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The effect of dietary supplements on frailty in older persons: a meta-analysis and systematic review of randomized controlled trials

Abstract

Frailty is a geriatric syndrome that predicts the onset of disability, morbidity and mortality in elderly people; it is a state of pre-disability and is reversible. This review aimed to assess the impact of dietary supplementation interventions in frail older adults. A systematic search of PubMed, Web of Science, Embase, and the Cochrane Library databases was performed to collect randomized controlled trials of dietary supplements for the treatment of frailty in the elderly published before March 2022. The frailty score, muscle mass, muscle strength and physical performance of the frail elderly were extracted for analysis. Meta-analysis was performed using Review Manager Version 5.4 and Stata version 15.0. Totally, 18 studies met the inclusion criteria, with 1204 participants (603 experiment group vs. 601 control group). Compared to control group, multi-nutrient nutrition intervention can significantly improve the frailty score of the elderly (MD = -0.19, 95% CI: -0.38 to -0.01, P = 0.04, I2 = 0). Protein supplementation intervention significantly improved body weight (MD = 4.86, 95% CI: 1.21 to 8.52, P = 0.009), muscle mass [lean mass (MD = 2.73, 95% CI:1.26 to 4.20, P = 0.0003)], muscle strength (MD = 1.90, 95% CI: 0.68 to 3.12, P = 0.002), and physical performance [chair stand test (MD = -2.15, 95% CI: -3.21 to -1.10, P < 0.0001)] in frail older adults compared to control. This meta-analysis and systematic review suggests that dietary supplements interventions positively influence in older people with frailty.

Keywords:
dietary supplements; frailty; muscle mass; muscle strength; physical performance; meta-analysis

1 Introduction

Frailty has been defined as a medical syndrome with multiple causes and contributors that is characterized by diminished strength, endurance, and reduced physiologic function and increases an individual’s vulnerability for developing disability, dependency, or death (Ekram et al., 2021Ekram, A. R. M. S., Woods, R. L., Britt, C., Espinoza, S., Ernst, M. E., & Ryan, J. (2021). The association between frailty and all-cause mortality in community-dwelling older individuals: an umbrella review. The Journal of Frailty & Aging, 10(4), 320-326. PMid:34549245.). Frailty is considered one of the important geriatric syndromes, and its prevention and management represent an important goal of geriatrics (Moraes et al., 2018Moraes, M. B., Araujo, C. F. M., Avgerinou, C., & Vidal, E. I. O. (2018). Nutritional interventions for the treatment of frailty in older adults: a systematic review protocol. Medicine, 97(52), e13773. http://dx.doi.org/10.1097/MD.0000000000013773. PMid:30593155.
http://dx.doi.org/10.1097/MD.00000000000...
). Studies have shown that the overall prevalence of frailty among community-dwelling older adults in the United States ranges from 7-12%. And the prevalence of frailty increased with age from 3.9% in the 65-74 group to 25% in the 85+ group (Xue, 2011Xue, Q. L. (2011). The frailty syndrome: definition and natural history. Clinics in Geriatric Medicine, 27(1), 1-15. http://dx.doi.org/10.1016/j.cger.2010.08.009. PMid:21093718.
http://dx.doi.org/10.1016/j.cger.2010.08...
). In addition, the prevalence of frailty among older adults in the community ranged from 4% to 59%, a systematic review found (Collard et al., 2012Collard, R. M., Boter, H., Schoevers, R. A., & Voshaar, R. C. O. (2012). Prevalence of frailty in community-dwelling older persons: a systematic review. Journal of the American Geriatrics Society, 60(8), 1487-1492. http://dx.doi.org/10.1111/j.1532-5415.2012.04054.x. PMid:22881367.
http://dx.doi.org/10.1111/j.1532-5415.20...
).

Frailty increases the risk of various negative outcomes, especially in the elderly. Frail older adults have increased hospitalizations, falls, fractures, long-term care and mortality, when compared to those who are nonfrail (Kojima et al., 2019Kojima, G., Taniguchi, Y., Iliffe, S., Urano, T., & Walters, K. (2019). Factors associated with improvement in frailty status defined using the frailty phenotype: a systematic review and meta-analysis. Journal of the American Medical Directors Association, 20(12), 1647-1649.E2. http://dx.doi.org/10.1016/j.jamda.2019.05.018. PMid:31301987.
http://dx.doi.org/10.1016/j.jamda.2019.0...
). It is also related to a broad range of other outcomes, such as loneliness, lower quality of life, depression, cognitive decline and dementia (Hoogendijk et al., 2019Hoogendijk, E. O., Afilalo, J., Ensrud, K. E., Kowal, P., Onder, G., & Fried, L. P. (2019). Frailty: implications for clinical practice and public health. Lancet, 394(10206), 1365-1375. http://dx.doi.org/10.1016/S0140-6736(19)31786-6. PMid:31609228.
http://dx.doi.org/10.1016/S0140-6736(19)...
). Once frailty has developed, it often leads to a downward spiral in overall health. However, frailty is not necessarily an irreversible process but a dynamic continuum state that can both worsen and improve over time.

Currently, it is believed that the risk factors of debility include heredity, comorbidity, multiple drug use, malnutrition and so on. Nutrition, as a modifiable factor, has attracted more and more attention. A meta-analysis of 5447 elderly people in the community showed that there was a significant correlation between frailty and the prevalence of malnutrition, and about 90% of the elderly with malnutrition were accompanied by frailty (Verlaan et al., 2017Verlaan, S., Ligthart-Melis, G. C., Wijers, S. L. J., Cederholm, T., Maier, A. B., & van der Schueren, M. A. E. (2017). High prevalence of physical frailty among community-dwelling malnourished older adults-a systematic review and meta-analysis. Journal of the American Medical Directors Association, 18(5), 374-382. http://dx.doi.org/10.1016/j.jamda.2016.12.074. PMid:28238676.
http://dx.doi.org/10.1016/j.jamda.2016.1...
).

A common approach to treat malnutrition is the use of dietary supplementations, i.e. foods defined as either intended to provide nutrients in order to increase the quantity of their consumption or to provide non-nutrient chemicals which are claimed to have a biologically beneficial effect (Traub et al., 2021Traub, J., Reiss, L., Aliwa, B., & Stadlbauer, V. (2021). Malnutrition in patients with liver cirrhosis. Nutrients, 13(2), 540. http://dx.doi.org/10.3390/nu13020540. PMid:33562292.
http://dx.doi.org/10.3390/nu13020540...
). More recently another systematic review concluded that dietary supplementation interventions may have beneficial effects on muscle mass, muscle strength (grip strength), and physical performance (gait speed and dynamic balance) in older adults (Wu et al., 2021Wu, P. Y., Huang, K. S., Chen, K. M., Chou, C. P., & Tu, Y. K. (2021). Exercise, nutrition, and combined exercise and nutrition in older adults with sarcopenia: a systematic review and network meta-analysis. Maturitas, 145, 38-48. http://dx.doi.org/10.1016/j.maturitas.2020.12.009. PMid:33541561.
http://dx.doi.org/10.1016/j.maturitas.20...
). But another systematic review reported that the interactive effect of dietary supplementation on muscle function appears limited (Beaudart et al., 2017Beaudart, C., Dawson, A., Shaw, S. C., Harvey, N. C., Kanis, J. A., Binkley, N., Reginster, J. Y., Chapurlat, R., Chan, D. C., Bruyère, O., Rizzoli, R., Cooper, C., & Dennison, E. M. (2017). Nutrition and physical activity in the prevention and treatment of sarcopenia: systematic review. Osteoporosis International, 28(6), 1817-1833. http://dx.doi.org/10.1007/s00198-017-3980-9. PMid:28251287.
http://dx.doi.org/10.1007/s00198-017-398...
).

Given this background, we aimed to summarize the effect of dietary supplementation on physical performance and muscle strength outcomes in frailty older people compared to placebo in RCTs involving only frailty older people, stratifying our results by the type of dietary supplementation.

2 Methods

The meta-analysis was conducted and reported in accordance with the PRISMA guidelines to ensure comprehensive and transparent reporting of our methods and results. We have registered our protocol in the PROSPERO database (CRD42022334747).

2.1 Search strategy and selection criteria

PubMed, Web of Science, Embase and the Cochrane Library were electronically searched for papers that were published until March 2022. The search strategy included various combinations of the terms “Frailty”, “Frailties”, “Frailness”, “Frailty Syndrome”, “Debility” and “Debilities”, with Dietary Supplements terms such as “Food Supplementations” or “Nutraceuticals” or “Herbal Supplements”. Randomized controlled trials were specifically targeted using the following search terms: “Randomized controlled trial”, “Controlled clinical trial”, or “Randomized” or “Randomly” or “Trial” or “Group”. The search was limited to human studies.

Studies meeting the following criteria were included: (1) Participants were defined as frailty; (2) Age ≥ 65-year-old; (3) the intervention group underwent nutritional intervention and the control group undergo placebo or daily diet; (4) the randomized control trials investigated the effects of any types of nutrition on muscle mass, muscle strength, and physical performance; and (5) papers published in English. Studies including old people with a specific health conditions such as cancer, diabetes, stroke, human immunodeficiency virus, chronic obstructive pulmonary disease, chronic kidney disease, liver cirrhosis, other critical illness, and recent transplants were excluded. Studies were also excluded if they were published as a pilot study, conference abstract, case report, commentary, editorial, protocol, review article, letter to editor, or duplicate.

2.2 Study selection

The study selection process is outlined in Figure 1. The eligibility assessment was performed by two independent reviewers in a standardized manner. All papers identified using the search strategy were assessed for eligibility, as indicated based on the previously defined inclusion criteria, by reviewing their titles and/or abstracts. If insufficient information was available to evaluate the inclusion or exclusion of an article, then a full-text version was obtained. Full-text versions of all the relevant studies were obtained and reviewed by two independent reviewers to ensure that the studies met the inclusion criteria. Disagreements were resolved by discussion with a third reviewer. When insufficient information or data were available in the included articles, the authors were contacted to obtain additional information if possible.

