Transgenerational hormesis in healthy aging and antiaging medicine from bench to clinics: Role of food components.

Neurodegenerative diseases have multifactorial pathogenesis, mainly involving neuroinflammatory processes. Finding drugs able to treat these diseases, expecially because for most of these diseases there are no effective drugs, and the current drugs cause undesired side effects, represent a crucial point. Most in vivo and in vitro studies have been concentrated on various aspects related to neurons (e.g. neuroprotection), however, there has not been focus on the prevention of early stages involving glial cell activation and neuroinflammation. Recently, it has been demonstrated that nutritional phytochemicals including polyphenols, the main active constituents of the Mediterranean diet, maintain redox balance and neuroprotection through the activation of hormetic vitagene pathway. Recent lipidomics data from our laboratory indicate mushrooms as strong nutritional neuronutrients with strongly activity against neuroinflammation in Meniere' diseaseas, a model of cochleovestibular neural degeneration, as well as in animal model of traumatic brain injury, or rotenone induced parkinson's disease. Moreover, Hidrox®, an aqueous extract of olive containing hydroxytyrosol, and Boswellia, acting as Nrf2 activators, promote resilience by enhancing the redox potential, and thus, regulate through hormetic mechanisms, cellular stress response mechanisms., Thus, modulation of cellular stress pathways, in particular vitagenes system, may be an innovative approach for therapeutic intervention in neurodegenerative disorders.

Recent discoveries on the historical foundations of cancer risk assessment: Shedding light on the limits of LNT.

Within the past three years there has been a spate of historical discoveries by our research team on various different facets of the historical foundations of cancer risk assessment. This series of discoveries was stimulated by the creation of a 22-episode documentary of the historical foundations of cancer risk assessment by the US Health Physics Society and the need to provide documentation. This process yielded nearly two dozen distinct historical findings which have been published in numerous papers in the peer-reviewed literature. These discoveries are itemized and summarized in the present paper, along with the significance of each discovery within the historical context of ionizing radiation research and cancer risk assessment.

Newly discovered letter: why Muller failed to cite the negative mouse mutation findings of Snell, preserving his chances to receive the Nobel Prize.

A recently acquired letter between Hermann Muller and his wife (March 21, 1933) reveals that Muller had learned that he had been nominated for the Nobel Prize in 1932 with about 1/3 of the total votes being supportive. Muller was hopeful that over time sufficient votes would lead to receiving the award. The knowledge of Muller on this matter and its timing provide a likely explanation why Muller never cited the negative mouse mutation findings of George Snell, performed under Muller's direction during that time period. This action of Muller, along with the failure of Snell to promote his discovery, greatly reduced the chances that those findings would complicate his attempt to garner support for his LNT single-hit model and its application to hereditary and cancer risk assessment. It also helped Muller achieve the Nobel Prize, allowing him the necessary international visibility to promote his ideologically driven ionizing radiation-related LNT-based paradigm.

First report of X-ray induced somatic mutation by Muller's department chair fails to support Muller's linearity hypothesis.

This paper reevaluates the first report of X-ray-induced somatic gene mutations. It was undertaken by John Patterson, Department Chair of Hermann Muller, using the same biological model, methods and equipment of Muller. Patterson reported X-ray induced mutation frequencies for X-chromosome-linked (sex-linked) recessive gene mutations in somatic cells of Drosophila melanogaster that resulted in color changes in the ommatidia of the eyes. Results were based on color changes detected in both male and female offspring irradiated while in egg, larval or pupal stages and for unirradiated controls. Patterson claimed that the observed dose response displayed linearity, with a clear implication that the linear response extended to background exposure levels of unirradiated controls. This reanalysis disputes Patterson's interpretation, showing that the dose response in the low-dose zone strongly supported a threshold model. The doses in the experiment, which were not clearly presented, were so high that it would preclude the assumption that the experiment provided any information of relevance to radiation exposures of humans at low doses, or even at high doses delivered at low-dose rates. Induced phenotypical changes that occurred at the higher doses, especially in female offspring, overwhelmingly resulted from X-ray-induced chromosome breaks instead of point mutations as initially expected by Patterson. The Patterson findings and linearity interpretations were an important contributory factor in the acceptance of the linear non-threshold (LNT) model during the formative time of concept consolidation. It is rather shocking now to see that the actual data provided no support for the LNT model.

