MULTIFACTORIAL HORMESIS

1. MULTIFACTORIAL HORMESIS PART 1 AN IMPORTANT CONTEXT FOR HEALTH AND LONGEVITY ON THE ROAD TO A GRAND UNIFIED THEORY (GUT) FOR BIOLOGY Investigating the Future of Medicine Symposium and Webcast Hawaii institute for Molecular Communications March 16, 2013 • Presentation by: • Vincent E. Giuliano, Ph.D. • Agingsciences.com

2. “Was mich nicht umbringt, macht mich starker.” Friedrich Nietzsche “What does not kill me, makes me stronger” The essence of Hormesis

3. Major points: Based on current understanding involving disparate bodies of research: • Hormesis is a phenomenon in biology involving stress-responses of a biological organism, system or subsystem. • Hormesis is found universally in biology, applying wherever there is stress. It is an essential characteristics of the biological networks making us up • Hormesis is exploited in extremely important existing health-producing applications • Hormesis has important general properties

4. Major points (continued) 6. Hormesis is a very useful framework for guiding and organizing health-oriented research 7. There are well-studied molecular pathways that produce hormesis. 8. Hormesis is a requirement of evolution and the systems dynamic nature of biological entities 9. Hormesis is likely a key component of an emerging grand unified theory of biology

5. MULTIFACTORIAL HORMESIS TOPICS • Introduction to hormesis • Some-familiar examples of hormesis • Hormesis and aging • Hormesis pathways • General properties of hormesis • Hormesis and dietary substances • Hormesis as part of a Grand Unified Theory for biology • Presentation by: • Vincent E. Giuliano, Ph.D. • Agingsciences.com

6. “biology is infinitely complex” “While physics is infinitely deep,”

7. Why hormesis, anyway? • Biological organisms consist of a vast network of interacting loops (pathways) with positive and negative feedback characteristics. E.g. Important process loops are highly interconnected Composite network of molecular pathways active in HCV-infected liver tissue.

8. Why hormesis, anyway? Purine metabolism – image source Image source • Understanding such loops and how we can affect their operation can: • Enable further understanding of disease processes • Lead to new disease therapies and preventative measures • Enhance health and likely expand human longevity • Hormesis is about how such loops respond to stresses to keep things in balance and further improve the situation.

9. Introduction to Hormesis – starting with the needs of evolution • Hormesis is about stress and how organisms adopt to deal with stress. • Organisms are shaped and limited by the stresses they encounter in their environments. • So, biological substructures and processes are adapted to function best under the stress conditions they normally experience. • Organisms have evolved so they function best with certain amounts of key stresses, not in the absence of stresses.

10. Introduction to Hormesis – starting with the needs of evolution • Biological systems react to stress in a nonlinear fashion so as to restore balance. • Moreover, within a certain quantitative “window” of amount of stress, the organism and its subsystems mount strong defenses and is as a result better off than if there were no stress at all. From a systems dynamics viewpoint, hormesis is an essential mechanism to keep the system going in dynamic equilibrium, e.g. dynamic homeostasis

11. Introduction to Hormesis – the dose-response curve Risk, Damage • the horizontal axis depicts level of applied stress, say as driven by ROS load in a cell.  • The vertical axis represents relative risk, level of probable pathological organism response where normal level is 1.  • The benefit tends to be in the 30% to 60% range Health

12. Introduction to Hormesis – the dose-response curve Below 1, there is a “health reserve,” such as an enhanced ability to do exercise or enhanced resistance to disease.   Above 1 there is a less than normal “health reserve,” such as a lessened ability to resist disease or to do additional exercise.  • To the left of the first axis crossing in the diagram (point b), positive body reactions to the stress situation is progressively kicking in, but not sufficiently so as to overcome the direct negative effects of the stress.  • Between stress levels b and D***  there is hormetic protection compared to what would be expected given a linear model of negative response to stress.  •   Starting at D** to D*** the stress load begins to overwhelm the hormetic defensive activities and the hormetic protection becomes less and less until at point D*** it vanishes.

13. The multifactorial nature of hormesis • Hormesis is important because inducing it is a way of enhancing health and possibly longevity. • Important practical, health and medical applications of hormesis are already in use • Many other health and medical applications are likely possible as well • Hormesis applies wherever there is stress, to multiple pathways, across all successful species, and is essential for survival. In that sense, it is multifactorial. • While the shape of the stress curve is the same, how to apply it in practice depends on the stress, the stress pathways activated, and the state of the organism and the biological subsystems affected.

14. Hormesis exists at multiple levels • Systematic whole organism training for environmental and societal accommodation • Whole organism biological conditioning • Organ/tissue, e.g. brain, muscles • Cells of differing types • Body system, e.g. immune system • Cell component, e.g. endoplasmic reticulum, nucleus, chromatin. mitochondria, etc. • Key cell pathways – OXPHOS, electron chain transport system, apoptosis, stem cell differentiation, mitosis, etc.

