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EFFECTS OF TIMING OF MEDIUM-CHAIN TRIGLYCERIDES (8:0 AND 10:0) SUPPLEMENTATION DURING THE DAY ON MUSCLE MASS, FUNCTION AND COGNITION IN FRAIL ELDERLY ADULTS

 

S. Abe1, O. Ezaki2, M. Suzuki1

 

1. Day Care SKY, Yokohama, Japan; 2. Institute of Women’s Health Science, Showa Women’s University, Tokyo, Japan

Corresponding Author: Osamu Ezaki, M.D. Institute of Women’s Health Science, Showa Women’s University, 1-7-57 Taishido, Setagaya-ku, Tokyo 154-8533, Japan, Tel: +81-3-3411-7450; Fax: +81-3-3411-7450, E-mail: ezaki1952@yahoo.co.jp

J Frailty Aging 2021;in press
Published online September 2, 2021, http://dx.doi.org/10.14283/jfa.2021.33

 


Abstract

Objectives: Supplementation with 6 g/day of medium-chain triglycerides (MCTs) at dinnertime increases muscle function and cognition in frail elderly adults relative to supplementation with long-chain triglycerides. However, suitable timing of MCT supplementation during the day is unknown.
Design: We enrolled 40 elderly nursing home residents (85.9 ± 7.7 years) in a 1.5-month randomized intervention trial. Participants were randomly allocated to two groups: one received 6 g/day of MCTs at breakfast (breakfast group) as a test group and the other at dinnertime (dinner group) as a positive control group.
Measurements: Muscle mass, strength, function, and cognition were monitored at baseline and 1.5 months after initiation of intervention.
Results: Thirty-seven participants completed the study and were included in the analysis. MCT supplementation in breakfast and dinner groups respectively increased right arm muscle area from baseline by 1.1 ± 0.8 cm2 (P<0.001) and 1.6 ± 2.5 cm2 (P<0.001), left arm muscle area by 1.1 ± 0.7 cm2 (P<0.001) and 0.9 ± 1.0 cm2 (P<0.01), right knee extension time by 39 ± 42 s (P<0.01) and 20 ± 32 s (P<0.05), leg open and close test time by 1.74 ± 2.00 n/10 s (P<0.01) and 1.67 ± 2.01 n/10 s (P<0.01), and Mini-Mental State Examination score by 1.5 ± 3.0 points (P=0.06) and 1.0 ± 2.1 points (P=0.06). These increases between two groups did not differ statistically significantly.
Conclusion: Supplementation with 6 g MCTs/day for 1.5 months, irrespective of ingestion at breakfast or dinnertime, could increase muscle mass and function, and cognition in frail elderly adults.

Key words: FIM, frailty, MCT oil, MMSE, sarcopenia.


Introduction

Sarcopenia (loss of skeletal muscle mass, strength, and function) and dementia (or cognitive impairment) are common in elderly adults but difficult to treat. Previously, in a randomized, controlled trial with a time course, we found that supplementation with medium-chain triglycerides (MCTs) (6 g/day) at dinnertime for 3 months in frail elderly adults increased their muscle strength, function, activities of daily living (ADL) (1), and cognition (2) relative to supplementation with long-chain triglycerides (LCTs). The muscle and cognitive functions in the LCT group gradually decreased with time, whereas those in the MCT group increased (1, 2). However, suitable timing of MCT supplementation during the day is unknown.
Our previous studies (1, 2) suggested that O-n-octanoylation of ghrelin by C8:0 in MCTs could be a mechanism by which dietary MCTs increase muscle function and cognition , rather than in its role as a ketogenic meal (3). O-n-octanoylation by ghrelin o-acyltransferase in the stomach is essential for the activation of ghrelin, which stimulates the release of growth hormone (GH) in rats (4). Also, the injection of acyl-ghrelin in humans released GH in a dose-dependent manner (5, 6). A decrease in GH secretion accompanies aging and may contribute to the sarcopenia that develops in older adults (7). Ingestion of MCTs leads to the activation (i.e., acylation) of ghrelin in mice (8), which may lead to an increase in the level of GH secretion and a subsequent increase in muscle mass (the MCTs/Ghrelin/GH hypothesis). In humans, ingestion of MCTs also leads to an increase in blood acyl-ghrelin concentration (9-11). However, it has not been shown that ingestion of MCTs can increase GH secretion.
Both ghrelin and GH are secreted with circadian rhythmicity. Plasma ghrelin levels rise before a meal and drop after feeding (12). Inter-meal ghrelin levels displayed a diurnal rhythm, rising throughout the day to a zenith at 1:00 a.m., then falling overnight to a nadir at 9:00 a.m. (12). This circadian rhythm of ghrelin secretion may affect GH secretion. The stimulatory actions of GH-releasing hormone and ghrelin on GH secretion from pituitary and the tonic inhibitory influence of somatostatin generate a pulsatile pattern of GH secretion (13), which is stimulated during sleep (14). A major secretory episode occurs shortly after sleep onset, in association with the first period of slow-wave sleep (15). However, during aging, slow-wave sleep and GH secretion decrease with the same chronology (16). Therefore, to increase GH secretion during sleep, the timing of MCT supplementation may be important.
In our previous studies (1, 2, 17, 18), MCTs were given at dinnertime. If MCTs are given at breakfast time, the favorable effects of MCTs might not be observed because the effects of MCTs might not be long enough to increase ghrelin and GH secretion during sleep. In the present study, to determine suitable timing of MCT supplementation during the day, we compared the effects of MCTs given either at breakfast or dinnertime for 1.5 months, as both times are suitable to add MCTs in served foods for most elderly adults.