Investigating hormesis, aging, and neurodegeneration: From bench to clinics.

Mitochondria-derived reactive oxygen species production at a moderate physiological level plays a fundamental role in the anti-aging signaling, due to their action as redox-active sensors for the maintenance of optimal mitochondrial balance between intracellular energy status and hormetic nutrients. Iron regulatory protein dysregulation, systematically increased iron levels, mitochondrial dysfunction, and the consequent oxidative stress are recognized to underlie the pathogenesis of multiple neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. Central to their pathogenesis, Nrf2 signaling dysfunction occurs with disruption of metabolic homeostasis. We highlight the potential therapeutic importance of nutritional polyphenols as substantive regulators of the Nrf2 pathway. Here, we discuss the common mechanisms targeting the Nrf2/vitagene pathway, as novel therapeutic strategies to minimize consequences of oxidative stress and neuroinflammation, generally associated to cognitive dysfunction, and demonstrate its key neuroprotective and anti-neuroinflammatory properties, summarizing pharmacotherapeutic aspects relevant to brain pathophysiology.

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.

Muller and mutations: mouse study of George Snell (a postdoc of Muller) fails to confirm Muller's fruit fly findings, and Muller fails to cite Snell's findings.

In 1931, Hermann J. Muller's postdoctoral student, George D. Snell (Nobel Prize recipient--1980) initiated research to replicate with mice Muller's X-ray-induced mutational findings with fruit flies. Snell failed to induce the two types of mutations of interest, based on fly data (sex-linked lethals/recessive visible mutations) even though the study was well designed, used large doses of X-rays, and was published in Genetics. These findings were never cited by Muller, and the Snell paper (Snell, Genetics 20:545-567, 1935) did not cite the 1927 Muller paper (Muller, Science 66:84, 1927). This situation raises questions concerning how Snell wrote the paper (e.g., ignoring the significance of not providing support for Muller's findings in a mammal). The question may be raised whether professional pressures were placed upon Snell to downplay the significance of his findings, which could have negatively impacted the career of Muller and the LNT theory. While Muller would receive worldwide attention, and receive the Nobel Prize in 1946 "for the discovery that mutations can be induced by X-rays," Snell's negative mutation data were almost entirely ignored by his contemporary and subsequent radiation genetics/mutation researchers. This raises questions concerning how the apparent lack of interest in Snell's negative findings helped Muller professionally, including his success in using his fruit fly data to influence hereditary and cancer risk assessment and to obtain the Nobel Prize.

Taurine induces hormesis in multiple biological models: May have transformative implications for overall societal health.

This paper represents the first integrative assessment and documentation of taurine-induced hormetic effects in the biological and biomedical areas, their dose response features, mechanistic frameworks, and possible public health, therapeutic and commercial applications. Taurine-induced hormetic effects are documented in a wide range of experimental models, cell types and for numerous biological endpoints, with most of these experimental findings being reported within the past five years. It is suggested that the concept of hormesis may have a transformative effect on taurine research and its public health and therapeutic applications.

RUTIN, a widely consumed flavonoid, that commonly induces hormetic effects.

Rutin is a flavonoid present in numerous fruits and vegetables and therefore widely consumed by humans. It is also a popular dietary supplement of 250-500 mg/day. There is considerable consumer interest in rutin due to numerous reports in the biomedical literature of its multi-system chemo-preventive properties. The present paper provides the first assessment of rutin-induced hormetic concentration/dose responses, their quantitative features and mechanistic basis, along with their biological, biomedical, clinical, and public health implications. The findings indicate that rutin-induced hormetic dose responses are widespread, being reported in numerous biological models and cell types for a wide range of endpoints. Of critical importance is that the optimal hormetic findings shown in in vitro systems are currently not achievable for human populations due to low gastrointestinal tract bioavailability. These findings have the potential to strengthen future experimental studies with rutin, particularly concerning study design parameters.

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.

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.

