PRECONDITIONING – Adaptive Response In Biology And Medicine – report on the 2014 annual meeting of the International Dose Response Society

By Vince Giuliano and Melody Winnig

Frequent readers of this blog are familiar with the fundamental importance that we have attributed to biological stresses and stress-responses in driving health and longevity.   The two of us attended the 2014 meeting of The professional society that is concerned with such stresses, the International Dose Response Society, held on the campus of the University of Massachusetts in Amherst Massachusetts April.22-23.  The conference was organized by Dr. Edward J. Calabrese, a pioneer and continuing contributor in the field of adaptive biological stress responses.  The theme of the Conference this year was Preconditioning – Adaptive Responses in Biology and Medicine – Building Biological Shields Against Disease and Injury. The purpose of this blog entry is to review and comment on some of the presentations at that meeting that we think have particular significance. We selectively quote from Conference abstracts.

GENERAL FRAMEWORK

What is preconditioning?

In the broadest context, preconditioning is the use of stress to yield an improved health outcome or set of outcomes.  The best known example is exercise which of course yields multiple benefits.  Another example is fasting or alternate-day fasting (ref) which also induces many health benefits including a number of reduced disease susceptibilities.  In a narrower medical context, preconditioning is the application of controlled stress to mitigate against the anticipated negative effect of from an anticipated later stress, or to produce a better specific health outcome.  Examples include: 1.Remote Ischemic/hypoxic conditioning: Inducing ischemia for brief periods with an arm pressure cuff to protect against ischemic reperfusion injury resulting from subsequent heart surgery, or to protect against brain injury due to stroke.  2 Use of low dose radiation to protect against diabetes-induced renal damage, and 3.  Use of heat or cold or hypoxic stress to protect against brain injury that could be incurred in a boxing match or football game, or as an unintended consequence of brain surgery.

Preconditioning has long been a topic of both research and practice in medicine.  Specific preconditioning techniques appear throughout the history of medicine. An example is the use of moxibustion in ancient as well as contemporary Chinese folk medicine(ref).   A search on the term “preconditioning: in Pubmed.org reveals 11,590 research publication citations going back to 1949, and many additional citations not in the database hark back to earlier dates.  Indeed, the idea of remote preconditioning goes back to 1933.

Preconditioning is the practical application of Hormesis

Early in the Conference, Ed Calabrese (Environmental Health Sciences, School of Public Health, University of Massachusetts Amherst) , pointed out that preconditioning is a central application of hormesis, a universal adaptive stress-response phenomenon of all biological systems.  We have often written about hormesis in this blog.  (See for example the PowerPoint presentation on Multifactorial Hormesis which can be downloaded by going to this link).  We have also argued that hormesis is an essential component of an emerging Grand Unified Theory of biology, health and aging(ref).

The 2008 publication Hormesis Defined by Mark P. Mattson (one of the key and initial speakers at the Conference), relates: “Hormesis is a term used by toxicologists to refer to a biphasic dose response to an environmental agent characterized by a low dose stimulation or beneficial effect and a high dose inhibitory or toxic effect. In the fields of biology and medicine hormesis is defined as an adaptive response of cells and organisms to a moderate (usually intermittent) stress. Examples include ischemic preconditioning, exercise, dietary energy restriction and exposures to low doses of certain phytochemicals. Recent findings have elucidated the cellular signaling pathways and molecular mechanisms that mediate hormetic responses which typically involve enzymes such as kinases and deacetylases, and transcription factors such as Nrf-2 and NF-κB. As a result, cells increase their production of cytoprotective and restorative proteins including growth factors, phase 2 and antioxidant enzymes, and protein chaperones. A better understanding of hormesis mechanisms at the cellular and molecular levels is leading to novel approaches for the prevention and treatment of many different diseases.”