Figure 1
PRISMA flow-chart.

2.3 Quality assessment

Two reviewers independently assessed the quality of all included studies, using the Downs and Black Quality Index. The scales are designed to assess the methodological quality of randomized studies of health care interventions (Downs & Black, 1998Downs, S. H., & Black, N. (1998). The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. Journal of Epidemiology and Community Health, 52(6), 377-384. http://dx.doi.org/10.1136/jech.52.6.377. PMid:9764259.
http://dx.doi.org/10.1136/jech.52.6.377...
) and include reporting, external validity, bias, confounding, and power, and their maximum scores are 11, 3, 7, 6, and 5, respectively. The maximum possible total score is 32. Quality was then rated on a four-category scale: poor (< 18), moderate (18-23), good (24-29), and excellent (≥ 30).

2.4 Data extraction

Data were extracted from the included articles using a data extraction form (Table 1). Data characteristics were extracted, including: (1) name of first author and year of publication, (2) study nation or area, (3) study source, (4) frailty diagnosis, (5) sample characteristics (intervention and control group sizes, male and female sample size and age), (6) intervention and control protocols (intervention category and duration), and (7) effects of the interventions, including frailty score, muscle mass, muscle strength and physical performance. One investigator performed the data extraction, which was checked by a second investigator.

Table 1
Characteristics of included studies.

Since the aim of our study was to explore the effect of dietary supplementations on physical performance and/or muscle strength, when more than two groups were present, only the data regarding dietary supplementations (without any physical regimen intervention) and placebo (without any physical regimen intervention) were extracted.

2.5 Statistical analysis

The meta-analysis was performed using Review Manager version 5.4 and Stata version 15.0. The I2 statistic tests were used to evaluate the heterogeneity among the included studies. The random-effects model was utilized to combine the results when heterogeneity was present among the studies (I2 > 50% or P < 0.05). Otherwise, the fixed-effects model would be used. The intervention effect sizes for continuous variables were measured by determining the MDs between the intervention and control groups with regard to the change observed between the baseline and follow-up scores and their corresponding 95% CI. The results were considered statistically significant when P < 0.05. Sensitivity analyses were conducted through sequential omission of individual studies and then comparison of the p-value. The results were identified as credible when the corresponding p-value was not substantially different. Publication bias was assessed using Begg and Egger’s test and funnel plot (Weng et al., 2019Weng, S., Wang, W., Wei, Q., Lan, H., Su, J., & Xu, Y. (2019). Effect of tranexamic acid in patients with traumatic brain injury: a systematic review and meta-analysis. World Neurosurgery, 123, 128-135. http://dx.doi.org/10.1016/j.wneu.2018.11.214. PMid:30529516.
http://dx.doi.org/10.1016/j.wneu.2018.11...
; Gao et al., 2020Gao, H., Ma, H. J., Li, Y. J., Yin, C., & Li, Z. (2020). Prevalence and risk factors of postoperative delirium after spinal surgery: a meta-analysis. Journal of Orthopaedic Surgery and Research, 15(1), 138. http://dx.doi.org/10.1186/s13018-020-01651-4. PMid:32272939.
http://dx.doi.org/10.1186/s13018-020-016...
). Results were considered statistically significant when P < 0.05.

3 Results

3.1 Search results

A total of 806 publications were identified by searching the databases and 12 were identified by other sources; 110 articles were excluded because of duplicate records. After excluding 528 articles based on title/abstract review, 126 articles were retrieved for full-text review and 108 studies were excluded. These studies were excluded because they did not assess frailty, reported incomplete data, their control group underwent an nutrition intervention, or they did not report muscle mass or muscle strength or physical performance as an outcome measurement. Consequently, 18 articles were included in the qualitative and quantitative synthesis (Figure 1).

