Viewpoint: A Contributory Role of Shell Ginger (Alpinia zerumbet) for Human Longevity in Okinawa, Japan?

2.1. Search and Identification Terms

The PubMed database was searched for identification of original publications and review articles referring to clinical, epidemiological, botanical, and experimental studies, using the following terms alone or combined: longevity, centenarians, Okinawa, Okinawa diet, Alpinia zerumbet, and shell ginger. The literature search was performed during October and November 2017.

2.2. Data Analysis

Publications were analysed for their clinical and scientific value, data quality, and relevance in relation to the topic of this article. Publications of good quality and in the English language were preferred and considered for evaluation, but some important studies published in other languages such as Japanese were also included in the analysis. Based on the retrieved publications and their reference lists, a manual search was added with a focus on reports not yet identified.

3.1. The Alpinia Genus and the Zingiberaceae (Ginger) Family

Alpinia is the largest genus of the family Zingiberaceae (ginger), classified by Charles Plumier and named after Prospero Alpino, a well-known Italian botanist of the sixteenth century [21]. Plants of the genus Alpinia and their constituents have numerous positive effects, including antimicrobial, antiparasitic, insecticidal, anticancer, antiproliferative, antiinflammatory, analgesic, antiallergic, neuroprotective, and antioxidant properties, as summarized previously [21]. Some plants of the Alpinia genus also may exert specific beneficial effects. Under discussion are abundant diseases or health conditions, leading to the proposal that Alpinia may even be a goldmine for future therapies [21]. As one of the most important genera of the Zingiberaceae family with around 230 species, Alpinia had received attention in 252 publications by 2015, with 544 compounds isolated overall from 35 Alpinia species, as described in detail [22].

3.2. Alpinia Zerumbet as A Plant

The plant A. zerumbet (Pers.) B.L. Burtt & R.M. Sm, syn. Alpinia speciosa, also called shell ginger, belongs to the large Alpinia genus. It grows widely in tropical and subtropical regions including the Okinawa Islands [14,15,16,17,18,19,20], where A. zerumbet can easily be studied, allowing for a detailed botanical description. With a height of up to 3.0 m in the free landscape, A. zerumbet is a perennial herb with rhizomes, which are aromatic when cut, with a typical ginger smell. The leaves are two-ranked and thin, approximately 25–35 cm long. Appreciated also as indoor plant with a smaller height, the flowers of this beautiful plant are pink when in bud, and resemble seashells, which thus led to the synonyms shell ginger, shell flower, pink porcelain lily, variegated ginger, butterfly ginger, and light galangal. The fruits are ball-shaped with striations of initially yellow colour, changing to red as the fruit matures (Figure 1).

Presently, in common use are the leaves and rhizomes of A. zerumbet for traditional Okinawa cuisine and herbal medicine. Based on current literature, all parts seem to be edible, but data on maximum amounts tolerated by humans without signs of toxicity are not available. The histogram of Alpinia zerumbet is presented in Table 1.

4.1. Kavalactones

There are two major kavalactones in A. zerumbet, dihydro-5,6-dehydrokavain (DDK) and its derivative 5,6-dehydrokawain (DK) [18,19]. According to their pyrone moieties, DDK belongs to the type D and DK to the type C, since at positions 7,8 DDK has an unsaturated linkage and DK a saturated one [19]. For DDK, the highest amounts per fresh weight were detected in leaves, followed by rhizomes, and stems, whereas the reversed constellation was found for DK with the highest contents in rhizomes and lowest ones in leaves (Figure 1). Overall, the plant contains much more of the mother phytochemical DDK than its derivative DK, and the biological activities of DDK are much greater than those of DK [19]. Consequently, and under usual conditions, bioactivities of kavalactones in A. zerumbet are mostly related to DDK rather than to DK, but variability in kavalactone amounts is known among leaves, stems, and rhizomes, depending on location of growing and time of harvest during the year [19]. Recently, with methytriacetolactone, another kavalactone was found in leaves of A. zerumbet (Table 2) [27]. However, this compound was detectable only after treatment by UV (ultraviolet)-C light and is likely a derivative of either DDK or DK on degradation due to exposure to UV-C light, because it was not present in the plant prior to treatment.

