MULTIFACTORIAL HORMESIS

AN IMPORTANT CONTEXT FOR HEALTH AND LONGEVITY

ON 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 1

“Was mich nicht umbringt, macht mich starker.”

Friedrich Nietzsche

“What does not kill me, makes me stronger”

The essence of Hormesis

1. Hormesis is a phenomenon in biology involving stress-responses of a biological organism, system or subsystem.

2. Hormesis is found universally in biology, applying wherever there is stress. It is an essential characteristics of the biological networks making us up

3. Hormesis is exploited in extremely important existing health-producing applications

4. Hormesis has important general properties

Major points: Based on current understanding involving disparate bodies of research:

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

Major points (continued)

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

biology

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

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.

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.

Why hormesis, anyway?Purine metabolism – image source

Image source

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 evolution

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.

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 homeostasis

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, Damage

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. 

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 well

The multifactorial nature of hormesis

Systematic whole organism training for environmental and societal accommodation

Whole organism biological conditioning

Organ/tissue, e.g. brain, muscles Cells of differing types

Hormesis exists at multiple levels

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.

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

Categories of hormesis

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

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

Categories of hormesis

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

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.

History of hormesis Image source

Some more familiar examples of hormesis

◦Immunization by vaccines◦Ischemic preconditioning; ◦Vascular hypoxic preconditioning◦“Grit” training◦Exercise training◦Radiation hormesis

No risk

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 traditional example of hormesis: Inoculations against infectious diseases

•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

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

Preconditioning

Image source

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 1981

Imag 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)

An important example of hormesis– Ischemic pre-conditioning (IPC)

Images source

7570 PubMed Publications since 1980

An important example of hormesis– Ischemic pre-conditioning (IPC)

Image source

Neuroprotective against ischemia Protective 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 preconditioning

142 Pubmed publications since 1992

Another name for a kind of ischemic preconditioning

Image source

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 action

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. 

Properties of ischemic preconditioning

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

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”

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 hormesis

At hormetic dose levels, radiation increases disease resistance and lowers mortality

Radiation hormesis

233 Pubmed publications since 1983

No risk

Studied at first in Japan since 1983, also in Russia

Radiation hormesisCancer mortality following nuclear radiation exposure accidents

233 Pubmed publications since 1983

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

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

Too much stress makes for problems

Image source So does too little stress

The right amount of stress makes you stronger and healthier

Exercise preconditioningPretty well understood in the popular culture

Multiple health benefits Mediated largely by PGC-1-alpha

Exercise hormesis250,099 PubMed publications since 1971

Image sourceImage source

END PART 1 Multifactorial hormesis