Preventive Treatment of Traditional Chinese Medicine As Antistress and Antiaging Strategy

Introduction

O ne of the strengths of traditional Chinese medicine (TCM) is the so-called “preventive treatment” and/or “causal treatment,” ^{1 –3} “to deal with premorbid conditions,” “to heal patients in their subhealthy conditions,” and “to handle diseases sharing essential etiologic factors.” ^1,3 These concepts have been practiced in TCM for over a thousand years. TCM has developed various strategies for tackling health problems early, with the aim to eliminate principal pathologic upstream factors entirely. Unfortunately, the theoretical framework of TCM does not provide a reasonable foundation to sustain ideas such as etiologic causes, pathologic basis, and pathogenic factors, etc. ^1,2 To interpret the ideas and concepts of the above notions using current scientific language, this paper will start with discussions of the research achievements of aging biochemistry in life science, and then further explain the above-mentioned TCM concepts of preventive/causal treatment relevant to aging biochemistry.

Stress, Subhealth, Biological Garbage, and Aging Alterations

A number of pathophysiologic stresses are now understood to be associated with the ill-defined “subhealth” conditions that are mainly due to a consequential accumulation of metabonomic byproducts. ⁴ Their correlation to morbid conditions includes various pathogenic factors such as: “environmental factors, metabolic side-reactions, and inflammatory toxins, will damage, accumulate, and form sediments in biologic vessels and organs, which eventually cause crosslinking-related stagnation of certain parts of organisms, particularly on long-life proteins like collagens and lens, and also resulting in malfunctions of the metabolism.” ^{5 –8} Similarly, a common etiologic description of such subhealth phenomena in TCM is given as: “pain is caused by stagnation, thus leading to diseases, and can be relieved with re-disclosing.” ^1,9 Accordingly, a therapeutic principle, namely “activating blood circulation and eliminating stagnation in time,” is used to heal these conditions. ^1,9

Therefore, it is important to discuss: (1) Where do the adhesive sediments or biowastes of blood stagnation come from? (2) What kind of substances are they? and (3) Can they be cleaned up?

First, it is now better understood that such biowastes come mainly from the process of energy metabolism. Although biowastes are undoubtedly by-products of lipids, proteins, carbohydrates, and nucleic acids, along with energy metabolism biochemistry, they are the side-products mainly from either free radical damage or nonenzymatic glycosylation stress. ^{7,10 –12} These biochemical side-reactions are the main causes of organic aging in different organs and tissues, and so are the etiologic bases for various senile degenerative diseases. ^5,11,13

Second, what kind of substances are they? In other words, what are the exact biochemical structures and functions of these “garbage” substances in biology, particularly in gerontology and geriatrics? Some common “garbage” examples that have been identified include senile plaque, age pigments, thickened basilar membrane, gradually maturing cataracts, stiffened blood vessels, and fiberized organs and tissues, all of which belong to side-products of energy metabolism and accumulate with time. ^7,11 The biochemical basis of these biowastes has been well explained by concurrent studies, such as the biochemical reactions related to the formation of age pigments, or ceroid/lipofuscin, ^11,14,15 among which unsaturated dicarbonyls have been recognized as a group of critical biochemical components during their formation. ^10,11 More recently, for instance, the glycation theory of the mechanism of atherosclerosis has been suggested for renomination, becoming a carbonyl stress theory.

Third, can these biowastes be cleaned up? Concerning the possibility of lipofuscin elimination from the intracellular environment, these biowastes can in general be effectively cleaned up by ubiquitin or lysosomal systems. However, once these by-products have cross-linked or have been knotted with organic macromolecules, they will form irreparable structures that may not be completely eliminated in life, and thus evolve into the typical entropy-related aging biochemistry, becoming permanent aging-associated alterations in organisms. ^{11,15 –17} These inevitable alterations, as the essential mechanisms of energy metabolism leading to aging, have been recently pinpointed by Yin and co-workers, ¹⁸ and have been proposed as the “carbonyl toxification theory of aging” in narrow sense, ^13,19 and illustrated as “the irreparable damage accumulation of biochemical side-reactions” in broad sense of biological aging. ¹⁸ Professors Holiday and Hayflick have recently responded positively to the concept from different perspectives, concluding that “aging is no more a problem in biology.” ^{20 –22} Professor de Grey, one of the greatest scientists in the field of antiaging, recently introduced a striking campaign of “ending aging” to the scientific world with seven attractive strategies. ^23,24

Correlation of Subhealth with Fatigue and the Preventive Treatment of the “Disease Root” in TCM

Subhealth conditions and fatigue bear interesting similarities. In the fatigue condition, the relevant biochemical process mainly include: (1) Accumulation of lactic acid, (2) consumption of adenosine triphosphate (ATP), (3) accumulation of biowastes, and (4) various tissue impairments. The first and the second processes are closely related to the acute consumption of energy metabolism. The subhealth conditions more possibly relate to the third and fourth processes and are often expressed as “tiredness accumulation results in illness” in TCM. In biochemistry, this pertains to the piling up of biowaste produced by biochemical side-reactions. Active cleaning and restoration are usually implemented during rest and sleep, typically the recovery of fatigue and stress of the central nervous system during sleep. ^25,26 Traditionally, Chinese people say that those who have inadequate sleep are likely to get sick, whereas those who have enough sleep are likely to get relief from their potential illness, implying that sleep can “help people to regain their vitality and youth” via one or a few of above-listed processes and diseases and even aging-related degenerative diseases can be avoided. ¹ Simply put, subhealth conditions carry the primary elements of diseases, or we may hypothesize that stress biochemistry is the “root” or the “base” of degenerative diseases and even aging. ²⁷

