The objective of anti-aging medicine is to live as long as possible in good health. It is medical treatment that not only prolongs human life, but also enables a person to live a healthy and happy life, maintain quality of life (QOL), and reduce the physical and mental deterioration of aging [1]. Medically, anti-aging medicine is classified as prophylactic medicine. Checkups and screenings for assessing the degree of aging are offered in Japan; a range of treatment options is available including diet, exercise, other lifestyle therapies, and drug therapies including nutritional supplement therapies and hormone replacement therapies.

Terms such as integrated medicine, alternative healthcare, Chinese herbal medicine, acupuncture therapy, and anti-aging medicine have been discussed in recent years, and numerous treatment methods are being proposed that differ from conventional Western medicine. Although numerous reports cite the efficacy of such treatment methods, the parameters used differ from one study to another. General physicians are currently left with the basic question, “To what degree are these treatments effective, and for what types of symptoms and diseases?”

The authors have used common parameters to investigate and study (a) the assessments of general physical examinations, (b) the physical and psychological influence as well as safety of dietary supplements, health foods, medical devices, exercise equipment, and cosmetics, and (c) obesity [2–4]. Our findings are shedding more light on the efficacies, limitations, and the range of effects of these products. Amino acids, in particular, exert a variety of influences on the body, and we have therefore conducted studies on health foods containing amino acids. In this study, we have focused on a food product for which one manufacturer has made health claims; the product contains L-carnitine, a type of amino acid, and Garcinia cambogia extract (65% hydroxycitric acid) manufactured by Nurex Corporation, Osaka; hereinafter referred to as “the Product”. We studied, using healthy middle-aged and older subjects, the effects of the Product on the body as a double-blind, non-cross-matching test. We also studied parameters that are deemed especially important to anti-aging medicine, for the purpose of determining whether or not the use of the Product enhances QOL in people aged in their 40s to 60s.

• those taking hormones, anti-osteoporosis drugs, and other medications

• those with diabetes, marked hepatic dysfunction, or other chronic diseases

• those with severe liver, kidney, heart, and/or blood diseases and other complications

• other individuals judged by a physician as unfit to participate in the study

Prior to the start of the test, we provided potential test subjects a thorough explanation not only of the duration, place, content, and methods of the test, but also on the benefits anticipated to be gained from participating in the study as well as disadvantages that may occur. The test subjects were assured that participation was completely voluntary, and that they would not suffer any disadvantages whatsoever, if they decided mid-way to withdraw from the testing, for any reason. The method of taking the Product was explained to all test participants by Nurex Corporation, either in writing or by holding an explanatory meeting.

• physical measurements: Height (cm), weight (kg), body fat percentage, systolic and diastolic blood pressures and others

• blood tests: Platelet count (10⁴/µl), erythrocyte count (RBC, 10⁴/µl), leukocyte count (WBC, /µl), hemoglobin content (HGB, g/dl), hematocrit (HCT, %), glutamate-oxaloacetate transaminase, glutamate-pyruvate transaminase (GOT, GPT, IU/l), γ-glutamyl transpeptase (γ-GTP, IU/l), alkaline phosphatase (ALP, IU/l), creatinine phosphokinase (CPK, mU/ml), C-reactive protein (CRP, mg/dl), blood urea nitrogen (BUN, mg/dl), blood creatinine (Cr, mg/dl), uric acid (UA, mg/dl), total cholesterol (T-Chol, mg/dl), HDL-cholesterol (HDL-C, mg/dl), LDL-cholesterol (LDL-C, mg/dl), triglycerides (TG, mg/dl), fasting blood sugar (FBS, mg/dl), glycohemoglobin A1C (HbA1c), lactic acid (mg/dl), cortisol, dehydroepiandrosterone sulfate (DHEA-s), IGF-I, insulin, lipid peroxides (LPO, nmol/ml), electrolytes: sodium (Na, mEq/l), potassium (K⁺, mEq/l), and chloride (Cl⁻, mEq/l).

• urine tests: Urinary 8-hydroxy-deoxyguanosine (8-OHdG) and urinary isoprostane

• observations on improvement of QOL using a common questionnaire sheet

If circumstances such as the following occurred, necessitating discontinuation of the test, the test was discontinued immediately, following the decision of the physician in charge of the test, and adequate treatment was provided.