Here is the abstract of Ed Calabrese’s opening remarks relating preconditioning to hormesis: “Optimizing Pre- and Post-conditioning Clinical Outcomes: A Dose Response Perspective: “This study assessed the dosage, temporal and mechanistic relationships between the conditioning dose and the protective effects of preconditioning experiments. Entry criteria for study evaluation required the occurrence of an hormetic-like biphasic dose response for the protective endpoint, and a mechanistic assessment of how the conditioning dose affected the protective endpoint response. The conditioning dose that demonstrated the largest increase in endpoint response during the conditioning period was the same dose that was the optimally protective dose. Cell signaling pathway inhibitors were commonly employed to block the conditioning effect; such inhibitory actions abolished the protective effect at the optimal conditioning dose, identifying a specific hormetic mechanism. Conditioning dose responses often had sufficient doses to assess the nature of the dose response. In each of these cases these mechanism-based endpoints displayed an hormetic dose response. The present analysis reveals that when preconditioning experiments demonstrate a biphasic dose response it can be directly linked to the actions of the conditioning dose based on optimal dosage, temporal relationship and receptor-based and/or cell signaling-based mechanisms. These findings indicate that preconditioning induced biological/biomedical effects represent a specific type of hormetic dose response.”

The cogency of relating preconditioning to hormesis is very important because it appears that many researchers have worked for years in specific areas of preconditioning focusing on specific interventions for very specific objectives like ischemic conditioning prior to cardiac surgery.  Some of these researchers have done important research but have never paid attention to the term “hormesis” and are not familiar with the general universality of stress-response mechanisms in biology.  As we have pointed out in multiple blog entries, hormesis applies to essentially all biological systems, on all levels of scale (e.g. cell, organ and whole organism), relates to all the stresses an organism ordinarily encounters, is essential for functioning of any organism from a basic control-systems perspective, and  is important for understanding the stress triggers of evolution(ref)(ref)(ref).

In the course of the Conference, there was also discussion of post-conditioning –applying a stress after a traumatic event such as a head injury or operation, and perconditioning,  simultaneous conditioning during a stress event, such as applying a stress during an operation.  In general, all of these seem to produce beneficial responses.

Conference content

The PDF book of abstracts for the Conference can be downloaded by clicking 2014_Abstract_book.  In this blog entry, we will cover and comment on only selected presentations and emphasize what we believe to be central themes of importance.  We do this within our own framework of organization.

Two of the most important stressors for inducing general health and neurological health in particular are our old familiar friends – exercise and fasting.

One of the first presentations in the opening general session was by Mark P. Mattson, Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, and entitled Intermittent Energetic Challenges, Adaptive Responses and Health: Lessons from the Brain. “Humans evolved in environments where food was not available ad libitum, and so possess robust adaptive physiological and behavioral responses to periods of food scarcity. Emerging research in this Laboratory and elsewhere has shown that intermittent fasting (IF; e.g., fasting for a period of 24 hours twice weekly) and vigorous exercise can increase numbers and strength of synapses and can enhance brain function (cognitive and sensory – motor performance) and mood. We find that the general mechanism by which IF and exercise benefit neurons is by challenging them by increasing their activation state and energy demand, which results in a coordinated engagement of signaling pathways that promote neuroplasticity and cellular stress resistance. The pathways activated by exercise and IF include those involving brain-derived neurotrophic factor (BDNF), mitochondrial biogenesis, DNA repair and removal of oxidatively damaged proteins and organelles. Peripheral changes in energy metabolism that occur during fasting and exercise may also contribute to their beneficial effects on the brain. In this regard, the depletion of glycogen stores in the liver triggers the mobilization of fatty acids from fat cells and the production of ketone bodies. Ketone bodies such as beta-hydroxybutyrate provide an alternative energy source for neurons and may also activate signaling pathways that enhance the ability of the brain to cope with stress. Our studies in animal models of chronic neurodegenerative disorders (Alzheimer’s and Parkinson’s diseases) and acute brain injury (stroke and severe epileptic seizures) demonstrate robust neuroprotective and neurorestorative effects of IF diets. IF protects the brain by bolstering antioxidant defenses and protein chaperone levels, and by suppressing inflammation. The implications of these findings for strategies for optimizing brain function and reducing the risk of neurodegenerative disorders will be described.”