3.2 Study and patient characteristics

The 18 RCTs (Na et al., 2021Na, W., Kim, J., Kim, H., Lee, Y., Jeong, B., Lee, S. P., & Sohn, C. (2021). Evaluation of oral nutritional supplementation in the management of frailty among the elderly at facilities of community care for the elderly. Clinical Nutrition Research, 10(1), 24-35. http://dx.doi.org/10.7762/cnr.2021.10.1.24. PMid:33564650.
http://dx.doi.org/10.7762/cnr.2021.10.1....
; Peng et al., 2021Peng, L. N., Cheng, Y. C., Yu, P. C., Lee, W. J., Lin, M. H., & Chen, L. K. (2021). Oral nutritional supplement with β-hydroxy-β-methylbutyrate (HMB) improves nutrition, physical performance and ameliorates intramuscular adiposity in pre-frail older adults: a randomized controlled trial. The Journal of Nutrition, Health & Aging, 25(6), 767-773. http://dx.doi.org/10.1007/s12603-021-1621-7. PMid:34179932.
http://dx.doi.org/10.1007/s12603-021-162...
; Hsieh et al., 2019Hsieh, T. J., Su, S. C., Chen, C. W., Kang, Y. W., Hu, M. H., Hsu, L. L., Wu, S. Y., Chen, L., Chang, H. Y., Chuang, S. Y., Pan, W. H., & Hsu, C. C. (2019). Individualized home-based exercise and nutrition interventions improve frailty in older adults: a randomized controlled trial. The International Journal of Behavioral Nutrition and Physical Activity, 16(1), 119. http://dx.doi.org/10.1186/s12966-019-0855-9. PMid:31791364.
http://dx.doi.org/10.1186/s12966-019-085...
; Kang et al., 2019Kang, L., Gao, Y., Liu, X. H., Liang, Y. H., Chen, Y. W., Liang, Y. H., Zhang, L., Chen, W., Pang, H. Y., & Peng, L. N. (2019). Effects of whey protein nutritional supplement on muscle function among community-dwelling frail older people: a multicenter study in China. Archives of Gerontology and Geriatrics, 83, 7-12. http://dx.doi.org/10.1016/j.archger.2019.03.012. PMid:30921603.
http://dx.doi.org/10.1016/j.archger.2019...
; Park et al., 2018Park, Y., Choi, J.-E., & Hwang, H.-S. (2018). Protein supplementation improves muscle mass and physical performance in undernourished prefrail and frail elderly subjects: a randomized, double-blind, placebo-controlled trial. The American Journal of Clinical Nutrition, 108(5), 1026-1033. http://dx.doi.org/10.1093/ajcn/nqy214. PMid:30475969.
http://dx.doi.org/10.1093/ajcn/nqy214...
; Wu et al., 2018Wu, S. Y., Hsu, L. L., Hsu, C. C., Hsieh, T. J., Su, S. C., Peng, Y. W., Guo, T. M., Kang, Y. W., & Pan, W. H. (2018). Dietary education with customised dishware and food supplements can reduce frailty and improve mental well-being in elderly people: a single-blind randomized controlled study. Asia Pacific Journal of Clinical Nutrition, 27(5), 1018-1030. PMid:30272850.; Dirks et al., 2017Dirks, M. L., Tieland, M., Verdijk, L. B., Losen, M., Nilwik, R., Mensink, M., Groot, L. C. P. G. M., & van Loon, L. J. C. (2017). Protein supplementation augments muscle fiber hypertrophy but does not modulate satellite cell content during prolonged resistance-type exercise training in frail elderly. Journal of the American Medical Directors Association, 18(7), 608-615. http://dx.doi.org/10.1016/j.jamda.2017.02.006. PMid:28377156.
http://dx.doi.org/10.1016/j.jamda.2017.0...
; Badrasawi et al., 2016Badrasawi, M., Shahar, S., Zahara, A. M., Fadilah, R. N., & Singh, D. K. A. (2016). Efficacy of L-carnitine supplementation on frailty status and its biomarkers, nutritional status, and physical and cognitive function among prefrail older adults: a double-blind, randomized, placebo-controlled clinical trial. Clinical Interventions in Aging, 11, 1675-1686. http://dx.doi.org/10.2147/CIA.S113287. PMid:27895474.
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; Buigues et al., 2016Buigues, C., Fernández-Garrido, J., Pruimboom, L., Hoogland, A. J., Navarro-Martínez, R., Martínez-Martínez, M., Verdejo, Y., Mascarós, M. C., Peris, C., & Cauli, O. (2016). Effect of a prebiotic formulation on frailty syndrome: a randomized, double-blind clinical trial. International Journal of Molecular Sciences, 17(6), 932. http://dx.doi.org/10.3390/ijms17060932. PMid:27314331.
http://dx.doi.org/10.3390/ijms17060932...
; Kim et al., 2015Kim, H., Suzuki, T., Kim, M., Kojima, N., Ota, N., Shimotoyodome, A., Hase, T., Hosoi, E., & Yoshida, H. (2015). Effects of exercise and milk fat globule membrane (MFGM) supplementation on body composition, physical function, and hematological parameters in community-dwelling frail Japanese women: a randomized double blind, placebo-controlled, follow-up trial. PLoS One, 10(2), e0116256. http://dx.doi.org/10.1371/journal.pone.0116256. PMid:25659147.
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; Ng et al., 2015Ng, T. P., Feng, L., Nyunt, M. S., Feng, L., Niti, M., Tan, B. Y., Chan, G., Khoo, S. A., Chan, S. M., Yap, P., & Yap, K. B. (2015). Nutritional, physical, cognitive, and combination interventions and frailty reversal among older adults: a randomized controlled trial. The American Journal of Medicine, 128(11), 1225-1236.E1. http://dx.doi.org/10.1016/j.amjmed.2015.06.017. PMid:26159634.
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; Kim & Lee, 2013Kim, C. O., & Lee, K. R. (2013). Preventive effect of protein-energy supplementation on the functional decline of frail older adults with low socioeconomic status: a community-based randomized controlled study. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 68(3), 309-316. http://dx.doi.org/10.1093/gerona/gls167. PMid:22879453.
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; Tieland et al., 2012Tieland, M., Dirks, M. L., van der Zwaluw, N., Verdijk, L. B., van de Rest, O., Groot, L. C., & van Loon, L. J. (2012). Protein supplementation increases muscle mass gain during prolonged resistance-type exercise training in frail elderly people: a randomized, double-blind, placebo-controlled trial. Journal of the American Medical Directors Association, 13(8), 713-719. http://dx.doi.org/10.1016/j.jamda.2012.05.020. PMid:22770932.
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; Gray-Donald et al., 1995Gray-Donald, K., Payette, H., & Boutier, V. (1995). Randomized clinical trial of nutritional supplementation shows little effect on functional status among free-living frail elderly. The Journal of Nutrition, 125(12), 2965-2971. PMid:7500174.; Fiatarone et al., 1994Fiatarone, M. A., O’Neill, E. F., Ryan, N. D., Clements, K. M., Solares, G. R., Nelson, M. E., Roberts, S. B., Kehayias, J. J., Lipsitz, L. A., & Evans, W. J. (1994). Exercise training and nutritional supplementation for physical frailty in very elderly people. The New England Journal of Medicine, 330(25), 1769-1775. http://dx.doi.org/10.1056/NEJM199406233302501. PMid:8190152.
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) included a total of 1204 older participants (603 experiment group vs. 601 control group). The majority of studies were conducted in Asia and Europe, with ten studies (Na et al., 2021Na, W., Kim, J., Kim, H., Lee, Y., Jeong, B., Lee, S. P., & Sohn, C. (2021). Evaluation of oral nutritional supplementation in the management of frailty among the elderly at facilities of community care for the elderly. Clinical Nutrition Research, 10(1), 24-35. http://dx.doi.org/10.7762/cnr.2021.10.1.24. PMid:33564650.
http://dx.doi.org/10.7762/cnr.2021.10.1....
; Peng et al., 2021Peng, L. N., Cheng, Y. C., Yu, P. C., Lee, W. J., Lin, M. H., & Chen, L. K. (2021). Oral nutritional supplement with β-hydroxy-β-methylbutyrate (HMB) improves nutrition, physical performance and ameliorates intramuscular adiposity in pre-frail older adults: a randomized controlled trial. The Journal of Nutrition, Health & Aging, 25(6), 767-773. http://dx.doi.org/10.1007/s12603-021-1621-7. PMid:34179932.
http://dx.doi.org/10.1007/s12603-021-162...
; Hsieh et al., 2019Hsieh, T. J., Su, S. C., Chen, C. W., Kang, Y. W., Hu, M. H., Hsu, L. L., Wu, S. Y., Chen, L., Chang, H. Y., Chuang, S. Y., Pan, W. H., & Hsu, C. C. (2019). Individualized home-based exercise and nutrition interventions improve frailty in older adults: a randomized controlled trial. The International Journal of Behavioral Nutrition and Physical Activity, 16(1), 119. http://dx.doi.org/10.1186/s12966-019-0855-9. PMid:31791364.
http://dx.doi.org/10.1186/s12966-019-085...
; Kang et al., 2019Kang, L., Gao, Y., Liu, X. H., Liang, Y. H., Chen, Y. W., Liang, Y. H., Zhang, L., Chen, W., Pang, H. Y., & Peng, L. N. (2019). Effects of whey protein nutritional supplement on muscle function among community-dwelling frail older people: a multicenter study in China. Archives of Gerontology and Geriatrics, 83, 7-12. http://dx.doi.org/10.1016/j.archger.2019.03.012. PMid:30921603.
http://dx.doi.org/10.1016/j.archger.2019...
; Park et al., 2018Park, Y., Choi, J.-E., & Hwang, H.-S. (2018). Protein supplementation improves muscle mass and physical performance in undernourished prefrail and frail elderly subjects: a randomized, double-blind, placebo-controlled trial. The American Journal of Clinical Nutrition, 108(5), 1026-1033. http://dx.doi.org/10.1093/ajcn/nqy214. PMid:30475969.
http://dx.doi.org/10.1093/ajcn/nqy214...
; Wu et al., 2018Wu, S. Y., Hsu, L. L., Hsu, C. C., Hsieh, T. J., Su, S. C., Peng, Y. W., Guo, T. M., Kang, Y. W., & Pan, W. H. (2018). Dietary education with customised dishware and food supplements can reduce frailty and improve mental well-being in elderly people: a single-blind randomized controlled study. Asia Pacific Journal of Clinical Nutrition, 27(5), 1018-1030. PMid:30272850.; Badrasawi et al., 2016Badrasawi, M., Shahar, S., Zahara, A. M., Fadilah, R. N., & Singh, D. K. A. (2016). Efficacy of L-carnitine supplementation on frailty status and its biomarkers, nutritional status, and physical and cognitive function among prefrail older adults: a double-blind, randomized, placebo-controlled clinical trial. Clinical Interventions in Aging, 11, 1675-1686. http://dx.doi.org/10.2147/CIA.S113287. PMid:27895474.
http://dx.doi.org/10.2147/CIA.S113287...
; Buigues et al., 2016Buigues, C., Fernández-Garrido, J., Pruimboom, L., Hoogland, A. J., Navarro-Martínez, R., Martínez-Martínez, M., Verdejo, Y., Mascarós, M. C., Peris, C., & Cauli, O. (2016). Effect of a prebiotic formulation on frailty syndrome: a randomized, double-blind clinical trial. International Journal of Molecular Sciences, 17(6), 932. http://dx.doi.org/10.3390/ijms17060932. PMid:27314331.
http://dx.doi.org/10.3390/ijms17060932...
; Kim et al., 2015Kim, H., Suzuki, T., Kim, M., Kojima, N., Ota, N., Shimotoyodome, A., Hase, T., Hosoi, E., & Yoshida, H. (2015). Effects of exercise and milk fat globule membrane (MFGM) supplementation on body composition, physical function, and hematological parameters in community-dwelling frail Japanese women: a randomized double blind, placebo-controlled, follow-up trial. PLoS One, 10(2), e0116256. http://dx.doi.org/10.1371/journal.pone.0116256. PMid:25659147.
http://dx.doi.org/10.1371/journal.pone.0...