Practically, many medical interventions, such as the preventive treatments of TCM, may stimulate and accelerate the process of restoration, which may, for instance, accelerate the biochemical elimination for biowaste such as toxic carbonyls. ^{14 –16} For example, the TCM treatment of cupping—a therapy that applies a hot cup with negative pressure on an acupoint—may be used. Cupping therapy is usually applied in clinical practice when the patient complains of a slight discomfort or catching cold, feeling somatic strain or coldness, or a local or general malaise, which is called “sensing himself is likely to get ill.” If a patient under these conditions goes to a hospital for a health examination, he usually received a verdict of “normal” as the result of the examination. However, if he visits a TCM doctor, the patient will receive the cupping therapy and will have red, purple, or black ecchymosis on the acupoints following cupping treatment; this is considered as evidence of the “drawing out of internal toxin.” The patient usually feels relieved from stresses after the therapy and can go back to work, probably the next day. On the other hand, some people under similar conditions prefer to take a hot water bath or sauna to regain their vitality by sweating. In addition, various nondrug interventions such as scraping, acupuncture, foot therapy, and massage are also applied in TCM to eliminate biological stresses by activating the metabolic mechanism of human body. ^1,2 Some methods, however, are risky, like phlebotomy (bloodletting therapy), which is believed to have been the direct cause of George Washington's death. Although the nondrug interventions of TCM are likely to be effective for disease prevention and remaining healthy, their effectiveness will be weak when the patient has been in a strengthened morbid condition.

To understand the mechanisms of above-described preventive/causal treatment in depth (beyond the commonly assumed physical effect featured by the accelerating of blood circulation), studies of side-reactions of metabonomics and related cell biology are addressed in the following sections.

Oxidative/Glycative Reactions Highlight Carbonyl Stress in Energy Metabolism

Numerous studies in life science have demonstrated that the most dangerous and massive accumulated metabolic waste or so-called organic toxin in the human body mainly belongs to a group of unsaturated carbonyls. ^{14 –16} These compounds occur inevitably and continuously during energy metabolism, and spontaneously activate a series of biochemical reactions that may potentially harm our biological molecules. In the metabolism of energy for the maintenance of life, various stress reactions, no matter whether originating from oxygen free radicals or from carbohydrate metabolism, will cause the increase of carbonyl toxins, ^{14 –18} or, in other words, cause conditions of stresses or subhealth. A massive volume of carbonyl toxins will be detected in the body fluids (e.g., blood, urine, sweat, etc.) of most organs and tissues. The most commonly used method for evaluating the stress levels caused by oxygen free radicals is measuring the concentration of thiobarbituric acid-reactive substances (TBARS), or also called lipid peroxides. ¹⁴ Different kinds of stresses will finally transform or activate the oxidative stress that causes the increase of TBARS. For instance, many conditions, such as hard work, fatigue, spiritual stress, intensive exercises, and inadequate sleep, can cause the rapid increase of TBARS in human body. ^25,28

In general, almost all of the physical changes in the human body relevant to disease can lead to the increase of TBARS. One remarkable example is inflammation. Its mechanism is simple—inflammation is a spontaneous physiological process to produce oxidative stress through producing hydrogen peroxide (H₂O₂) to eliminate the pathogens, but it will simultaneously harm normal cells and tissues. ^28,29 Therefore, the amount of TBARS basically represents the stress level of human body; it demonstrates the subhealth condition in nonmorbid people. At an early stage, one can effectively intervene in subhealth conditions by cleaning up TBARS or carbonyl toxins with simple diets (vitamins) and preclinical “tricks,” which obviously reflect the preventive treatment of stress or stress-induced diseases, as the so called “causal treatment” in TCM. ³

For most organisms on earth, the first defensive line against subhealth conditions or stress-induced diseases is the antioxidative system, which includes the integrative function of antioxidants and antioxidases. ²⁹ The second defensive line is an antidote for carbonyl toxins, which were found to be closely related to important biochemical mechanisms of aging. ¹⁸ The third defensive line involves gene-dependent repair and renewal systems, which represent the ultimate determination of organisms to live with or without the damaged molecules. In the following discussion, we will focus on the second line and attempt to explain its key function, the core defensive mechanism, as well as the common biochemical basis of degenerative diseases.

It is well-known that human body depends on its antioxidative system to remove TBARS; however, the biochemical process of eliminating TBARS (e.g., malondialdehyde and 4-hydroxylnonenal) consumes a massive amount of sulfhydryl biomolecules, in which the key component is glutathione, a kind of reducible tripeptide capable of efficiently cleaning carbonyl toxins. ^14,29 Once the TBARS level increases, the amount of internal reductive glutathione is bound to decrease. ^29,30 This phenomenon reflects the actual glutathione consumption. The authors propose that it also indicates the consumption of “health or the vital condition.”