Note a common theme here that applies to hormesis and preconditioning in general:  A hormetic stress response can and usually does involve simultaneous upgrading of multiple pathways producing multiple health benefits for the whole organism.  This is very unlike the kind of response typically sought by pharmaceutical company researchers – which is to find a particular kinase drug which upgrades one particular biological pathway to achieve a specific health objective.  Thus, hormesis is not subject to a basic limitation of this drug-oriented approach.  Because of the multiplicity of interacting pathways which exist in-vivo, a kinase drug approach which works in test tubes may not work or produce the opposite effect in-vivo.  This, we believe, is a basic reason why so many clinical trials of seemingly good drug candidates fail.

An excellent example of preconditioning researched over a period of more than 80 years is remote ischemic preconditioning

The abstract for the Conference presentation Remote Ischemic Conditioning: From Inspiration to Clinical Translation by Karin Przyklenk of the Cardiovascular Research Institute and Departments of Physiology & Emergency Medicine, Wayne State University School of Medicine is: “Remote ischemic conditioning is the phenomenon whereby brief episodes of ischemia-reperfusion applied in a distant organ or tissue render the heart resistant to damage caused by a prolonged ischemic stress. The discovery of remote conditioning, first reported by our laboratory in 1993, was not a serendipitous finding, but, rather, was predicted by mathematical modeling. In the ensuing years, the paradigm has been expanded to encompass a spectrum of remote triggers, including the seminal observation that repeated 5 min periods of limb ischemia, achieved by inflation-deflation of a blood pressure cuff, initiated a profound cardioprotective response. The hallmark of remote ischemic conditioning – i.e., reduction of myocardial infarct size – has been documented and confirmed in multiple models and species. Two major, remaining challenges are to elucidate the cellular and molecular mechanisms responsible for this intriguing form of cardioprotection, and successfully exploit the infarct-sparing effect of remote ischemic conditioning for the treatment of patients with acute myocardial infarction.”

Some common themes identified here are 1.  Conditioning can be remote, it does not have to be a procedure exercised on the target organ to be effective, 2.  Conditioning can be initiated by a variety of different stress triggers, 3.  Conditioning can be via a very simple and easy to administer stress such as by employing a blood pressure cuff.  Remote ischemic preconditioning has been the subject of at least 24 randomized clinical trials related to a multiplicity of clinical situations including abdominal aortic aneurysm repair, open heart surgery, percutaneous coronary intervention, living donor renal transplantation, coronary angiography, elective decompression surgery, carotid endarterectomy, recent stroke, or transient ischemic attack combined with intracranial carotid artery stenosis(ref).

Conditioning can provide long-lasting additional benefits beyond immediate protection against event-induced injury

Another presentation on ischemic preconditioning was by Andrew N Redington, Division of Cardiology, Department of Paediatric Cardiology, Hospital for Sick Children, University of Toronto entitled Assessing the Promise of Remote Conditioning for Cardioprotection: New Clinical Developments. “Remote ischemic conditioning (RIC) is a powerful, innate, mechanism of protection against ischemia-reperfusion injury. This simple, non-invasive stimulus can be induced in patients by 3-4 cycles of 5-10 minutes inflation (ischemia) and deflation (reperfusion) of a standard blood pressure cuff, placed on a limb. Following our original description of the method in 2002, and our ‘first-in-human’ RCT showing reduced markers of cardiac damage, and improved myocardial and lung function in children receiving RIC prior to open heart surgery, there have been multiple adult cardiac surgical trials. Most, but not all studies have shown benefit, with recent meta-analyses showing an overall benefit in terms of biomarkers of injury, and in a recently published 5-year follow-up study of one of the largest studies showing early benefit, those randomized to RIC, had a lower rate of adverse events and lower mortality compared to the controls. Other proof-of-principle RCT’s show that RIC; reduces myocardial injury and renal failure in abdominal aortic aneurysm surgery; reduces incidence of renal dysfunction due to contrast-induced nephropathy; improves early outcomes in elective percutaneous coronary intervention (PCI); and our own study by Botker et al showing improved myocardial salvage overall, and reduced infarct size, when RIC is administered prior to emergency PCI. The late outcome data from these studies are also emerging. In a follow-up of the CRISP study (RIC in elective PCI) there was a significant reduction in major adverse cardiovascular events (MACE) at 6 years, and both MACE and mortality rates were reduced at 5 year follow up of Botkers original study of RIC in emergency PCI for evolving myocardial infarction (MI). Finally, early experimental data suggests that repeated, daily, RIC may have additional benefits on post-MI remodeling, and a single RCT suggests that daily RIC improves stroke recovery.”