; Ng et al., 2015Ng, T. P., Feng, L., Nyunt, M. S., Feng, L., Niti, M., Tan, B. Y., Chan, G., Khoo, S. A., Chan, S. M., Yap, P., & Yap, K. B. (2015). Nutritional, physical, cognitive, and combination interventions and frailty reversal among older adults: a randomized controlled trial. The American Journal of Medicine, 128(11), 1225-1236.E1. http://dx.doi.org/10.1016/j.amjmed.2015.06.017. PMid:26159634.
http://dx.doi.org/10.1016/j.amjmed.2015....
; Kim & Lee, 2013Kim, C. O., & Lee, K. R. (2013). Preventive effect of protein-energy supplementation on the functional decline of frail older adults with low socioeconomic status: a community-based randomized controlled study. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 68(3), 309-316. http://dx.doi.org/10.1093/gerona/gls167. PMid:22879453.
http://dx.doi.org/10.1093/gerona/gls167...
) in Asia and six studies (Dirks et al., 2017Dirks, M. L., Tieland, M., Verdijk, L. B., Losen, M., Nilwik, R., Mensink, M., Groot, L. C. P. G. M., & van Loon, L. J. C. (2017). Protein supplementation augments muscle fiber hypertrophy but does not modulate satellite cell content during prolonged resistance-type exercise training in frail elderly. Journal of the American Medical Directors Association, 18(7), 608-615. http://dx.doi.org/10.1016/j.jamda.2017.02.006. PMid:28377156.
http://dx.doi.org/10.1016/j.jamda.2017.0...
; Buigues et al., 2016Buigues, C., Fernández-Garrido, J., Pruimboom, L., Hoogland, A. J., Navarro-Martínez, R., Martínez-Martínez, M., Verdejo, Y., Mascarós, M. C., Peris, C., & Cauli, O. (2016). Effect of a prebiotic formulation on frailty syndrome: a randomized, double-blind clinical trial. International Journal of Molecular Sciences, 17(6), 932. http://dx.doi.org/10.3390/ijms17060932. PMid:27314331.
http://dx.doi.org/10.3390/ijms17060932...
; Tieland et al., 2012Tieland, M., Dirks, M. L., van der Zwaluw, N., Verdijk, L. B., van de Rest, O., Groot, L. C., & van Loon, L. J. (2012). Protein supplementation increases muscle mass gain during prolonged resistance-type exercise training in frail elderly people: a randomized, double-blind, placebo-controlled trial. Journal of the American Medical Directors Association, 13(8), 713-719. http://dx.doi.org/10.1016/j.jamda.2012.05.020. PMid:22770932.
http://dx.doi.org/10.1016/j.jamda.2012.0...
; Smoliner et al., 2008Smoliner, C., Norman, K., Scheufele, R., Hartig, W., Pirlich, M., & Lochs, H. (2008). Effects of food fortification on nutritional and functional status in frail elderly nursing home residents at risk of malnutrition. Nutrition, 24(11-12), 1139-1144. http://dx.doi.org/10.1016/j.nut.2008.06.024. PMid:18789649.
http://dx.doi.org/10.1016/j.nut.2008.06....
; Bonnefoy et al., 2003Bonnefoy, M., Cornu, C., Normand, S., Boutitie, F., Bugnard, F., Rahmani, A., Lacour, J. R., & Laville, M. (2003). The effects of exercise and protein-energy supplements on body composition and muscle function in frail elderly individuals: a long-term controlled randomised study. British Journal of Nutrition, 89(5), 731-738. http://dx.doi.org/10.1079/BJN2003836. PMid:12720593.
http://dx.doi.org/10.1079/BJN2003836...
; Jong et al., 2000Jong, N., Paw, M. J. C. A., Groot, L. C., Hiddink, G. J., & van Staveren, W. A. (2000). Dietary supplements and physical exercise affecting bone and body composition in frail elderly persons. American Journal of Public Health, 90(6), 947-954. http://dx.doi.org/10.2105/AJPH.90.6.947. PMid:10846514.
http://dx.doi.org/10.2105/AJPH.90.6.947...
) in Europe. The mean age ranged from 68.2 years to 89.2 years and the majority were females (67%). Ten RCTs (Na et al., 2021Na, W., Kim, J., Kim, H., Lee, Y., Jeong, B., Lee, S. P., & Sohn, C. (2021). Evaluation of oral nutritional supplementation in the management of frailty among the elderly at facilities of community care for the elderly. Clinical Nutrition Research, 10(1), 24-35. http://dx.doi.org/10.7762/cnr.2021.10.1.24. PMid:33564650.
http://dx.doi.org/10.7762/cnr.2021.10.1....
; Peng et al., 2021Peng, L. N., Cheng, Y. C., Yu, P. C., Lee, W. J., Lin, M. H., & Chen, L. K. (2021). Oral nutritional supplement with β-hydroxy-β-methylbutyrate (HMB) improves nutrition, physical performance and ameliorates intramuscular adiposity in pre-frail older adults: a randomized controlled trial. The Journal of Nutrition, Health & Aging, 25(6), 767-773. http://dx.doi.org/10.1007/s12603-021-1621-7. PMid:34179932.
http://dx.doi.org/10.1007/s12603-021-162...
; Dirks et al., 2017Dirks, M. L., Tieland, M., Verdijk, L. B., Losen, M., Nilwik, R., Mensink, M., Groot, L. C. P. G. M., & van Loon, L. J. C. (2017). Protein supplementation augments muscle fiber hypertrophy but does not modulate satellite cell content during prolonged resistance-type exercise training in frail elderly. Journal of the American Medical Directors Association, 18(7), 608-615. http://dx.doi.org/10.1016/j.jamda.2017.02.006. PMid:28377156.
http://dx.doi.org/10.1016/j.jamda.2017.0...
; Badrasawi et al., 2016Badrasawi, M., Shahar, S., Zahara, A. M., Fadilah, R. N., & Singh, D. K. A. (2016). Efficacy of L-carnitine supplementation on frailty status and its biomarkers, nutritional status, and physical and cognitive function among prefrail older adults: a double-blind, randomized, placebo-controlled clinical trial. Clinical Interventions in Aging, 11, 1675-1686. http://dx.doi.org/10.2147/CIA.S113287. PMid:27895474.
http://dx.doi.org/10.2147/CIA.S113287...
; Kim et al., 2015Kim, H., Suzuki, T., Kim, M., Kojima, N., Ota, N., Shimotoyodome, A., Hase, T., Hosoi, E., & Yoshida, H. (2015). Effects of exercise and milk fat globule membrane (MFGM) supplementation on body composition, physical function, and hematological parameters in community-dwelling frail Japanese women: a randomized double blind, placebo-controlled, follow-up trial. PLoS One, 10(2), e0116256. http://dx.doi.org/10.1371/journal.pone.0116256. PMid:25659147.
http://dx.doi.org/10.1371/journal.pone.0...
; Ng et al., 2015Ng, T. P., Feng, L., Nyunt, M. S., Feng, L., Niti, M., Tan, B. Y., Chan, G., Khoo, S. A., Chan, S. M., Yap, P., & Yap, K. B. (2015). Nutritional, physical, cognitive, and combination interventions and frailty reversal among older adults: a randomized controlled trial. The American Journal of Medicine, 128(11), 1225-1236.E1. http://dx.doi.org/10.1016/j.amjmed.2015.06.017. PMid:26159634.
http://dx.doi.org/10.1016/j.amjmed.2015....
; Kim & Lee, 2013Kim, C. O., & Lee, K. R. (2013). Preventive effect of protein-energy supplementation on the functional decline of frail older adults with low socioeconomic status: a community-based randomized controlled study. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 68(3), 309-316. http://dx.doi.org/10.1093/gerona/gls167. PMid:22879453.
http://dx.doi.org/10.1093/gerona/gls167...
; Tieland et al., 2012Tieland, M., Dirks, M. L., van der Zwaluw, N., Verdijk, L. B., van de Rest, O., Groot, L. C., & van Loon, L. J. (2012). Protein supplementation increases muscle mass gain during prolonged resistance-type exercise training in frail elderly people: a randomized, double-blind, placebo-controlled trial. Journal of the American Medical Directors Association, 13(8), 713-719. http://dx.doi.org/10.1016/j.jamda.2012.05.020. PMid:22770932.
http://dx.doi.org/10.1016/j.jamda.2012.0...
; Jong et al., 2000Jong, N., Paw, M. J. C. A., Groot, L. C., Hiddink, G. J., & van Staveren, W. A. (2000). Dietary supplements and physical exercise affecting bone and body composition in frail elderly persons. American Journal of Public Health, 90(6), 947-954. http://dx.doi.org/10.2105/AJPH.90.6.947. PMid:10846514.
http://dx.doi.org/10.2105/AJPH.90.6.947...
; Gray-Donald et al., 1995Gray-Donald, K., Payette, H., & Boutier, V. (1995). Randomized clinical trial of nutritional supplementation shows little effect on functional status among free-living frail elderly. The Journal of Nutrition, 125(12), 2965-2971. PMid:7500174.) were made among community-dwelling older adults, among the conditions considered, 7 RCTs (Kim et al., 2015Kim, H., Suzuki, T., Kim, M., Kojima, N., Ota, N., Shimotoyodome, A., Hase, T., Hosoi, E., & Yoshida, H. (2015). Effects of exercise and milk fat globule membrane (MFGM) supplementation on body composition, physical function, and hematological parameters in community-dwelling frail Japanese women: a randomized double blind, placebo-controlled, follow-up trial. PLoS One, 10(2), e0116256. http://dx.doi.org/10.1371/journal.pone.0116256. PMid:25659147.
http://dx.doi.org/10.1371/journal.pone.0...
; Kim & Lee, 2013Kim, C. O., & Lee, K. R. (2013). Preventive effect of protein-energy supplementation on the functional decline of frail older adults with low socioeconomic status: a community-based randomized controlled study. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 68(3), 309-316. http://dx.doi.org/10.1093/gerona/gls167. PMid:22879453.
http://dx.doi.org/10.1093/gerona/gls167...
; Smoliner et al., 2008Smoliner, C., Norman, K., Scheufele, R., Hartig, W., Pirlich, M., & Lochs, H. (2008). Effects of food fortification on nutritional and functional status in frail elderly nursing home residents at risk of malnutrition. Nutrition, 24(11-12), 1139-1144. http://dx.doi.org/10.1016/j.nut.2008.06.024. PMid:18789649.
http://dx.doi.org/10.1016/j.nut.2008.06....
; Bonnefoy et al., 2003Bonnefoy, M., Cornu, C., Normand, S., Boutitie, F., Bugnard, F., Rahmani, A., Lacour, J. R., & Laville, M. (2003). The effects of exercise and protein-energy supplements on body composition and muscle function in frail elderly individuals: a long-term controlled randomised study. British Journal of Nutrition, 89(5), 731-738. http://dx.doi.org/10.1079/BJN2003836. PMid:12720593.
http://dx.doi.org/10.1079/BJN2003836...
; Jong et al., 2000Jong, N., Paw, M. J. C. A., Groot, L. C., Hiddink, G. J., & van Staveren, W. A. (2000). Dietary supplements and physical exercise affecting bone and body composition in frail elderly persons. American Journal of Public Health, 90(6), 947-954. http://dx.doi.org/10.2105/AJPH.90.6.947. PMid:10846514.
http://dx.doi.org/10.2105/AJPH.90.6.947...
; Gray-Donald et al., 1995Gray-Donald, K., Payette, H., & Boutier, V. (1995). Randomized clinical trial of nutritional supplementation shows little effect on functional status among free-living frail elderly. The Journal of Nutrition, 125(12), 2965-2971. PMid:7500174.; Fiatarone et al., 1994Fiatarone, M. A., O’Neill, E. F., Ryan, N. D., Clements, K. M., Solares, G. R., Nelson, M. E., Roberts, S. B., Kehayias, J. J., Lipsitz, L. A., & Evans, W. J. (1994). Exercise training and nutritional supplementation for physical frailty in very elderly people. The New England Journal of Medicine, 330(25), 1769-1775. http://dx.doi.org/10.1056/NEJM199406233302501. PMid:8190152.
http://dx.doi.org/10.1056/NEJM1994062333...
) included only frailty people, whilst 11 RCTs included frailty and prefrailty people.

