MULTIFACTORIAL - PowerPoint Presentation

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MULTIFACTORIAL

HORMESIS

AN IMPORTANT CONTEXT FOR HEALTH AND LONGEVITYON THE ROAD TO A GRAND UNIFIED THEORY (GUT) FOR BIOLOGY

Presentation by:Vincent E. Giuliano, Ph.D.Agingsciences.com

Investigating the Future of MedicineSymposium and WebcastHawaii institute for Molecular CommunicationsMarch 16, 2013

PART 1Slide2

“

Was mich nicht umbringt,

macht mich starker.”

Friedrich Nietzsche“What does not kill me, makes me stronger”The essence of HormesisSlide3

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 applicationsHormesis

has important general properties Major points: Based on current understanding involving disparate bodies of research:Slide4

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 entities9. Hormesis is likely a key component of an emerging grand unified theory of biologyMajor points (continued) Slide5

MULTIFACTORIAL HORMESIS

TOPICS

Presentation by:Vincent E. Giuliano, Ph.D.Agingsciences.com

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 biologySlide6

“While physics is infinitely deep,”

“biology is infinitely complex”Slide7

Biological organisms consist of a vast network of interacting loops (pathways) with positive and negative feedback characteristics. E.g.

Why hormesis, anyway?

Important process loops are highly interconnected

Composite network of molecular pathways active in HCV-infected liver tissue.Slide8

Understanding such loops and how we can affect their operation can:

Enable further understanding of disease processesLead to new disease therapies and preventative measuresEnhance 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.

Why hormesis, anyway?Purine metabolism – image sourceImage sourceSlide9

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.

Introduction to Hormesis – starting with the needs of evolutionSo, 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. Slide10

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.

Introduction to Hormesis – starting with the needs of evolution

From a systems dynamics viewpoint, hormesis is an essential mechanism to keep the system going in dynamic equilibrium, e.g. dynamic homeostasisSlide11

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

Introduction to Hormesis – the dose-response curve

Health

Risk, DamageSlide12

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.

Introduction to Hormesis – the dose-response curveBelow 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. Slide13

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.

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 wellThe multifactorial nature of hormesisSlide14

Systematic whole organism training for environmental and societal accommodation

Whole organism biological conditioningOrgan/tissue, e.g. brain, musclesCells of differing types

Hormesis exists at multiple levels

Body system, e.g. immune systemCell component, e.g. endoplasmic reticulum, nucleus, chromatin. mitochondria, etc.

Key cell pathways – OXPHOS, electron chain transport system, apoptosis, stem cell differentiation, mitosis, etc.Slide15

There are many kinds of hormesis

identifable by type of stressRadiation

InflammationExercise Cold HeatDietary restriction Absence of key nutrients Blood flow restriction Pathogens Interrupted sleep Stresses in cellular processes (e.g. OXPHOS)

Mental/emotional stressHormesis is sometimes discussed in terms of the biological system involved, e.g.MitohormesisNeural hormesisVascular hormesisCategories of hormesis

Often a given kind of stress may activate multiple hormesis l pathwaysSlide16

Hormesis can also be characterized by the biological pathways involved, E.g.

The adaptive immune systemROS-mediated pathwaysPathways activated by other reactive species

The unfolded protein responseThe mitochondrial unfolded protein responseHeat shock and chaperone protein mediated pathwaysCell membrane-mediated pathwaysSecond-messenger mediated hormesis

The autophagy responseCategories of hormesisOften a given kind of stress may activate multiple hormesis l pathwaysSlide17

Concept first proposed in 1888

At first, very controversialAnd still is, among some

Often viewed as a fringe theoryNow, steadily gaining acknowledgement922 PubMed listings since 1947 for “hormesis”

260 of these in last three yearsStill being studied in a very disjointed mannerThere are many important forms of hormesis known by different names and not seen as relatedActually, over 400,000 PubMed publications for various forms of hormesis, mostly not called thatOn the timescale of evolution, the idea of hormesis is being accepted quite fast.History of hormesis

Image sourceSlide18

Some more familiar examples of hormesis

Immunization by vaccines

Ischemic preconditioning;

Vascular hypoxic preconditioning“Grit” trainingExercise trainingRadiation hormesis

No riskSlide19

One of the oldest, important and obvious examples of hormesis

A vaccine is a stress-inducing substance that contributes to creating immunity to a diseaseMajor 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 1771A traditional example of hormesis:

Inoculations against infectious diseasesA vast worldwide initiative coordinated by the World Health OrganizationMany infectious diseases like polio virtually eliminated110,878 PubMed publications since 1819,

2.8 million Google entriesSlide20

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

ExamplesIschemic preconditioning can involves temporarily restricting vascular blood flow prior to heart surgery where flow is seriously restrictedRanger and seal training toughens up men before they are sent out on dangerous missions outnumbered by enemiesPlants and food crops are routinely frost hardened – they express cold shock and drought-responsive proteinsAthletes train for competitive sports eventsPreconditioning

Image sourceSlide21

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

An important application of hormesis

– ischemic pre-conditioning (IPC)7559 Pubmed publications since 1981Imag source“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)Slide22

An important example of hormesis

– Ischemic pre-conditioning (IPC)

Images source

7570 PubMed Publications since 1980Slide23

An important example of hormesis

– Ischemic pre-conditioning (IPC)

Image sourceSlide24

Neuroprotective

against ischemiaProtective of bone marrow multipotent stromal cells

increase proliferation rates and enhance differentiation along the different mesenchymal lineages. modulates the paracrine activity of MSCs

And more, Vascular hypoxic preconditioning142 Pubmed publications since 1992

Another name for a kind of ischemic preconditioningImage sourceSlide25

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 tolerance is a way of proving that hormesis

is a scientific principle for the given stressor.Giving a blocking compound that extinguishes the effects of preconditioning provides evidence for the mechanism of actionSeveral studies suggest that ischemic preconditioning even works when administered remotelyRemote 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. Properties of ischemic preconditioningSlide26

Training for “Grit” and personal toughness

Endurance training for athletesMilitary basic training; obstacle coursesRanger and astranaught

trainingOutward Bound experiencesTribal initiation ceremonies where a young person is forced to survival alone in the outdoors“Tough love” training for young people

Systematic whole organism training for environmental and societal accommodationSlide27

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”

Systematic whole organism training for environmental and societal accommodation

We do not normally think of these matters as hormesis, but they are. And it demonstrates the multi-level applicability of hormesisSlide28

At

hormetic dose levels, radiation increases disease resistance and lowers mortality

Radiation hormesis

233 Pubmed publications since 1983No riskSlide29

Studied at first in Japan since 1983, also in Russia

Radiation

hormesisCancer mortality following nuclear radiation exposure accidents

233 Pubmed publications since 1983Slide30

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 explosionsNuclear radiation-release accidentsCosmic ray exposuresRadon exposureAstronauts health studiesSmall-animal experimentsRadiation hormesis

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 1950sSlide31

Too much stress makes for problems

Image source

So does too little stress

The right amount of stress makes you stronger and healthier

Exercise preconditioning

Pretty well understood in the popular cultureSlide32

Multiple health benefits

Mediated largely by PGC-1-alpha

Exercise hormesis250,099

PubMed publications since 1971Image sourceImage sourceSlide33

END PART 1

Multifactorial

hormesis