Here we encounter additional general properties of remote conditioning, again reflecting that conditioning is an application of hormesis:  1. Although the stress may have been applied to protect against specific damage due to a specific event like a pending surgery, unexpected benefits or forms of protection may show up (e.g. increased lung capacity for a stress induced to protect against ischemia-reperfusion injury) 2. The beneficial results may be very long lasting or permanent, 3 . Application of the stress can lead to reduction in mortality, and 4. Daily or periodic repetition of the stress can lead to additional benefits.  Indeed, 5. conditioning for one purpose in one system can possibly produce benefits in other body systems, e.g. ischemic pre-surgery conditioning can possibly produce neurological benefits such as greater capability to focus and perform cognitive tasks, better body balance, etc.

The cardioprotective effects of exercise appear to be associated with an enhanced capability to buffer ROS stress, and that the protective adaptive response is triggered by exercise-induced ROS

This point was made in the Conference presentation by David A. Brown, Department of Physiology, Brody School of Medicine, East Carolina University, Cellular Mechanisms Underlying the Cardioprotective Effects of Exercise: “Numerous pre-clinical and epidemiological studies have documented the cardioprotective efficacy of exercise, yet the mechanisms that underlie exercise-induced preconditioning of the heart are not fully understood. During conditions when reactive oxygen species (ROS) overwhelm endogenous buffering systems, the loss of mitochondrial function is closely linked with the onset of cardiac electromechanical dysfunction. In a series of studies using both short- and long-term treadmill-running protocols, we have established that exercise preconditions the rat heart in the absence of markers of systemic stress. Fluorescence studies in cardiac myocytes from exercised rats indicated that endogenous ROS buffering-capacity was augmented, and correlated with a lower propensity for cell death. During cardiac ischemia-reperfusion, glutathione levels in exercised hearts were better maintained in Langendorff-perfused hearts, which was associated with lower arrhythmia scores and smaller infarct sizes. While resting myocardial glutathione levels were not different between sedentary and exercised animals, the replenishment of glutathione was enhanced in exercised hearts, due to up-regulated glutathione reductase enzyme activity. The beneficial effects of exercise were abolished when NADPH oxidase activity was pharmacologically inhibited during exercise, but remained intact when mitochondrial ROS production was blunted during exercise. These data lead us to believe that ROS produced during exercise ‘trigger’ adaptive responses, and that the source of ROS does not appear to be mitochondrial in origin. Our most recent studies have directly examined mitochondrial energetics in the intact heart using multi-photon microscopy, and preliminary data indicate that the preservation of mitochondrial membrane potential was directly linked to prevention of reperfusion arrhythmia. In conclusion, our studies provide novel insight into adaptive responses following exercise that protects the heart during acute coronary syndromes.”

Protection against damage induced by stroke is another benefit of ischemic conditioning, an objective not achieved by recognized pharmacological approaches.

