Introduction

Over the past several decades there has been a substantial increase in the reporting of hormetic dose response relationships and their assessment in the biological and biomedical literature. In the decade of the 1980s the terms hormesis or hormetic were cited about ten times per year in the Web of Science database; in 2013 and 2014 alone these terms were cited over 6000 times, a greater than 600-fold yearly increase. This increase is widespread affecting a broad range of biological and biomedical areas. There have been eight recent books on hormesis from various perspectives (Costantini 2014; Elliott 2011; Krenz et al. 2013; Le Bourg and Rattan 2009; Mattson and Calabrese 2010; Rattan and Le Bourg 2014; Saunders 2010; Stebbing 2011), reflecting the broad range of its interest and implications. Likewise, hormesis has been a focus of numerous conference symposia within established professional scientific societies (e.g., Society of Toxicology, Society for Risk Analysis, American Chemical Society, Health Physics Society, American Nuclear Society, and others), and the focus of several recent journal special issues (e.g. Journal of Cell Communication of Signaling-2014; Homeopathy-2015) and the foundation of a government funded Ph.D. training program in Germany (i.e. Friedrich-Schiller University—Jena) on hormetic molecular mechanisms. Hormesis has also received widespread discussion in more general publications (Ahuja 2003; Bailey 2003; Begley 2003; Bell 2004; Boyce 2004; Cook 2003; Hively 2003; Lambert 2003; Pike 2004; Raloff 2007; Renner 2003; Roberts 2003; Stipp 2003) and in leading scientific journals (Calabrese and Baldwin 2003a, b; Kaiser 2003).

While this reawakening of intense interest in hormesis is a recent phenomenon, renewed interest began to emerge about 40 years ago with the publications of Donald Luckey concerning ionizing radiation (Luckey 1980, 1991), Anthony Stebbing concerning marine toxicology (Stebbing 1976, 1982, 1987, 1998) and Elmer Szabadi (Szabadi 1977) concerning pharmacology. These notable independent developments were followed by researchers in other fields (e.g., immunology, epidemiology, cancer research, plant science, wound healing) who reported the widespread occurrence of hormetic-like biphasic or U-shaped dose responses. However, unlike the false starts of earlier decades, the intellectual and scientific convergence of hormetic findings have been sustained and significantly expanded over the past several decades. It is thus timely to consider the relevance of hormesis for aging research, including what hormesis is, why this concept was essentially unknown only several decades ago, why it is receiving considerable interdisciplinary attention, what may be its biological significance and potential applications, and how it may affect the future of aging research.

Hormesis in historical perspective

The term hormesis, from the Greek meaning to excite, was first employed in the scientific literature in 1943 by Southam and Erhlich (1943) based on their extensive findings with fungal responses to various plant extracts. The term hormesis would eventually come to replace several earlier descriptors such as the Arndt-Schulz Law or Hueppe’s Rule (Calabrese 2005a). Hormesis is a biphasic dose response that is characterized by a low dose stimulation and a high dose inhibition (Calabrese 2010; Calabrese and Baldwin 2002). As such it is a type of biphasic dose response, but one with specific quantitative features with respect to its amplitude and width and its relationship to the onset of the threshold response or zero equivalent point/dose for toxic and pharmacological effects (Fig. 1). This dose response was not only widely ignored by the scientific and medical communities for the entire twentieth century, but often the object of ridicule (Calabrese 2011, 2004). Despite its widespread reporting in the scientific literature by numerous highly regarded investigators during the first half of the past century (Calabrese and Baldwin 2000a, b, c, d, e), it was omitted from all leading textbooks of pharmacology and toxicology during this period and for the remainder of that century, never included as a topic at symposia of major professional societies and ignored by national regulatory agencies in the framing and execution of public health policies and regulations for the assessment of ionizing radiation, drugs and chemicals and not included for research funding by federal and international governmental agencies (Calabrese 2005b).

