Hormesis Articles 1

© 2011

Curcumin's biphasic hormetic response on proteasome activity and heat-shock protein synthesis in human keratinocytes

         (Ali and Rattan 2006) Download

Curcumin (diferuloylmethane), is a component of the yellow powder prepared from the roots of Curcuma longa (Zingiberaceae), also known as tumeric or turmeric. It is widely cultivated and used as a food ingredient in tropical areas of Asia and Central America. Treatment of mid-passage human epidermal keratinocytes with curcumin resulted in a biphasic hormetic dose-response with respect to proteasome activity. Curcumin treatment (up to 1 microM for 24 h) increased chymotrypsin-like activity by 46% compared to that in untreated keratinocytes. However, higher concentrations of curcumin were inhibitory, and at 10 microM the proteasome activity decreased to 46% of its initial value. Furthermore, the preincubation of human keratinocytes at 43 degrees C for 1 h, followed by 24-h treatment with 3 microM curcumin, led to an increase in heat-shock protein (hsp70 and hsp90) levels by 24% and 19%, respectively, and the effect was sustained at concentrations up to 10 microM. On the other hand, the level of the small hsp27 was unaffected by curcumin concentrations of 0.3-1 microM, while it decreased by 34% at 10 microM.

Cellular stress responses, mitostress and carnitine insufficiencies as critical determinants in aging and neurodegenerative disorders: role of hormesis and vitagenes

            (Calabrese, Cornelius et al. 2010) Download

The widely accepted oxidative stress theory of aging postulates that aging results from accumulation of oxidative damage. A prediction of this theory is that, among species, differential rates of aging may be apparent on the basis of intrinsic differences in oxidative damage accrual. Although widely accepted, there is a growing number of exceptions to this theory, most contingently related to genetic model organism investigations. Proteins are one of the prime targets for oxidative damage and cysteine residues are particularly sensitive to reversible and irreversible oxidation. The adaptation and survival of cells and organisms requires the ability to sense proteotoxic insults and to coordinate protective cellular stress response pathways and chaperone networks related to protein quality control and stability. The toxic effects that stem from the misassembly or aggregation of proteins or peptides, in any cell type, are collectively termed proteotoxicity. Despite the abundance and apparent capacity of chaperones and other components of homeostasis to restore folding equilibrium, the cell appears poorly adapted for chronic proteotoxic stress which increases in cancer, metabolic and neurodegenerative diseases. Pharmacological modulation of cellular stress response pathways has emerging implications for the treatment of human diseases, including neurodegenerative disorders, cardiovascular disease, and cancer. A critical key to successful medical intervention is getting the dose right. Achieving this goal can be extremely challenging due to human inter-individual variation as affected by age, gender, diet, exercise, genetic factors and health status. The nature of the dose response in and adjacent to the therapeutic zones, over the past decade has received considerable advances. The hormetic dose-response, challenging long-standing beliefs about the nature of the dose-response in a lowdose zone, has the potential to affect significantly the design of pre-clinical studies and clinical trials as well as strategies for optimal patient dosing in the treatment of numerous diseases. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing stress responses, including carnitines. This paper describes in mechanistic detail how hormetic dose responses are mediated for endogenous cellular defense pathways, including the possible signaling mechanisms by which the carnitine system, by interplaying metabolism, mitochondrial energetics and activation of critical vitagenes, modulates signal transduction cascades that confer cytoprotection against chronic degenerative damage associated to aging and neurodegenerative disorders.

Adverse effects of nutritional inadequacy and excess: a hormetic model

            (Hayes 2008) Download

I address and explain the increased risk of adverse effects from nutrients by using the paradigm of hormesis, the biological and toxicological concept that small quantities have opposite effects from large quantities. To provide necessary background, I categorize, depict, discuss, and contrast hormetic and other dose-response relations. I review some of the different hormetic mechanisms that others have proposed. I then use the hormetic paradigm to explain adverse effects from essential nutrients, including vitamin D. The hormesis paradigm could be useful to nutritional scientists in their consideration of nutritional adverse effects.