This topic was discussed in a Conference presentation Ischemic Tolerance and Neurological Protection was offered by John M. Hallenbeck, Chief, Stroke Branch, NINDS, NIH. “Ischemic tolerance can be interpreted as a form of hormesis in which a stress that is gauged to be sub-lethal can activate evolutionarily conserved, endogenous protective mechanisms and induce a time-limited tolerance to an otherwise damaging or lethal stress. There are various forms of induced tolerance to ischemic stress that have been modeled preclinically. They include preconditioning in which the sublethal stress is applied shortly before the otherwise damaging ischemia (immediate preconditioning) or that precedes the damaging ischemia by 24-72 hours (delayed preconditioning). Additional forms of induced tolerance include perconditioning (stress superimposed during damaging ischemia) , post-conditioning (stress imposed after damaging ischemia), remote conditioning (another organ or tissue site than brain is exposed to ischemic stress that then induces tolerance to damaging brain ischemia), and cross-conditioning (a non-ischemic stress induces tolerance to ischemia). The stroke field is broadly interested in developing an understanding of the molecular mechanisms that regulate tolerance in order to help guide efforts to develop cytoprotective therapies for strokes. This interest is understandable when one realizes that vascular neurology research has yet to translate a cytoprotective therapy that has been identified by standard reductionist techniques and have it show efficacy in a Phase III clinical stroke trial.”

Conditioning for stroke was also discussed in the Conference presentation Post-conditioning and the Transition from Animal Models to Humans for the Treatment of Stroke by

Roger Simon, MD, Neuroscience Institute, of the Morehouse School of Medicine  “Endogenous mechanisms of protection against stroke and acute injury can be demonstrated in brain and other organs. Such therapies might replace or enhance putative pharmacotherapy. The induction of endogenous protection is via a response to sub lethal stress which induces “preconditioning”. The preconditioned organ is then “tolerant” to injury from subsequent severe stress of the same or different etiology (ie brief ischemic stress protects against injury from prolonged epileptic seizures and vice versa). Ischemic preconditioning provides protection against subsequent stroke. Protection is substantial (70% reduction) but delayed and transient (onset at two days, maximum at three days and gone by seven days). Gene expression is unique between brains preconditioned, injured (stroke) or made tolerant. Thus, preconditioning reprograms the brains response to lethal stress (stroke); reprogrammed from an injury induction response to a neuroprotective processes. Transcriptional down regulation is the central feature of the reprogrammed response to injury. This process of neuroprotective gene silencing is driven epigenetically via polycomb group proteins which suppress transcription broadly. — Postconditioning refers to attenuation of injurious processes which occur during reperfusion of ischemic brain (the only approved treatment for acute stroke). Mechanically inturupting referfusion induces postconditioning which can attenuate reperfusion injury. Postconditioning protects ischemic brain by decreasing reperfusion induced oxygen free radical formation. The free radicals produce injury via mitochondrial damage which can be repaired experimentally with resultant neuroprotection as potent as experimental postconditioning. The recognition of broad based gene silencing (suppression of thousands of genes) as the phenotype of the ischemic tolerant brain, may explain the failure of all single target drugs for stroke. The risks of reperfusion treatment for stroke may be attenuated by induction of endogenous repair processes. Thus endogenous neuroprotective and repair mechanisms offer translational stroke therapy.”

We underlined the final point here because we believe it identifies a very important distinction between hormetic stress interventions and most pharmacological interventions. If we want to realize significant objectives like protecting ourselves against stroke or heart damage or if we want to create other significant health benefits, in most cases that involves upregulation or down regulation of hundreds or thousands of genes.  This happens naturally through mobilization of our endogenous stress response pathways but can’t be done using a single protein kinase.

Another general property of preconditioning and hormesis appears to be that repeated intermittent periods of stress can build a stronger and longer lasting stress response capability than that achievable by a single application of the stress.