Fig. 1
figure 1

Dose response curve depicting the quantitative features of hormesis and its application to the concept of enhanced biological performance

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The hormesis concept formally originated with the research of the German pharmacologist Hugo Schulz in the early to mid-1880s (Schulz 1887, 1888). In this research Schulz sought an alternative chemical disinfectant for carbolic acid, which had been used by Joseph Lister with great success for aseptic surgery. However, carbolic acid had a range of unattractive features, thereby generating Schulz’s interest in alternatives. In a series of experiments he evaluated nearly a dozen agents on yeast. While he was expecting all the agents to kill the yeast in a dose dependent manner, Schulz became surprised when experiments consistently revealed enhanced metabolism at low concentrations while being inhibitory at the higher concentrations. Schulz thought that he had introduced a methodological error into the experiments but repeated testing confirmed the reproducibility and legitimacy of his initial observations (Crump 2003). These findings should have been of considerable potential value to people such as Lister as they broadened the domain of disinfectant options. However, Schulz failed to emphasize this point, while claiming that his findings provided the explanatory principle of the controversial medical practice of homeopathy, unleashing a storm of criticism and skepticism within the traditional medical and academic communities profoundly subduing what should have been considerable biomedical interest in the implications of his findings (Bohme 1986).

The “explanatory principle” claim of Schulz was based on his linking of several disparate findings into a unified dose response concept. First, Schulz was aware that the homeopathic agent veratrine was reported to effectively treat gastroenteritis (Bloedau 1884). Second, Schulz was not successful in showing that veratrine could kill or inhibit the growth of the bacterium that caused this disease regardless of the dose (Bohme 1986). Nonetheless, he still believed that the veratrine treatment was successful but it was not due to killing the disease causing organism but via an alternative mechanism. Third, Schulz linked these observations with veratrine to his low dose yeast data and asserted that the veratrine most likely affected a cure via the induction of adaptive processes at low dose. Fourth, he then generalized this perspective to other homeopathic drugs and many pharmaceutical agents.

Schulz and his work were soon marginalized by his colleagues within the medical and academic communities who were engaged in a long term and intense conflict with the homeopathic movement. By siding with the opponents of what we may today call traditional medicine, Schulz quickly became professionally ostracized and would have his career profoundly marginalized (Wels 1933). The conflict would continue his entire professional life as he was the object of long term criticism (Clark 1933, 1937). Despite the fact that Schulz promoted the biphasic dose response he placed this concept in serious peril since his opponents were organized and often outstanding leaders, including some of the most accomplished and broadly influential researchers in pharmacology and toxicology. The net result was the marginalizing and trivializing of the biphasic dose response within the scientific and biomedical communities. Thus, almost before he started, the career of Schulz and his dose response theory were significantly curtailed.

There were many highly regarded investigators during the five decade professional lifetime of Schulz who observed biphasic dose response relationships in their experimental research (Calabrese 2009a, b). However, their published findings were never well integrated within a broad multi-disciplinary scientific framework. In general, they failed to organize, develop a focus, and appreciate the quantitative features of hormetic responses or study design features needed to adequately assess them. Lacking adequate leadership and a scientific framework, the hormesis concept failed to mature, especially in the face of unrelenting opposition, especially by leaders in pharmacology such as Alfred J. Clark (1933, 1937) who’s influential writings helped to ensure that Schulz’s “explanatory principle” of homeopathy (i.e., the biphasic dose response) would not be accepted. It should be noted that Schulz did not accept the high dilutionist philosophy of Hahnemann but rather a “low” dilution framework for homeopathy, with readily quantifiable molecules in homeopathic treatments (Bohme 1986). Nonetheless, inaccurate and unfair criticism by Clark (1933, 1937) resulted in Schulz being seen as a follower of Hahnemann’s high dilutionist views, a criticism that would not only strongly taint his career, but also strongly marginalize his biphasic dose–response theory.

While the medical community was strongly opposed to the homeopathically-associated biphasic dose response of Schulz, it needed a dose response of its own. Since it could not adopt the dose response model of its opponent, it eventually settled on the threshold dose response which had considerable support in the literature (Clark 1933, 1937; Shackell 1923, 1925; Shackell et al. 1924/1925) and was consistent with broad personal experience. Thus, the choice was easy. The adoption of the threshold dose response model by the medical community became progressively accepted and carried over to the regulatory community. The threshold dose response would eventually become the default model for essentially all regulatory actions (Lehman and Fitzhugh 1953).