4.2. Non-Kavalactones

Many non-kavalactones have been identified in plant parts of A. zerumbet and are listed with their respective references in Table 2. Leaves of this ginger variety are rich in essential oils, mostly monoterpenes and terpenes [27]. Other plant parts such as stems, rhizomes, and flowers also contain essential oils but in much smaller amounts [27]. Additional phytochemicals are phenols, fatty acids, flavonoids, phenolic acids, labdadienes, zerumins, rutin, catechins, chalcones, and steroids (Table 2), distributed in all plant parts. In addition to kavalactones, essential oils and flavonoids have been shown to play a principal role in the biological activities of A. zerumbet [19,27].

Among the identified phytochemicals presented in Figure 2 and Table 2, and on a quantitative basis, DDK accounted for most of the ingredients (80–410 mg g⁻¹ fresh weight), as compared to essential oils (<150 mg g⁻¹), phenols (108 mg g⁻¹), and DK (10–100 mg g⁻¹). Negligible quantities were described for phenolic acids (<1 mg g⁻¹) and fatty acids (62 µg g⁻¹). Other compounds were found in much lower amounts as compared to phenolics acids and fatty acids; these other compounds were assessed by percentages of total peaks determined by gas chromatography-mass spectrometry (GC-MS), or remained unquantifiable due to missing published data (Table 2).

4.3. Antioxidative Phytochemicals

Many phytochemicals identified in different parts of A. zerumbet provide scavenging activities for free radicals and reactive oxygen species (ROS) to variable degrees (Table 2). Most important were essential oils, preferentially found in the leaves [18,19,20,24,27,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46]. Less important were other compounds such as phenolic acids and flavonoids [15,18,19,27,28,30,50]. By comparison, DK and DDK failed to exert strong and specific radical scavenging activity, but this was mostly compensated by their high amounts found in every plant part [51]. Finally, the antioxidant activity of other compounds such as rutin, zerumins, quercetin, and labdadience (Table 2) was much lower as compared to essential oils, flavonoids, phenolic acids, and kavalactones. Consequently, whenever the positive antioxidative capacities of Alpinia zerumbet are evaluated, the percentage and total activity of each plant part must be considered. Uncertainty prevails presently with respect to which of the various phytochemicals are responsible for the Okinawa longevity or are at least partially involved.

5.1. Animal Longevity

Lifespan and in particular longevity are important parameters in clinical medicine, influenced by various exogenous and endogenous factors. With respect to these factors, animal models for studying lifespan or longevity have become popular, in view of the long period required for robust results of longevity studies in humans. One animal (nematode) model using the free-living, transparent round worm (Caenorhabditis elegans) was applied to study the effect of water-based extracts of A. zerumbet leaves on lifespan [20]. Fresh leaves were used, suggesting the A. zerumbet under investigation was of local Okinawan origin. In this trial, this plant significantly extended the lifespan of C. elegans by 22.6%. The extension was attributed to the plant’s free radical scavenging effects and its upregulation of stress-resistant gene proteins, including superoxide dismutase-3 (SOD-3) and the heat-shock protein (HSP-16.2). Genes such as Sirtuin-1 and Sirtuin-2 are increasingly under discussion for their role of determining experimental lifespan, but robust data on A. zerumbet are lacking.

Of note, the water fraction of the A. zerumbet leaves contained considerable amounts of total polyphenols, an important fact with respect to their use as teas, spices, or vegetables in the Okinawan cuisine. Overall, these animal studies show many beneficial properties of A. zerumbet, which suggests its potential use as a promising ingredient of a dietary supplement or as an efficient herbal drug under regulatory surveillance.