Nutritional hormesis and aging

            (Hayes 2009) Download

Nutritional hormesis has the potential to serve as a pro-healthy aging intervention by reducing the susceptibility of the elderly to various chronic degenerative diseases and thereby extending human healthspan. Supportive evidence for nutritional hormesis arising from essential nutrients (vitamins and minerals), dietary pesticides (natural and synthetic), dioxin and other herbicides, and acrylamide will be reviewed and discussed.

Dietary factors, hormesis and health

            (Mattson 2008) Download

The impact of dietary factors on health and longevity is increasingly appreciated. The most prominent dietary factor that affects the risk of many different chronic diseases is energy intake -- excessive calorie intake increases the risk. 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. Some specific dietary components may also exert health benefits by inducing adaptive cellular stress responses. Indeed, recent findings suggest that several heavily studied phytochemicals exhibit biphasic dose responses on cells with low doses activating signaling pathways that result in increased expression of genes encoding cytoprotective proteins including antioxidant enzymes, protein chaperones, growth factors and mitochondrial proteins. Examples include: activation of the Nrf-2 -- ARE pathway by sulforaphane and curcumin; activation of TRP ion channels by allicin and capsaicin; and activation of sirtuin-1 by resveratrol. Research that establishes dose response and kinetic characteristics of the effects of dietary factors on cells, animals and humans will lead to a better understanding of hormesis and to improvements in dietary interventions for disease prevention and treatment.

Lifestyle-induced metabolic inflexibility and accelerated ageing syndrome: insulin resistance, friend or foe?

            (Nunn, Bell et al. 2009) Download

ABSTRACT: The metabolic syndrome may have its origins in thriftiness, insulin resistance and one of the most ancient of all signalling systems, redox. Thriftiness results from an evolutionarily-driven propensity to minimise energy expenditure. This has to be balanced with the need to resist the oxidative stress from cellular signalling and pathogen resistance, giving rise to something we call 'redox-thriftiness'. This is based on the notion that mitochondria may be able to both amplify membrane-derived redox growth signals as well as negatively regulate them, resulting in an increased ATP/ROS ratio. We suggest that 'redox-thriftiness' leads to insulin resistance, which has the effect of both protecting the individual cell from excessive growth/inflammatory stress, while ensuring energy is channelled to the brain, the immune system, and for storage. We also suggest that fine tuning of redox-thriftiness is achieved by hormetic (mild stress) signals that stimulate mitochondrial biogenesis and resistance to oxidative stress, which improves metabolic flexibility. However, in a non-hormetic environment with excessive calories, the protective nature of this system may lead to escalating insulin resistance and rising oxidative stress due to metabolic inflexibility and mitochondrial overload. Thus, the mitochondrially-associated resistance to oxidative stress (and metabolic flexibility) may determine insulin resistance. Genetically and environmentally determined mitochondrial function may define a 'tipping point' where protective insulin resistance tips over to inflammatory insulin resistance. Many hormetic factors may induce mild mitochondrial stress and biogenesis, including exercise, fasting, temperature extremes, unsaturated fats, polyphenols, alcohol, and even metformin and statins. Without hormesis, a proposed redox-thriftiness tipping point might lead to a feed forward insulin resistance cycle in the presence of excess calories. We therefore suggest that as oxidative stress determines functional longevity, a rather more descriptive term for the metabolic syndrome is the 'lifestyle-induced metabolic inflexibility and accelerated ageing syndrome'. Ultimately, thriftiness is good for us as long as we have hormetic stimuli; unfortunately, mankind is attempting to remove all hormetic (stressful) stimuli from his environment.