How Hermann J. Muller Viewed the Ernest Sternglass Contributions to Hereditary and Cancer Risk Assessment.

ABSTRACT: As one of the most influential radiation geneticists of the 20th century, Hermann J. Muller had a major role in the development and widespread acceptance of the linear no-threshold (LNT) dose response for hereditary and cancer risk assessments worldwide. However, a spate of historical reassessments have challenged the fundamental scientific foundations of the LNT model, drawing considerable attention to issues of ethical probity and the scientific leadership of Muller. This review paper raises further questions about the objectivity of Muller with respect to the LNT model. It is shown that Muller supported Ernest Sternglass's findings and interpretations concerning radiation-induced childhood leukemia, which have been widely and consistently discredited. These findings provide further evidence that Muller's actions with respect to radiation cancer risk assessment were far more ideologically than scientifically based.

Blood-Labyrinth Barrier in Health and Diseases: Effect of Hormetic Nutrients.

Significance: The stria vascularis, located in the inner ear, consists of three layers, one of which is the blood-labyrinth barrier (BLB). It is formed by endothelial cells, sealed together to prevent the passage of toxic substances from the blood to the inner ear, by pericytes and perivascular-resident macrophage-like melanocyte. Recent Advances: There are various causes that lead to hearing loss, and among these are noise-induced and autoimmune hearing loss, ear disorders related to ototoxic medication, Ménière's disease, and age-related hearing loss. For all of these, major therapeutic interventions include drug-loaded nanoparticles, via intratympanic or intracochlear delivery. Critical Issues: Since many pathologies associated with hearing loss are characterized by a weakening of the BLB, in this review, the molecular mechanisms underlying the response to damage of BLB cellular components have been discussed. In addition, insight into the role of hormetic nutrients against hearing loss pathology is proposed. Future Directions: BLB cellular components of neurovascular cochlear unit play important physiological roles, owing to their impermeable function against all ototoxic substances that can induce damage. Studies are needed to investigate the cross talk occurring between these cellular components to exploit their possible role as novel targets for therapeutic interventions that may unravel future path based on the use of hormetic nutrients. Antioxid. Redox Signal. 40, 542-563.

Muller's genetic load/species extinction hypothesis.

The genetic load hypothesis of Hermann Muller raised the profound question of possible species extinction, even for humans, following a prolonged accumulation of recessive genes due to ionizing radiation exposure within the population. Two major mouse radiation research teams in the United States provided the most extensive tests of Muller's hypothesis. One group continued its study for more than two decades, over 82 consecutive generations, approximating 2500 human years. Even though Muller had stressed for decades his fear of species-threatening effects, no significant effects were observed for related factors such as reproductive fitness and longevity. Yet, the paper presenting the data of the 82-generation negative study has only been cited five times in 45 years. Altogether numerous laboratories worldwide collected vast amounts of data on mice, rats, and swine in an unsuccessful attempt to see if there was convincing evidence to support the genetic load theory and claims that species might deteriorate or be rendered extinct. This paper re-examines Muller's genetic load hypothesis with a new evaluation of how that hypothesis was tested and the significance of the findings, with most of those studies being completed before the BEIR I Committee Report in 1972. That committee briefly discussed the available evidence, mostly ignoring those results as they proceeded to make hereditary risk estimates both for (1) the first generation after a radiation exposure and (2) for the time, in the distant future, when a hypothetical genetic equilibrium would be reached. Their estimates assumed accumulation of harmful mutations and a linear no-threshold dose response extending all of the way down to a single ionization. More recent data on induction by ionizing radiation of dominant mutations that affect the skeletons of mice provide further robust supporting evidence that the generationally cumulative and LNT-based assumptions underpinning Muller's genetic load hypothesis are not correct.

Muller misled the Pugwash Conference on radiation risks.