5.2. Anti-Obesity

Obesity is a complex and complicated metabolic disease of increased body weight due to excessive fat accumulation, caused by an imbalance between caloric uptake and energy consumption, favouring a positive energy balance [52,53,54,55]. Calculated as weight in kilograms divided by the square of height in meters, the body mass index (BMI) is a good diagnostic marker to differentiate obesity from overweight [52]. Whereas obesity is defined as BMI ≥ 30 kg m⁻², overweight is considered as a BMI between 25 and 30 kg m⁻². Various risk factors are closely associated with obesity, including early death, metabolic syndrome, type 2 diabetes mellitus, insulin resistance, dyslipidemia, atherosclerosis, hypertension, cardiovascular disease, and non-alcoholic fatty liver disease with potential progression to liver cirrhosis, hepatocellular carcinoma, and end-stage liver disease or acute liver failure requiring liver transplantation [52,53].

Obesity is a major global health and economic burden with an increasing tendency at an alarming rate in many countries [53]. This is a problem not shared by the Okinawa population [56]. Considering the pathogenesis of obesity and its associated diseases at the molecular level, oxidative stress with generation of toxic free radicals and reactive oxygen species (ROS), appears to play a critical role [55]. Therefore, using plants such as shell ginger with its high radical scavenging potency to counteract the injurious effects of free radicals is likely part of the efficient prevention of complications related to obesity in individuals of Okinawa to gain longevity. To achieve these positive goals, various mechanistic approaches are under consideration, as listed and discussed below.

5.3. Anti-Tumor

Epidemiological data have shown an association between obesity defined by increased BMI and cancer across populations worldwide [55]. In men, increased risks were observed for rectal and prostate cancers, and in women for gastrointestinal, endometrial, and postmenopausal breast cancers. Ample evidence exists that cancer susceptibility in obesity is mediated in part by oxidative stress through generation of ROS. Described as strong antioxidants, most phytochemicals of A. zerumbet are capable of scavenging these free radicals [14,16,17,27]. This results in aqueous extracts, which commonly provide stronger antioxidant activities than the ethanol extract (Table 3) [12]. This supports the experimental studies on human tumour cell lines showing anticancer activities of A. zerumbet and its isolated compounds [25,26]. Among compounds isolated from A. zerumbet, several showed anticancer activities, reflected for example in the IC₅₀ values for labdadiene: 52.1 µM; (2,5-bis(1E,3E,5E)-6-methoxyhexa-1,3,5-trien-1-yl)-2,5-dihydrofuran (MTD): 58.6 µM; (E)-2,2,3,3-tetramthyl-8-methylene-7-(oct-6-en-1-yl) octahydro-1H-quinolizine (TMOQ): 49.3 µM; and kaempferol-3-O-β-D-glucuronide (KOG): 12.9 µM on p21-activated kinase 1 (PAK1) (Table 3). More specifically, hydroalcoholic extract from Alpinia zerumbet leaves inhibited cellular proliferation only at high concentrations, while the dichloromethane extract showed a moderate antiproliferative effect against human leukaemia and lung tumour cells. Among the isolated phytochemicals, DK showed a potent cytostatic effect against glioblastoma cells and a moderate effect on all other tumour cell lines [25]. However, it is premature to introduce presently Alpinia zerumbet or one of its phytochemicals in clinical oncology.

7.1. Genetic Background

Early studies in Okinawa provided clear evidence for a genetic background of longevity in Okinawa [9]. For instance, the frequencies of 80 human leucocyte antigen (HLA) antigen phenotypes in 82 centenarians and 20 nonagenarians in Okinawa were compared with those in other healthy adults in various age brackets. Subjects aged over 90 had an extremely low frequency of HLA-DRw9 and an increased frequency of DR1. The DRw9 antigen, which occurs with a relatively high frequency in Japanese and a very low frequency in Caucasians, whilst the DR1 is associated with seronegative, rheumatoid arthritis, penicillamine-induced myasthenia, and schizophrenia. In this age group, the relative risk of HLA-DRw9 was 5.2 and for HLA-DR1, this value was 13.3. Since a high frequency of DRw9 and a low frequency of DR1 are associated with autoimmune or immune deficiency diseases, the genetic protection against these disorders may contribute to longevity [9]. In a subsequent study, HLA class II alleles of Okinawan centenarians were analysed in detail by using the polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) method to clarify primary genetic factors in the major histocompatibility complex (MHC) region associated with human Okinawan longevity [62]. DRB1 (associated with an increased incidence of rheumatoid arthritis) × 1401, DQB1 (associated with an increased risk of developing type 1 diabetes) × 0503, DQA1 (provides instruction for making a protein that plays a critical role in the immune system) × 0101 = 0104 and DQA1 × 05 were significantly increased in the centenarians. The significant increase of HLA-DQB 1 × 0503 and/or DQA 1 × 0101 = 0104 in the centenarians can be explained by a linkage disequilibrium with DRB 1*1401, or vice versa. Further, the tendency was observed to increase with respect to DRB1 × 0101 and DRB1 × 1201. These data suggest that several alleles of the HLA-DRB1 and/or HLA-DQ (cells can serve as antigen presenting cells in the small intestinal mucosa) are involved in human longevity [62].