There seems to be much folk knowledge and evidence that this is true when exercise and fasting are adapted as regular practices.  An interesting question is the extent to which it is true for other types of stress like ischemic conditioning. The presentation Promoting Long-lasting Protection in the CNSdiscusses repeated hypoxic stress.It is by Jeffrey M Gidday, of the Department of Neurosurgery, Department of Ophthalmology & Visual Sciences, and Department of Cell Biology & Physiology, Washington University School of Medicine. “Significant reductions in the extent of acute injury in the CNS can be achieved by exposure to a preconditioning stimulus, but the duration of the protective phenotype is short-lasting. Our work has been directed at extending the period over which such epigenetic changes persist, thereby enhancing translational relevance. Having established in adult mice that a single exposure to systemic hypoxia (2 h of 11% oxygen) provides transient (a few days) protection against cerebral (Miller BA et al., NeuroReport, 2000) and retinal (Zhu Y et al., IOVS, 2002) ischemia, we then documented that repetitive presentations of this same hypoxic stimulus over a two-week period (six total exposures to 2-h of 11% oxygen, every other day over two wks) extended the duration of ischemic tolerance to one month after the last preconditioning stimulus (Zhu Y et al., IOVS, 2007). Protection against stroke for two months could be afforded by a 2-wk intermittent hypoxic preconditioning regimen (Stowe AM et al., Annals Neurol, 2011), but only with stochastic increases in stimulus frequency, duration, and intensity, suggestive of tissue- or cell-dependent hormetic dose-response relationships. Given this protracted ‘therapeutic window’, we then sought to determine whether repetitive hypoxic conditioning (RHC) could also enhance cell survival in chronic neurodegenerative disease. In an inducible mouse model of glaucoma defined by progressive loss of retinal ganglion cell soma and axons over a 10-wk period of elevated intraocular pressure (IOP), significant protection of both soma and axons could be demonstrated − without a reduction in IOP − when animals completed the 2-wk RHC treatment before IOP elevation (Zhu Y et al., Mol Med, 2012), or received it during the period of elevated IOP (manuscript in preparation). Thus, extending the duration of the adaptive epigenetic phenotype by RHC represents a fundamentally new therapeutic approach for treating glaucoma and other chronic neurodegenerative diseases.”

With regard to hypoxia. we have frequently heard skeptics say things like “It is not worth holding your breath if you are waiting for a big breakthrough in health and longevity.” We think there is a better basis for saying “Holding your breath may provide you a small breakthrough in health and longevity.”

Many different stresses can be used for preconditioning for multiple health objectives

The sheer numbers of stresses and health benefits may appear amazing, that is until we remember that stress conditioning is applied hormesis and that a biphasic stress response probably applies to every kind of stress that biological organisms and their subsystems have encountered and adapted to in their evolutionary histories.  These presentations discussed different stimuli for conditioning for different objectives:

• Pre-conditioning with Low Level Laser (Light) Therapy Tanupriya Agrawal, MD, Wellman Center for Photomedicine at Massachusetts General Hospital; James D Carroll, FRSM, Thor Photomedicine Ltd; Michael R Hamblin, Ph.D., Wellman Center for Photomedicine at Massachusetts General Hospital
• Dose-Response Effects of Low-Level Light Therapy on Brain and MuscleF. Gonzalez-Lima, Departments of Psychology, Pharmacology and Toxicology, University of Texas at Austin,
• Neuromodulation with Weak Transcranial Electrical Stimulation: Small Things Making a Big Difference Marom Bikson, Neural Engineering Lab, Department of Biomedical Engineering, The City College of New York of CUNY,
• Increased Threat Detection, Learning and Attention using Low-Level Transcranial Direct Current Stimulation (tDCS) Vincent P. Clark, Psychology Clinical Neuroscience Center, University of New Mexico and MIND Research Network, Dept. Psychology, University of New Mexico.

There are multiple examples of preconditioning that can provide health benefits to us humans where we are not the actual targets of the preconditioning.

