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Low-level oxidative stress induces an adaptive response commonly defined as hormesis; this type of stress is often related to reactive oxygen species (ROS) originating from the mitochondrial respiratory chain (mitochondrial hormesis or mitohormesis). The accumulation of transient low doses of ROS either through chronic physical activity or caloric restriction influences signaling from the mitochondrial compartment to the cell, reduces glucose metabolism, induces mitochondrial metabolism, increases stress resistance and ultimately, increases lifespan. Mitochondrial formation of presumably harmful levels (chronic and/or excessive) of ROS within skeletal muscle has been observed in insulin resistance of obese subjects, type 2 diabetes mellitus, as well as in impaired muscle function associated with normal aging. Advances in mitochondrial bioimaging combined with mitochondrial biochemistry and proteome research have broadened our knowledge of specific cellular signaling and other related functions of the mitochondrial behavior. In this review, we describe mitochondrial remodeling in response to different degrees of oxidative insults induced in vitro in myocytes and in vivo in skeletal muscle, focusing on the potential application of a combined morphological and biochemical approach. The use of such technologies could yield benefits for our overall understanding of physiology for biotechnological research related to drug design, physical activity prescription and significant lifestyle changes.
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. 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. 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.
The Concept of Hormesis
The term hormesis (see Calabrese et al., 2007 for a detailed consideration of the definition and uses of hormesis) has been most widely used in the toxicology field where investigators use it to describe a biphasic dose response with a low dose stimulation or beneficial effect and a high dose inhibitory or toxic effect. The response of the cell or organism to the low dose of the toxin is considered an adaptive compensatory process following an initial disruption in homeostasis. Thus, a short working definition of 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’. The prevalence in the literature of hormetic dose responses to environmental toxins has been reviewed comprehensively (Calabrese and Blain, 2005), as have the implications of toxin-mediated hormesis for understanding carcinogenesis and its prevention (Calabrese, 2005). Several different terms are commonly used to describe specific types of hormetic responses including “preconditioning” and “adaptive stress response”.
Mitochondrial dysfunctions during aging are also connected with hormesis, a concept on which a number of aging research lines have recently converged (Calabrese et al., 2011). According to this concept, mild toxic treatments trigger beneficial compensatory responses that surpass the repair of the triggering damage, and actually produce an improvement in cellular fitness when compared to the starting pre-damage conditions. Thus, although severe mitochondrial dysfunction is pathogenic, mild respiratory deficiencies may increase lifespan, perhaps due to a hormetic response (Haigis and Yankner, 2010).
Such hormetic reactions may consist in the induction of a mitochondrial stress response either in the same tissue in which mitochondria are defective, or even in distant tissues, as shown in C. elegans (Durieux et al., 2011).
There is compelling evidence that compounds such as metformin and resveratrol are mild mitochondrial poisons that induce a low energy state characterized by increased AMP levels and activation of AMPK (Hawley et al., 2010). Importantly, metformin extends lifespan in C. elegans through the induction of a compensatory stress response mediated by AMPK and the master anti-oxidant regulator Nrf2 (Onken and Driscoll, 2010). Recent studies have also shown that metformin retards aging in worms by impairing folate and methionine metabolism of their intestinal microbiome (Cabreiro et al., 2013). Regarding mammals, metformin can increase mouse lifespan when administered from early life (Anisimov et al., 2011). In the cases of resveratrol and the sirtuin activator SRT1720, there is convincing evidence that they protect from metabolic damage and improve mitochondrial respiration in a PGC-1α-dependent fashion (Baur et al., 2006; Feige et al., 2008; Lagouge et al., 2006; Minor et al., 2011), although resveratrol does not extend mouse lifespan under normal dietary conditions (Pearson et al., 2008; Strong et al., 2012).
Further support for the role of PGC-1α in longevity comes from the observation that PGC-1α overexpression suffices to extend Drosophila lifespan in association with improved mitochondrial activity (Rera et al., 2011). Finally, mitochondrial uncoupling, either genetically through the overexpression of the uncoupling protein UCP1 or by administration of the chemical uncoupler 2-4-dinitrophenol can increase lifespan in flies and mice (Caldeira da Silva et al., 2008; Fridell et al., 2009; Gates et al., 2007; Mookerjee et al., 2010).
The Importance of Hormesis to Public Health
Hormesis is a specific type of nonmonotonic dose response whose occurrence has been documented across a broad range of biological models, diverse types of exposure, and a variety of outcomes. The effects that occur at various points along this curve can be interpreted as beneficial or detrimental, depending on the biological or ecologic context in which they occur.
Because hormesis appears to be a relatively common phenomenon that has not yet been incorporated into regulatory practice, the objective of this commentary is to explore some of its more obvious public health and risk assessment implications, with particular reference to issues raised recently within this journal by other authors.
Hormesis appears to be more common than dose–response curves that are currently used in the risk assessment process [e.g., linear no-threshold (LNT)]. Although a number of mechanisms have been identified that explain many hormetic dose–response relationships, better understanding of this phenomenon will likely lead to different strategies not only for the prevention and treatment of disease but also for the promotion of improved public health as it relates to both specific and more holistic health outcomes.
We believe that ignoring hormesis is poor policy because it ignores knowledge that could be used to improve public health.
The acceptance of the concept of hormesis, a specific type of nonmonotonic dose response, has accelerated in recent years (Academie Nationale de Medecine 2005; Cendergreen et al. 2005; Kaiser 2003; Puatanachokchai et al. 2005; Randic and Estrada 2005; Renner 2003). Nonetheless, it has not been without its detractors. One article critical of the concept was published last year in Environmental Health Perspectives (Thayer et al. 2005). It provided a summary of the major points of contention and thus a convenient vehicle for us to use in responding to opposing perspectives.