How increased oxidative stress promotes longevity and metabolic health: The concept of mitochondrial hormesis (mitohormesis)

            (Ristow and Zarse 2010) Download

Recent evidence suggests that calorie restriction and specifically reduced glucose metabolism induces mitochondrial metabolism to extend life span in various model organisms, including Saccharomyces cerevisiae, Drosophila melanogaster, Caenorhabditis elegans and possibly mice. In conflict with Harman's free radical theory of aging (FRTA), these effects may be due to increased formation of reactive oxygen species (ROS) within the mitochondria causing an adaptive response that culminates in subsequently increased stress resistance assumed to ultimately cause a long-term reduction of oxidative stress. This type of retrograde response has been named mitochondrial hormesis or mitohormesis, and may in addition be applicable to the health-promoting effects of physical exercise in humans and, hypothetically, impaired insulin/IGF-1-signaling in model organisms. Consistently, abrogation of this mitochondrial ROS signal by antioxidants impairs the lifespan-extending and health-promoting capabilities of glucose restriction and physical exercise, respectively. In summary, the findings discussed in this review indicate that ROS are essential signaling molecules which are required to promote health and longevity. Hence, the concept of mitohormesis provides a common mechanistic denominator for the physiological effects of physical exercise, reduced calorie uptake, glucose restriction, and possibly beyond.

Hormetic dietary phytochemicals

            (Son, Camandola et al. 2008) Download

Compelling evidence from epidemiological studies suggests beneficial roles of dietary phytochemicals in protecting against chronic disorders such as cancer, and inflammatory and cardiovascular diseases. Emerging findings suggest that several dietary phytochemicals also benefit the nervous system and, when consumed regularly, may reduce the risk of disorders such as Alzheimer's and Parkinson's diseases. The evidence supporting health benefits of vegetables and fruits provide a rationale for identification of the specific phytochemicals responsible, and for investigation of their molecular and cellular mechanisms of action. One general mechanism of action of phytochemicals that is emerging from recent studies is that they activate adaptive cellular stress response pathways. From an evolutionary perspective, the noxious properties of such phytochemicals play an important role in dissuading insects and other pests from eating the plants. However at the subtoxic doses ingested by humans that consume the plants, the phytochemicals induce mild cellular stress responses. This phenomenon has been widely observed in biology and medicine, and has been described as 'preconditioning' or 'hormesis.' Hormetic pathways activated by phytochemicals may involve kinases and transcription factors that induce the expression of genes that encode antioxidant enzymes, protein chaperones, phase-2 enzymes, neurotrophic factors, and other cytoprotective proteins. Specific examples of such pathways include the sirtuin-FOXO pathway, the NF-kappaB pathway, and the Nrf-2/ARE pathway. In this article, we describe the hormesis hypothesis of phytochemical actions with a focus on the Nrf2/ARE signaling pathway as a prototypical example of a neuroprotective mechanism of action of specific dietary phytochemicals.


References

Ali, R. E. and S. I. Rattan (2006). "Curcumin's biphasic hormetic response on proteasome activity and heat-shock protein synthesis in human keratinocytes." Ann N Y Acad Sci 1067: 394-9.

Calabrese, V., C. Cornelius, et al. (2010). "Cellular stress responses, mitostress and carnitine insufficiencies as critical determinants in aging and neurodegenerative disorders: role of hormesis and vitagenes." Neurochem Res 35(12): 1880-915.

Hayes, D. P. (2008). "Adverse effects of nutritional inadequacy and excess: a hormetic model." Am J Clin Nutr 88(2): 578S-581S.

Hayes, D. P. (2009). "Nutritional hormesis and aging." Dose Response 8(1): 10-5.

Mattson, M. P. (2008). "Dietary factors, hormesis and health." Ageing Res Rev 7(1): 43-8.

Nunn, A. V., J. D. Bell, et al. (2009). "Lifestyle-induced metabolic inflexibility and accelerated ageing syndrome: insulin resistance, friend or foe?" Nutr Metab (Lond) 6: 16.

Ristow, M. and K. Zarse (2010). "How increased oxidative stress promotes longevity and metabolic health: The concept of mitochondrial hormesis (mitohormesis)." Exp Gerontol 45(6): 410-8.

Son, T. G., S. Camandola, et al. (2008). "Hormetic dietary phytochemicals." Neuromolecular Med 10(4): 236-46.