Hormesis

Intermittent Hypoxia and High Altitude: An Introduction

Achieving optimal health is a top goal for many of us and at a fundamental level, this is based on how well our bodies function on the cellular level. Each of our cells then contains the various cellular machinery of life: the organelles. The quest to discover means for cellular optimization is essential for discovering and implementing methods that could potentially lead to higher levels of wellness, healthspan, and longevity.

A practice with significant potential to increase cellular health is intermittent hypoxia, which is the intentional and periodic exposure to decreased physiologic oxygen exposure and cellular levels. To understand why this practice, which can certainly seem counterintuitive, would be beneficial, it is helpful to understand the framework underlying this technique. Intermittent hypoxia will be reviewed in the subsequent article in this series and in this article, the mechanism underlying hypoxic exposure will be reviewed: hormesis.

Topics explored include:

A definition and short history of hormesis
Evolutionary origins of hormesis
Mechanisms of hormesis
Health benefits of hormesis

Hormesis is a process in which exposure to a low dose of a chemical agent or environmental factor that is damaging at higher doses induces an adaptive beneficial effect on the cell or organism . Although the applied practice of hormesis is still debated regarding efficacy and safety, the science around the benefits of wisely implemented hormesis is consistently expanding.

The term hormesis was initially introduced into the scientific lexicon in 1943 by Chester Southam and John Ehrlich based on their observations that extracts from the Red Cedar tree enhanced the metabolism of fungal species at low concentrations . While this was the first use of the term hormesis, a term that comes from the Greek ‘to excite’, there was an extensive history of biphasic dose responses that started in the 1880s with the first experimental evidence concerning the effects of numerous disinfectants on the metabolism of yeast , .

Hormesis: Evolutionary Origins

Hormesis likely evolved due to evolutionary environmental pressures on organisms resulting in adaptations on the cellular level that promoted continued survival. Hormesis can be considered a major mechanism underlying Darwin’s and Wallace’s theory of evolution by natural selection . The ability of organisms to respond adaptively to low levels of exposure to environmental hazards in a manner that increases their resistance to more severe similar or different hazards is fundamental to the evolutionary process . The organisms that survive and reproduce are those best able to tolerate or avoid environmental hazards while competing successfully for limited energy (food) resources . Therefore, many of the genes selected for their survival value encode proteins that protect cells against stress (heat-shock proteins, antioxidant enzymes, antiapoptotic proteins, etc.) or that mediate behavioral responses to environmental stressors (neurotransmitters, hormones, muscle cell growth factors, etc.) .

There are a range of practices targeted at building resilience through hormetic stress (hormesis). Some of these are familiar to many and may even be a surprise in terms of their classification as a hermetic stress. Others may present as esoteric and arcane and seem extreme or dangerous (and can be if not approached with care, knowledge, and wisdom). Integrating hormetic protocols into one’s wellness routines can be a powerful addition on the journey to optimal wellness and longevity, providing increased resilience, energy, rejuvenation, and mental balance and clarity.

Forms of Hormesis

Examples of biological hormesis include:

Higher intensity exercise
Cold exposure
Heat exposure
Fasting
Caloric restriction
Glycohormesis (intentional glucose spikes)
Various plant-based ‘nutrients’ such as phytonutrients that are technically toxins
Various supplements
Various medications
Vaccines
Radical oxygen species (ROS) exposure
Radiation exposure
Increased oxygen intake
Decreased oxygen intake

Hormesis can also be neuro-psychological and may include:

Mental activities requiring significant focus
Meditation
Deadlines
Applied discipline
Setting and achieving goals
Psychological stress

Mechanisms of Hormesis

Hormesis functions through a variety of mechanisms and pathways.

These mechanisms include:

Dose-dependent relationship
Adaptive response
Type of stressor (examples above)
Cellular mechanisms
Context

The interaction of these mechanisms and pathways produces outcomes of hormetic responses in organisms.

Hormesis: Dose-Response Relationship

Hormesis Dose Curve

Source: Defining Hormesis: Evaluation of a Complex Concentration Response Phenomenon

An important component of hormesis is dose. As the saying goes, ‘the dose makes the poison’ and this is a central tenant of applying hormetic stressors. Hormesis has a curve where too little of the stressor won’t provide sufficient stimulus for beneficial impact and too much of the stressor will potentially damage the organism – the goldilocks principle. Although there is some truth to the now-cliché statement from Nietzsche, ‘what doesn’t kill you makes you stronger’, the concept of hormesis would qualify this and say something like, ‘what doesn’t kill you in a very specific range of stimulus makes you stronger’.

To Read About Blog Topic, Scroll Down

Want To Work With Our Clinic?

Do you have a chronic or mystery illness that no one has been able to help you with? Are you simply wanting to re-connect with a healthier version of yourself? It’s Time To Finally Feel Better!

Hormesis Dose Curve

Hormesis Dose Curves: Inverted U and J

There are two primary curve shapes in relation to hormesis. The U-shaped dose response model is commonly referred to as hormesis, a dose response phenomenon characterized by a low-dose stimulation and a high dose inhibition . This dose response may take the shape of either the inverted U or a J-shaped dose response depending on the endpoint that is measured. In the case of the inverted U-shaped dose response, this may be observed when endpoints such as growth, fecundity and longevity are measured. In the case of J-shaped dose response relationships, this may be observed when endpoints such as disease incidence are measured .

