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This paper tells the story of how hormesis became recognized as a fundamental concept in biology, affecting toxicology, microbiology, medicine, public health, agriculture, and all areas related to enhancing biological performance. This paper assesses how hormesis enhances resilience to normal aging and protects against a broad spectrum of neurodegenerative, cardiovascular, and other diseases, as well as trauma and other threats to health and well-being. This paper also explains the application of hormesis to several neurodegenerative diseases such as Parkinson’s and Huntington’s disease, macrophage polarization and its systematic adaptive protections, and the role of hormesis in enhancing stem cell functioning and medical applications.

Hormesis, which describes the stimulatory effect of low doses of toxic substances on growth, is a well-known phenomenon in the plant and animal kingdoms. However, the mechanisms that are involved in this phenomenon are still poorly understood. We performed preliminary studies on corn coleoptile sections, which showed a positive correlation between the stimulation of growth by Cd or Pb and an increase in the auxin and H2O2 content in the coleoptile sections. Subsequently, we grew corn seedlings in hydroponic culture and tested a wide range of Cd or Pb concentrations in order to determine hormetic growth stimulation. In these seedlings the gas exchange and the chlorophyll a fluorescence, as well as the content of chlorophyll, flavonol, auxin and hydrogen peroxide, were measured. We found that during the hormetic stimulation of growth, the response of the photosynthetic apparatus to Cd and Pb differed significantly. While the application of Cd mostly caused a decrease in various photosynthetic parameters, the application of Pb stimulated some of them. Nevertheless, we discovered that the common features of the hormetic stimulation of shoot growth by heavy metals are an increase in the auxin and flavonol content and the maintenance of hydrogen peroxide at the same level as the control plants.

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. Analyzing data from the Adolescent Brain and Cognitive Development study ( = 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. 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. 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.

Heat hormesis describes the beneficial adaptations resulting from transient exposure to mild heat stress, which enhances stress resilience and promotes healthy aging. While heat hormesis is widely observed, much remains to be learned about its molecular basis. This study bridges a critical knowledge gap through a comprehensive multiomic analysis, providing key insights into the transcriptomic and chromatin accessibility landscapes throughout a heat hormesis regimen in Caenorhabditis elegans . We uncover highly dynamic, dose-dependent molecular responses to heat stress and reveal that while most initial molecular changes induced by mild stress revert to baseline, key differences emerge in response to subsequent heat shock challenge that likely contribute to physiological benefits. We further demonstrate that heat hormesis extends life span specifically in wild-type animals, but not in germline-less mutants, likely due to transient disruption of germline activities during mild heat exposure, which appears sufficient to trigger pro-longevity mechanisms. This finding points to tissue-specific responses in mediating the physiological outcomes of heat hormesis. Importantly, we identify several highly conserved regulators of heat hormesis that likely orchestrate gene expression to enhance stress resilience. Among these regulators, some (MARS-1/MARS1, SNPC-4/SNAPc, FOS-1/c-Fos) are broadly required for heat-hormesis-induced benefits, whereas others (ELT-2/GATA4, DPY-27/SMC4) are uniquely important in specific genetic backgrounds. This study advances our understanding of stress resilience mechanisms, points to multiple new avenues for future investigations, and provides a molecular framework for promoting healthy aging through strategic mid-life stress management.

Cellular adaptive mechanisms emerging after exposure to low levels of toxic agents or stressful stimuli comprise an important biological feature that has gained considerable scientific interest. Investigations of low-dose exposures to diverse chemical compounds signify the non-linear mode of action in the exposed cell or organism at such dose levels in contrast to the classic detrimental effects induced at higher ones, a phenomenon usually referred to as hormesis. The resulting phenotype is a beneficial effect that tests our physiology within the limits of our homeostatic adaptations. Therefore, doses below the region of adverse responses are of particular interest and are specified as the hormetic gain zone. The manifestation of redox adaptations aiming to prevent from disturbances of redox homeostasis represent an area of particular interest in hormetic responses, observed after exposure not only to stressors but also to compounds of natural origin, such as phytochemicals. Findings from previous studies on several agents demonstrate the heterogeneity of the specific zone in terms of the molecular events occurring. Major factors deeply involved in these biphasic phenomena are the bioactive compound per se, the dose level, the duration of exposure, the cell, tissue or even organ exposed to and, of course, the biomarker examined. In the end, the molecular fate is a complex toxicological event, based on beneficial and detrimental effects, which, however, are poorly understood to date.