Multi-nutrient products were the most common nutritional supplementations used (n = 10 studies) including vitamin D/E associated with proteins, hypercaloric products, or amino acids associated with minerals.

The quality of the majority of the studies was moderate, with a mean score of 22.94. Four studies (Kang et al., 2019Kang, L., Gao, Y., Liu, X. H., Liang, Y. H., Chen, Y. W., Liang, Y. H., Zhang, L., Chen, W., Pang, H. Y., & Peng, L. N. (2019). Effects of whey protein nutritional supplement on muscle function among community-dwelling frail older people: a multicenter study in China. Archives of Gerontology and Geriatrics, 83, 7-12. http://dx.doi.org/10.1016/j.archger.2019.03.012. PMid:30921603.
http://dx.doi.org/10.1016/j.archger.2019...
; Park et al., 2018Park, Y., Choi, J.-E., & Hwang, H.-S. (2018). Protein supplementation improves muscle mass and physical performance in undernourished prefrail and frail elderly subjects: a randomized, double-blind, placebo-controlled trial. The American Journal of Clinical Nutrition, 108(5), 1026-1033. http://dx.doi.org/10.1093/ajcn/nqy214. PMid:30475969.
http://dx.doi.org/10.1093/ajcn/nqy214...
; Wu et al., 2018Wu, S. Y., Hsu, L. L., Hsu, C. C., Hsieh, T. J., Su, S. C., Peng, Y. W., Guo, T. M., Kang, Y. W., & Pan, W. H. (2018). Dietary education with customised dishware and food supplements can reduce frailty and improve mental well-being in elderly people: a single-blind randomized controlled study. Asia Pacific Journal of Clinical Nutrition, 27(5), 1018-1030. PMid:30272850.; Badrasawi et al., 2016Badrasawi, M., Shahar, S., Zahara, A. M., Fadilah, R. N., & Singh, D. K. A. (2016). Efficacy of L-carnitine supplementation on frailty status and its biomarkers, nutritional status, and physical and cognitive function among prefrail older adults: a double-blind, randomized, placebo-controlled clinical trial. Clinical Interventions in Aging, 11, 1675-1686. http://dx.doi.org/10.2147/CIA.S113287. PMid:27895474.
http://dx.doi.org/10.2147/CIA.S113287...
) were rated as of good quality, and 14 studies were deemed to be of moderate quality.

3.3 Effect of dietary supplementation on frailty

Four studies reported the effect of dietary supplementation interventions on frailty scores in older adults. Three of these studies were multi-nutrient nutritional interventions (Na et al., 2021Na, W., Kim, J., Kim, H., Lee, Y., Jeong, B., Lee, S. P., & Sohn, C. (2021). Evaluation of oral nutritional supplementation in the management of frailty among the elderly at facilities of community care for the elderly. Clinical Nutrition Research, 10(1), 24-35. http://dx.doi.org/10.7762/cnr.2021.10.1.24. PMid:33564650.
http://dx.doi.org/10.7762/cnr.2021.10.1....
; Hsieh et al., 2019Hsieh, T. J., Su, S. C., Chen, C. W., Kang, Y. W., Hu, M. H., Hsu, L. L., Wu, S. Y., Chen, L., Chang, H. Y., Chuang, S. Y., Pan, W. H., & Hsu, C. C. (2019). Individualized home-based exercise and nutrition interventions improve frailty in older adults: a randomized controlled trial. The International Journal of Behavioral Nutrition and Physical Activity, 16(1), 119. http://dx.doi.org/10.1186/s12966-019-0855-9. PMid:31791364.
http://dx.doi.org/10.1186/s12966-019-085...
; Ng et al., 2015Ng, T. P., Feng, L., Nyunt, M. S., Feng, L., Niti, M., Tan, B. Y., Chan, G., Khoo, S. A., Chan, S. M., Yap, P., & Yap, K. B. (2015). Nutritional, physical, cognitive, and combination interventions and frailty reversal among older adults: a randomized controlled trial. The American Journal of Medicine, 128(11), 1225-1236.E1. http://dx.doi.org/10.1016/j.amjmed.2015.06.017. PMid:26159634.
http://dx.doi.org/10.1016/j.amjmed.2015....
) and one study (Badrasawi et al., 2016Badrasawi, M., Shahar, S., Zahara, A. M., Fadilah, R. N., & Singh, D. K. A. (2016). Efficacy of L-carnitine supplementation on frailty status and its biomarkers, nutritional status, and physical and cognitive function among prefrail older adults: a double-blind, randomized, placebo-controlled clinical trial. Clinical Interventions in Aging, 11, 1675-1686. http://dx.doi.org/10.2147/CIA.S113287. PMid:27895474.
http://dx.doi.org/10.2147/CIA.S113287...
) used prebiotic interventions. There was no significant heterogeneity among these studies (P = 0.70, I2 = 0), so the fixed effect model was used for meta-analysis. The results showed that multi-nutrient nutrition intervention can significantly improve the frailty score of the elderly (MD = -0.19, 95% CI: -0.38 to -0.01, P = 0.04) (Table 2).

Table 2
Meta-analysis of randomized controlled trials by type of nutritional intervention on frailty.

None of these outcomes suffered on publication bias as revealed by the visual inspection of the funnel plots and/or using the Egger’s test (P > 0.05).

3.4 Effect of dietary supplementation on weight and muscle mass

As reported in Table 3, among the single nutritional component examined, proteins supplementation were able to significantly improve weight in 2 RCTs (Dirks et al., 2017Dirks, M. L., Tieland, M., Verdijk, L. B., Losen, M., Nilwik, R., Mensink, M., Groot, L. C. P. G. M., & van Loon, L. J. C. (2017). Protein supplementation augments muscle fiber hypertrophy but does not modulate satellite cell content during prolonged resistance-type exercise training in frail elderly. Journal of the American Medical Directors Association, 18(7), 608-615. http://dx.doi.org/10.1016/j.jamda.2017.02.006. PMid:28377156.
http://dx.doi.org/10.1016/j.jamda.2017.0...
; Tieland et al., 2012Tieland, M., Dirks, M. L., van der Zwaluw, N., Verdijk, L. B., van de Rest, O., Groot, L. C., & van Loon, L. J. (2012). Protein supplementation increases muscle mass gain during prolonged resistance-type exercise training in frail elderly people: a randomized, double-blind, placebo-controlled trial. Journal of the American Medical Directors Association, 13(8), 713-719. http://dx.doi.org/10.1016/j.jamda.2012.05.020. PMid:22770932.
http://dx.doi.org/10.1016/j.jamda.2012.0...
), (MD = 4.86, 95% CI: 1.21 to 8.52, P = 0.009), even if this outcome was characterized by a high heterogeneity (I2 = 60%). A study of HP-HMB reported weight gain in people randomized to this intervention (Peng et al., 2021Peng, L. N., Cheng, Y. C., Yu, P. C., Lee, W. J., Lin, M. H., & Chen, L. K. (2021). Oral nutritional supplement with β-hydroxy-β-methylbutyrate (HMB) improves nutrition, physical performance and ameliorates intramuscular adiposity in pre-frail older adults: a randomized controlled trial. The Journal of Nutrition, Health & Aging, 25(6), 767-773. http://dx.doi.org/10.1007/s12603-021-1621-7. PMid:34179932.
http://dx.doi.org/10.1007/s12603-021-162...
). On the contrary, we did not observe improvement for the multi-nutrient supplementation in 4 RCTs (Na et al., 2021Na, W., Kim, J., Kim, H., Lee, Y., Jeong, B., Lee, S. P., & Sohn, C. (2021). Evaluation of oral nutritional supplementation in the management of frailty among the elderly at facilities of community care for the elderly. Clinical Nutrition Research, 10(1), 24-35. http://dx.doi.org/10.7762/cnr.2021.10.1.24. PMid:33564650.
http://dx.doi.org/10.7762/cnr.2021.10.1....
; Wu et al., 2018Wu, S. Y., Hsu, L. L., Hsu, C. C., Hsieh, T. J., Su, S. C., Peng, Y. W., Guo, T. M., Kang, Y. W., & Pan, W. H. (2018). Dietary education with customised dishware and food supplements can reduce frailty and improve mental well-being in elderly people: a single-blind randomized controlled study. Asia Pacific Journal of Clinical Nutrition, 27(5), 1018-1030. PMid:30272850.; Kim & Lee, 2013Kim, C. O., & Lee, K. R. (2013). Preventive effect of protein-energy supplementation on the functional decline of frail older adults with low socioeconomic status: a community-based randomized controlled study. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 68(3), 309-316. http://dx.doi.org/10.1093/gerona/gls167. PMid:22879453.
http://dx.doi.org/10.1093/gerona/gls167...
; Smoliner et al., 2008Smoliner, C., Norman, K., Scheufele, R., Hartig, W., Pirlich, M., & Lochs, H. (2008). Effects of food fortification on nutritional and functional status in frail elderly nursing home residents at risk of malnutrition. Nutrition, 24(11-12), 1139-1144. http://dx.doi.org/10.1016/j.nut.2008.06.024. PMid:18789649.
http://dx.doi.org/10.1016/j.nut.2008.06....
) (MD = 0.86, 95% CI: -4.00 to 5.73, P = 0.73).

Table 3
Meta-analysis of randomized controlled trials by type of nutritional intervention on weight and muscle mass.

Two studies (Dirks et al., 2017Dirks, M. L., Tieland, M., Verdijk, L. B., Losen, M., Nilwik, R., Mensink, M., Groot, L. C. P. G. M., & van Loon, L. J. C. (2017). Protein supplementation augments muscle fiber hypertrophy but does not modulate satellite cell content during prolonged resistance-type exercise training in frail elderly. Journal of the American Medical Directors Association, 18(7), 608-615. http://dx.doi.org/10.1016/j.jamda.2017.02.006. PMid:28377156.
http://dx.doi.org/10.1016/j.jamda.2017.0...
; Tieland et al., 2012Tieland, M., Dirks, M. L., van der Zwaluw, N., Verdijk, L. B., van de Rest, O., Groot, L. C., & van Loon, L. J. (2012). Protein supplementation increases muscle mass gain during prolonged resistance-type exercise training in frail elderly people: a randomized, double-blind, placebo-controlled trial. Journal of the American Medical Directors Association, 13(8), 713-719. http://dx.doi.org/10.1016/j.jamda.2012.05.020. PMid:22770932.
http://dx.doi.org/10.1016/j.jamda.2012.0...
) effect of protein supplementation on lean mass meta-analysis showed that the intervention increases lean mass (MD = 2.73, 95% CI:1.26 to 4.20, P = 0.0003). Na et al. (2021)Na, W., Kim, J., Kim, H., Lee, Y., Jeong, B., Lee, S. P., & Sohn, C. (2021). Evaluation of oral nutritional supplementation in the management of frailty among the elderly at facilities of community care for the elderly. Clinical Nutrition Research, 10(1), 24-35. http://dx.doi.org/10.7762/cnr.2021.10.1.24. PMid:33564650.
http://dx.doi.org/10.7762/cnr.2021.10.1....
and Jong et al. (2000)Jong, N., Paw, M. J. C. A., Groot, L. C., Hiddink, G. J., & van Staveren, W. A. (2000). Dietary supplements and physical exercise affecting bone and body composition in frail elderly persons. American Journal of Public Health, 90(6), 947-954. http://dx.doi.org/10.2105/AJPH.90.6.947. PMid:10846514.
http://dx.doi.org/10.2105/AJPH.90.6.947...
studies showed that multi-nutrient supplementation did not increase lean mass.