 

Materials and methods

Participants

This trial was announced in early April 2019 at the Day Care SKY facility in Yokohama, Japan. All participants who resided in this nursing home and who required special care from a helper were targeted (n = 68; mean age, 86.1 ± 7.7 years) (Figure 1). The registration was started on April 6, 2019 and ended on April 18, 2019. During this interval, 21 participants were excluded by the criteria of a body mass index (BMI) of >23 kg/m2 (to avoid a further increase in body weight); <65 years of age; parenteral nutrition; difficulty in swallowing; severe heart failure, lung, liver, kidney, or blood disease; a fasting blood glucose level of ≥200 mg/dL; a blood creatinine level of ≥1.5 mg/dL; or a CRP level of ≥2.0 mg/dL, and 7 participants were moved to other facilities, as described in Figure 1. Thus, 40 participants (5 men, 35 women; mean age, 85.9 ± 7.7 years) were enrolled and allocated to each group on April 18, 2019. Data collection at baseline was started on April 19, 2019 and ended by May 2, 2019. The intervention took place from May 3, 2019 to June 14, 2019 at Day Care SKY. Data collection after the intervention was started on June 16, 2019 and ended by June 20, 2019.

Figure 1. Trial profile

Participants (n = 40) were randomly allocated to two groups: the breakfast group (6 g/day of medium-chain triglycerides at breakfast time, n =20) and dinner group (6 g/day of medium-chain triglycerides at dinnertime, n =20). Thirty-seven participants completed the study and were included in the analysis. FIM = Functional Independence Measure; MCT = medium-chain triglycerides; RSST = repetitive saliva swallowing test.

 

The participants and their family members were informed of the nature of the experimental procedures before their written informed consent was obtained. In patients with cognitive decline or difficulty in writing (n = 12), informed consent was obtained from the patient’s family members. The present study was approved by the Human Ethics Committee of Japan Society of Nutrition and Food Science (Approval No. 87). The procedures were conducted in accordance with either the ethical standards of the institutional committee on human experimentation or the Helsinki Declaration of 1975 (as revised in 2000).

Study design

We performed a 1.5-month randomized, single blinded, parallel group intervention trial in which the 40 participants were randomly allocated into two groups (Figure 1). Sealed envelopes containing the written informed consent of the individual participants (or their family members) were thoroughly shuffled. Twenty participants (envelopes) each were allocated to the group that received 6 g/day MCTs at breakfast time (7:30~8:15 a.m.) and the group that received 6 g/day MCTs at dinnertime (6:00~6:45 p.m.). Allocation was conducted by a non-member of this study.
The intervention duration was 1.5 months, which was half that of the previous trial design (3 months) (1, 2, 17, 18), because significant dropouts in participants had been expected after the 1.5-month intervention. Due to legal limitations on the period of residency in this nursing home, some of the participants were required to leave this nursing home during the study period.
The participants’ body weight, appendicular muscle mass, strength, function, cognition, and ADL as described previously (1, 2) were assessed at baseline and 1.5 months after the initiation of the intervention. To avoid the possible acute effects of MCTs, assessment of the MCT intervention was conducted 2 days after the last MCT supplementation. Additionally in the present study, body composition (body fat percentage, fat mass, and muscle mass) in the whole body was measured by bioelectrical impedance method (ONE SMARTDIET, South Korea).

