Effects of oral oligopeptide preparation and exercise intervention in older people with sarcopenia: a randomized controlled trial

Sarcopenia was defined as age-related loss of muscle mass, plus low muscle strength, and/or low physical performance [1]. Data have shown that the prevalence of sarcopenia in the older population over 65 years in Asia is about 5.5%—25.7% [2]. The prevalence of sarcopenia in older adults in China was approximately 18% in men and 16.4% in women [3]. It is expected that by 2050, the number of people over 65 years old in China will increase to 366 million. The severe aging trend has increased the attention given to age-related diseases such as sarcopenia.

Sarcopenia may increase the incidence of falls and fractures in the older population, increase the risk of disability [4], seriously affect the quality of life and health status, and impose a heavy burden on the health care system and society [5]. Exercise and nutrition are important interventions for sarcopenia [2, 6]. Available evidence suggests that interventions which included resistance exercise plus nutritional supplements can significantly increase physical function, muscle mass and strength [2].

Regular activity especially resistance exercise is essential for healthy aging and offers a range of health benefits [7], but older people have difficulty achieving or not achieve 150 min of physical activity per week recommended activity level to maintain or improve health-related levels of physical fitness. Therefore, it is crucial to find safe and effective exercise methods and carry out sustainable exercise intervention for older population [8].

In studies on nutritional intervention for older people with sarcopenia, the most commonly used protein sources include whey protein, casein and soy protein. Compared with proteins, oligopeptides have faster transport speed and lower energy consumption, can eliminate absorption competition with free amino acids, and have higher digestibility and utilization.

In this study, the older people with sarcopenia recruited from rural areas in Chengdu, Sichuan Province, were randomly divided into 4 groups. Exercise and nutrition intervention were given to observe the changes in muscle strength, muscle quality and activity ability. The intervention preparation used in the study was a compound enteral nutrition preparation with oligopeptide as the main protein source. The purpose of this study was to verify the effectiveness of compound oligopeptide enteral nutrition preparation alone or in combination with exercise in the older population with sarcopenia.

Studies have shown that exercise and nutritional intervention may effectively improve muscle strength and function and improve physical activity in the older population [10, 11]. The combined intervention of exercise and nutrition can significantly improve the muscle strength of the lower extremities of the older people in Asia with sarcopenia compared with the exercise intervention alone [12]. Many guidelines regard exercise and nutrition interventions as important measures to prevent and treat sarcopenia [2, 13].

Dietary and nutritional status are closely related to the occurrence of sarcopenia. A higher quality diet was associated with better physical performance among older adults [14]. The older population with sarcopenia have a lower intake of proteins than their non-sarcopenic peers [15, 16]. Increasing protein intake, especially at breakfast and lunch, contributes to alleviating muscle loss with aging [17]. It is recommended that each meal should provide 20 to 30 g protein, to achieve maximum stimulation of the muscle protein fractional synthetic rate [18]. In this study, the average protein intake of older people with sarcopenia before intervention was approximately 0.8 g/ (kg·d), which was much lower than the recommended intake.

Oral supplementation with protein-rich dietary supplements may play an important role in the prevention and control of sarcopenia [19]. The findings of a meta-analysis suggest that dairy proteins, at an amount of 14 to 40 g can significantly increase the AMM in middle-aged and older adults without a significant clinical effect on handgrip strength and leg press [20]. Oral protein supplementation or protein-rich nutritional supplements combined with exercise intervention can improve muscle mass and strength and improve activity in the older people [19, 21‐25], and protein supplements for sarcopenic older adults along with exercise showed a larger effect size than exercise alone and no intervention [24]. Study showed that oral whey protein-rich supplements could significantly improve the SMM, muscle strength and function, and this effect was not related to the time of oral whey protein supplements [26]. There were also studies using amino acid preparations such as leucine and L-citrulline to intervene in older people and found that some amino acid preparations could improve walking speed and lean body mass index and improve muscle mass and physical function in the older population [27, 28].

However, some studies suggest that increasing nutrition intervention while exercise intervention does not have additional benefits for the body composition, muscle strength and function of the older population [29]. Compared to exercise or nutritional intervention alone, interventions that combined exercise and nutrition may not confer additional beneficial effects on body composition, grip strength, walking speed, physical performance, or metabolic and inflammatory biomarkers in the sarcopenic obesity population [30, 31]. The existing research results were not consistent regarding whether nutrition intervention can improve muscle mass, strength and function of older people with sarcopenia, and for subjects with good nutritional status, the effect of nutrition intervention may not be significant [32]. Additionally, the effect of nutrition intervention may also be related to the formula and dose of the intervention preparation, the daily dietary intake of the subjects, the duration of intervention and other factors.

