis of C. elegans strain P X 627, a specific model for aging, were assessed in 2-day and 10-day old nematodes. Mitochondrial membrane potential (ΔΨm) and ATP generation were measured. mRNA expression levels of longevity and energy metabolism-related genes were determined using qRT-PCR. RESULTS: All phenolic acids were able to significantly increase the nematodes lifespan, heat-stress resistance and chemotaxis at micromolar concentrations. While ΔΨm was only affected by age, vanillic acid (VA) significantly decreased ATP concentrations in aged nematodes. Longevity pathways, were activated by all phenolic acids, while VA also induced glycolytic activity and response to cold. CONCLUSION: While life- and health span parameters are positively affected by the investigated phenolic acids, the concentrations applied were unable to affect mitochondrial performance. Therefore we suggest a hormetic mode of action, especially by activation of the sirtuin-pathway.