Hormesis Can and Does Work in Humans

Abstract

If we accept the validity of the general concept of physiological hormesis as being the phenomenon of achieving health beneficial effects by exposure to mild stress, then hormesis is being applied already and successfully to humans. The evidence for this is the well-demonstrated health benefits of regular and moderate exercise. Mild stress-induced activation of one or more intracellular pathways of stress response are central to this. Experimental studies performed on human cells in culture exposed to mild heat shock and other stresses provide biochemical and molecular evidence in support of the application of hormesis to human systems. Although several issues remain to be resolved by more research with respect to the extent and duration of hormetic exposure, making use of the cellular stress response pathways can facilitate discovering novel hormetins for human applications.

INTRODUCTION

If the general concept of physiological hormesis as being the phenomenon of achieving health beneficial effects by exposure to mild stress is accepted, then hormesis is being applied already and successfully to humans. The evidence for this is the well demonstrated health benefits of regular and moderate exercise. These benefits range from improved physique and enhanced pulmonary-cardio stamina to a delay or prevention of onset of age-related metabolic diseases, and to an increase in the mental, hormonal and emotional functionality. The expectation that such an increase in the general well being and the quality of life also leads to increased health-span and total lifespan is its logical extension, with emerging epidemiological data in its support (Khaw et al., 2008; Landi et al., 2008; Yates et al., 2008; Fisher-Wellman and Bloomer, 2009). The beneficial effects of exercise can best be understood within the framework of stress-induced hormesis. This is because exercise increases the production of potentially harmful substances, such as reactive oxygen species (ROS), reactive nitrogen species (RNS), other free radicals, acids and aldehydes. The most significant physiological change that occurs during exercise is up to 20-fold enhanced mitochondrial respiration and oxidative phosphorylation leading to increased metabolic rate and its potentially damaging byproducts (Goto et al., 2007; Radak et al., 2008; Rattan, 2008a, b; Goon et al., 2009).

The question, therefore, is not whether hormesis is applicable as an aging intervention, but how to apply it in the context of our present understanding of aging and its consequent age-related diseases. In order to do so, it maybe useful to recapitulate what has been understood so far in biogerontology with respect to the general principles of aging and longevity, which form the basis of applying hormesis as an intervention.

AGING AS A PROGRESSIVE SHRINKAGE OF THE HOMEODYNAMIC SPACE

Aging, senescence and death are the final manifestations of unsuccessful homeostasis or failure of homeodynamics (Rattan, 2006). A wide range of molecular, cellular and physiological pathways of repair are well known, and these include multiple pathways of nuclear and mitochondrial DNA repair, free radical counteracting mechanisms, protein turnover and repair, detoxification mechanisms, and other processes including immune- and stress-responses. All these processes involve numerous genes whose products and their interactions give rise to a “homeodynamic space” or the “buffering capacity”, which is the ultimate determinant of an individual’s chance and ability to survive and maintain a healthy state (Rattan, 2006; Holliday, 2007). A progressive shrinking of the homeodynamic space, mainly due the accumulation of molecular damage, is the hallmark of aging and the cause of origin of age-related diseases (Rattan, 2008c).

HORMETIC MODULATION OF AGING IN HUMAN CELLS

A critical component of the homeodynamic property of living systems is their capacity to respond to stress. In this context, the term “stress” is defined as a signal generated by any physical, chemical or biological factor (stressor), which in a living system initiates a series of events in order to counteract, adapt and survive. While a successful and over-compensatory response to low doses of stressors improve the overall homeodynamics of cells and organisms, an incomplete or failed homeodynamic response leads to the damaging and harmful effects of stress. It is this homeodynamic space as a whole or the individual components of the homeodynamic machinery, which are the targets of hormetic interventions.

Aging modulatory effects of hormesis have been reported for various human cell types in vitro. For example, using a regimen of repeated mild heat shock at 41°C, for 1 hr twice a week, given to cultured normal human skin fibroblasts, keratinocytes, endothelial cells, and telomerase-immortalised bone marrow mesenchymal stem cells, we have reported a variety of hormetic effects. These effects include slowing down of cellular aging, some extension of replicative lifespan, maintenance of youthful morphology, reduction in the levels of oxidatively- and glycoxidatively-damgaed proteins, stimulation of proteasomal activities, increased levels of chaperones, enhancement of stress tolerance, and improvement in differentiation, wound healing and angiogenesis (Rattan et al., 2009). Other hormetic conditions, which have been shown to have some anti-aging effects in human cells, are irradiation, mechanical stretching and electromagnetic field shock (Holliday, 1991; Perez et al., 2008; Rattan, 2008b). Thus, the proof of the principle regarding the applicability of hormesis as a modulator of aging in human cells is well demonstrated. However, further short term and long term studies, using a wide variety of human cell types, and a combination of stressors, are required in order to establish the universality of the phenomenological and mechanistic aspects of this issue.