• if other serious diseases are seen to have developed

• if existing symptoms (including complications) worsened

• if a physician determines that continuation of the test is impossible for other reasons

Our present study targeted 35 healthy individuals (18 men and 17 women) {48.3 ± 6.9 years, body mass index (BMI): 26.3 ± 1.7} who were randomly divided into the Test Group and the Control Group. At least 6 cases in each group are necessary for detection of the significant difference in any of more than 50 items in the Anti-Aging QOL Common Questionnaire (AAQol) [2–4], and the number should be doubled or tripled for the classified analysis according to 2 or 3 classes. There were 18 individuals in the Test Group (age: 48.6 ± 6.0 years, height: 163.1 ± 7.9 cm; weight: 69.9 ± 7.2 kg, and BMI: 26.3 ± 1.7; mean ± SD), and 17 in the Control Group (age: 48.0 ± 7.9 years, height: 163.5 ± 11.2 cm, weight: 66.5 ± 11.9 kg, and BMI: 24.7 ± 2.9; mean ± SD). The Test Group took 6 doses of the Product, including L-carnitine (600 mg/day) and Garcinia cambogia extract (500 mg/day as hydroxycitric acid) for 8 weeks, while the Control Group took 6 doses of a placebo drug for 8 weeks. The method of taking these test drugs was explained by a nutritionist to all of the test subjects.

The Product is manufactured by Nurex Corporation of Osaka Prefecture, Japan, and has the following composition.

Raw materials:

L-carnitine, L-tartrate, Garcinia cambogia extract, corn starch, edible purified oil-processed fat and oil (hydrogenated oil), gelatin, caramel coloring, calcium pantothenate, vitamin B₁. Nutritional ingredients (for every 3 doses of the Product): calories: 4.58 kcal, protein: 0.38 g, fat: 0.06 g, carbohydrates: 0.61 g, sodium: 1.26 mg, vitamin B₁: 1.2 mg, pantothenic acid: 10 mg, L-carnitine: 300 mg, hydroxycitric acid (Garcinia cambogia extract): 250 mg. The amounts of vitamin B₁ and pantothenic acid are subtle compared with those of daily dietary intake.

As indicators for the degree of oxidation stress, we used serum lipid peroxide, 8-OHdG (8-hydroxy-2' deoxy-guanosine), and isoprostane (8-isoprostane F-2α) [5–7]. These indicators were measured at the Japan Institute for the Control of Aging. Moreover, the 8-OHdG, isoprostane, and creatinine contained in the first urine in the early morning were measured to calculate the rate of 8-OHdG/CRE· isoprostane production and the creatinine correction volume (8-OHdG/CRE·isoprostane/CRE), based on the volume of urine and urine collection period (the time from the last urination of the previous night to the first urination the following morning).

Subjective symptoms were divided into physical and mental symptoms and evaluated on a scale of 1 to 5, using the Anti-Aging QOL Common Questionnaire (AAQol) [2–4].

Table 1 Physical measurements of Test Group

Table 2 Physical measurements of Control Group

In the general laboratory tests (Tables 3 and 4), the Test Group showed significant changes in their total cholesterol (4.5%) from 214.0 ± 31.1 to 223.7 ± 31.44 (p = 0.046), fasting blood sugar (4.1%) from 91.9 ± 10.6 to 95.7 ± 7.5 (p = 0.016), and HbA1c (3.4%) from 4.73 ± 0.43 to 4.89 ± 0.39 (p = 0.000). Significant fluctuations were also seen in MCV (1.4%) from 93.5 ± 3.3 to 94.8 ± 3.2 (p = 0.000) and MCH (1.3%) from 30.6 ± 1.5 to 31.0 ± 1.4 (p = 0.000), but they were slight changes within the range of 1.4%. The Control Group showed significant variations in the leukocyte count (−10.9%) from 7244.0 ± 2665.9 to 6456.7 ± 2120.0 (p = 0.020) and HbA1c (2.9%) from 4.89 ± 0.40 to 5.03 ± 0.43 (p = 0.001). Although a significant fluctuation was seen in MCV (1.0%) from 92.6 ± 5.6 to 93.5 ± 5.7 (p = 0.038), the change was only 1.0%. Intra-group analysis showed no significant differences between the two groups.

Table 3 Clinical tests of Test Group

Table 4 Clinical tests of Control Group

The Test Group showed no significant variations in lactic acid, insulin, IGF-I, cortisol, or DHEA-s (Tables 3 and 4). The Control Group, meanwhile, showed a significant variation in IGF-I (−8.8%) from 197.9 ± 68.9 to 180.6 ± 60.4 (p = 0.007). An intra-group analysis showed no significant differences between the two groups.