Although Thayer et al. (2005) tacitly acknowledged the existence of the phenomenon, they argued that no consideration should be given to hormesis in assessments of chemical risks for regulatory purposes. We disagree with their conclusion, but believe some of their points have merit—with important clarifications. We also believe that the proper understanding and utilization of hormesis will do a much better job of both protecting and promoting public health than the policy-based defaults that are currently in use.
Contrary to the assertion of Thayer et al. (2005) that hormesis is rare, it is a ubiquitous natural phenomenon (Calabrese and Blain 2005). Although given many names, hormesis has been observed in the fields of medicine (Brandes 2005; Celik et al. 2005), molecular biology (Randic and Estrada 2005), pharmacology (Chiueh et al. 2005), nutrition (Lindsay 2005), aging and geriatrics (Lamming et al. 2004; Rattan 2004a, 2004b, 2004c, 2005; Sinclair et al. 2005), agriculture (Brandt et al. 2004; Shama and Alderson 2005), microbiology (Brugmann and Firmani 2005), immunology (Dietert 2005; Liu 2003), toxicology (Stebbing 2000), exercise physiology (Radak et al. 2005), and carcinogenesis (Fukushima et al. 2005)—literally, across the biological spectrum. It has also been observed in relation to disparate outcomes from the isolated single cellular process to the more holistic (e.g., growth, longevity, disease, death) that likely result from a complex interplay of multiple factors and mechanisms (Calabrese 2005d).
In worms, glucose restriction increases lifespan (R).
Reduced glucose availability promotes formation of reactive oxygen species (ROS), induces catalase activity, and increases oxidative stress resistance and survival rates. These effects lead to “mitochondrial hormesis” (R).
Cell Metab. 2007 Oct;6(4):280-93.
Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress.
Increasing cellular glucose uptake is a fundamental concept in treatment of type 2 diabetes, whereas nutritive calorie restriction increases life expectancy. We show here that increased glucose availability decreases Caenorhabditis elegans life span, while impaired glucose metabolism extends life expectancy by inducing mitochondrial respiration. The histone deacetylase Sir2.1 is found here to be dispensable for this phenotype, whereas disruption of aak-2, a homolog of AMP-dependent kinase (AMPK), abolishes extension of life span due to impaired glycolysis. Reduced glucose availability promotes formation of reactive oxygen species (ROS), induces catalase activity, and increases oxidative stress resistance and survival rates, altogether providing direct evidence for a hitherto hypothetical concept named mitochondrial hormesis or “mitohormesis.” Accordingly, treatment of nematodes with different antioxidants and vitamins prevents extension of life span. In summary, these data indicate that glucose restriction promotes mitochondrial metabolism, causing increased ROS formation and cumulating in hormetic extension of life span, questioning current treatments of type 2 diabetes as well as the widespread use of antioxidant supplements.
Heat stress acts as a hormetic response that reduces protein damage and build up by boosting antioxidant activity, as well as repair and degradation processes (autophagy)
Saunas are the best way to experience thermal stress
Hormesis is the concept of introducing an acute stress to the body, in which case the body will have a reaction that will prep it for future stressors that are even stronger. By being prepped, the body can be shifted into a state of higher performance.
Vaccines work in this manner. You introduce a tiny dose of a pathogen and the body responds with developing immunity to an even bigger onslaught of that pathogen.
When you introduce small stressors, the body will super-compensate and become stronger.
Exercise mainly works by hormesis as well, which is why it’s an effective enhancement tool for people who are already very healthy.
The American ethos, though, has a hard time digesting this concept and using it properly. We like the concept of becoming stronger but we lack the culture of moderation and the wisdom that less is more.
We view hormesis as what doesn’t kill you makes you stronger.
In reality, what doesn’t harm you too much makes you stronger. We like to take things to the extreme, though. If something is good we’ll do more of it. Exercise is healthy? Great. Time to run marathons.
The dose used in hormesis must be carefully applied according to the individual’s initial condition. For example, someone who hasn’t exercised in years shouldn’t suddenly engage in exhaustive exercise. In the same vein, someone with a ‘leaky gut’ should not be exercising exhaustively or drinking alcohol because these things exacerbate such a condition. With hormesis, the dose is key. A little is great and a lot is terrible.
The conditional nature of hormesis adds complexity and naturally humans don’t like this because we tend to view the world in a binary fashion, where things are either good or bad. If it’s good, we like it and if it’s not we don’t. A nuanced approach is missing here, where the answer isn’t “yes” or “no” but rather “it depends.”
Examples of Hormesis in Health
•Interval exercise – sprints, weight lifting
•Using an oxygen tank- or breathing exercises
•Meditation – has some aspects of it
•Getting glycogen depletes
•Herbal supplements – Adaptogens, Curcumin, Resveratrol, Berberine, Gynostemma, Grapeseed extract, etc..
•Vegetables, plant-based foods – plant toxins
•Caffeine – alkaloids in general work by hormesis
•Short-term nutrient deficiency
•Very low doses of environmental toxins – even heavy metals. The problem is we’re exposed to them chronically often….
•Getting sick – I don’t recommend it for adults, but kids growing up have a better developed immune system when they play with germs.
Low dose radiation
Low dose inflammation ?
Tips for Using Hormesis
•It’s better to have all the basic building blocks(i.e. proper diet and nutrition) before you start hormetic types of enhancements.
•The dose is everything.
•The proper dose can be different for different people in different circumstances.
•Less is more.
•Do not “stack”.
•You must fully heal before taking the next dose.
•Take breaks. Use different kinds of stressors during these breaks that stress different aspects of the body/mind.
•Do not use stressors to improve performance during or immediately after. Performance actually takes a dip right after the stimulus. Effects accrue over time, though.
•When you stop feeling an effect, up the dosage by a little.