Blinding

The participants in both groups were blinded for group allocation. They did not know whether they belonged to the breakfast or dinner group because they could not detect the foods containing MCTs. This might be due to the faint smell of the MCTs oil itself, the relatively small amounts of MCTs added to the foods, or the decreased sense of taste in the elderly participants.
To assess the outcomes, the examiners who oversaw the walking speed test and undertook the Functional Independence Measure (FIM) and the Nishimura geriatric rating scale for mental status (NM scale) were unaware of each participant’s group (blinded). Other assessments (anthropometric measurements, hand grip strength, knee leg extension time, leg open and close test, peak expiratory flow [PEF] test, repetitive saliva swallowing test [RSST], and Mini-Mental State Examination [MMSE]) were conducted by an expert with a certificate of training but who was aware of the participant’s group assignment (unblinded).

Study products

The MCTs (75% 8:0 and 25% 10:0 from total fatty acids) were purchased from Nisshin OilliO Group Ltd. (Kanagawa, Japan). Six grams of MCTs (50 kcal; 8.3 kcal/g) per day was mixed with foods such as steamed rice or miso soup at breakfast or dinnertime.

Daily time schedule of the participants

The daily time schedule in this nursing home was as follows: hour of rising, 5:30~6:30 a.m.; breakfast, 7:30~8:15 a.m.; lunch, 12:00~12:45 p.m.; snack, 3:00~3:30 p.m.; dinner, 6:00~6:45 p.m.; bedtime, 8:00~9:00 p.m.

Dietary intake

Breakfast, lunch, and dinner were served daily in the nursing care home. The habitual daily energy and nutrient intake of the individual participants during the baseline and intervention periods was measured as described previously (17). Then, the mean daily energy and macronutrient intakes of the two groups were calculated based on the daily energy and nutrient intakes of the individual participants (Table 1).

Table 1. Habitual energy and macronutrients intake at baseline and during the 1.5-month intervention and their changes in the breakfast and dinner groups (excluding MCT supplement)

Values are mean + SD. †P values represent the differences in the changes of variables between the two groups as assessed by 1-factor ANCOVA adjusted by each baseline value. MCFA = medium-chain fatty acid.

 

Daily activity and rehabilitation/exercise

Daily activities of this nursing care home were follows: at 7:15 a.m., exercises for the mouth were started for 10 min. At 10:00 a.m., exercises for the arms and fingers were started for 20 min. At 3:30 p.m., recreational therapy was started for 1 hour as described previously (1). At other times, residents spent their free time watching TV, lying in bed, and doing other activities. In addition, rehabilitation/exercise protocols were individually conducted. Several types of exercises such as walking, resistance training, leg stretches, stair stepping, or balance training were individually conducted for 20 min twice a week. The individual daily activities and rehabilitation/exercise were not changed during the baseline and intervention periods. The conductors of the daily activity and individual rehabilitation/exercise were unaware of the group to which each participant was assigned.

Medications

Medical drugs (antihypertensive, antiplatelet, antipsychotic, antilipemic, antidiabetic, antiosteoporosis, laxative, and hypnotic drugs), which were used by some of the participants, were not changed during the baseline or intervention periods.

Participants excluded from the analysis

Two participants in the breakfast group had paralysis of the right hand and another participant suffered from Parkinson’s disease and were excluded from the analysis of right-hand grip strength (Figure 1). One participant in the breakfast group had paralysis of the right leg and was excluded from the analysis of right knee extension time. One participant in the breakfast group had paralysis of the left leg and was excluded from the analysis of left knee extension time.
Three participants in the breakfast group had right foot paralysis, a fourth participant had low-back pain, and another participant refused to undergo the analysis of walking speed. One participant from the dinner group had difficulty in standing up due to increased body weight. All 6 participants were excluded from this test.
Three participants in the breakfast group and one from the dinner group had difficulty in understanding how to perform the PEF test and were excluded from the analysis of PEF. One participant in the breakfast group had motor apraxia and was excluded from the analysis of RSST. One participant in the dinner group changed from use of a walker to use of a wheelchair during the intervention (i.e., ADL were changed) and was excluded from the analysis of the FIM score.