A presentation at the Conference discussed stress-conditioning stem cells to increase their survivability, vitality and potency prior to transplantation into humans.  The presentation Preconditioning Strategy for Improved Therapeutic Potential of Stem Cell Transplantation Therapy after Ischemic Stroke was by Shan Ping Yu, Emory University School of Medicine, Atlanta. “Ischemic stroke is a serious threat to human life and health but clinical treatment for stroke is very limited. Stem cell transplantation has emerged as a promising regenerative medicine for stroke and neurodegenerative disorders. It is expected the repair of damaged brain tissues/structures can be achieved using pluripotent/multipotent stem cells derived from embryos, fetuses, or even adult tissues. However, many issues and problems remain to be resolved before successful clinical applications of the cell-based therapy. Among them, poor cell survival, uncertain neuronal differentiation and low efficacy of tissue repair in the harsh microenvironment of the injured brain are some primary issues. We have initiated an effort to develop a combination strategy in stem cell transplantation therapy in order to improve the therapeutic potential of transplanted cells. One of the major focuses has sought to benefit from well-known mechanisms of ischemic/hypoxic preconditioning that activates cellular defense mechanisms and shows marked protective effects against multiple insults found in ischemic stroke and other acute attacks. A sub-lethal hypoxic exposure significantly increases the expression of pro-survival and pro-regenerative factors. So far, a variety of preconditioning triggers have been tested on different stem cells and progenitor cells. Preconditioned cells show much better cell survival, increased neuronal differentiation, and enhanced paracrine effects that lead to increased trophic support and tissue repair. Transplantation of preconditioned cells helps to suppress inflammatory factors and immune responses. The combination therapy also includes strategies for increasing migration and homing of transplanted cells to the lesion site. More importantly, the combination stem cell therapy shows much improved morphological repair as well as functional recovery after ischemic stroke. Although the combination strategy in stem cell transplantation is still an emerging research area, accumulating information from reports over the last few years already indicates it as an attractive, if not essential, prerequisite for transplanted cells.”

We have been concerned with another category of non-human preconditioning that can benefit humans: stress-preconditioning fruits and vegetables to lead them to produce and contain enhanced amounts of health-producing phytochemicals when we eat them.  We have discussed such interventions in this blog(ref)(ref)(ref).

One topic of central concern in the Conference was why the adoption of preconditioning in standard medical procedures has been so slow to happen even though the benefits have been known for a great many years.  This applies both to preconditioning for specific purposes, such as protection against adverse consequences of surgery, and for creating a more general health state and longevity. 

One example is that the benefits of calorie restriction  for health and longevity in mammals has been researched extensively since 1934, but that calorie restriction practices such as intermittent fasting have not been adopted in mainline medicine.  In the Conference, Mark Mattson commented on this situation and what might be done about it in his presentation Implementation of Intermittent Fasting Prescriptions: Breaking Through the Barriers: “Compelling evidence from studies of rodents and humans suggest that intermittent fasting (IF), consisting of periodic (1-4 days per week) short (16-36 hours) fasts, can promote optimal health and can prevent and reverse disease processes in many chronic conditions including diabetes, cancers, cardiovascular disease and neurodegenerative brain disorders. In overweight human subjects, IF diets promote long-term weight loss with retention of lean mass, increased insulin sensitivity, and reduced inflammation and oxidative stress. Why, despite the fact that IF is a safe and effective intervention, do health care providers not prescribe IF diets to their patients? Regrettably, the reason for this lack of effort by the medical community is that no one profits from IF prescriptions. The processed food and agriculture industries would lose money if people ate less, and the pharmaceutical industry would ‘suffer’ if fewer people developed the diseases for which Pharma peddles their drugs. Medical training and practice is focused on technologically advanced treatments and specialists (cardiologists, neurologist, orthopedists, etc.) that it is not their job to tackle the underlying cause (which is often a couch potato lifestyle) of their patients’ diseases; instead, they have become drug-dispensing, scalpel-wielding robots. Medical school curricula are devoid of training on the profound health benefits of IF and exercise, and primary physicians often assume that patients will not comply with IF diets. In this presentation I will describe strategies for the implementation of IF diets in which patients are given a specific plan for the diet and for monitoring their progress. The physician and/or an assistant is in close communication with the patient via text messaging, social media, etc. with the purpose of guiding them through the 1 – 2 month period that is often required for a person to adjust to the IF eating pattern.”