15. Categories of hormesis • There are many kinds of hormesis identifable by type of stress • Radiation • Inflammation • Exercise • Cold • Heat • Dietary restriction Absence of key nutrients Blood flow restriction Pathogens • Interrupted sleep • Stresses in cellular processes (e.g. OXPHOS) • Mental/emotional stress • Hormesis is sometimes discussed in terms of the biological system involved, e.g. • Mitohormesis • Neural hormesis • Vascular hormesis Often a given kind of stress may activate multiple hormesis l pathways

16. Categories of hormesis • Hormesis can also be characterized by the biological pathways involved, E.g. • The adaptive immune system • ROS-mediated pathways • Pathways activated by other reactive species • The unfolded protein response • The mitochondrial unfolded protein response • Heat shock and chaperone protein mediated pathways • Cell membrane-mediated pathways • Second-messenger mediated hormesis • The autophagy response Often a given kind of stress may activate multiple hormesis l pathways

17. History of hormesis Image source • Concept first proposed in 1888 • At first, very controversial • And still is, among some • Often viewed as a fringe theory • Now, steadily gaining acknowledgement • 922 PubMed listings since 1947 for “hormesis” • 260 of these in last three years • Still being studied in a very disjointed manner • There are many important forms of hormesis known by different names and not seen as related • Actually, over 400,000 PubMed publications for various forms of hormesis, mostly not called that • On the timescale of evolution, the idea of hormesis is being accepted quite fast.

18. Some more familiar examples of hormesis • Immunization by vaccines • Ischemic preconditioning; • Vascular hypoxic preconditioning • “Grit” training • Exercise training • Radiation hormesis No risk

19. A traditional example of hormesis: Inoculations against infectious diseases • One of the oldest, important and obvious examples of hormesis • A vaccine is a stress-inducing substance that contributes to creating immunity to a disease • Major historical contributor to world health and longevity impacting the lives of many billion people • Underlying science and pathways related to vaccines and immune responses studied since 1771 • A vast worldwide initiative coordinated by the World Health Organization • Many infectious diseases like polio virtually eliminated 110,878 PubMed publications since 1819, 2.8 million Google entries

20. Preconditioning • Preconditioning is a term that refers to a process where a hormetic dose of stress is given prior to a suprahormetic dose. • It is not a synonym for hormesis though it utilizes hormesis • Examples • Ischemic preconditioning can involves temporarily restricting vascular blood flow prior to heart surgery where flow is seriously restricted • Ranger and seal training toughens up men before they are sent out on dangerous missions outnumbered by enemies • Plants and food crops are routinely frost hardened – they express cold shock and drought-responsive proteins • Athletes train for competitive sports events Image source

21. An important application of hormesis– ischemic pre-conditioning (IPC) • IPC is an process whereby repeated short episodes of ischemia protect the myocardium against a subsequent ischemic insult. • Of interest as a technique for improving the outcomes of surgical techniques that entail ischemia. E.g. administered prior to heart surgery “Ischemic preconditioning has been proved to be the most effective mode of endogenouse myocardial protection. However, studies of IP effects in cardiac surgery are rare and controversal.” (ref) 7559 Pubmed publications since 1981 Imag source

22. An important example of hormesis– Ischemic pre-conditioning (IPC) 7570 PubMed Publications since 1980 Images source

23. An important example of hormesis– Ischemic pre-conditioning (IPC) Image source

24. Vascular hypoxic preconditioning • Neuroprotective against ischemia • Protective of bone marrow multipotentstromal cells • increase proliferation rates and enhance differentiation along the different mesenchymal lineages. • modulates the paracrine activity of MSCs • And more,  142 Pubmed publications since 1992 Another name for a kind of ischemic preconditioning Image source

25. Properties of ischemic preconditioning • Several studies suggest that ischemic preconditioning even works when administered remotely • Remote ischemic preconditioning is administered by restricting blood flow for 20 minutes or so using a cuff on an arm or leg. • The result is release of humoral factors that protect the heart from ischemic events. • There is a window of "tolerance" to the given supra-hormetic stress dose that occurs 2-10 days after preconditioning. • Doing preconditioning followed by a large stress dose during the time window of toleranceis a way of proving that hormesisis a scientific principle for the given stressor. • Giving a blocking compound that extinguishes the effects of preconditioning provides evidence for the mechanism of action

26. Systematic whole organism training for environmental and societal accommodation • Training for “Grit” and personal toughness • Endurance training for athletes • Military basic training; obstacle courses • Ranger and astranaught training • Outward Bound experiences • Tribal initiation ceremonies where a young person is forced to survival alone in the outdoors • “Tough love” training for young people

27. Systematic whole organism training for environmental and societal accommodation • Wisdom and capabilities acquired through hard interpersonal experiences such as divorces, deaths • Every obstacle in life overcome contributes to grit and enhanced capability to survive and succeed: “that determination in life that cannot be denied” We do not normally think of these matters as hormesis, but they are. And it demonstrates the multi-level applicability of hormesis

28. Radiation hormesis • At hormetic dose levels, radiation increases disease resistance and lowers mortality 233 Pubmed publications since 1983 No risk

29. Radiation hormesisCancer mortality following nuclear radiation exposure accidents • Studied at first in Japan since 1983, also in Russia 233 Pubmed publications since 1983

30. Radiation hormesis • Health applications researched include • Cancer immunity, Cardiological health, aging, benign prostate enlargement, biochemical and physiological cellular responses, caloric restriction, cardiovascular function, cancer and tumor development, chemo-sensitization, chemotherapy, dermatology, drug binding, hair growth, sexual dysfunction, ocular diseases, osteoporosis, oxidative stress, prion diseases and synaptic plasticity • Research based on data from • Nuclear explosions • Nuclear radiation-release accidents • Cosmic ray exposures • Radon exposure • Astronauts health studies • Small-animal experiments • Radiation hormesis exists, is measurable and can have significant health impacts • Yet the radiology establishment still clings to the linear no-threshold (LNT) theory from the 1950s

31. Too much stress makes for problems • So does too little stress Image source Exercise preconditioning Pretty well understood in the popular culture • The right amount of stress makes you stronger and healthier

32. Exercise hormesis 250,099 PubMed publications since 1971 • Multiple health benefits • Mediated largely by PGC-1-alpha Image source Image source

33. END PART 1 Multifactorial hormesis