Primary and secondary outcome variables

The primary outcome of the trial was the result of right knee extension time, which showed the largest increase (26 s, 43.3%, P < 0.001) in the 1.5-month intervention from baseline in the MCT group among the muscle tests conducted in our previous study (1). The other test results were considered the secondary outcomes. For the primary efficacy measure of right knee extension time, 36 participants were required in one group (n = 72 in two groups) for a power of 80% at a two-sided P of 0.05 to detect a treatment difference of 26 s with an SD of 39 s between the two groups by t-test.

Statistical analysis

All data are expressed as the mean + SD. In the within-group analysis, values at baseline and at the end of the intervention in each group were compared by Wilcoxon signed-rank test.
In the between-group analysis, to compare the groups with respect to the effects of MCTs on the measurements, differences in the change (change value = intervention value – baseline value) between the groups were assessed with analysis of covariance (ANCOVA), with adjustment for the baseline values in each measurement, age, sex, and BMI as covariates. The variances of change in all measurements were homogeneous between the groups by Levene’s test.
The percentage of relative change (% change) was calculated as follows: % change = (mean of the intervention value – mean of the baseline value) / mean of baseline value × 100. This value was then used to describe the degree of effect.
Missing data (data that could not be collected at baseline and/or after the intervention due to difficulty in performing tests) were not included in the analyses. A P level of 0.05 was used to determine statistical significance. All statistical analyses were performed with the SPSS 20.0 software program (IBM, Chicago, IL).

 

Results

Participants and compliance

We enrolled 40 participants in the trial (Figure 1). Three participants dropped out during the study: one participant in the breakfast group due to bone fracture following a fall and 2 participants in the dinner group due to signs of acute heart failure. Thus, the remaining 37 participants (breakfast group: n = 19; 2 men, 17 women; mean age, 85.6 ± 7.9 years and the dinner group: n = 18; 2 men, 16 women; mean age, 86.4 ± 8.3 years) completed the study, and their data were used for the following analysis. No side effects, including diarrhea, or any other claims were reported.

Dietary intake (excluding supplemental MCTs)

Habitual intakes of energy and macronutrients at baseline and during the intervention period for the two groups are shown in Table 1. The MCTs that were administered are not included in this table. No differences between the baseline and intervention period were observed in either group with regard to the habitual intake of energy, protein, fat, and carbohydrate.

Anthropometric measures

Table 2 shows the anthropometric measures obtained at baseline and at the end of the 1.5-month intervention and their changes from baseline in the two groups. MCT supplementation did not affect body weight and BMI in either group. However, MCTs increased whole-body muscle mass from baseline by 0.3 ± 0.7 kg (non-significant, P = 0.11) in the breakfast group and 0.4 ± 0.5 kg (P < 0.01) in the dinner group and decreased whole-body fat mass by -0.9 ± 1.4 kg (P < 0.01) and –1.0 ± 1.5 kg (P < 0.01), respectively. In both groups, in agreement with the changes in body composition, increases in calculated right/left arm muscle area (AMA) and decreases in right/left triceps skinfold thickness (TSF) were noted. However, the increase in the right calf circumference (CC) was significant in the dinner group (0.4 ± 0.5 cm, P < 0.01) but not in the breakfast group (0.1 ± 0.6 cm, P = 0.23), whereas the increase in the left CC was significant in the breakfast group (0.2 ± 0.4 cm, P < 0.05) but not in the dinner group (0.3 ± 0.5 cm, P = 0.06). These changes between the two groups did not differ statistically significantly.

Table 2. Anthropometric measurements at baseline and 1.5-month intervention and their changes from baseline in the breakfast and dinner groups

Values are expressed as the mean ± SD. Asterisks indicate a statistically significant difference from baseline *P < 0.05, **P < 0.01, ***P < 0.001 by Wilcoxon signed-rank test. †P value represents the difference in the change in a variable between the two groups as assessed by a 1-factor ANCOVA adjusted for the baseline value in each measurement, age, sex, and BMI. AC = arm circumference; AMA = arm muscle area; BMI = body mass index; CC = calf circumference; TSF = triceps skinfold thickness.

