Basis of the biological hormesis
Hormesis is the term used to describe biological phenomena that are often adverse or detrimental but become beneficial when applied at low levels.
The concept of biological hormesis is as important as that of homeostasis for the survival of the organism.
The basic biological trait is the organismís ability to resist and adapt appropriately to both internal and external stresses, and the hallmark of aging is the organismís inability to withstand stress.
The hormetic phenomenon in aging is characterized as beneficial responses to stress through the physiological adaptations, as exemplified in lifespan extension by irradiation and calorie restriction.
Thus, hormesis in aging is the biological adaptive function to resist or blunt the age-related deleteriousness.
Such a remarkable biological hormetic effect was shown experimentally by exposing mice to a low dose of gamma irradiation, which extended the lifespan of mice rather than shortening by turmorigenesis.
The plausible explanation on this interesting radiation hormesis is that the irradiated mice were able to resist better, because the mild radiation itself is the most effective factor in conditioning for the activation of adaptation.
In response to stress, an organism is expected to go through three distinct phases: alarm reaction, resistance phase, and exhaustion phase.
According this schema, the adaptability can be developed during the resistance period.
This notion is in line with the evolutionary view on the survival for the fittest theory, for which the only possible way to attain the survivability is through the organismís metabolic and defensive adaptation to deleterious stress.
Evidence of hormesis in aging
The relationship between stress and aging has a long history.
One early proposal on the question of stress on aging was so called "the stress theory of agingí.
The implication of this stress theory is that exposure to chronic stress accelerates the aging process, thus shortening the lifespan, in contrast to what was found with a mild stress effect of hormetic response.
Excessive secretion of stress hormones such as ACTH, cortisol, and catecholamines are blamed for such life-shortening effect indicating the possibility of the aforementioned exhaustion phase.
Thus, in terms of hormesis, this stress theory of aging concerned only the adverse, lethal aspect of stress far beyond the optimal level of stimulation.
Among many examples of the beneficial effects of hormesis, physical exercise can easily be observed, because proper exercise, not exhaustive, can improve the body function and deter the occurrence of diseases, extend the average lifespan, and resist to oxidative stress.
Defense against infection by immunization, and a growth stimulation of bacteria treated by a sub-lethal pesticide are another examples.
Life extension by dietary restriction, which is the hallmark of the intervention of the aging process may be the strongest evidence yet supporting the idea of its anti-aging hormetic phenomenon.
Evidence reveals that dietary restricted animals are able to withstand various stresses.
How well calorie-restricted animals can resist stress was well illustrated by the suppression of chemically or radiation induced turmorigenesis.
Resistance to internal stress by calorie restriction is exhibited by the fact that in spite of life-shortening hyperglucocorticoid state in these restricted animals, they can live as long as 40Ė50% longer than ad libitum fed control.
Furthermore, calorie restricted animals have shown a greater capacity to resist oxidative stress (see below), inflammatory insults, and physical exhaustion.
Thus, the caveat revealed from calorie restriction research is that the intervention of the aging process may be possible by increasing the animalís innate resistance capacity against life-threatening stresses or insults.
Calorie restriction as a potent suppressor of oxidative stress
Research on oxidative stress has proved calorie restriction to be an effective suppressor of life-shortening free radicals and redox-imbalance that destroy cellular homeostasis.
Accumulated evidence consistently shows that the redox status of restricted animals is well maintained by reducing the generation of free radicals, lipid peroxidation, oxidatively damaged proteins, DNA, lipids, and carbohydrates.
More significantly, the antioxidative defense systems in these restricted animals are far better maintained by the elevated scavenging ability and various antioxidants, and detoxification.
One more outstanding feature of calorie restriction is the maintenance of the membrane stability such as mitochondrial membranes with a strong resistance against membrane perturbants.
Based on these and other data, it has been concluded that calorie restriction is not only the best experimental evidence supporting the oxidative stress hypothesis, but also proving the efficacy of nutritional intervention of aging and the pathological process.
The recent investigation on changes in the gene profile by calorie restriction produced interesting data showing the gene adaptation at molecular levels.
This molecular probing revealed clues on how animals mobilize innate survival strategies under calorie deprivation.
Under the calorically deprived conditions, the animals were able to turn on the activation of many stress-related genes, the up-regulation of gluconeogenesis and protein synthesis and turnover for the increased energy efficiency.
It appears that restricted animals seem to "reset" the metabolic priority under limited energy availability for survival, resulting in a longer lifespan.
Gene profiling showed that genes involved in detoxification, antioxidative defenses, repair enzyme systems, and anti-inflammatory process were selectively up-regulated.
Hormetic action of anti-aging calorie restriction
One crucial question to be asked is that how this simple, reduced calorie intake can produce such diverse and effective anti-aging benefits.
Is there any possibility that all these diverse effects of calorie restriction share a common mechanism? The answer may be found in the concept of hormesis.
Among several hypotheses that have been proposed to explain such remarkable robust anti-aging actions, recent discussions on hormesis-derived stress resistance by calorie restriction draw nutritionistsí attention.
Hormetic resistance for stimulation seems to be an evolutionarily acquired survival mechanism by adapting to challenges to overcome the adverse environmental conditions.
Examples of hormetic response are readily observed in both animal as well as plant kingdoms: vaccination for the stimulation of immune defense activity, physical exercise for the vigor, or pruning trees for growth stimulation.
The prime example of the radiation hormetic response was demonstrated by the life span extension (about 20%) by a mild low dose of gamma irradiation of mice.
Within this context, nutrition wise, as a mild stress imposed by a reduced calorie intake acts as a stimulant for the survival against insults of disease-causing oxidative stress.
It is believed that this resistive ability was acquired through the evolutionary process by maximizing the energy utilization by allocating only for the essential life supporting systems.
Recent studies on gene expression profiles of calorie restricted animals using DNA chip produced supporting data.
Lee et al. reported that out of 6347 genes activated under calorie restricted condition, 16% were stress response, and 13% were related energy metabolism, suggesting that the metabolic shifts are directed to prioritize the energy utilization only for essential defense processes.
The resistive responses are very impressive in that turmorigenesis by irradiation or carcinogens were significantly suppressed by calorie restriction.
Perhaps a more interesting effect of calorie restriction is how quickly the animals react to reduced feeding by turning on the molecular machinery for the metabolic adjustment within a few weeks as exhibited by the differential gene expression reported by Cao et al.
Aging research based on hormesis principle
The future search for new interventive measures against the aging process may gain more important insights by utilizing the hormetic response at the whole organism level.
Currently, most anti-aging strategy is limited to the use of supplementations of various antioxidants to curb oxidative stress.
This approach is beneficial, but expected to have only a limited success, unlike dietary restrictionís powerful and diversified action.
Hormetic stimulation of the organismís selective immune components to its optimal levels is worth considering as an anti-aging intervention, although the precise techniques to achieve this require extensive research.
In summary, the introduction of the hormesis concept to biology, particularly to aging, is quite promising, but requires extensive experimental substantiations of mechanistic bases, and how well its concept can be applicable to the aging process and the intervention depend on the resolution of several key questions.
Included in this are what constitutes "optimal" stress, what are underlying mechanisms for a specific mode of stress, how to quantify accurately stress responses, and selection of the age for a maximal effect.