The twentieth century was, therefore, one in which acceptance of the biphasic dose response was linked early on to the fate and status of homeopathy. With the demise of homeopathy during the early decades of that century (Coulter 1972, 1982), the biphasic dose response experienced a similar fate, principally due to the strategic mistake of Schulz starting in the 1880s and its continuance well into the next century.

Hormesis: the modern era

While the twentieth century would witness numerous publications concerning biphasic dose responses, such findings were not widely appreciated and failed to influence key scientific leaders, developments and judgements. This would begin to change as the twentieth century was drawing to a close due, in part, to the fact that the U.S. environmental/public health regulatory agencies had adopted the highly conservative linear dose response model for cancer risk assessment, being guided by a strong precautionary principle. The use of the linear dose response model imposed very high costs upon regulated industries that tried to challenge government regulatory decisions based upon it. A common industry strategic plan was simple enough: convince regulatory agencies to soften the highly conservative approach, reverting back to the threshold dose response model. However, such efforts failed as most toxicological studies lack sufficient doses to adequately distinguish, in a statistical manner, between linear and threshold dose response models in the low dose zone. As a result, the regulatory agencies would invariably default to the more conservative (i.e., protective) linear model. After numerous failed challenges to regulatory agency risk-based decisions, many industrial associations recognized that this debate was futile. As a result of their stymied position, the regulated industry, especially the nuclear industry, became intrigued with an alternative dose response perspective offered by University of Missouri Professor Thomas Luckey (1980) in his book, Ionizing Radiation and Hormesis. Although not fully persuasive, the Luckey (1980) book was important as it provided copious and detailed documentation of hormetic dose responses, arguing that it was more valid than linear or threshold models. Five years earlier the intuitive Luckey (1975) recommended that regulatory agencies consider the hormesis concept in the emerging domain of environmental human risk assessment. However, this suggestion was never heeded nor formally considered.

Luckey (1980) provided a key stimulus for the electric power industries of Japan and the U.S. to conduct the first conference on hormesis in August 1985 in Oakland, California, with proceedings published 2 years later in the journal Health Physics. The meeting would give new visibility to the hormesis concept and stimulate others to reconsider the nature of the dose response in the low dose zone, raising the question of whether hormesis was a real, reproducible phenomenon and, if valid, what were its implications for medicine and environmental risk assessment. By the late 1980s multiple factors were converging that would propel the assessment of hormesis forward (Sagan 1989; Wolff 1989). Along with the growing dissatisfaction with the regulation of carcinogens, these included the integration of basic scientific discoveries (e.g., DNA repair, apoptosis, adaptive response/preconditioning, immune defense mechanisms, epigenetic cancer mechanisms) that could affect the shape of the dose response in the low dose zone. Furthermore, there was also growing recognition that high dose damage mechanisms, as may occur in the standard chronic cancer bioassay, were not appropriate for estimating low dose cancer risks (Ames 1987; Ames et al. 1987; Ames and Gold 1990).

The hormetic challenge

These efforts led to a series of integrated activities to explore the concept of hormesis involving annual interdisciplinary conferences, the creation of an hormetic dose response data base using a priori evaluative criteria (Calabrese and Blain 2005, 2009, 2011) and other more specialized hormesis data bases (Calabrese and Baldwin 2003b; Calabrese et al. 2006, 2008, 2010) to estimate the frequency of hormesis and assess other scientific questions.

The creation of the various databases provided a robust volume of studies demonstrating hormetic dose responses that were compliant with rigorous evaluative criteria. This permitted reliable evaluations of the quantitative features of the hormetic dose response, as well as its generality across a broad range of biological models, ranging from plants to microorganisms to invertebrate and vertebrate models. The databases also permitted the assessment of hormesis across different levels of biological organization, ranging from the cell to the organ to the organism. These collective assessments revealed that hormesis was highly generalizable, being independent of biological model, level of biological organization, inducing agent and mechanism. Furthermore, the hormetic dose response also was unexpectedly shown to have specific quantitative features, with the amplitude of the low dose stimulatory response being modest, with about 80 % of the dose responses in the hormetic data base having a maximum response less than twice the control group, with most of these only 30–60 % greater than the control at the maximum response. The width of the stimulatory dose response was more variable but typically in the 5–20-fold zone starting immediately below the zero equivalent point or threshold dose. For about 5 % of the database the width of the stimulatory response range exceeded 1000 fold in reproducible assays (Calabrese and Blain 2005, 2009, 2011).