7.2. Physical and Social Activities

Most Okinawan centenarians enjoy physical exercise, are active as walkers, and grow or once grew gardens as a form of daily physical activity. Okinawan households rarely have furniture for sitting, forcing residents to take their meals and beverages by sitting on the floor using tatami mats. Sitting down to and standing up from the floor at several occasions during the day is a crucial part of the daily physical exercise of older individuals, providing and improving body strength and balance. This also facilitates protection from falls leading to deleterious bone fractures. The role of physical activity in the healthy aging of Okinawans has been emphasized, as they keep physically active in a natural way, for instance by farming or karate. Particular exercise interventions are under study [61]. Lifestyle determinants of Okinawan women include regular exercise in the form of dance, soft historical martial arts, walking, and gardening. As such, elderly Okinawans have complete independence in terms of physical activity [56]. The levels of physical activity of male centenarians range between the categories of being completely independent and being independent but slow. In female centenarian participants, their physical activities are independent but slow or independent with difficulty [56]. Although studies on physical activities in Okinawa are limited [56,61], additional results from a large-scale population-based cohort study in Japan, the Japan Public Health Center (JPHC) Prospective Study, indicate that increased daily total physical activity is associated with significantly decreased risk of all-cause mortality in both sexes [63], conditions likely applicable also to Japanese Okinawans.

Although not quantifiable, longevity in Okinawa is facilitated likely by the local tradition of moai, established as secure social networks. These safety nets lend emotional support in times of need and give their members emotional and health security. Such psychological and social aspects are considered of utmost importance [61].

7.3. Caloric and Dietary Restriction

Caloric restriction is viewed as a key element of the advantage in longevity in Okinawan generations born before World War II [7,64]. This has to be differentiated from dietary restriction that may cause undernutrition or malnutrition, associated with dietary deficiencies, health problems, and reduced life span [65], conditions not observed among elderly Okinawans [56]. Indeed, this population is of a short stature, while their body weight and body mass index (BMI) values are not low, especially in elderly women, who seek to reduce their food intake for reasons of weight control [56]. As expected with advancing age, the energy intake of female centenarians is low. Among this cohort, the activities of daily life (ADL) are positively related to energy, suggesting that the low energy intake of the female centenarians was mainly due to their low levels of ADL. In the centenarian cohort as compared to the elderly, virtually all anthropometric, haematological, and biochemical variables are lower with statistical significance or near the lower reference limit, particularly in females [56]. The conclusion was reached that the nutritional status assessed by ADL and various parameters was poor in the centenarians but it was maintained (except for height) in the elderly Okinawans, and diet was not the major factor of their problems of reduced nutritional status.

If not accompanied by nutritional deficiencies, the caloric restriction implicated in Okinawan longevity is reproducible in animal models for delaying morbidity and extending average and maximum lifespan. However, the effects in humans require specific attention [64], since the anti-aging effect appears robust until the restriction reaches about half the typical calorie intake of the studied animal models [6,66]. In one human epidemiology study of Japanese-American men on calorie intake, there was a trend toward lower mortality of participants who consumed 15% less calories than the group mean, whereas an increased mortality was observed in individuals, whose caloric intake was below 50% of the group mean [66]. It seems that moderate rather than striking calorie restriction is the preferred approach for longevity.