Poster Presentations

As is usually the case at the annual International Dose Response Society Meetings, there were a number of quite interesting poster presentations dealing with related topics.  Many of these are summarized in the abstract book.  The titles are:

• Astrocyte Preconditioning by Severe Stress is Glutathione- but not Heat Shock Protein 70-Dependent

• Drosophila melanogaster Show a Threshold Effect in Response to Radiation

• How Radiotherapy Was Historically Used to Treat Pneumonia: Could it be Useful Today?

• Use of X-rays to Treat Shoulder Tendonitis/Bursitis: A Historical Assessment

• Model Uncertainty in Cancer Risk Assessment

• Risk Assessment Report Card

• Low-dose radiation Prevents Diabetic Complications Protection of Hearts Against Ischemic Insult: Changes in Iron Homeostasis Explain Myocardial Response to Preconditioning

• Investigation of the Cellular and Molecular Mechanisms of Radiation-induced Bystander Effects in a Human Keratinocyte Cell Line

• Low-level radiation and heart disease death rates in four states: An ecological study Inter-Relationships between Low Dose Hypersensitivity, Induced Radioresistance and Bystander Effects in Human Cell Lines

• Comparative Acute Toxicity of Silver Nanoparticles Produced by Physical (Top-Down) and Chemical (Bottom-Up) Methods in Zebrafish (Danio rerio)

• Ultraviolet-A photoemission from cells upon β-irradiation and consequent bystander effects

• Physiological Conditioning Hormesis Improves Post-Irradiation Performance in Young and Aging Fruit Flies

• Communication of Protective Signals from Fish Sub-Lethally Challenged with Vibrio anguillarum VIB1 to Naïve Fish

• Assessing Predictive Factors and Radiation-Induced Non-Targeted Effects in Blood Serum from Cancer Patients

• The Effects of Chronic Exposure to Low Levels of Alpha-Emitting Radionuclides on the Health and Reproductive Fitness of Mammals

• Pre-operative Stress Conditioning: Role for Hyperbaric Oxygen Therapy

• Drosphila melanogaster Show a Threshold Effect in Response to Radiation

• Protection of Hearts against Ischemic Insult: Changes in Iron Homeostasis Explain Myocardial Response to Preconditioning

• Correcting deficiencies in our societal structure for the Application of Science in Medicine

The final wrapup session

The final session of the conference was devoted to a Integrative Discussion Of How Can Pre-Post Conditioning Being Used. Among the topics treated there were therapeutic applications, protecting military personnel, preventing athletic injuries and enhancing recovering, enhancing athletic and job performance, and improving public health.  Again, a major focus of the discussion was inquiring why penetration of conditioning techniques into mainline medicine has been so painfully slow despite the fact that the efficacy and safety of such techniques have been known for many years.   A number of barriers were identified, including ones referred to above in Mark Mattson’s presentation, ones related to the current structuring of medical practice and the reward patterns in that field, and ones related to the nature of the pharmaceutical industry. One of the barriers identified was the continuing absence of identifying a common molecular mechanism that could allow so very many different stress stimuli to produce similar or identical effects.  In the discussion this unknown mechanism was called Factor X.  We point out that Jim Watson has suggested a strong candidate for Factor X in the previous blog entry Nuclear Aging: The View from the Telomere end of the Chromosome, the Section near the end entitled Towards a GUT, looked at from the end of the chromosome suggests that Factor X is none other but our old molecular friend P53 which serves as a hormetic signaling molecule at low doses and a death signaling (apoptotic) molecule at high doses.