Of considerable importance was that a specialized database using rigorous a priori entry and evaluative criteria provided an estimate of the frequency of hormesis within the biomedical and toxicological literature. The estimated frequency approached 40 % and far exceeded that of other commonly employed models. For example, the hormetic dose response was shown to occur approximately 2.5-fold more often than the threshold model which itself was more common than a linear model (Calabrese and Baldwin 2003b). When tested with several other large data sets the threshold model performed poorly in each case while the opposite was true for hormesis (Calabrese et al. 2006, 2008, 2010). Thus, it seemed clear that the threshold model might be very limited and seriously flawed while the long neglected and marginalized hormetic model was a consistently strong performer.

These striking findings lead to the question of whether and how the scientific and regulatory communities had validated the threshold model as it was the foundation for substantial regulatory activities in many countries throughout the twentieth century. However, a prolonged and detailed investigation of this question failed to reveal that any organization or person ever attempted to validate the threshold model prior to our above cited direct head-to-head comparisons. Thus, it appears that the adoption of the threshold dose response model was made without ever having been validated for low dose responses, the zone where humans principally reside.

Features of the hormetic dose response

The hormetic dose response occurs via the induction of a direct stimulatory response or as a result of a modest overcompensation to an initial disruption in homeostasis (Calabrese 1999, 2001; Calabrese and Baldwin 2001a). In this later case, the hormesis dose response would require a time component in order to be detected and studied. The quantitative features of such dose responses were similar whether the response occurred via a direct stimulation or via an overcompensation response. This revealed that the quantitative features of hormesis was independent of mode of action. This convergence of observations suggested an answer to why hormetic effects were modest, often difficult to observe. Overcompensation stimulation appeared to be an evolutionary adaptation to disruptions in homeostasis to ensure that mild toxicities could be rapidly repaired/reversed with little waste of limited biological resources.Footnote 1 Thus, it would make little sense for a compensatory system to overshoot its set point goal by orders of magnitude. Furthermore, the modest stress not only led to an overcompensation recovery but also provided protection against a subsequent more massive and even life threatening challenge, which is now referred to as a preconditioning response (Calabrese 2007; Calabrese et al. 2007). The preconditioning response also displays a hormetic-biphasic dose response, further generalizing this dose–response concept within an optimization framework.

Further extension of the hormesis/preconditioning phenomenon to other experimental modalities has been reported. That is, an hormetic response may also occur via treatment of a biological system that has been seriously damaged by a prior massive exposure such as a heart attack or stroke (Krenz et al. 2013). This therapeutically beneficial treatment has been designated as post-conditioning. The hormetic dose response may, therefore, be elicited via multiple experimental protocols based upon direct stimulation and overcompensation stimulation following a disruption in homeostasis, which can incorporate both pre- and post-conditioning contexts. Furthermore, the quantitative features of these dose responses in each experimental context are similar. How could the quantitative features of the hormetic dose response be similar regardless of the biological model, endpoint measured, inducing agent, level of biological organization (cell, organ, organism), and mechanism?

The extensive generality of the hormetic response and its dose–response constraints suggest that it provides a reliable quantitative estimation of the limits of biological plasticity with a description how much gain is in the system. The assessment of hormesis indicates that the limits of plasticity is evolutionarily-based, highly conserved, common across all phyla, as well as being allometrically-based, being a function of body weight and/or body surface area (Calabrese 2013a; Calabrese and Mattson 2011). This suggests that the hormetic concept may be viewed as a biological blueprint or architectural design trait whose functions may be mediated by an allometric gene cluster that orchestrates structure/functional control patterns, at all levels of biological organization (Bernstein 2010). Such generic, multi-tiered, and integrated biological organizational mechanistic regulation provides a theoretical framework for placing the hormetic concept within a broad biological context.

While the above discussion focused on why the quantitative features of the hormetic dose response are modest and highly generalizable, large numbers of specific/proximate mechanisms have been reported that mediate hormetic dose responses. In 2013, 400 examples of specific hormetic mechanisms were published in which the hormetic stimulation was mediated via a specific receptor and/or cell signaling pathway (Calabrese 2013b). Thus, despite a plethora of specific mechanisms in multiple systems and experimental contexts, the quantitative features of the dose responses were similar.