In addition, new concepts focus on compounds including sirtuins that mimic the biochemical and functional effects of caloric restriction, as detailed in several reports presenting variable proposals [6,67]. For instance, these caloric restriction mimetics (CRMs) are thought to stimulate autophagy by favouring the deacetylation of cellular proteins in common body cells. Plausible on theoretical grounds, such deacetylation processes can be achieved by three approaches: depletion of acetyl coenzyme A, inhibition of acetyl transferases, or stimulation of deacetylase activities [67]. In our opinion, this definition of caloric restriction mimetics should be expanded specifically also to lipocytes as an additional cell type target, which would allow inclusion of lipolytic compounds that remove calories by another kind of autophagy process, namely by lysis of fat (triglycerides) out of these lipocytes. Conceptually, we suggest therefore that such a dual autophagy model better explains cellular targets involving calorie restriction mimetics, but this new hypothesis requires confirmation by further investigations. Combined with some true caloric restriction in the usual way, this additional dual autophagy process of caloric restriction mimetics should provide an optimal approach for Okinawan individuals, who use the traditional Okinawa diet and attempt not to gain weight. There is also the note that both the usual caloric restriction and the traditional Okinawan functional foods with CRM properties likely will contribute to improving health and increasing the lifespan [6].

Presumably, active but not yet identified phytochemicals of shell ginger function act as caloric restriction mimetics in the dual autophagy process. Expanding these considerations, we also propose that this dual autophagy process renders some kind of empty calories that do not count in the context of energy supply in the bodies of individuals consuming Alpinia zerumbet.

7.4. Westernized Lifestyle

As compared to other prefectures in Japan, the life expectancy advantage was previously high in Okinawa for all age groups, but it has declined since 1960 and is now limited to Okinawans of older ages due to a residual effect related to use of the traditional Okinawa diet [3]. In fact, younger Okinawans have made the switch from the traditional Okinawa cuisine to the Western food and living style. These changes in food consumption resulting in lower life expectancy clearly support the relevance of the traditional Okinawa diet for the longevity of its consumers.

9.1. Current Issues

Shell ginger, as described for culinary use in connection with food or beverages, is better classified as A. zerumbet for botanical purposes to clearly identify the plant, differentiating it from common ginger in the English language, which is the botanical Zingiber officinale used as ginger for ginger ice cream, ginger bread, ginger beverages, ginger beer, or ginger ale in many countries. Shell ginger is an exceptional multi-targeted plant for human use, considering various organs, diseases, and mechanistic actions. As it presently stands, the plant’s potential for human life is likely underestimated. The large number of highly qualified agricultural, analytical, chemical, and epidemiological studies on A. zerumbet and longevity in Okinawa is amazing and qualifies this topic as an important one. Many positive effects have been described for A. zerumbet, using experimental models that may or may not be transferrable to human conditions. Under these aspects and to err on the side of caution, it would be premature to classify Alpinia zerumbet as a hidden champion of preventive or therapeutic measures, although the chances are excellent, if additional compelling evidence is provided, that shell ginger is indeed a major contributor towards longevity in Okinawa.

This present paper will help in the development of herbal drugs with A. zerumbet as ingredient, marketed under strict regulatory guidance. Since this plant has a long history of safe use as traditional medicine, timely regulatory approval should be received, provided clinical studies confirm its efficacy and lack of adverse effects. Less desirable is the manufacture of A. zerumbet in herbal dietary supplements with a much lower level of regulatory marketing restriction, insufficient to ensure consumer safety. An internet search specified a single marketed herbal dietary supplement with A. zerumbet as ingredient manufactured from its leaves, with a proposed daily usage of two capsules containing 250 mg each. However, additional data in publications of peer reviewed journals are not available, especially regarding efficacy, adverse effects, and contraindications; its use is therefore limited and presently not encouraged.