Regarding oxidation stress markers (Tables 3 and 4), the Test Group showed a significant reduction in blood lipid peroxide (−12.8%) from 0.39 ± 0.07 to 0.34 ± 0.08 (p = 0.001) but no significant changes in the speed of urinary 8-OHdG formation, or the speed of isoprostane formation, 8-OHdG/CRE, or isoprostane/CRE. The Control Group, on the other hand, showed no significant changes in lipid peroxides, and no significant variations in other urinary markers. An intra-group analysis showed no significant differences between the two groups.

Tables 5, 6, 7, 8 show the results of the analysis on the Anti-Aging QOL Common Questionnaire (AAQol). Regarding physical symptoms, the Test Group showed significant improvements in scores of the following 8 out of 30 items: “tired eyes” (p = 0.015), “blurry eyes” (p = 0.035), “muscle pain/stiffness” (p = 0.017), “early satiety” (p = 0.042), “epigastralgia” (p = 0.010), “dizziness” (p = 0.003), “arthralgia” (p = 0.037), and “easily breaking into a sweat” (p = 0.026). The Control Group did not show improvements in any of the scores. Intra-group analysis showed a significant difference between the two groups in terms of changes in the score for “dizziness” (p = 0.008).

Table 5 Physical symptoms of Test Group

Table 6 Physical symptoms of Control Group

Table 7 Mental symptoms of Test Group

Table 8 Mental symptoms of Control Group

As for mental symptoms, the Test Group showed no items (of the 21 items) whose scores had improved. The Control Group showed a significant improvement in the score for a single item: “sleeping disturbance” (p = 0.019). An intra-group analysis showed no significant differences between the two groups.

Regarding physical symptoms, slightly more men than women suffered “diarrhea” and “lumbago” (p<0.05), while more women than men suffered “excessive sensitivity to cold” (p<0.01). No gender differences were seen in mental symptoms.

Regarding general laboratory test items, men showed significantly higher values than women in their erythrocyte count, hemoglobin content, hematocrit, GPT, γ-GTP, creatinine, and uric acid levels. Special tests such as hormone levels showed that men had significantly higher values than women in terms of cortisol (p<0.05) and DHEA-s (p<0.05). In oxidation stress marker tests, men showed a significantly higher 8-OHdG/CRE value than did the women. However, none of the other items showed any gender differences. Improvement rates of oxidation stress markers before and after the tests showed no gender differences.

The improvement in scores for “tired eyes” was most marked in subjects with high cortisol values (r = −0.38, p<0.05), and in subjects who were extremely “irritable” (r = –0.38, p<0.05) or “easily angered/short-tempered” (r = –0.35, p<0.05). The degree of change in scores for “blurry eyes” was most marked in subjects with low insulin levels (r = 0.36, p<0.05) and low diastolic pressure (r = 0.37, p<0.05). The improvement in scores for “muscle pain/stiffness” was most marked in younger subjects (r = 0.44, p<0.05), but less so for subjects with “shallow sleep” (r = 0.43, p<0.05). Scores for “early satiety” (r = 0.42, p<0.05) and “epigastric pain” (r = 0.51, p<0.01) tended to improve less readily in subjects with “shallow sleep.” There were no factors that affected the improvement rates in the score for “dizziness.” The improvement in score for “arthralgia” was most marked in heavy smokers (r = −0.36, p<0.05), subjects who were “irritable” (r = −0.39, p<0.05), “easily angered/short-tempered” (r = −0.35, p<0.05), or “depressed” (r = −0.38, p<0.05). The scores tended to improve less in those who engaged in regular and vigorous exercise (r = 0.53, p<0.05). The degree of improvement in the scores for “easily breaking into a sweat” tended to be low in subjects with high cortisol values (r = −0.36, p<0.05), but was higher in subjects who had a “loss of motivation” (r = 0.41, p<0.05).

In the course of protein being synthesized from amino acids in vivo, it requires the aid of vitamin B₆ and other substances. Antioxidants such as vitamin C and E are also useful in suppressing the free radicals that develop during this process.

The human body is composed of 20 types of amino acids. There are ten amino acids that cannot be synthesized in vivo and therefore must be obtainable from food: valine, leucine, isoleucine, histidine, phenylalanine, tryptophan, lysine, methionine, arginine, and threonine. There are ten nonessential amino acids that can be synthesized in vivo: glutamine, proline, glycine, asparagine, glutamic acid, aspartic acid, cysteine, tyrosine, serine, and alanine.