These general and quantitative features of hormesis have profound biological implications since they describe and determine the limits to which integrative responses in biological systems can be enhanced. Such hormetic control features are reported for an extremely broad range of biological processes that depend upon dose/concentration gradients. For example, during developmental periods the hormetic dose/concentration gradient may affect the creation of biological curvatures such as with the shape of the eye, capillaries, the head of the femur, etc. (Fosslien 2002, 2009). Such curvatures may occur due to concentration gradients (Calabrese and Baldwin 2001b) that stimulate cell proliferation via multiple growth factors at low concentrations while being inhibitory at higher concentrations, much like how an airplane obtains lift. This provides a means to enhance rapid growth on one side of a cellular plane as compared to the other side which is inhibited by the higher concentrations. The net result would be the formation of curvature-like growth. Such a process could result in the growth around a lumen, with the formation of a capillary structure principally due a hormetic-biphasic concentration relationship.

Hormetic-like biphasic dose responses are also the means by which numerous receptor systems work (Calabrese 2001, a, b, c, d, e, f, g, h). Such systems affect essential functions in most, if not all, cell types. Thus, a central biological strategy that has been largely preserved from bacteria to humans is the use of ligand concentration gradients that mediate how cells, organs and organisms develop, grow, maintain themselves, migrate, reproduce, repair and defend.

The hormetic concept also affects the search for new pharmaceuticals (Calabrese 2008a) with most anxiolytic (Calabrese 2008b), anti-seizure (Calabrese 2008c), and memory drugs (Calabrese 2008d) displaying hormetic/biphasic responses (Calabrese 2008e). This has important implications such that drugs that are intended to improve biological performance (e.g., grow hair, accelerate wound healing, strengthen bones) are stimulated at most only by about 30–60 %, the plasticity constraint described by the hormetic dose response. Such enhancements can be readily observed in microbe, plant and animal models under controlled experimental conditions. This can be more difficult to demonstrate in the case of human testing where there is considerable interindividual variation in genetic background, health status, dietary practices and other factors. This presents important challenges in the efficacy testing of performance enhancing drugs in people.

Hormesis and aging

Lifespan

Hormesis has long been shown to affect an increase in the lifespan. Davey (1917) reported that low doses of ionizing radiation increased the lifespan of the Confused Beetle (Tribulium confusion). The investigations of Davey (1917, 1919) were remarkable for the era, incorporating key concepts of study reproducibility, sample size, confounding variables, dose range, and spacing and number of doses as well as statistical analysis. The findings of Davey (1917, 1919) were replicated by Cork (1957) using the same biological model but a gamma ray source, rather than X-rays. Similar enhancements of lifespan with various insect models by ionizing radiation have now been widely reported, showing strong consistency with the hormetic dose response (Calabrese 2012, 2013c).

The basic concept of Davey that a low dose of a stressor agent might prolong lifespan has been extended by numerous investigators using chemical agents and various forms of ionizing radiation in multiple biological models, such as nematodes (Cypser and Johnson 2002; Olsen et al. 2006; Ristow and Schmeisser 2011), insects (Le Bourg 2011; Sarup and Loeschcke 2011), and mammalian models (Calabrese and Baldwin 2000f; Kahn and Olsen 2010; Marques et al. 2010; Pardon 2010; Salminen and Kaarniranta 2010). Extensive experimental research by Kitani et al. (2002, 2005) indicated that antioxidant enzyme activity was closely associated with the capacity of deprenyl to enhance longevity at low doses, displaying an hormetic effect. The convergence of these and many other consistent observations led Hunt et al. (2011) to suggest that these multiple ways of increasing lifespan support the hypothesis that functioning stress response pathways merge or converge with prolongevity pathways. Such inter-relationships between stress and aging further support the premise that activation of specifically targeted hormetic mechanisms may prolong life and/or retard the occurrence of age-related functional impairments. These findings generally reflect the capacity to increase life span within the quantitative constraints seen with the hormetic dose response.