The Pugwash Conferences have been a highly visible attempt to create profoundly important discussions on matters related to global safety and security at the highest levels, starting in 1957 at the height of the Cold War. This paper assesses, for the first time, the formal comments offered at this first Pugwash Conference by the Nobel Prize-winning radiation geneticist, Hermann J. Muller, on the effects of ionizing radiation on the human genome. This analysis shows that the presentation by Muller was highly biased and contained scientific errors and misrepresentations of the scientific record that resulted in seriously misleading the attendees. The presentation of Muller at Pugwash served to promote, on a very visible global scale, continued misrepresentations of the state of the science and had a significant impact on policies and practices internationally and both scientific and personal belief systems concerning the effects of low dose radiation on human health. These misrepresentations would come to affect the adoption and use of nuclear technologies and the science of radiological and chemical carcinogen health risk assessment, ultimately having a profound effect on global environmental health.

Comet assay and hormesis.

The paper provides the first assessment of the occurrence of hormetic dose responses using the Comet assay, a genotoxic assay. Using a priori evaluative criteria based on the Hormetic Database on peer-reviewed comet assay experimental findings, numerous examples of hormetic dose responses were obtained. These responses occurred in a large and diverse range of cell types and for agents from a broad range of chemical classes. Limited attempts were made to estimate the frequency of hormesis within comet assay experimental studies using a priori entry and evaluative criteria, with results suggesting a frequency in the 40% range. These findings are important as they show that a wide range of genotoxic chemicals display evidence that is strongly suggestive of hormetic dose responses. These findings have significant implications for study design issues, including the number of doses selected, dose range and spacing. Likewise, the widespread occurrence of hormetic dose responses in this genotoxic assay has important risk assessment implications.

Quercetin induces its chemoprotective effects via hormesis.

Quercetin is a polyphenol present in numerous fruits and vegetables and therefore widely consumed by humans with average daily dietary intakes of 10-20 mg/day. It is also a popular dietary supplement of 250-1000 mg/day. However, despite the widespread consumer interest in quercetin, due to its possible chemopreventive properties, the extensively studied quercetin presents a highly diverse and complex array of biological effects. Consequently, the present paper provides the first assessment of quercetin-induced hormetic concentration/dose responses, their quantitative features and mechanistic foundations, and their biological, biomedical, clinical, and public health implications. The findings indicate that quercetin-induced hormetic dose responses are widespread, being independent of biological model, cell type, and endpoint. These findings have the potential to enlighten future experimental studies with quercetin especially with respect to study design parameters and may also affect the appraisal of possible public health benefits and risks associated with highly diverse consumer consumption practices.

Polyphenols in Inner Ear Neurobiology, Health and Disease: From Bench to Clinics.

There is substantial experimental and clinical interest in providing effective ways to both prevent and slow the onset of hearing loss. Auditory hair cells, which occur along the basilar membrane of the cochlea, often lose functionality due to age-related biological alterations, as well as from exposure to high decibel sounds affecting a diminished/damaged auditory sensitivity. Hearing loss is also seen to take place due to neuronal degeneration before or following hair cell destruction/loss. A strategy is necessary to protect hair cells and XIII cranial/auditory nerve cells prior to injury and throughout aging. Within this context, it was proposed that cochlea neural stem cells may be protected from such aging and environmental/noise insults via the ingestion of protective dietary supplements. Of particular importance is that these studies typically display a hormetic-like biphasic dose-response pattern that prevents the occurrence of auditory cell damage induced by various model chemical toxins, such as cisplatin. Likewise, the hormetic dose-response also enhances the occurrence of cochlear neural cell viability, proliferation, and differentiation. These findings are particularly important since they confirmed a strong dose dependency of the significant beneficial effects (which is biphasic), whilst having a low-dose beneficial response, whereas extensive exposures may become ineffective and/or potentially harmful. According to hormesis, phytochemicals including polyphenols exhibit biphasic dose-response effects activating low-dose antioxidant signaling pathways, resulting in the upregulation of vitagenes, a group of genes involved in preserving cellular homeostasis during stressful conditions. Modulation of the vitagene network through polyphenols increases cellular resilience mechanisms, thus impacting neurological disorder pathophysiology. Here, we aimed to explore polyphenols targeting the NF-E2-related factor 2 (Nrf2) pathway to neuroprotective and therapeutic strategies that can potentially reduce oxidative stress and inflammation, thus preventing auditory hair cell and XIII cranial/auditory nerve cell degeneration. Furthermore, we explored techniques to enhance their bioavailability and efficacy.