Establishment of a Comprehensive List of Candidate Antiaging Medicinal Herb Used in Korean Medicine by Text Mining of the Classical Korean Medical Literature, “Dongeuibogam,” and Preliminary Evaluation of the Antiaging Effects of These Herbs

The major objectives of this study were to provide a list of candidate antiaging medicinal herbs that have been widely utilized in Korean medicine and to organize preliminary data for the benefit of experimental and clinical researchers to develop new drug therapies by analyzing previous studies. “Dongeuibogam,” a representative source of the Korean medicine literature, was selected to investigate candidate antiaging medicinal herbs and to identify appropriate terms that describe the specific antiaging effects that these herbs are predicted to elicit. In addition, we aimed to review previous studies that referenced the selected candidate antiaging medicinal herbs. From our chosen source, “Dongeuibogam,” we were able to screen 102 terms describing antiaging effects, which were further classified into 11 subtypes. Ninety-seven candidate antiaging medicinal herbs were selected using the criterion that their antiaging effects were described using the same terms as those employed in “Dongeuibogam.” These candidates were classified into 11 subtypes. Of the 97 candidate antiaging medicinal herbs selected, 47 are widely used by Korean medical doctors in Korea and were selected for further analysis of their antiaging effects. Overall, we found an average of 7.7 previous studies per candidate herb that described their antiaging effects.


Introduction
Recently, a number of studies have been conducted that pursue the active development of antiaging drugs. Many researchers develop novel drugs by exploring the antiaging constituents of herbs that are widely used in traditional medicine in many countries around the world. For example, in previous studies, preliminary data were identified by searching for candidate herbs in the traditional medicinal literature and then evaluating the antiaging effects of these candidates (e.g., [1,2]). However, thus far, such studies have been conducted only within the traditional Chinese literature, while the Korean literature remains to be analyzed. Therefore, we have reviewed a representative source of classical Korean medical literature as a means of providing useful preliminary data, as has been done previously with the Chinese literature. There are several justifications for selecting "Dongeuibogam, " which was published in 1613, for analysis in the present study; (1) it was published by the royal physicians, who were contemporary experts that strictly upheld the traditions of basic Korean medicine (KM); from ancient to present times, KM has been developed via 2 Evidence-Based Complementary and Alternative Medicine exchange with adjacent countries such as China and Japan. Recently, this traditional medicinal science has contributed to academic development as well as to the improvement of human health through exchange with Western medicine; (2) "Dongeuibogam" is the comprehensive summary of all the traditional medicines of North-East Asia prior to the 17th century, because it is based on a rigorous selection of 189 of the major medicinal literature sources of the region [3]; (3) it had a significant impact not only on KM after the 17th century but also on medicinal practices in other surrounding countries (e.g., China and Japan) [4]; (4) except for minor content related to superstitions, which were contemporary standards at the time of publication, most of its content is still widely used in modern KM by Korean medical doctors (KMDs); and (5) the medicinal herbs which it describes constitute many of the major herbs prescribed in KM [5]. Taken together, it seems reasonable to conclude that "Dongeuibogam" is a principal piece of KM literature and summarizes all the achievements of traditional KM. Therefore, we determined that analyzing, screening, and organizing terms describing antiaging effects (TAE) in the "Dongeuibogam" is an efficient approach for creating lists of candidate antiaging medicinal herbs (CAMH). Furthermore, pursuing this approach may help to organize preliminary data for future experimental and clinical studies on the antiaging effects of previously investigated medicinal herbs.

Materials and Methods
The present study consisted of three steps. In the first step, TAEs were screened to construct lists of TAEs. In the second step, CAMHs were screened to construct lists of CAMHs. In the last step, previous studies of CAMHs were analyzed. TAEs and CAMHs were defined by analyzing various sources of the Northeast Asian medicinal literature; TAEs in "Dongeuibogam" were defined as terms describing potency for delaying/improving specific aging symptoms that are recognized by one's human sense or others. In contrast, CAMHs were defined as medicinal herbs containing one or more TAEs in their medicinal potency [6]. Each step was performed as described in the following paragraphs.