Aging and preconditioning

Preconditioning has become a prominent area of research in the biomedical domain, with particular focus on cardiovascular and brain diseases although substantial research has been extended to kidney, lung, liver, skin and stem cells. Preconditioning is a phenomenon in which a prior stress affords protection against a subsequent and more severe challenging exposure/dose. While this was first shown to occur within the context of ischemic preconditioning providing substantial protection from damage due to a massive myocardial infarction in dogs (Murry et al. 1986), these findings were quickly replicated and generalized to other organs and animal models. Since the reporting of preconditioning by Murry et al. (1986) there have been over 5000 studies in mammalian models which have confirmed and extended this concept and its potential applications. The preconditioning methodology has been extended to include a post-conditioning aspect in which the conditioning treatment is administered during and/or after the reperfusion phase of the challenging dose. Furthermore, both pre-and post-conditioning can be induced remotely (i.e., at a site other than the tissue and organ of interest) as well as pharmacologically (Heusch et al. 2015).

Even though preconditioning can affect a clinically significant protective multi-organ adaptive response, considerable evidence indicates that its effects can be significantly diminished in aged animals in experimental settings and in elderly humans (>65 years). This age-related ischemic preconditioning adaptive response reduction was first reported by Abete et al. (1996) using an isolated and perfused heart model with benefits seen in 4 month old rats being lost in 24 month old rats. This seminal observation paved the way for numerous follow up studies showing a comparable age-related loss of preconditioning induced heart benefits in mice (Boengler et al. 2007), rats (Ebrahim et al. 2007; Fenton et al. 2000; Lu et al. 2001; O’Brien and Howlett 2008; Schulman et al. 2001; Tani et al. 1997), rabbits (McCully et al. 1998), and humans (Abete et al. 1997; Bartling et al. 2003; Ishihara et al. 2001; Lee et al. 2002; Longobardi et al. 2000; Napoli et al. 1999). While the mechanisms affecting such reductions in preconditioning performance in the aged animal/elderly human remains to be clarified, it appears to be related, at least in part, to a decrease of norepinephrine release via α1-adrenoreceptor stimulation following ischemic preconditioning (Abete et al. 2010). Despite the collective consistency and strength of such observations on age and related reductions in the preconditioning responses, others have not reported similar losses of protective effects in aged rats (Yin et al. 2009), sheep (Burns et al. 1996), and humans (Loubani et al. 2003), highlighting the importance of further examination of the complex interactions between aging and the preconditioning phenomenon.

According to Krenz et al. (2013) the mechanisms underlying the effect of aging to diminish the capacity of preconditioning to protect the heart and other organs may be due to impaired activation of signaling. They suggested that this may be overcome, at least in part, by increasing the amplitude of the triggering stimulus, by increasing the duration or number of bouts of preconditioning ischemia/reperfusion as well as by the overexpression of pathway receptors such as adenosine A1 receptors. In a complementary approach, several studies reported partial restorations of age-related hormetic preconditioning protective responses following some types of exercise training (Abete et al. 2000; Kwak et al. 2006; Masoro 1998; Powers et al. 2004) and caloric restriction procedures (Abete et al. 2002a, b; Jahangir et al. 2007; Long et al. 2002; Pepe 2001; Rohrbach et al. 2014).

Although studied to a more limited degree, similar age-related decrements in the protective effect are seen in the brains of animals. For example, the protective effects of ischemic preconditioning against global cerebral ischemia was reduced in 24 month old as compared to 4 month old rats (He et al. 2015, 2006). While more limited studies have exploited the capacity for preconditioning methods (e.g., caloric restriction, physical activity, etc.) to affect neuroprotection than with the cardiovascular domain, the trend is similar with exercise (Barrientos et al. 2011; Chrysostomou et al. 2014; Garcia-Mesa et al. 2014; Park 2010), caloric restriction/intermittent fasting (Newton et al. 2008; Tesic et al. 2015; Vasconcelos et al. 2015) and remote preconditioning (Meng et al. 2015) which show significant restoration of function in aged subjects. For example, caloric restriction increases brain–derived neurotrophic factor (BDNF) in key brain regions such as the CA1 (Newton et al. 2008), in a manner similar to the age-related increase in BDNF in the DG and CA3 regions, suggesting that it may enhance adaptive mechanisms that typically occur during aging to ensure proper maintenance of homeostasis.