Oligopeptides are the hydrolysates of proteins. The molecular weight of oligopeptides is smaller than that of proteins, so they are easier to digest and absorb, and have some physiological functions. Some researchers believe that oligopeptides may have a better effect on sarcopenia intervention in the older population than proteins. Some in vitro and animal experiments have shown that oligopeptides may play a role in slowing the degradation of proteins in cells, promoting protein synthesis and improving muscle atrophy in animals [33, 34]. The combination of wheat oligopeptides, soybean oligopeptides and pea oligopeptides can effectively improve the reduction in muscle protein content in C2C12 cells caused by TNF-α, reduce protein degradation and promote protein synthesis by regulating the expression of E3 ubiquitin ligase and improving the protein phosphorylation level of Akt/mTOR [34]. An animal experiment found that corn oligopeptides can increase grip strength and improve the muscle atrophy induced by dexamethasone in mice [33]. In a randomized double-blind placebo-controlled trial, a protein supplement rich in collagen peptides was used to intervene in male sarcopenia patients with resistance exercise. After 12 weeks of intervention, the fat free mass, isokinetic quadriceps strength and sensory motor control of all subjects were significantly increased, the fat mass was significantly decreased, and the effect of the intervention group treated with oral administration of 15 g collagen peptide per day was more significant [35]. Based on the results of our previous studies [33, 34], a preparation with plant oligopeptides as the main protein source was designed, which was used in this study to intervene in sarcopenia older patients alone or in combination with exercise to verify the effect of the oligopeptide preparation alone or in combination with exercise intervention in sarcopenia. In this study, oral oligopeptide nutrition preparation and exercise were used to intervene the older people with sarcopenia.

After 16 weeks of intervention, it was found that the weight and grip strength of the older people receiving exercise intervention increased, while the weight, grip strength and gait speed of the subjects receiving nutritional intervention increased. However, neither exercise nor nutrition intervention alone could maintain the fat free mass of older people. Only the subjects in the combined group maintained the muscle mass and fat free mass of each segment after the intervention.

Low-grip strength is predictive of mortality, longer hospital stays, and limited physical function. The handgrip strength is rarely used as the indicator for the detection and diagnosis of clinical diseases. However, studies have shown that grip strength is one of the important indicators for evaluating muscle strength, and it is also closely related to cognitive function, the occurrence of tumors, diabetes and frailty, the mortality of older people and the prognosis of hospitalized patients [36‐41]. Low HGS was associated with a higher mortality risk in male older hospitalized patients. In medical inpatients at nutritional risk, each decrease of 10 kg in HGS was associated with increased risk of 30-d mortality and 180-d mortality [42]. Higher baseline GS and 5-year increase in GS were protective of mortality, whilst GS decline was associated with an increased risk of mortality in the very old over 9.6 years, especially in women. Men and women with a negative slope had a 16 and 33% increased risk of mortality, respectively, with every kg/year decline in GS (P ≤ 0.005) [43]. In this study, the right handgrip strength of the combined group increased from23.06 ± 7.05kg to 25.11 ± 6.56kg, and the left handgrip strength increased form 21.91 ± 6.21kg to 24.65 ± 6.56kg. We believe that such an increase is of practical health benefits for the subjects. Gait speed can be useful in predicting falls and expected survival, and might be included as part of a comprehensive evaluation for older adults [44‐46]. In fact, many frailty or functional disability studies define slowness as 6-m walk < 1.0 m/s. Therefore, in this study, the gait speed of the nutrition group increased from 0.96 ± 0.23m/s to 1.10 ± 0.21m/s, and we believe that such an increase is of practical health benefits for the subjects.

In this study, no increase in muscle mass or SMI was observed in any intervention group, which may be related to the low daily dietary protein intake of the subjects. Some studies suggest that the effect of nutrition intervention on muscle mass is related to the nutritional status and dietary intake of the subjects, and the effect may be better in subjects with good nutritional status and adequate dietary protein intake. During the intervention, all the subjects received individualized diet guidance and nutrition education provided by professional dietitians and provided individualized recipes and recommendations for dietary intake. However, although the dietary intake of the subjects increased at the end of the intervention, the dietary protein intake did not reach the recommended amount of 1.2 g/(kg·d). Only subjects of the nutrition group and combined group, whose total average daily protein intake reached 1.34 g/(kg·d) and 1.29 g/(kg·d), respectively, reaching the recommended intake amount.