Two studies (Dirks et al., 2017Dirks, M. L., Tieland, M., Verdijk, L. B., Losen, M., Nilwik, R., Mensink, M., Groot, L. C. P. G. M., & van Loon, L. J. C. (2017). Protein supplementation augments muscle fiber hypertrophy but does not modulate satellite cell content during prolonged resistance-type exercise training in frail elderly. Journal of the American Medical Directors Association, 18(7), 608-615. http://dx.doi.org/10.1016/j.jamda.2017.02.006. PMid:28377156.
http://dx.doi.org/10.1016/j.jamda.2017.0...
; Kim et al., 2015Kim, H., Suzuki, T., Kim, M., Kojima, N., Ota, N., Shimotoyodome, A., Hase, T., Hosoi, E., & Yoshida, H. (2015). Effects of exercise and milk fat globule membrane (MFGM) supplementation on body composition, physical function, and hematological parameters in community-dwelling frail Japanese women: a randomized double blind, placebo-controlled, follow-up trial. PLoS One, 10(2), e0116256. http://dx.doi.org/10.1371/journal.pone.0116256. PMid:25659147.
http://dx.doi.org/10.1371/journal.pone.0...
) results of the meta-analysis showed that after the protein supplementation intervention, the appendicular lean mass did not change in the frail elderly (MD = 0.80, 95% CI: -1.36 to 2.95, P = 0.470). Na et al. (2021)Na, W., Kim, J., Kim, H., Lee, Y., Jeong, B., Lee, S. P., & Sohn, C. (2021). Evaluation of oral nutritional supplementation in the management of frailty among the elderly at facilities of community care for the elderly. Clinical Nutrition Research, 10(1), 24-35. http://dx.doi.org/10.7762/cnr.2021.10.1.24. PMid:33564650.
http://dx.doi.org/10.7762/cnr.2021.10.1....
study showed that multi-nutrient supplementation did not increase appendicular lean mass.

None of these outcomes suffered on publication bias as revealed by the visual inspection of the funnel plots and/or using the Egger’s test (P > 0.05).

3.5 Effect of dietary supplementation on muscle strength tests

As reported in Table 4, among the single nutritional component examined, proteins supplementatios were able to significantly improve handgrip strength in 3 RCTs (Kang et al., 2019Kang, L., Gao, Y., Liu, X. H., Liang, Y. H., Chen, Y. W., Liang, Y. H., Zhang, L., Chen, W., Pang, H. Y., & Peng, L. N. (2019). Effects of whey protein nutritional supplement on muscle function among community-dwelling frail older people: a multicenter study in China. Archives of Gerontology and Geriatrics, 83, 7-12. http://dx.doi.org/10.1016/j.archger.2019.03.012. PMid:30921603.
http://dx.doi.org/10.1016/j.archger.2019...
; Dirks et al., 2017Dirks, M. L., Tieland, M., Verdijk, L. B., Losen, M., Nilwik, R., Mensink, M., Groot, L. C. P. G. M., & van Loon, L. J. C. (2017). Protein supplementation augments muscle fiber hypertrophy but does not modulate satellite cell content during prolonged resistance-type exercise training in frail elderly. Journal of the American Medical Directors Association, 18(7), 608-615. http://dx.doi.org/10.1016/j.jamda.2017.02.006. PMid:28377156.
http://dx.doi.org/10.1016/j.jamda.2017.0...
; Tieland et al., 2012Tieland, M., Dirks, M. L., van der Zwaluw, N., Verdijk, L. B., van de Rest, O., Groot, L. C., & van Loon, L. J. (2012). Protein supplementation increases muscle mass gain during prolonged resistance-type exercise training in frail elderly people: a randomized, double-blind, placebo-controlled trial. Journal of the American Medical Directors Association, 13(8), 713-719. http://dx.doi.org/10.1016/j.jamda.2012.05.020. PMid:22770932.
http://dx.doi.org/10.1016/j.jamda.2012.0...
), (MD = 1.90, 95% CI: 0.68 to 3.12, P = 0.002). A study of prebiotic supplementation (Buigues et al., 2016Buigues, C., Fernández-Garrido, J., Pruimboom, L., Hoogland, A. J., Navarro-Martínez, R., Martínez-Martínez, M., Verdejo, Y., Mascarós, M. C., Peris, C., & Cauli, O. (2016). Effect of a prebiotic formulation on frailty syndrome: a randomized, double-blind clinical trial. International Journal of Molecular Sciences, 17(6), 932. http://dx.doi.org/10.3390/ijms17060932. PMid:27314331.
http://dx.doi.org/10.3390/ijms17060932...
) reported handgrip strength improved in people randomized to this intervention. On the contrary, we did not observe improvement for the multi-nutrient supplementation in 6 RCTs (Na et al., 2021Na, W., Kim, J., Kim, H., Lee, Y., Jeong, B., Lee, S. P., & Sohn, C. (2021). Evaluation of oral nutritional supplementation in the management of frailty among the elderly at facilities of community care for the elderly. Clinical Nutrition Research, 10(1), 24-35. http://dx.doi.org/10.7762/cnr.2021.10.1.24. PMid:33564650.
http://dx.doi.org/10.7762/cnr.2021.10.1....
; Hsieh et al., 2019Hsieh, T. J., Su, S. C., Chen, C. W., Kang, Y. W., Hu, M. H., Hsu, L. L., Wu, S. Y., Chen, L., Chang, H. Y., Chuang, S. Y., Pan, W. H., & Hsu, C. C. (2019). Individualized home-based exercise and nutrition interventions improve frailty in older adults: a randomized controlled trial. The International Journal of Behavioral Nutrition and Physical Activity, 16(1), 119. http://dx.doi.org/10.1186/s12966-019-0855-9. PMid:31791364.
http://dx.doi.org/10.1186/s12966-019-085...
; Wu et al., 2018Wu, S. Y., Hsu, L. L., Hsu, C. C., Hsieh, T. J., Su, S. C., Peng, Y. W., Guo, T. M., Kang, Y. W., & Pan, W. H. (2018). Dietary education with customised dishware and food supplements can reduce frailty and improve mental well-being in elderly people: a single-blind randomized controlled study. Asia Pacific Journal of Clinical Nutrition, 27(5), 1018-1030. PMid:30272850.; Kim & Lee, 2013Kim, C. O., & Lee, K. R. (2013). Preventive effect of protein-energy supplementation on the functional decline of frail older adults with low socioeconomic status: a community-based randomized controlled study. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 68(3), 309-316. http://dx.doi.org/10.1093/gerona/gls167. PMid:22879453.
http://dx.doi.org/10.1093/gerona/gls167...
; Smoliner et al., 2008Smoliner, C., Norman, K., Scheufele, R., Hartig, W., Pirlich, M., & Lochs, H. (2008). Effects of food fortification on nutritional and functional status in frail elderly nursing home residents at risk of malnutrition. Nutrition, 24(11-12), 1139-1144. http://dx.doi.org/10.1016/j.nut.2008.06.024. PMid:18789649.
http://dx.doi.org/10.1016/j.nut.2008.06....
; Gray-Donald et al., 1995Gray-Donald, K., Payette, H., & Boutier, V. (1995). Randomized clinical trial of nutritional supplementation shows little effect on functional status among free-living frail elderly. The Journal of Nutrition, 125(12), 2965-2971. PMid:7500174.) (MD = 0.29, 95% CI: -0.83 to 1.41, P = 0.45). Moreover Peng et al. (2021)Peng, L. N., Cheng, Y. C., Yu, P. C., Lee, W. J., Lin, M. H., & Chen, L. K. (2021). Oral nutritional supplement with β-hydroxy-β-methylbutyrate (HMB) improves nutrition, physical performance and ameliorates intramuscular adiposity in pre-frail older adults: a randomized controlled trial. The Journal of Nutrition, Health & Aging, 25(6), 767-773. http://dx.doi.org/10.1007/s12603-021-1621-7. PMid:34179932.
http://dx.doi.org/10.1007/s12603-021-162...
and Badrasawi et al. (2016)Badrasawi, M., Shahar, S., Zahara, A. M., Fadilah, R. N., & Singh, D. K. A. (2016). Efficacy of L-carnitine supplementation on frailty status and its biomarkers, nutritional status, and physical and cognitive function among prefrail older adults: a double-blind, randomized, placebo-controlled clinical trial. Clinical Interventions in Aging, 11, 1675-1686. http://dx.doi.org/10.2147/CIA.S113287. PMid:27895474.
http://dx.doi.org/10.2147/CIA.S113287...
came to similar conclusions.

Table 4
Meta-analysis of randomized controlled trials by type of nutritional intervention on muscle strength.

None of these outcomes suffered on publication bias as revealed by the visual inspection of the funnel plots and/or using the Egger’s test (P > 0.05).

