Biological systems respond differently to high and low amounts of the same substances and to continuous and intermittent application of the same stimuli. Hormesis is very important to understand for designing programs for medical treatment, exercise, weight loss and more. As stated in a paper published in the journal Ageing Research Reviews:

“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.”

In other words, something that can be damaging or toxic at a higher dose may elicit a beneficial response at a lower one. This applies to calorie restriction and exercise as well as medicines. Research on hormesis has advanced in the past decade:

“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.

Thus plants from vegetables to wine grapes subject to moderate stress produce a richer yield of beneficial substances, and…

“A better understanding of hormesis mechanisms at the cellular and molecular levels is leading to and to novel approaches for the prevention and treatment of many different diseases.”

Intermittent caloric restriction is emerging as an effective and practical method for  successful long term weight loss and the longevity promoting effects of diet (see the earlier post on intermittent versus continuous calorie restriction and weight loss). Understanding the principle of hormesis is at the core of the Lapis Light Program for Weight Loss and Gene Modulation. As stated in another paper in the same journal:

“Reducing energy intake by controlled caloric restriction or intermittent fasting increases lifespan and protects various tissues against disease, in part, by hormesis mechanisms that increase cellular stress resistance.”

Regarding brain health in particular the author of another paper notes:

“It is likely that the capacity of the brain to remain healthy during aging depends upon its ability to adapt and nurture in response to environmental challenges. In these terms, main principles involved in hormesis can be also applied to understand relationships at a higher level of complexity such as those existing between the CNS and the environment.”

And yet another paper on aging in general beautifully articulates the practical meaning of hormesis:

“Hormesis in aging is represented by mild stress-induced stimulation of protective mechanisms in cells and organisms resulting in biologically beneficial effects. Single or multiple exposure to low doses of otherwise harmful agents, such as irradiation, food limitation, heat stress, hypergravity, reactive oxygen species and other free radicals have a variety of anti-aging and longevity-extending hormetic effects. Detailed molecular mechanisms that bring about the hormetic effects are being increasingly understood, and comprise a cascade of stress response and other pathways of maintenance and repair. Although the extent of immediate hormetic effects after exposure to a particular stress may only be moderate, the chain of events following initial hormesis leads to biologically amplified effects that are much larger, synergistic and pleiotropic. A consequence of hormetic amplification is an increase in the homeodynamic space of a living system in terms of increased defence capacity and reduced load of damaged macromolecules. Hormetic strengthening of the homeodynamic space provides wider margins for metabolic fluctuation, stress tolerance, adaptation and survival. Hormesis thus counter-balances the progressive shrinkage of the homeodynamic space, which is the ultimate cause of aging, diseases and death. Healthy aging may be achieved by hormesis through mild and periodic, but not severe or chronic, physical and mental challenges, and by the use of nutritional hormesis incorporating mild stress-inducing molecules called hormetins. The established scientific foundations of hormesis are ready to pave the way for new and effective approaches in aging research and intervention.”

An interesting paper published in the journal Molecular Neurobiology examines the hormetic effects of caloric restriction on the extremely important process of neuroplasticity.

“Aging is associated with the decline of cognitive properties. This situation is magnified when neurodegenerative processes associated with aging appear in human patients. Neuronal synaptic plasticity events underlie cognitive properties in the central nervous system.”

The authors comment on the hormetic effects of intermittent caloric restriction on the aging brain and nervous system:

“Caloric restriction (CR; either a decrease in food intake or an intermittent fasting diet) can extend life span and increase disease resistance. Recent studies have shown that CR can have profound effects on brain function and vulnerability to injury and disease. Moreover, CR can stimulate the production of new neurons from stem cells (neurogenesis) and can enhance synaptic plasticity, which modulate pain sensation, enhance cognitive function, and may increase the ability of the brain to resist aging.”

As in all other systems of the body…

“The beneficial effects of CR appear to be the result of a cellular stress response stimulating the production of proteins that enhance neuronal plasticity and resistance to oxidative and metabolic insults; they include neurotrophic factors, neurotransmitter receptors, protein chaperones, and mitochondrial biosynthesis regulators.”

The authors of a paper published in the journal Neurochemical Research also consider the role of hormesis in neuroprotection and brain aging.

“The predominant molecular symptom of aging is the accumulation of altered gene products. Moreover, several conditions including protein, lipid or glucose oxidation disrupt redox homeostasis and lead to accumulation of unfolded or misfolded proteins in the aging brain. Alzheimer’s and Parkinson’s diseases or Friedreich ataxia are neurological diseases sharing, as a common denominator, production of abnormal proteins, mitochondrial dysfunction and oxidative stress, which contribute to the pathogenesis of these so called “protein conformational diseases”. The central nervous system has evolved the conserved mechanism of unfolded protein response to cope with the accumulation of misfolded proteins. As one of the main intracellular redox systems involved in neuroprotection, the vitagene system is emerging as a neurohormetic potential target for novel cytoprotective interventions. Vitagenes encode for cytoprotective heat shock proteins (Hsp) Hsp70 and heme oxygenase-1, as well as thioredoxin reductase and sirtuins.”

Furthermore…

“Nutritional studies show that ageing in animals can be significantly influenced by dietary restriction. Thus, the impact of dietary factors on health and longevity is an increasingly appreciated area of research. Reducing energy intake by controlled caloric restriction or intermittent fasting increases lifespan and protects various tissues against disease.”

A fascinating study recently published in the Journal of Surgical Research examines the hormetic benefits of short-term preoperative caloric restriction on the response to surgical trauma. The authors state:

“Lifespan extension is achieved through long-term application of dietary restriction (DR), and benefits of short-term dietary restriction on acute stress and inflammation have been observed….We hypothesized that short-term DR in humans reduces the acute phase response following a well defined surgical trauma.”