First
Step (Figure 1) [319], oxidative stress theory [320], molecular inflammation hypothesis [321,322], neuroendocrine theory [323], wear and tear theory [324], waste accumulation theory [325], Hayflick limit theory [326], and the telomerase theory [327]). Additional studies were included after discussion with   the advisory panel. Next, studies were specifically divided into in vitro studies, in vivo studies, clinical studies, and reviews, and then analyzed again for research performance status.

Searching the Database.
In addition to commonly used scientific databases (such as PubMed, Cochrane, and Scopus), Korean databases (Ndsl, Oasis, and Riss) were used since we were searching specifically for studies related to KM. The starting period for these study searches was not defined; however, July 31, 2014 was set as the final time point.

Searching Keywords.
We used the following terms for the searches: "scientific names of CAMH + aging, age" and "names of herbal medicines of CAMH + aging, age. "

Results and Discussion
3.1. List of TAEs from the "Dongeuibogam". The TAEs of 928 IMHs in the "Dongeuibogam" were divided by simple descriptive units to achieve 3,808 TAEs. In the first step, TAEs for disease treatments were excluded, resulting in 593 TAEs. Of this subset, overlapping TAEs were combined into a singular TAE list containing 333 TAEs. In the second step, 299 TAEs were excluded as they described general health. Thus, 104 TAEs specifically related to aging were selected. In order to validate the above processes, we consulted a survey of experts. Ten out of 11 respondents agreed with the validity of the first step, while one respondent disagreed (90.9% versus 9.1%). With regard to the validity of the second step, 8 out of 10 respondents agreed (80% versus 20%) ( Table 1). TAEs selected through the processes described above were further divided into 11 types of lists: 21 skin-related TAEs, 15 hair-related TAEs, 15 musculoskeletal TAEs, 14 sensory organ-related TAEs, 12 TAEs related to the extension of life span, 13 cognitive function-related TAEs, 5 toothrelated TAEs, 5 sexual function-related TAEs, 2 urinationrelated TAEs, 1 oral health-related TAE, and 1 respiratory function-related TAE. Classified TAEs were further assessed for proper categorization via questionnaires. In the end, depending upon the TAE, the agreement ratio for validation Publication identified (n = 3, 146) In vitro studies (n = 143) In vivo studies (n = 149) Clinical studies (n = 24) Reviews (n = 47)   Lastly, these were classified utilizing TAEs as well (since there were medicinal herbs possessing one or more TAEs, some items overlapped; as explained previously).

Preliminary Evaluation of the Antiaging Effects of CAMHs via Analysis of Previous Studies.
Through discussion with advisory panels, the authors selected 47 kinds of CAMHs (i.e., 43 plant-derived kinds and 4 animal-derived kinds) that are commercially available and widely utilized by KMDs. A total of 3,146 studies of 47 CAMHs were found; of these, 363 studies were concerned with antiaging effects, resulting in an average of 7.7 publications per candidate herb ( Table 2).

Evidence-Based Complementary and Alternative Medicine
Since the present study was performed with a focus on the selection and cataloging of an entire candidate group of antiaging medicinal herbs written about in the "Dongeuibogam, " the characteristics of each medicinal herb were not analyzed in detail during both the discovery processes from the classical Korean medical literature and the analysis processes of preceding studies. This constitutes a limitation of the present study but is also an advantage because the scope of this study is comprehensive. This part will be included in a follow-up study on the verification of the antiaging effects of each CAMH.
Furthermore, additional investigation is warranted for the "Compound formulae" (mixture of medicinal herbs) identified in "Dongeuibogam" as an expansion of the present study that limited putative candidates to IMHs.

Conclusions
In the present study, we finally selected 47 CAMHs from the "Dongeuibogam" and reviewed the results of previous studies regarding antiaging effects in order to provide a comprehensive list of Korean medicinal herbs that may harbor antiaging potential. Even though further investigations are needed in regard to the medicinal herbs included in these lists, the present study may be an important step towards the development of experimental and clinical studies with the aim of discovering new drugs or novel antiaging constituents.

Conflict of Interests
The authors declare that there are no conflict of interests regarding the publication of this paper.