The standard book of Barnes et al. published in 2007 on herbal medicines broadly discusses the family species Zingiber officinale Rocoe (Zingiberaceae) under the heading of ginger, representing edible plants similar to shell ginger (A. zerumbet), which is not explicitly mentioned [70]. As outlined, ginger is listed by the Council of Europe as a natural source of food flavouring with the category N2, which indicates that ginger can be added to foodstuffs in small quantities, with a possible limitation of a yet unspecified active principle in the final product. Used widely in food as spice, ginger has been listed as generally recognized as safe (GRAS), but some warnings and contraindications have also been added [70]. Whether these limitations apply to shell ginger has not yet been determined. However, good safety news with respect to the overall Okinawa diet can be derived from serum laboratory data of liver tests with normal values of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) from supercentenarians in Okinawa [71]. Nevertheless, the efficacy and safety issues of shell ginger, and its relation to longevity in Okinawa are still a puzzle with pieces that have to be put together by additional research.

9.2. Future Research

The key question will be whether shell ginger can be introduced as drug to aid body weight loss or prevent body weight gain. For these indications and outside the focus of the present report, other herbs such as green tea (Camelia sinensis (L.) Kuntze) extracts or the chemical drug orlistat are on the market but there are conflicts with respect to potential hepatotoxicity. Also not specifically considered are chemicals and plants such as grape resveratrol, polyphenols from blueberries, phenolic antioxidants from spinach, epicatechin from green tea, and ginkgo (Ginkgo biloba L.), all with life-expanding effects on C. elegans [20].

With respect to A. zerumbet and longevity in Okinawa, the pioneering work at Ryukyus University of the Okinawa Islands has provided many interesting details. Future animal studies should now focus on the identification of those phytochemical(s) responsible for lifespan extension. For this research, suspected phytochemicals of Alpinia zerumbet should be isolated for studies using the C. elegans model. Experiments are encouraged for comparing lifespan extension by various plants of the Okinawa cuisine. However, since the potential efficacy is based likely on the joint actions of all phytochemicals of Alpinia zerumbet, the use of a single promising chemical in humans can be problematic. Likewise, efficacy of Alpinia zerumbet will probably be improved if used as an adjunct to the Okinawa diet or a food with similar components.

It will be the most important goal for future clinical and epidemiological investigations or new reviews to establish the exact ideal intake of shell ginger and eventually its bioactive compounds. Indeed, there is still some uncertainty from the published reports about the quantity of shell ginger (including plant parts) that the centenarians in Okinawa have actually used over their lifetimes. This question can easily be addressed by retrospective assessment of their food history with the help of expert dietitians and a special questionnaire. On this occasion, other plants with their special parts used by these individuals should also be identified and quantified. Answering all these questions will allow for recommendations that are more specific on how best to use these plants.

Clinical data are missing on to what extent shell ginger and the other plants as part of the Okinawa cuisine have actually caused a reduction in body weight. However, this would require a strict protocol designed as a metabolic ward study as in a manner published previously [72,73]. Short term efficacy is best tested using as an endpoint goal the reduction of body weight as a surrogate marker since the treatment effect on life span extension itself is impracticable in the context of initial studies. Proof of treatment efficacy requires a standard approach, using the principles of randomized clinical trials (RCTs). Consensus exists among clinicians, scientists, and manufacturers that placebo-controlled, randomized, double-blind clinical trials are the gold standard for obtaining valid results of efficiency prior to treatment initiation using herbal products [74,75]. In particular, both evidence-based medicine (EBM) and the Cochrane collaboration efforts resulted in guidelines for planning and reporting of RCTs [76]. The medical community has adopted quality criteria as per the consolidated standards of reporting trials (CONSORT) criteria. Only such metabolic ward studies combined with RCTs will provide clear-cut answers for potential consumers of shell ginger. Using this plant as a herbal drug or herbal dietary supplement may be recommendable if a there is positive benefit in relation to the risk profile. Many nutraceuticals and herbal products are highly appreciated in developed countries and are often used despite a lack of established efficacy and some suspected but not necessarily proven safety concerns [76,77,78,79,80,81,82], and the question has been raised as to whether there is good science behind the hype [74].