It is suggested that although dietary guidance intervention for the older people has effect on increasing dietary intake, it is difficult to change its natural dietary pattern and achieve the ideal intervention effect. A study compared the effects of high protein dietary supplements (Supp group) and adequate protein intake dietary guidance (Diet group) on maintaining muscle mass and strength in the older people with sarcopenia. The results showed that the total energy and protein intake of both groups increased after intervention but the intake of Supp group was higher than that of Diet group. The AMMI increased in the older people with sarcopenia as long as they consumed enough protein per day (1.2–1.5 g per kilogram of body weight). However, compared with dietary guidance, nutritional supplementation makes it easier for the older population with sarcopenia to achieve the sufficient protein they need [47]. The results are similar to those of this study.

The effects of exercise intervention on muscle mass, muscle strength and physical function in sarcopenia subjects may be related to different exercise types, intensity, duration, and whether to combine other intervention measures [11]. A study used resistance exercise to intervene in older women with sarcopenia for 16 weeks and found that the physical function, grip strength and walking speed of the subjects increased, but no increase in muscle mass was observed [48]. Another study used low-intensity and moderate-intensity resistance training to intervene in people aged 50 to 79 years old in the community. After 24 weeks of intervention, an increase in the cross-sectional area of contractile muscle was observed in the moderate-intensity exercise group, while only an increase in the cross-sectional area of the quadriceps femoris was observed in the low-intensity exercise group [49]. The exercise intervention duration of studies in the older people with sarcopenia usually lasted between 3 and 18 months, and improvements in muscle strength and function could be observed at the end of the study, but only a few studies could observe an increase in muscle mass [50].In this study, exercise intervention increased the muscle strength of the subjects, but the muscle mass did not increase significantly. The muscle mass of the subjects in the exercise group showed a decreasing trend. Only for the subjects in the combined group who received both exercise and nutrition interventions, the muscle mass observed to maintain preintervention levels at the end of the study. The reason may be related to the duration and intensity of intervention, the compliance of subjects, and the dietary intake and nutrition status of subjects.

There were still some limitations in this study. First, the exercise intervention was used in this study, so the subjects and researchers were difficult to be blinded. Second, there was no whey protein intervention group, so it didn’t compare the effect of oligopeptides and whey protein on sarcopenia. For sarcopenia patients without other diseases, it is not clear whether oligopeptides have advantages compared with whey protein, but for some older people with poor digestive function and intolerance to whole protein preparations, the oligopeptide nutrition preparation in this study may have important implications. Further research will be conducted on the older population with sarcopenia and poor digestive function. Third, some subjects were not willing to accept the intervention according to the plan, so there were some subjects with poor compliance and high loss rate. Fourth, the intervention period of 16 weeks may be too short to observed the increase of skeletal muscle mass in the subjects, and longer intervention should be conducted to explore the effects of exercise and nutrition intervention on skeletal muscle mass. Fifth, in this study, we used the Segmental Multi-Frequency BIA to measure the body composition of the subjects, using the Inbody 770 instrument. MRI, CT, and DXA were not used in this study in the older people due to cost, accessibility, and the problem of radiation exposure. But we found in the literature that the correlation between appendicular skeletal muscle mass obtained by using BIA and DXA was high in both men and women. The Pearson correlation coefficient and standard error of the estimate of the regression equation were 0.94 and 1.05 kg in the men, and 0.90 and 0.93 kg in the women, respectively (both p > 0.05). No significant method-related biases were found [51]. The concordance correlation coefficient between fat free mass measured by using DXA and BIA was 0.98(95%CI 0.97,0.98) [52]. Sixth, the results of some studies show that the increase in muscle mass, strength, and physical function of the lower extremity may be more obvious after intervention [53, 54], but the outcome indicators reflecting muscle strength and function in this study were relatively simple, so the intervention effect may be underestimated.

This study used oligopeptide preparation and exercise alone or in combination to intervene in the older people with sarcopenia in the community. The results showed that exercise and nutrition intervention could improve the muscle strength or function of the older population, but short-term intervention could not alleviate the declining trend of muscle mass. Only the older people in the combined group who received both nutrition and exercise interventions maintained the muscle mass after the intervention. At the same time, for the older people with insufficient energy and protein intake, dietary guidance is not ideal to increase intake, and oral nutritional supplements should be actively adopted.