When approaching pragmatic applications of hormesis for the purpose of health, knowing the point of optimal results with minimal detriment is one of the most important components. Not applying enough of the stimulus will produce no or at least sub-par results. Applying excess stimulus could both reduce the positive impact and also cause potential damage. While this balance is more crucial in the context of some forms of hormetic stress than others, it is important to keep the concept in mind when implementing hormetic practices generally. Unfortunately, this optimal balance is not always clearly defined and hormetic applications are sometimes a balance of both science and art.

Hormesis: Adaptive Response

Hormesis, by definition, is the adaptive response of an organism to a stressor. In order to withstand future exposure to a similar exposure, physiology adapts to ensure a more robust capacity to withstand whatever the insult was. The response of the cell or organism to the low dose of the toxin is considered an adaptive and compensatory process following an initial disruption in homeostasis . Interestingly, hormesis may be considered in the context of both exogenous (from the outside) or endogenous (from the inside) pathways and it should also be recognized that hormesis is integral to the normal physiological function of cells and organisms . For example, exposure of neurons to the excitatory neurotransmitter glutamate during their normal activity results in energetic and oxidative stress accompanied by activation of hormetic pathways that help the neurons cope with more severe stress; however, excessive activation of glutamate receptors can kill neurons in a process called excitotoxicity .

In this series of articles, the focus is on exogenous hormetic pathways, though keeping in mind the consistent process of hormesis within our bodies is a revealing concept to internalize.

Hormesis: Stressors

Examples of potential hormetic stressors have been previously noted and different stressors may act through different cellular pathways to provide appropriate hormetic responses. This is important to note in the context of hormetic utilization as a targeted tool as the need for given individuals will frequently differ. Specific health conditions or goals may necessitate the stimulation of certain hormetic pathways, which becomes both the science and art of hormetic application. The initial focus here is hypoxic hormesis though future articles will explore a range of hormetic protocols.

Hormesis: Cellular Mechanisms

Hormetic Mechanisms

Although the hormetic stressor itself may seem a blunt tool for instigating positive changes in health, there is a very intricate network of processes being stimulated on the cellular level.

Some of the cellular processes involved in hormetic responses include:

Upregulation of antioxidant pathways, including glutathione
Upregulation of Nuclear factor erythroid 2-related factor 2 (NRF2) , which is a transcription factor that regulates the cellular defense against toxic and oxidative insults through the expression of genes involved in oxidative stress response and drug detoxification.
Upregulation of NF-kappaB
Upregulation of AMPK (Adenosine 5‘-monophosphate (AMP)-activated protein kinase
Upregulation of heat shock proteins (HSPs)
Upregulation of cold shock proteins (CSPs)
Upregulation of brain derived neurotrophic factor (BDNF)
Upregulation of cell survival genetics
Sirtuin upregulation
Mechanistic target of rapamycin (mTOR) mediated lysosomal autophagy (removal of damaged cellular components or cells)
Mitohormesis (potentially positive stress on mitochondria)
Mitochondrial biogenesis (creation of new mitochondria)
DNA repair
Apoptosis (destruction of damaged/dysfunctional cells)

The wide-ranging cellular mechanisms induced through hormetic pathways demonstrates the potentially significant capacity of hormesis in pursuit of targeted therapeutic applications and general wellness optimization. As a tool in the kit of health, the utilization of hormesis presents attractive opportunities.

Hormesis: Context

The context in which hormetic stress is applied is an additional consideration. If the intended outcome doesn’t match the circumstance in which a particular hormetic strategy is applied, it is likely that the desired outcome won’t be achieved. For example, certain individuals may present with a higher capacity to withstand increased hormetic exposure and reap greater benefit from elevated application intensity. This exemplified individual may be seeking a trajectory from good to optimized health. If the same hormetic intensity were applied to a frail individual, the dose-response curve framework may overwhelm biological responses and cause significant damage rather than benefit. This could be compared to a medication (which can also act through hormetic means): the proper dose should be considered based on individual circumstances to maximize the probability of the desired outcome being achieved.

Hormesis: Health Benefits

Although it is helpful to understand the mechanisms and pathways through which hormesis functions, the most important component is the knowledge of what this technique can contribute to our health and wellbeing.

There are a variety of potential health benefits provided by hormesis and these may include:

Reduced oxidative stress
Reduced inflammation levels
Mitigation of cellular senescence (cellular dysfunction)
Emergence of a beneficial aging phenotype (the overall presentation of a biological organism)
Positive cellular homeostasis
Tissue repair
Increased biological defense systems and adaptability (resilience)
Neuroprotection
Increased neuroplasticity
Improved metabolic health
Increased cognitive capacity and memory
Reduced cancer risk
Reduced risk of cardiovascular diseases
Enhanced overall health

Conclusion

Hormesis is a potentially powerful tool in the quest for optimal health and is based in mechanisms deeply conserved and generated through evolutionary processes. Through evidence-based and targeted application of hormetic protocols, it may be possible to significantly increase wellness.

In this article, the following topics regarding hormesis have been reviewed.

Evolutionary origins of hormesis
Mechanisms of hormesis including:
- Dose-response relationship
- Adaptive response
- Stressors
- Cellular mechanisms
- Context

In the following article, the specific hormetic application of intermittent hypoxia (targeted oxygen deprivation) will be explored along a biological pathway upregulated through this practice: HIF1-alpha.

Are You Suffering From A Chronic Illness?

Does your current health situation look like this…

Do you feel that you have tried many things and either nothing works, or the treatment does not hold?
Have you been told that there is nothing that can be done to reverse your illness and you just need to manage symptoms?
Does your illness impact your work, your family, your happiness and your social life?

We specialize in finding answers and solutions for complicated chronic illness when people feel like they have tried everything. If this sounds like you, book a free call with us to see if we are the right fit for your health goals.