Other studies have reported that hypoxia preconditioning of bone marrow cells from aged mice (20–22 months of age) was effective in enhancing angiogenic potential, with little decline with age (Kubo et al. 2012). These results were sufficiently encouraging to further efforts to explore the therapeutic effectiveness of cell-based angiogenesis in clinical trials. The mixed results of preconditioning in aged animals and elderly humans represents a significant challenge and opportunity.

Adaptive response to ionizing radiation: aging effects

The adaptive response to ionizing radiation induced damage is also affected by the aging process. For example, in 1998 Gadhia (1998) first reported that the adaptive response may be age dependent for X-ray induced damage in human lymphocytes. In this study, adaptive response was evident over ages ranging from 5 to 45 years, with a typical decrease in mutation rate of 60–80 %. However, in those aged >65 years, the protection was not apparent. Such findings were expanded by Miura et al. (2002) to glial cells in Wistar rats when the radiation adaptive response was evident at 1 month of age but lost by 24 months. Similar findings with differing inducing agents and a broad range of conditioning doses on glial cells supported the initial findings (Miura 2004; Miura and Endo 2010; Calabrese 2008f). These age dependent findings are consistent with those reported for preconditioning in the biomedical sciences for age-related decrements.

Discussion

Hormesis is a highly conserved general dose response strategy providing the means by which numerous cell types, probably all organs and whole organisms carry out development, growth, maintenance and repair processes via a vast array of receptor based signaling and other mechanisms (Table 1) (Calabrese 2008f). It is also an adaptive dose response strategy that anticipates potential threats as seen with preconditioning but also can prevent damage even after potentially harmful exposures as seen within a post-conditioning framework (Calabrese et al. 2007; Roberge et al. 2008). Of critical importance is that these dose response survival enhancing activities are achieved via a manifestation of the parsimony principle in which a tightly integrated and managed system ensures that biological resources are carefully allocated and conserved as seen in the modest quantitative stimulatory features of the hormetic dose response. The redundant flexibility of the hormetic dose response is manifest via its direct stimulation or rebound/overcompensation response to a disruption in homeostasis. Regardless of the activating process, the quantitative features of their dose responses are similar. In addition to its generality across experimental models and levels of biological organization, the hormetic dose response is also independent of the endpoint measured, the inducing agent and the specific mechanisms mediating the dose response. The hormetic dose response therefore represents a fundamental and broad strategy for regulatory maintenance and an adaptive resistance employed under stress-related conditions.

Table 1 Hormesis characteristics
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The significance of pre/post-conditioning is now widely recognized, with strong attempts being made to affect both clinical medicine and public health practices. Such activities involve both the chronic activation of conditioning mechanisms, as well as in attempts to regenerate/activate such processes which have been diminished by various co-morbidities (e.g. diabetes, atherosclerosis) and/or aging.

Of broad interest is the role of hormesis in natural selection/evolution. While hormesis/adaptive mechanisms are essential for survival, it is also evident that gradual diminution of such hormetic mechanisms across multiple systems will essentially lead to maladaptive responses and death. Hormesis is therefore essential for life and its erosion with aging along with its concomitant co-morbidities is a key factor affecting lifespan.

Biological systems typically display a limited plasticity that is described by the quantitative features of the hormetic dose response (Calabrese 2013a; Calabrese and Mattson 2011). There are therefore clear bounds within which adaptation and enhanced biological performance occur. Hormesis represents a gyroscopic-like function, providing a molecular/physiological navigation system, keeping the system on track (i.e., within the bounds of plasticity) and exhibiting moderate flexibility. While this plasticity conferring dose response process mediates optimal responsiveness, it also limits the extent to which biological performance can be enhanced. This highly selected and conserved plasticity limit places a significant biological constraint on what can be achieved via pharmacological intervention. It also places significant challenges when assessing performance-based drug efficacy within heterogeneous study subjects.

From a scientific perspective the modest amplitude of the low dose/concentration response set within a background of normal variability and within an historical framework in which high dose experimentation was widespread has been a significant factor obscuring the recognition of the hormetic-biphasic dose response as a central biological principle. This recognition was further blunted by the longstanding rivalry and conflicts between homeopathy and traditional medicine which contributed in a significant way to the marginalizing of the hormetic dose response. These converging factors prevented an objective and substantial evaluation of the hormetic dose response throughout most of the twentieth century and also lead to an acceptance of alternative dose response models without proper validation. Thus, it is only within the past several decades in which the hormetic dose response has begun to be prospectively evaluated within a very broad biological and biomedical context, using rigorous study designs, and mechanistic evaluation.