 

Muscle strength and function

Muscle strength and function at baseline and at the end of the 1.5-month intervention and their changes from baseline in the two groups are shown in Table 3. MCT supplementation in the breakfast and dinner groups increased the right knee extension time from baseline by 39 ± 42 s (P < 0.01) and 20 ± 32 s (P < 0.05); the left knee extension time by 37 ± 36 s (P < 0.01) and 28 ± 32 s (P < 0.01); and the leg open and close test results by 1.74 ± 2.00 n/10s (P < 0.01) and 1.67 ± 2.01 n/10s (P < 0.01), respectively. However, the increase in the right-hand grip strength was significant only in the dinner group (0.9 ± 1.8 kg, P < 0.05) and not in the breakfast group (0.9 ± 2.3 kg, P = 0.24). These increases between the two groups did not differ statistically significantly.

Table 3. Muscle strength and function at baseline and 1.5-month intervention and their changes from baseline in the breakfast and dinner groups

Values are expressed as the mean ± SD. Asterisks indicate a statistically significant difference from baseline *P < 0.05, **P < 0.01 by Wilcoxon signed-rank test. †P value represents the difference in the change in a variable between the two groups as assessed by a 1-factor ANCOVA adjusted for the baseline values in each measurement, age, sex, and BMI. RSST = repetitive saliva swallowing test.

 

ADL and cognition

The FIM, MMSE, and NM scale scores at baseline and at the end of the 1.5-month intervention and their changes from baseline in the two groups are shown in Table 4. In these tests, a high score indicates better function. MCT supplementation in the breakfast and dinner groups increased the FIM score from baseline by 5.1 ± 6.0 points (P < 0.01) and 3.7 ± 5.0 points (P < 0.01); the MMSE score by 1.5 ± 3.0 points (P = 0.06) and 1.0 ± 2.1 points (P = 0.06); and the NM scale score by 3.5 ± 2.7 points (P < 0.01) and 2.2 ± 2.8 points (P < 0.01), respectively. These increases between the two groups also did not differ statistically significantly.

Table 4. FIM, MMSE, and NM scale scores at baseline and 1.5-month intervention and their changes from baseline in the breakfast and dinner groups

Values are means ± SD. In these tests, a high score indicates better function. Asterisks indicate a statistically significant difference from baseline *P < 0.05, **P < 0.01, ***P < 0.001 by Wilcoxon signed-rank test. †P values represent the differences in the changes of variables between the two groups as assessed by 1-factor ANCOVA adjusted for the baseline values in each measurement, age, sex, and BMI. FIM = Functional Independence Measure; MMSE = Mini-Mental State Examination; NM scale = Nishimura geriatric rating scale for mental status.

 

Discussion

The present study showed that irrespective of the timing of MCT supplementation during the day (either at breakfast or at dinnertime), supplementation with 6 g MCTs/day for 1.5 months increased muscle mass and function, cognition, and ADL of frail elderly adults from baseline measurements. These results suggested that ingestion of MCT at either time could lead to similar activation of the MCTs/Ghrelin/GH axis.
A negative control (or placebo) group could not be included due to the small number of participants in the present trial. However, because our previous studies included an unsupplemented control group (inert control group) (17, 18) or negative placebo group (LCT group) (1, 2), it is clear that 6 g/day MCT supplementation increased muscle strength, function, ADL, and cognition relative to the control groups (inert or placebo).
The results are promising, but a future larger randomized study is needed. In addition, considering the reported adverse effects of the administration of ghrelin (19) and GH (20), long-term studies of MCT supplementation will be required to examine potential adverse effects, including risks of diabetes mellitus, cancer, and hyperplasia in some tissues.

Effects of MCTs on dietary intake

We did not observe any differences in habitual energy or nutritional intake between baseline and the intervention period in either group (Table 1), in agreement with our previous studies (1, 17). These results suggest that intakes of other daily nutrients did not alter the effects of MCT supplementation.
MCTs have been shown to be more satiating (i.e., decrease appetite) and promote weight loss compared with LCTs (21, 22), whereas ghrelin administration increases appetite (19). We speculated that either the dose of 6 g/day MCTs in our studies was not enough to promote weight loss, or an increase in appetite generated by ghrelin might counteract the effect of MCTs to decrease appetite.