Glutathione is involved in either the first or second defensive line as a pivotal molecule to counteract both oxidative stress and carbonyl stress, because it has the capability of both antioxidation and anticarbonylation. ²⁹ Nonetheless, an organism can renew its consumed reductive glutathione while it receives antioxidants, which is a crucial pharmacologic process of antistress and/or antiaging. However, this process has been largely overlooked to date by many biomedical researchers and physicians. The organic enzymes that help glutathione eliminate carbonyl toxin are called glutathione transferases; they are commonly found in humans and animals, and, for example, comprise 3–5% of total liver proteins in humans. ^14,31

It is necessary to emphasize that the elimination of carbonyl toxicity establishes a biological basis for the continuing clean up of the stress-induced “garbage” in metabolism. ^7,11 This largely reflects the notion “treating the root of diseases” of TCM. ³ Therefore, the authors hypothesize that this elimination of carbonyl toxicity may indeed represent a general biochemical process for both stress-induced degenerative disease and aging-related alterations. Readers who are interested in this topic may refer to the author's relevant papers about the biochemistry of age pigment formation and the carbonyl toxification theory of biological aging. ^11,13,19

Mechanisms of “Preventive Treatment” of TCM Implicated in the Decarbonylation Cell Biology

The preventive/causal treatment principle seems also to be well confirmed and explained by the antistress data of cell biology. A number of studies found that if mild stress is applied to a certain biologic system (e.g., cell culture), an increase of carbonyl toxins will be detected. At this moment, the expression of the glutathione-related defensive system will also increase to counteract carbonyl stress and restore homeostasis. ^31,32 The so-called mild stresses include: A mild heating (at 42°C for 30 min, a situation similar to a hot water bath or high fever); minor oxidative stress (50 μmol/L H₂O₂, 20 min, a situation similar to inflammation or an active macrophage condition); and mild ultraviolet A (UVA) exposure (3 mW/cm² for 5 min, a situation similar to mild sunbathing). Studies have found that mild stress produces no obvious toxic trauma to cells and there is no increased expression of antioxidases. However, the affected cells revealed a transient increase of 4-hydroxylnonenal (an important example of carbonyl toxin). ^{31 –33} This phenomenon indicates the exposure to these typical stress conditions will cause the production of toxic carbonyls. After 2 h of the stress condition, the concentration of 4-hydroxylnonenal was reduced to the subnormal level, whereas the cell culture system demonstrated a significant rise (about 20 times) in the glutathione transferase hGST5.8 (there are more than 10 members of glutathione transferase in the human body) and introduced expression of the protein RLIP76 as a transporter for carbonyl derivatives. ³³ All of the above findings indicate a feedback-defensive mechanism of the human body to the subhealth condition.

A more interesting finding is that the preprocessed cells that have undergone mild stress can acquire supplemental resistance (i.e., more robust) to the trauma of H₂O₂, UVA, and toxic unsaturated carbonyls. Increased expression of glutathione transferase was observed as an urgent activation of the biosystem, or a combined protective mechanism to resist the carbonyl stress, which is similar to the immune feedback system. ³¹ By applying the above biochemical process, we may explain that the mechanism of traditional treatments in TCM (e.g., repetitive scraping and cupping therapy) is to induce a mild stress by local trauma and to eventually activate the defensive mechanism of anticarbonyl stress, and thus restore the normal healthy condition. The other relevant studies (e.g., the expression of heat shock protein and overexpression of glutathione transferase) have also supported such data in different models. ³⁴ All of these data imply that the mechanism of TCM's intervention methods that apply mild stress on the body, such as the above-mentioned rash scraping, cupping, and other traditional exercise and regimen methods including Tai-ji, hot water bath, foot washing treatment, and massage therapy, is not only to accelerate blood circulation or relieve the stress of muscles and ligaments, but also to involve complex functions with pathophysiological and biochemical bases. All of these can be interpreted as within the principle of treating subhealth conditions or treating diseases with an essential etiologic basis, as has been suggested in the earlier sections of this article.

Nevertheless, the prevention of carbonyl toxicity of various stresses may be an ideal access point in both traditional and modern medicine to tackle the early situations of morbid and aging conditions because it focuses on the “roots” and “foundations” of various chronic diseases, which are missing upstream metabonomic information of most, if not all, degenerative diseases beyond genes. ^35,36 In the near future, the attention and efforts of relevant exploration in this field should promise valuable results regarding the preventive treatments of TCM's antiaging strategies.

Conclusions

The biochemical process of aging is involved in common life activities and processes, such the metabolism of energy, and in the accumulation and elimination mechanisms of biotoxic metabolites, such as the formation process of age pigments. The mechanism of TCM's “preventive treatment” principle of “treating patients before their morbidity” was interpreted biochemically in this paper. The preventive strategies of TCM have been shown to be connected with antistress biochemistry and are suggested for the first time as a preclinical practice of antiaging.