3.6 Effect of dietary supplementation on physical performance tests

The results of the chair stand test of 3 RCTs (Kang et al., 2019Kang, L., Gao, Y., Liu, X. H., Liang, Y. H., Chen, Y. W., Liang, Y. H., Zhang, L., Chen, W., Pang, H. Y., & Peng, L. N. (2019). Effects of whey protein nutritional supplement on muscle function among community-dwelling frail older people: a multicenter study in China. Archives of Gerontology and Geriatrics, 83, 7-12. http://dx.doi.org/10.1016/j.archger.2019.03.012. PMid:30921603.
http://dx.doi.org/10.1016/j.archger.2019...
; Kim et al., 2015Kim, H., Suzuki, T., Kim, M., Kojima, N., Ota, N., Shimotoyodome, A., Hase, T., Hosoi, E., & Yoshida, H. (2015). Effects of exercise and milk fat globule membrane (MFGM) supplementation on body composition, physical function, and hematological parameters in community-dwelling frail Japanese women: a randomized double blind, placebo-controlled, follow-up trial. PLoS One, 10(2), e0116256. http://dx.doi.org/10.1371/journal.pone.0116256. PMid:25659147.
http://dx.doi.org/10.1371/journal.pone.0...
; Tieland et al., 2012Tieland, M., Dirks, M. L., van der Zwaluw, N., Verdijk, L. B., van de Rest, O., Groot, L. C., & van Loon, L. J. (2012). Protein supplementation increases muscle mass gain during prolonged resistance-type exercise training in frail elderly people: a randomized, double-blind, placebo-controlled trial. Journal of the American Medical Directors Association, 13(8), 713-719. http://dx.doi.org/10.1016/j.jamda.2012.05.020. PMid:22770932.
http://dx.doi.org/10.1016/j.jamda.2012.0...
) for protein interventions on the frail elderly showed that the heterogeneity was high. After excluding the study of Kim et al. (2015)Kim, H., Suzuki, T., Kim, M., Kojima, N., Ota, N., Shimotoyodome, A., Hase, T., Hosoi, E., & Yoshida, H. (2015). Effects of exercise and milk fat globule membrane (MFGM) supplementation on body composition, physical function, and hematological parameters in community-dwelling frail Japanese women: a randomized double blind, placebo-controlled, follow-up trial. PLoS One, 10(2), e0116256. http://dx.doi.org/10.1371/journal.pone.0116256. PMid:25659147.
http://dx.doi.org/10.1371/journal.pone.0...
, the heterogeneity was reduced and the model was stable (P = 0.45, I2 = 0). Protein supplementation intervention can improve its chair stand test results (MD = -2.15, 95% CI: -3.21 to -1.10, P < 0.0001). And a study of multi-nutrient supplementation (Kim & Lee, 2013Kim, C. O., & Lee, K. R. (2013). Preventive effect of protein-energy supplementation on the functional decline of frail older adults with low socioeconomic status: a community-based randomized controlled study. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 68(3), 309-316. http://dx.doi.org/10.1093/gerona/gls167. PMid:22879453.
http://dx.doi.org/10.1093/gerona/gls167...
) reported improved chair stand test in people randomized to this intervention. Conversely, Badrasawi et al. (2016)Badrasawi, M., Shahar, S., Zahara, A. M., Fadilah, R. N., & Singh, D. K. A. (2016). Efficacy of L-carnitine supplementation on frailty status and its biomarkers, nutritional status, and physical and cognitive function among prefrail older adults: a double-blind, randomized, placebo-controlled clinical trial. Clinical Interventions in Aging, 11, 1675-1686. http://dx.doi.org/10.2147/CIA.S113287. PMid:27895474.
http://dx.doi.org/10.2147/CIA.S113287...
and Peng et al. (2021)Peng, L. N., Cheng, Y. C., Yu, P. C., Lee, W. J., Lin, M. H., & Chen, L. K. (2021). Oral nutritional supplement with β-hydroxy-β-methylbutyrate (HMB) improves nutrition, physical performance and ameliorates intramuscular adiposity in pre-frail older adults: a randomized controlled trial. The Journal of Nutrition, Health & Aging, 25(6), 767-773. http://dx.doi.org/10.1007/s12603-021-1621-7. PMid:34179932.
http://dx.doi.org/10.1007/s12603-021-162...
study showed that L-carnitine and HP-HMB intervention did not change the chair stand test (Table 5).

Table 5
Meta-analysis of randomized controlled trials by type of nutritional intervention on physical performance.

Five studies showed no significant effect of dietary supplementation interventions on physical performance in frail older adults, two (Peng et al., 2021Peng, L. N., Cheng, Y. C., Yu, P. C., Lee, W. J., Lin, M. H., & Chen, L. K. (2021). Oral nutritional supplement with β-hydroxy-β-methylbutyrate (HMB) improves nutrition, physical performance and ameliorates intramuscular adiposity in pre-frail older adults: a randomized controlled trial. The Journal of Nutrition, Health & Aging, 25(6), 767-773. http://dx.doi.org/10.1007/s12603-021-1621-7. PMid:34179932.
http://dx.doi.org/10.1007/s12603-021-162...
; Kim & Lee, 2013Kim, C. O., & Lee, K. R. (2013). Preventive effect of protein-energy supplementation on the functional decline of frail older adults with low socioeconomic status: a community-based randomized controlled study. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 68(3), 309-316. http://dx.doi.org/10.1093/gerona/gls167. PMid:22879453.
http://dx.doi.org/10.1093/gerona/gls167...
) of which were multi-nutrient interventions(MD = 0.34, 95% CI: -0.18 to 0.87, P = 0.20) and three (Kang et al., 2019Kang, L., Gao, Y., Liu, X. H., Liang, Y. H., Chen, Y. W., Liang, Y. H., Zhang, L., Chen, W., Pang, H. Y., & Peng, L. N. (2019). Effects of whey protein nutritional supplement on muscle function among community-dwelling frail older people: a multicenter study in China. Archives of Gerontology and Geriatrics, 83, 7-12. http://dx.doi.org/10.1016/j.archger.2019.03.012. PMid:30921603.
http://dx.doi.org/10.1016/j.archger.2019...
; Park et al., 2018Park, Y., Choi, J.-E., & Hwang, H.-S. (2018). Protein supplementation improves muscle mass and physical performance in undernourished prefrail and frail elderly subjects: a randomized, double-blind, placebo-controlled trial. The American Journal of Clinical Nutrition, 108(5), 1026-1033. http://dx.doi.org/10.1093/ajcn/nqy214. PMid:30475969.
http://dx.doi.org/10.1093/ajcn/nqy214...
; Dirks et al., 2017Dirks, M. L., Tieland, M., Verdijk, L. B., Losen, M., Nilwik, R., Mensink, M., Groot, L. C. P. G. M., & van Loon, L. J. C. (2017). Protein supplementation augments muscle fiber hypertrophy but does not modulate satellite cell content during prolonged resistance-type exercise training in frail elderly. Journal of the American Medical Directors Association, 18(7), 608-615. http://dx.doi.org/10.1016/j.jamda.2017.02.006. PMid:28377156.
http://dx.doi.org/10.1016/j.jamda.2017.0...
) were proteins interventions(MD = 0.02, 95% CI: -1.05 to 1.09, P = 0.97) (Table 5).

None of these outcomes suffered on publication bias as revealed by the visual inspection of the funnel plots and/or using the Egger’s test (P > 0.05).

4 Discussion

In this systematic review and meta-analysis including 18 RCTs placebo-controlled and 1204 older pre-frail or frail participants, we found that proteins and multi-nutrient supplementations (i.e. nutritional supplements made of several nutritional components) appeared to have a positive effect on improving frailty, muscle mass, certain physical functions, and muscle strength tests in older people.

The pathological loss of muscle mass is an important topic in geriatric medicine and poor nutritional status seems to play an important role in the development of frailty. It is widely known that there is a significant decline in food and energy intake with increasing age, estimated in an average fall of around 25% between the ages of 40 and 70 years (Nieuwenhuizen et al., 2010Nieuwenhuizen, W. F., Weenen, H., Rigby, P., & Hetherington, M. M. (2010). Older adults and patients in need of nutritional support: review of current treatment options and factors influencing nutritional intake. Clinical Nutrition, 29(2), 160-169. http://dx.doi.org/10.1016/j.clnu.2009.09.003. PMid:19828215.
http://dx.doi.org/10.1016/j.clnu.2009.09...
). Therefore, the European Society of Parenteral and Enteral Nutrition (ESPEN) recommends, with an evidence level A, the use of nutritional supplements to improve or maintain the health status of frail elderly people (Cederholm et al., 2017Cederholm, T., Barazzoni, R., Austin, P., Ballmer, P., Biolo, G., Bischoff, S. C., Compher, C., Correia, I., Higashiguchi, T., Holst, M., Jensen, G. L., Malone, A., Muscaritoli, M., Nyulasi, I., Pirlich, M., Rothenberg, E., Schindler, K., Schneider, S. M., van der Schueren, M. A., Sieber, C., Valentini, L., Yu, J. C., Van Gossum, A., & Singer, P. (2017). ESPEN guidelines on definitions and terminology of clinical nutrition. Clinical Nutrition, 36(1), 49-64. http://dx.doi.org/10.1016/j.clnu.2016.09.004. PMid:27642056.
http://dx.doi.org/10.1016/j.clnu.2016.09...
).