The synthetic capability in vivo of nonessential amino acids generally declines with age. What is especially important is not chronological age, but hormonal age, as revealed in a reduction in DHEA, growth hormones and IGF-I. Growth hormones and IGF-I directly affect amino acid synthesis, and decreased DHEA that is synthesized in the adrenal gland indirectly affects the synthesis of amino acids and proteins via reductions in protein-synthesizing hormones that are synthesized based on DHEA and in androgens that have protein anabolic activity.

A study that measured the amount of carnitine in the plasma and the liver of 68 pediatric chronic liver disease and 36 cirrhosis patients showed that the latter patients had low plasma carnitine concentrations [14]. Meanwhile, in a study using 382 hyperlipidemia patients taking statin drugs (167 males and 215 females; mean age: 63.17 years), patients given oral statins had higher CPK levels than normal populations, and had significantly lower plasma acylcarnitine levels. This suggests the possibility that, for some unknown reason, individuals on oral statin drugs have fatty acid metabolic abnormalities due to abnormal carnitine metabolism, and that this may be one of the causes of the rise in CPK levels and myopathy [15].

Carnitine also affects the gastrointestinal tract. There is a reduction in gastric mucins and prostaglandin E₂ of rats subjected to cold stress. However, the administration of L-carnitine suppresses this reduction as well as the development of gastric mucosal lesions and formation of lipid peroxide. Administration of L-carnitine is also shown to elevate catalase activity in the blood and inside the gastric mucosal membrane [19].

Carnitine also acts on the sensory organs. In a study in which palmitoyl-DL-carnitine (1 × 10⁻⁴ M) was administered to guinea pigs via perilymphatic reflux, measurements of the endocochlear DC potential and cochlear microphonics showed the former to have dropped to +8 ~ +16 mV, and the latter to 30 ~ 39%, suggesting a direct effect of palmitoyl-DL-carnitine on cochlear hair cells [20].

Several reports have been published on the effects of carnitine on the heart. Administration of adriamycin reduces free carnitine in rat cardiac muscle and boosts acylcarnitine levels. These, however, were shown to improve after 500 mg/kg of L-carnitine was administered intra-abdominally on a daily basis, showing that L-carnitine counteracts cardiotoxicity of adriamycin [21]. In a study using rat models of ischemic myocardial disorders, administration of L-carnitine prior to re-reflux was shown to increase free carnitine, activating fatty acid metabolism after re-reflux and improving glycolytic metabolism that was impaired because of ischemia, thereby improving myocardial metabolism and promoting the recovery of myocardial function [22]. In another study that investigated the effects of L-carnitine in which extracted reflux heart of diabetic rats (a state of diabetic cardiac dysfunction such as reduction in systolic and diastolic functions) was used, reduced intra-myocardial carnitine content was seen to improve with oral administration of propionyl-L-carnitine. The drug also increased intra-myocardial carnitine and improved cardiac function [23].

There are also reports on the use of L-carnitine as a dietary supplement for patients with renal failure. In a study of 17 hemodialysis patients who were undergoing continuous maintenance therapy comprising erythropoietin, the maintenance dosage of erythropoietin correlated negatively to serum free carnitine concentration. Twenty weeks after taking 500 mg/day of carnitine chloride, four patients saw an over 20% improvement in their hematocrit values, three of whom were able to reduce the dose of erythropoietin [29]. In a study targeting 7 chronic renal failure patients undergoing hemodialysis (mean: 61 ± 17 years, mean history of dialysis: 17 ± 10 years), as a result of administration of L-carnitine (1,000 mg/day for the first month and 500 mg/1–2 days after the second month; the drug was continued for 2 or more years), serum total carnitine concentration improved, the dose of erythropoietin could be decreased, and palpitations as well as post-dialysis fatigue and lethargy improved. These results suggest that dietary supplementation with L-carnitine is useful for improving the QOL of dialysis patients [30].

Recently, reports related to supplements containing carnitine have also been published. In an open test in which ten healthy individuals (4 males; mean age, 40.0 ± 4.2 years; BMI, 27.2 ± 2.2; 6 females; mean age, 35.2 ± 9.4 years; BMI, 26.9 ± 2.8) took Metabolic L-Carnitine Plus® for 40 days, both men and women saw a significant reduction in weight, BMI, body fat percentage, bust, waist, hip, upper arm, thigh, and calf circumference; a significant rise in total carnitine, free carnitine, and acylcarnitine; and a significant drop in total cholesterol, triglycerides, blood sugar and lactic acid. The results show the potential usefulness of supplements containing carnitine in promoting lipolysis and energy production in obese individuals [31].