It is widely acknowledged that aging, mitochondrial dysfunction, and cellular phenotypic abnormalities are intricately associated with the degeneration of bone and cartilage. Consequently, gaining a comprehensive understanding of the regulatory patterns governing mitochondrial function and its underlying mechanisms holds promise for mitigating the progression of osteoarthritis, intervertebral disc degeneration, and osteoporosis. Mitochondrial hormesis, referred to as mitohormesis, represents a cellular adaptive stress response mechanism wherein mitochondria restore homeostasis and augment resistance capabilities against stimuli by generating reactive oxygen species (ROS), orchestrating unfolded protein reactions (UPRmt), inducing mitochondrial-derived peptides (MDP), instigating mitochondrial dynamic changes, and activating mitophagy, all prompted by low doses of stressors. The varying nature, intensity, and duration of stimulus sources elicit divergent degrees of mitochondrial stress responses, subsequently activating one or more signaling pathways to initiate mitohormesis. This review focuses specifically on the effector molecules and regulatory networks associated with mitohormesis, while also scrutinizing extant mechanisms of mitochondrial dysfunction contributing to bone and cartilage degeneration through oxidative stress damage. Additionally, it underscores the potential of mechanical stimulation, intermittent dietary restrictions, hypoxic preconditioning, and low-dose toxic compounds to trigger mitohormesis, thereby alleviating bone and cartilage degeneration.

This paper provides a broad overview of hormesis, a specific type of biphasic dose response, its historical and scientific foundations as well as its biomedical applications, especially with respect to aging. Hormesis is a fundamental component of adaptability, neutralizing many endogenous and environmental challenges by toxic agents, thereby enhancing survival. Hormesis is highly conserved, broadly generalizable, and pleiotrophic, being independent of biological model, endpoint measured, inducing agent, level of biological organization and mechanism. The low dose stimulatory hormetic response has specific characteristics which defines both the quantitative features of biological plasticity and the potential for maximum biological performance, thereby estimating the limits to which numerous medical and pharmacological interventions may affect humans. The substantial degrading of some hormetic processes in the aged may profoundly reduce the capacity to respond effectively to numerous environmental/ischemic and other stressors leading to compromised health, disease and, ultimately, defining the bounds of longevity.

Evolutionary biologists have been interested in the negative interactions among life history traits for nearly a century, but the mechanisms that would create this negative interaction remain poorly understood. One variable that has emerged as a likely link between reproductive effort and longevity is oxidative stress. Specifically, it has been proposed that reproduction generates free radicals that cause oxidative stress and, in turn, oxidative stress damages cellular components and accelerates senescence. We propose that there is limited support for the hypothesis because reactive oxygen species (ROS), the free radicals implicated in oxidative damage, are not consistently harmful. With this review, we define the hormetic response of mitochondria to ROS, termed mitochondrial hormesis, and describe how to test for a mitohormetic response. We interpret existing data using our model and propose that experimental manipulations will further improve our knowledge of this response. Finally, we postulate how the mitohormetic response curve applies to variation in animal performance and longevity.

A historical assessment of the origin of the dose–response in modern toxicology and its integration as a central concept in biology and medicine is presented. This article provides an overview of how the threshold, linear and biphasic (i.e., hormetic) dose–response models emerged in the late 19th and early 20th centuries and competed for acceptance and dominance. Particular attention is directed to the hormetic model for which a general description and evaluation is provided, including its historical basis, and how it was marginalized by the medical and pharmacology communities in the early decades of the 20th century.

•Poor dietary choices and physical inactivity are the leading causes of death from stroke, heart disease, and cancer worldwide.•Chronic overnutrition triggers can lead to diabetes, atherosclerosis, and hypertension through mechanisms triggered by chronic glycemic and lipid overload.•“Cellular exercise” is a concept where low levels of cellular stress, induced by chronic calorie restriction or physical exercise, can lead to molecular adaptations on the cellular level that can protect the body from cancer and cardiovascular disease.•An increase in reactive oxygen species induced by caloric restriction and physical exercise can activate nuclear factor erythroid and phase II improvements in redox equilibrium that can result in a more adaptive capable cell.•Insulin-like growth factor-1 has a dual effect wherein calorie restriction downregulates insulin-like growth factor-1 inhibiting pathways of carcinogenic proliferation and metastasis and physical exercise can upregulate insulin-like growth factor-1 to promote mitochondrial biogenesis and protein synthesis thereby strengthening healthy muscle against hypoxic ischemic damage and muscular regenerative properties.•Transcription of Nrf2 is also upregulated to attenuate inflammation induced by nuclear factor-κB, AMPK upregulates genes through PGC-1α to prevent sarcopenia and induce lipolysis.•This molecular melody is the complex composition that explains the cellular adaption that occurs to strengthen the body from cognitive dysfunction, cardiometabolic failure and carcinogenic implantation and metastasis via mechanisms of redox equilibrium, oxidative protection, attenuation of inflammation, and attenuation of carcinogenic proliferation and growth. 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.