Possible reasons for similar effects of MCT supplementation at either breakfast or dinnertime

The circadian profile of acyl-ghrelin and GH concentrations in blood after MCT supplementation, in which frequent blood sampling (i.e., more than 30 times throughout a 24-h period) was required (12, 16), have not been examined. However, blood acyl-ghrelin concentration after acute or chronic MCT supplementation, in which blood sampling is required several times throughout a 24-h period, has been reported in several human studies (9-11).
A time lag from oral MCT supplementation to an increase in ghrelin concentration was observed in two studies (8, 9). In one study in mice, the n-octanoyl ghrelin concentration in the stomach increased significantly at 3 h after glyceryl trioctanoate supplementation (8). In another experiment in mice from the same study, plasma acyl-ghrelin, which does not naturally occur in mammals, appeared after 4 h following supplementation of either glyceryl triheptanoate or n-heptanoic acid (7:0) (8). In a clinical study, 2–5 h was required to observe an increase in acyl-ghrelin concentration after the single oral ingestion of 3.0 g of a MCT supplement in an energy-containing formula in cachectic patients relative to patients without administration of the formula (9). Surprisingly, this increase in blood acyl-ghrelin concentration was maintained for at least another 10 h (9). Considering the shorter half-life of acyl-ghrelin in blood (10 min) (23), the longer activation of ghrelin by MCT supplementation suggested that medium-chain fatty acids (MCFAs), which are stored as triglyceride (TG) in X/A-like cells of the stomach, might be used for the production of acyl-ghrelin.
Although a part of ingested MCFAs and MCTs are directly used for ghrelin acyl modification in X/A-like cells of the stomach (8), the fate of MCFAs in these cells is not clear. Most MCFAs entering the cells may be used for ATP production in mitochondria or synthesis of TG in cytosol (24, 25). MCFAs stored as TG in cells and MCFAs directly entering from the circulation could also be used for acyl-ghrelin synthesis. Therefore, a time lag to the increase in acyl-ghrelin concentration in blood is expected after MCT supplementation due to the time necessary for formation of acyl-ghrelin, and the duration of this increased acyl-ghrelin concentration in blood may depend on the bio-availability of MCFAs (mostly from storage in the TG form) in the X/A-like cells of the stomach.
In the present study, MCTs were given in the dinner group at 6:00~6:45 p.m., which was 1–3 h before sleeping time (8:00~9:00 p.m.). Blood acyl-ghrelin concentration may increase at the initiation of sleeping time when GH secretion also increases. MCTs in the breakfast group were given at 7:30~8:15 a.m., which was 11–14 h before sleeping time (8:00~9:00 p.m.), and blood acyl-ghrelin concentrations that derived from TG in cells of the stomach, may still be elevated at this time. Therefore, irrespective of the timing of MCT supplementation during the day (at breakfast or dinner), supplementation with 6 g MCTs/d for 1.5 months could increase muscle mass and function, cognition, and ADL of the frail elderly adults from baseline.

Limitations

Limitations of the present study are as follows. 1) The number of participants might be too small to observe significant effects of MCTs in some measures and non-significant differences in measures between the breakfast and dinner groups due to a lack of statistical power. A large-scale intervention study or meta-analysis may clarify these issues. 2) The examiners were not completely blinded to treatment allocation, which could bias the results. There was a chance that the examiner might favorably judge cognition in some groups, although the examiner kept in mind the responsibility of precisely assessing cognition. 3) Changes in the circadian rhythm of ghrelin and GH after MCT supplementation were not measured. However, frequent blood sampling will be necessary to elucidate the mechanisms of the effects of MCTs in the future. 4) Because this study targeted only frail elderly Japanese individuals, we did not address whether similar favorable effects of MCTs would be observed in western populations with a larger body size or in non-frail subjects.

 

Conclusions

Whether 6 g MCTs/day was supplemented either at breakfast or dinnertime, the increases in muscle mass and muscle function, cognition, and ADL of frail elderly individuals by MCT supplementation did not differ. MCTs are promising nutrients for elderly frail adults.

 

Acknowledgements: The authors thank all our study participants and all personnel at the Day Care SKY nursing home for collaborating with us.

Author contributions: SA, OE, and MS designed the research; SA and MS conducted the research; SA and OE analyzed the data or performed the statistical analysis; OE wrote the manuscript; and SA has the primary responsibility for the final content. All of the authors read and approved the final manuscript.

Funding sources: This study was supported by a grant from the Policy-Based Medical Services Foundation, 2019 (to SA).

Author disclosures: SA, OE, and MS have nothing to disclose.

Ethical Standards: The authors declare that the study procedures comply with the current ethical standards for investigation involving human participants in Japan.

 

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