Regarding ocular symptoms, a number of reports have been released. One states that there was a reduction in carnitine inside the ocular lens of diabetic rats [33], while another found carnitine to be effective for ischemic re-reflux disorder in the retina of guinea pigs [34]. There is also a report of a clinical test with human subjects that showed a supplement containing carnitine to counter macular degeneration [35]. The fact that ocular symptoms such as “tired eyes” and “blurry eyes” significantly improved in the Test Group may be attributable to this recovery of the concentration of carnitine in the ocular tissue.

In our laboratory tests, a significant rise was seen in total cholesterol, fasting blood sugar, and HbA1c. Although past reports have shown that carnitine corrects lipid and sugar metabolism [8, 10, 13], our test produced a different result, showing that “early satiety” and “epigastric pain” were alleviated, so it is highly likely that other elements may have come into play, such as increased appetite and improved caloric intake from food. As for oxidation stress markers, lipid peroxides decreased significantly in the Test Group. Carnitine plays an important role in lipid metabolism [8] and possesses anti-oxidation activity [19, 22, 34, 36], so a decrease in lipid peroxides is not contradictory.

These findings suggest that the consumption of the supplement can reduce the oxidative damage and some symptoms in the human; however, the effect on QOL was equivocal from the results of the effect on lipid metabolism. Garcinia cambogia extract did not show dietary efficacy.

In our test, scores for “muscle pain/stiffness” changed from 3.4 ± 1.3 to 2.8 ± 1.3 (−17.6%, p = 0.017) in the Test Group, and from 2.7 ± 1.3 to 2.5 ± 1.0 (−7.4%) in the Control Group, showing no significant differences in the improvement rate between the two groups. However, it improved significantly in the Test Group only. An important activity of carnitine is that it combines with acyl-CoA, which is produced from free fatty acids inside the cells, to enable the passage of acyl-CoA through the mitochondrial endosporium [8–13]. This is most likely because, even in muscle cells, which are packed with mitochondria, replenishing carnitine improves the status of metabolism to bring about favorable effects.

The fact that total cholesterol increases in proportion to the number of cigarettes smoked implies that total cholesterol and smoking, which are risk factors for arteriosclerosis, may work synergistically. This reconfirms the importance of reducing these risk factors one by one to prevent diseases related to arteriosclerosis such as cerebral apoplexy and heart disease. We were not able to identify the relationship between the degree of change in fasting blood sugar and insulin values and 8-OHdG/CRE.

Lipid peroxides are believed to be relatively high in women who have high body fat percentages, in young people who drink heavily, and in individuals with high values for height, body water content, muscle volume, lean muscle mass, and skeletal muscle volume; these values are liable to drop because of antioxidative substances contained in the Product. It appears, however, that elderly individuals do not demonstrate antioxidative effects very readily. The relationship with cortisol is not clear.

Individuals who have high cortisol values, and who show extreme “irritability” or who are “easily angered/short-tempered” are believed to suffer extensive “tired eyes.” It may be that it was relatively easy to see their symptoms related to “tired eyes” improve because of the Product. The causal relationship between the degree of change in the scores for “blurry eyes,” insulin value and diastolic blood pressure is not clear. It appears that the older the individual, the more difficult for his or her “muscle pain/stiffness” to improve; the more a person suffers “shallow sleep,” the more difficult for it to improve because of insufficient tissue restoration during sleep. It appears that symptoms of “early satiety” and “epigastralgia” are difficult to improve in individuals who often experience “shallow sleep.” This suggests the importance of sleep. Heavy smokers and people who have major symptoms of “irritability”, “easily angered/short-tempered,” and being depressed tend to manifest symptoms of “arthralgia” more strongly than others, so it may be that these symptoms tend to improve more readily as a result of using the Product. People who exercise extensively to begin with have their “arthralgia” already in a steady state, so it may be that their symptoms do not change very readily, even as a result of using the Product. We were unable to identify any relationship between “easily breaking into a sweat” and cortisol value or “loss of motivation.”

Research for the project was supported by Antiaging Bank Inc. Tokyo, Japan (www.yonei-labo.com), Gingakobo Inc., Nagoya, Japan (www.gingakobo.jp) and the Wellness Research Institute, Osaka, Japan (www.natural-life.jp).