Despite these exciting and notable advances, the concept of hormesis is still not widely known or ostensibly influential at the level of drug development, therapeutic application and within governmental regulatory programs. While the impact of hormesis in these respective domains seems negligible, this is actually not the case. For example, in the cases of anxiolytic (Calabrese 2008b), anti-seizure (Calabrese 2008c) and memory drugs (Calabrese 2008d), all essentially show an hormetic dose response in their preclinical testing. That is, these dose responses are hormetic. In practice, the optimal hormetic dose is selected for human trials. Most human trials, therefore, are based on the hormetic dose response without pharmaceutical companies nor federal regulatory agencies using the term or perhaps even being aware of the significance of this dose–response concept. This is also the case for the many applications of the pre-and post-conditioning concept to clinical medicine and public health. Thus, major segments of the biomedical and public health communities use the hormesis concept and derive their findings from it without perhaps knowing or fully appreciating it. There is evidence that such understandings and perceptions are changing.

The field of biogerontology is perhaps the one with the most extensive and broadest acculturation of the topic of hormesis. Such concept acceptance and integration can be traced to the influence of Professor Edward Masoro’s (University of Texas at San Antonio) work on caloric restriction and his linking it to hormesis. While Masoro’s first such paper was published in 1998, he cited several publications in the proceedings of the first hormesis conference about a decade earlier (Calabrese et al. 1987; Congdon 1987; Furst 1987). The 1998 paper of Masoro (1998) would be followed by several others by him of considerable influence, in 2000 (cited more than 400 times by mid-2015) (Masoro 2000) and in 2005 (cited more than 500 times by mid-2015) (Masoro 2005), with these papers being currently the fifth and second most cited papers in the Web of Science database on hormesis. The field has been also significantly affected by the research, publications and strong leadership of Suresh Rattan/Eric LeBourg in Europe, and Tom Johnson and Mark Mattson in the U.S., starting in the late 1990s as well. Of note was the extension of the hormesis concept into the field of aging and neurodegenerative disease and neuroprotection as led by Mattson.

The leadership of the biogerontology field in the acceptance and extension of hormesis has been both by the use of the term and the extension of the concept. These two decades of leadership by aging-related research has made significant inroads for the concept of hormesis into many related biological and biomedical areas, although there is still limited knowledge, understanding and use of the term in many biomedical domains. In fact, there is still widespread use of alternative terms for what amounts to the same concept (e.g. biphasic, U-shaped, Hueppe’s Law, Arndt-Schulz Law). For example, the term Arndt-Schulz Law remains widely used for application of laser induced biological effects such as wound healing acceleration principally because the initial significant scientific discoveries in this area were made in East Germany during the Cold War and Schulz worked at the University of Greifswald in East Germany. In fact, since language is important, a proposal to use a common similar terminology for similar biological stresses within a hormesis context was proposed in 2007 by nearly 60 researchers (Calabrese et al. 2007).

Final perspectives

In summary, the biological and biomedical sciences are in the midst of a dose response revolution in which the biphasic dose response which was rejected and marginalized by these fields nearly a century ago, has been found to occur often, reproducibly, with generality, and to have important applications especially in the area of therapeutics. It is also expected that the concept of hormesis will play a significant role in the public health domain as a component of lifespan enhancement practices increasing adaptive capacities that resist on the onset of acute and chronic diseases, including diabetes, cardiovascular diseases, neurodegenerative diseases and numerous others. Hormesis will be an important feature in all areas in which there is a need to improve biological performance such as in learning, athletics, sexual behavior, as well as areas such in the growing of hair and in the strengthening of bone. Hormesis should also have an important role in the area of environmental and occupational risk assessment of potentially harmful agents including carcinogens, reproductive toxins and the broad spectrum of regulated toxic substances. Substantial scientific literature already exists that documents each of these areas of hormesis significance. Since enhancing public health, biological performance and therapeutic efficacy are high priorities within society it is expected that the importance of the hormesis concept will continue to rapidly grow as well as its applications.