They randomized thirty live kidney donors to either 30% preoperative dietary restriction followed by 1 d of fasting or a 4 d ad libitum diet prior to surgery. In addition to white blood cell subsets and numbers, they measured serum cytokine production after stimulation of whole blood with lipopolysaccharide (LPS). An excellent response to short-term caloric restriction was documented:

“A clear trend towards lower numbers of postoperative circulating leukocytes was observed in the DR group. IL-8 serum levels were significantly higher in the DR group over the first 6 postoperative days. After LPS stimulation, significantly less TNF-α was produced by blood obtained postoperatively compared with preoperative blood from the DR group. This was not observed in the control group.”

In other words, the short-term caloric restriction group expressed a much ‘better’ (less damaging) inflammatory response to surgical trauma compared to the control group. This begs for more research into the adoption of short-term or intermittent caloric restriction as the standard of care in preparation for surgery.

The phenomenon of hormesis in biology is a vast subject that every clinician must be familiar with to most effectively calibrate the dose of a wide range of interventions from medicines and supplements to exercise, caloric restriction and therapies that stimulate the body by the use of hands, needles or any other sensory-based modality—even subtle aspects of counseling and imagery. It is fundamental to our system of weight loss and gene modulation.

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Another outcome study to add to the massive body of evidence that the psychopharmaceutical model for treating depression is seriously flawed was published in the journal Psychosomatic Medicine. The authors pitted sertraline (Zoloft, an SSRI) against exercise and placebo as they set out to…

“…assess whether patients receiving aerobic exercise training performed either at home or in a supervised group setting achieve reductions in depression comparable to standard antidepressant medication (sertraline) and greater reductions in depression compared to placebo controls.”

They randomly assigned 202 adults diagnosed with major depression were to either supervised exercise in a group setting; home-based exercise; antidepressant medication (sertraline, 50–200 mg daily); or placebo pill for 16 weeks. This was followed by a structured clinical interview for depression and completed the Hamilton Depression Rating Scale (HAM-D). Typically, the data showed little difference between the placebo and Zoloft, and virtually no difference between the medication and exercise:

“After 4 months of treatment, 41% of the participants achieved remission, defined as no longer meeting the criteria for major depressive disorder (MDD) and a HAM-D score of <8. Patients receiving active treatments tended to have higher remission rates than the placebo controls: supervised exercise = 45%; home-based exercise = 40%; medication = 47%; placebo = 31%. All treatment groups had lower HAM-D scores after treatment; scores for the active treatment groups were not significantly different from the placebo group.”

There is an enormous amount of science showing that this class of medications profoundly perturbs the brain in such a way that attempting to stop taking them after 6 weeks or continuing them long-term can result in the dismal trap of a brain sensitized to depression. This study would have been even more striking had they compared the unmedicated exercise group to those who were medicated after attempting to stop. As it is, the authors conclude:

“The efficacy of exercise in patients seems generally comparable with patients receiving antidepressant medication and both tend to be better than the placebo in patients with MDD. Placebo response rates were high, suggesting that a considerable portion of the therapeutic response is determined by patient expectations, ongoing symptom monitoring, attention, and other nonspecific factors.”

Historically, before the age of psychopharmaceuticals most cases of major depression tended to be self-limiting. For an objective, meticulous, articulate and gripping scientific and historical narrative on how anti-depressants, tranquilizers and anti-psychotic medications have promoted the skyrocketing levels of mental disability, I suggest Anatomy of an Epidemic by Robert Whitaker. Anyone considering taking or prescribing these medications should be aware of the science reviewed comprehensively in this text.

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A surprising paper of great practical significance was just published in the journal Obesity that documents a significantly greater improvement in cardiovascular risk-related variables (triglycerides, insulin, metabolic syndrome score) with moderate-intensity exercise than with vigorous exercise. The authors offer this life-style pearl: “That all three of these strong, independent, cardiovascular risk factors were significantly affected by moderate-intensity exercise suggests that regular walking exercise might be as effective, if not more so, than more vigorous exercise in favorably modifying cardiovascular risk.” Further research will have to validate my expectation that the adrenocortical stress response plays a role here. Don’t forget the importance of interval training (see earlier posts), but at least get out for a walk.

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Not intended to ‘crack the whip’, this study just published in the British Medical Journal concludes: “Slow walking speed in older people is strongly associated with an increased risk of cardiovascular mortality.” It’s important to understand that when the elderly walk more slowly or have trouble with balance it is because of neurodegeneration, a brain problem. The connection is not just that the brain needs oxygen (from blood pumped by the heart)—neurodegeneration includes less control of inflammation, blood pressure, adrenal circadian rhythm, etc.

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As outlined in this recent paper, insulin resistance is a major risk factor for female cardiac health. A low glycemic, paleo-Mediterranean diet and interval-based exercise without over-training, plus supplemental nutrients according to individual genetic needs, are key life-style factors.

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In another study of the benefits of interval exercise training emphasizing extremely short bursts of high intensity exertion alternating with relaxation improved insulin sensitivity by 23%, a “remarkable” result. The exercise regime that achieved this outstanding result was 15 minutes of cycling 3 times per week for 2 weeks. Each 15 minute session included 4-6  sprints lasting 30 seconds each. 6 sprints would mean 30 seconds of high intensity alternating with 2 minutes of ‘relaxed cruising’. Those familiar with Heart Rate Variability Analysis will recognize the principle of exercising the parasympathetic relaxation phase in alternation with the sympathetic exertion with its benefits for the whole organism. This study is interesting in that it documents improvement specifically in insulin sensitivity.

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