INDIVIDUALISTIC NATURE OF AGING AND PERSONALIZED HORMESIS

A crucial aspect of aging is the individualistic nature of age-related changes. The rate and progress of aging differs among individuals, among different parts of the individual, and among different tissues, cell types and molecular types within. A combination of genes, milieu and chance or stochastic events is what effectively determines the duration and quality of life (Rattan, 2007). As is being increasingly realized for any kind of biomedical, therapeutic and interventionary approaches personalized strategies will have to be developed in the case of hormesis too (Bains, 2008). Some of the main factors that will have to be considered for this include genetic polymorphism, and epigenetic factors involving pre- and post-natal exposures to stress, nutritional and lifestyle habits, and disease- and infection-history of the individual. Additionally, varied response of different cell types to single or multiple stressors as a function of age will also be a critical factor to be taken into consideration. The knowledge about all such factors will be essential for applying appropriate hormetic challenge at appropriate time and age at an appropriate level and combination.

DISCOVERING NOVEL HORMETINS

A hormetin is defined as any condition that may be potentially hormetic in physiological terms, by invoking one or more pathways of stress response (SR) within a cell. Table 1 gives a list of the main and immediate molecular SR pathways, that are integral to the organismic property of homeodynamics. Based on the involvement of one or more molecular SR, higher order responses (cellular, organ level and body level) are manifested, which include down-stream expression of numerous genes, and the resultant cellular and physiological phenotypes, such as apoptosis, inflammation, and hyperadrenocorticism.

TABLE 1:

Main molecular level stress responses in a cell.

Response	Stressors	Effectors	References
Heat shock response	Heat, heavy metals, antibiotics, protein denaturation	Heat shock proteins, proteasome and other proteases	(Liberek et al., 2008)
Unfolded protein response	Unfolded and misfolded proteins in endoplasmic reticulum	Chaperones, co-chaperones	(Yoshida, 2007)
Antioxidant response	Free radicals, reactive oxygen species, pro-oxidants	Nrf-2, heme-oxygenase, FOXO	(Ishii et al., 2002)
NF-κB inflammatory response	Pathogens, allergens, damaged macromolecules	cytokines, nitric oxide synthase	(Medzhitov, 2008)
Autophagic response	Food starvation, hypoxia, damaged organelles	Lysosomes	(Yen and Klionsky, 2008)
DNA-repair response	Radiation, oxidants, free radicals	DNA-repair enzymes	(Hakem, 2008)
Sirtuin response	Energy depletion	Sirtuins	(Longo, 2009)

Not all pathways of SR respond to every stressor, and although there may be some overlap, generally SR pathways are quite specific. The specificity of the response is mostly determined by the nature of the damage induced by the stressor and the variety of downstream effectors involved. For example, cytoplasmic induction of protein denaturation by heat, heavy metals and antibiotics will initiate the so-called heat shock response by inducing the synthesis of heat shock proteins, followed by the activation of proteasome-mediated protein degradation (Verbeke et al., 2001; Liberek, et al., 2008). But, unfolded proteins in the endoplasmic reticulum (ER) will induce unfolded protein response (UPR), and will initiate the induction of synthesis of a totally different set of proteins and their downstream effectors (Banhegyi et al., 2007; Yoshida, 2007). Furthermore, often the source of activation (stressor) cannot be easily identified, and may involve more than one stressor and their effectors. Examples of such SR include early inflammatory SR and neuroendocrinal SR, which lead to the synthesis and release of interleukins and corticoid hormones, respectively. Similarly, pathways involving NF-kB, Nrf2, FOXO, sirtuins and heme-oxygenase activation may involve more than one type of stressors and stress signals, including pro-oxidants, free radicals, ROS, and nutritional components.

The seven major pathways of SR listed above can be used as the screening platform for discovering, testing and monitoring the effects of novel hormetins. Such hormetins may be categorized as: (1) physical hormetins, such as exercise, heat and radiation; (2) biological and nutritional hormetins, such as infections, micronutrients, spices and other sources; and (3) psychological hormetins, such as mental challenge and focused attention or meditation.

Finally, although the precise mode and extent of application of hormesis for maintaining and/or improving human health and longevity still needs resolving several important issues discussed above, many of the commonly issued public health recommendations involving lifestyle modifications make use of hormetic principles knowingly or unknowingly. What is important and demands serious and urgent attention of scientists and science-policy makers is recognizing that hormesis can be a powerful public health tool that can help to maintain health and extend health-span and longevity.