Focusing more on the topics of physical performance and muscle strength, several systematic reviews have reported findings on these outcomes with nutritional supplementation, but no definitive findings, mainly because the randomized controlled trials included in these meta-analyses only involved very good, Nutrient-rich individuals, small sample size, heterogeneous age, and different physical activity regimens (Beaudart et al., 2017Beaudart, C., Dawson, A., Shaw, S. C., Harvey, N. C., Kanis, J. A., Binkley, N., Reginster, J. Y., Chapurlat, R., Chan, D. C., Bruyère, O., Rizzoli, R., Cooper, C., & Dennison, E. M. (2017). Nutrition and physical activity in the prevention and treatment of sarcopenia: systematic review. Osteoporosis International, 28(6), 1817-1833. http://dx.doi.org/10.1007/s00198-017-3980-9. PMid:28251287.
http://dx.doi.org/10.1007/s00198-017-398...
; Denison et al., 2015Denison, H. J., Cooper, C., Sayer, A. A., & Robinson, S. M. (2015). Prevention and optimal management of sarcopenia: a review of combined exercise and nutrition interventions to improve muscle outcomes in older people. Clinical Interventions in Aging, 10, 859-869. PMid:25999704.). We tried to overcome these limitations with our work, using very strict criteria (i.e. only randomised controlled trials, including only pre-frail or frail older adults), if possible, without the use of physical exercise in the available arm, but our results are essentially the same as those that have been published. We can be sure that the effect of nutritional supplements is limited to some physical performance tests, and to further improve muscle strength, resistance exercise should be performed (Beaudart et al., 2017Beaudart, C., Dawson, A., Shaw, S. C., Harvey, N. C., Kanis, J. A., Binkley, N., Reginster, J. Y., Chapurlat, R., Chan, D. C., Bruyère, O., Rizzoli, R., Cooper, C., & Dennison, E. M. (2017). Nutrition and physical activity in the prevention and treatment of sarcopenia: systematic review. Osteoporosis International, 28(6), 1817-1833. http://dx.doi.org/10.1007/s00198-017-3980-9. PMid:28251287.
http://dx.doi.org/10.1007/s00198-017-398...
). Unfortunately, several RCTs included in our meta-analysis did not report sufficient information on the characteristics of the applied physical activity regimen, and we decided to focus as much as possible on the role of nutritional supplements and therefore did not consider the arm randomized to the physical activity program. (If there is). In addition, multiple nutrients appear to improve frailty conditions in old age. As frailty in the elderly is multifactorial (Cereda et al., 2018Cereda, E., Veronese, N., & Caccialanza, R. (2018). The final word on nutritional screening and assessment in older persons. Current Opinion in Clinical Nutrition and Metabolic Care, 21(1), 24-29. http://dx.doi.org/10.1097/MCO.0000000000000431. PMid:29035968.
http://dx.doi.org/10.1097/MCO.0000000000...
), multicomponent nutritional supplementations can work better than supplementations with single components, but other studies are needed in this sense since only a few outcomes were improved by this kind of supplementation.

Another interesting finding of our study is that protein supplementation appears to be superior to multi-nutrient supplements and other single-nutrient supplements (HP-HMB, prebiotic, L-carnitine) on muscle mass, muscle strength, and physical performance tests of frail older adults. The likely reason is that frailty exacerbates the effects of age on protein metabolism through a range of factors, such as loss of muscle mass and increased muscle catabolism, implying that supplementation is insufficient to counteract this effect if its use is limited over time (Morais et al., 2000Morais, J. A., Ross, R., Gougeon, R., Pencharz, P. B., Jones, P. J., & Marliss, E. B. (2000). Distribution of protein turnover changes with age in humans as assessed by whole-body magnetic resonance image analysis to quantify tissue volumes. The Journal of Nutrition, 130(4), 784-791. http://dx.doi.org/10.1093/jn/130.4.784. PMid:10736330.
http://dx.doi.org/10.1093/jn/130.4.784...
). Studies have observed that a higher intake of amino acids and proteins is associated with a lower prevalence of frailty in women (Verlaan et al., 2017Verlaan, S., Ligthart-Melis, G. C., Wijers, S. L. J., Cederholm, T., Maier, A. B., & van der Schueren, M. A. E. (2017). High prevalence of physical frailty among community-dwelling malnourished older adults-a systematic review and meta-analysis. Journal of the American Medical Directors Association, 18(5), 374-382. http://dx.doi.org/10.1016/j.jamda.2016.12.074. PMid:28238676.
http://dx.doi.org/10.1016/j.jamda.2016.1...
). And an assessment of 2066 elderly people study demonstrated the association between protein intake and changes in lean mass, elderly people in the highest quintile in terms of protein intake lost 40% less lean mass and appendicular lean mass over three years than those in the lowest intake quintile (Houston et al., 2008Houston, D. K., Nicklas, B. J., Ding, J., Harris, T. B., Tylavsky, F. A., Newman, A. B., Lee, J. S., Sahyoun, N. R., Visser, M., & Kritchevsky, S. B. (2008). Dietary protein intake is associated with lean mass change in older, community-dwelling adults: the Health, Aging, and Body Composition (Health ABC) study. The American Journal of Clinical Nutrition, 87, 150-155. http://dx.doi.org/10.1093/ajcn/87.1.150. PMid:18175749.
http://dx.doi.org/10.1093/ajcn/87.1.150...
). Another possible reason is that the sample size included in this study is limited, and more large-sample randomized controlled studies are needed to verify the results in the future.

In order to avoid, postpone, or reverse the severity of frailty and lessen the negative health effects of frailty upon persons, effective dietary treatments for frailty syndrome must be used (Davinelli et al., 2021Davinelli, S., Corbi, G., & Scapagnini, G. (2021). Frailty syndrome: a target for functional nutrients? Mechanisms of Ageing and Development, 195, 111441. http://dx.doi.org/10.1016/j.mad.2021.111441. PMid:33539905.
http://dx.doi.org/10.1016/j.mad.2021.111...
). It has been shown in the past that a number of dietary supplements may prevent or lessen severe symptoms. A diet rich in protein benefits health, aids in the recovery of sick people, and maintains functional status in elderly people (Prokopidis et al., 2022aProkopidis, K., Giannos, P., Triantafyllidis, K. K., Kechagias, K. S., Mesinovic, J., Witard, O. C., & Scott, D. (2022a). Effect of vitamin D monotherapy on indices of sarcopenia in community-dwelling older adults: a systematic review and meta-analysis. Journal of Cachexia, Sarcopenia and Muscle, 13(3), 1642-1652. http://dx.doi.org/10.1002/jcsm.12976. PMid:35261183.
http://dx.doi.org/10.1002/jcsm.12976...
). An efficient method for improving muscle growth and strength as well as overall physical performance in older persons is the combination of resistance training and post-exercise protein supplementation (Khor et al., 2022Khor, P. Y., Vearing, R. M., & Charlton, K. E. (2022). The effectiveness of nutrition interventions in improving frailty and its associated constructs related to malnutrition and functional decline among community-dwelling older adults: a systematic review. Journal of Human Nutrition and Dietetics, 35(3), 566-582. http://dx.doi.org/10.1111/jhn.12943. PMid:34494314.
http://dx.doi.org/10.1111/jhn.12943...
; Velasco et al., 2022Velasco, G. S., Ribeiro, C. B., Ramos, G. L. P. A., Silva, G. V. L. C., Silva, M. C., Silva, M. A. P., & Cappato, L. P. (2022). Supplement consumption profile by strength training practitioners in Brazil: a literature review. Food Science and Technology, 42, e113021. http://dx.doi.org/10.1590/fst.113021.
http://dx.doi.org/10.1590/fst.113021...
). Vitamin D intake is critical for older adults because of its widely recognized links to bone health, muscle strength and function (Li et al., 2022Li, A., Shen, P., Liu, S., Wang, J., Zeng, J., & Du, C. (2022). Vitamin D alleviates skeletal muscle loss and insulin resistance by inducing vitamin D receptor expression and regulating the AMPK/SIRT1 signaling pathway in mice. Food Science and Technology, 42, e47921. http://dx.doi.org/10.1590/fst.47921.
http://dx.doi.org/10.1590/fst.47921...
; Prokopidis et al., 2022bProkopidis, K., Mazidi, M., Sankaranarayanan, R., Tajik, B., McArdle, A., & Isanejad, M. (2022b). Effects of whey and soy protein supplementation on inflammatory cytokines in older adults: a systematic review and meta-analysis. British Journal of Nutrition, 1-12. Ahead of print. http://dx.doi.org/10.1017/S0007114522001787. PMid:35706399.
http://dx.doi.org/10.1017/S0007114522001...
; Wang et al., 2022Wang, G., Zhang, J., Zhang, K., Zhao, Q., Zhou, F., Xu, J., Xue, W., Zhang, C., & Fu, C. (2022). Possible action mechanisms of vitamin D supplementation in combating obesity and obesity-related issues of bone health: a mini review. Food Science and Technology, 42, e114621. http://dx.doi.org/10.1590/fst.114621.
http://dx.doi.org/10.1590/fst.114621...
). The predominant form of vitamin D found in circulation is 25-hydroxyvitamin D (25(OH)D) (Bollen et al., 2022Bollen, S. E., Bass, J. J., Fujita, S., Wilkinson, D., Hewison, M., & Atherton, P. J. (2022). The vitamin D/vitamin D receptor (VDR) axis in muscle atrophy and sarcopenia. Cellular Signalling, 96, 110355. http://dx.doi.org/10.1016/j.cellsig.2022.110355. PMid:35595176.
http://dx.doi.org/10.1016/j.cellsig.2022...
). Falls, fractures, discomfort, and low levels of 25(OH)D are all related to alterations in balance (Kupisz-Urbańska et al., 2021Kupisz-Urbańska, M., Płudowski, P., & Marcinowska-Suchowierska, E. (2021). Vitamin D deficiency in older patients-problems of sarcopenia, drug interactions, management in deficiency. Nutrients, 13(4), 1247. http://dx.doi.org/10.3390/nu13041247. PMid:33920130.
http://dx.doi.org/10.3390/nu13041247...
). All of these factors might result in a life of inactivity and weakness because of frailty.

The findings of our meta-analysis should be interpreted within its limitations. First, the number of studies included for each outcome was not sufficient. Second, it is possible that the different period of exposure to an oral supplementation can lead to different results in terms of efficacy. Finally, the median follow-up period was only 12 weeks. Despite these limitations, our study has some important strengths. For example, no low-quality literature was included and frail or pre-frail older adults were included (with frailty diagnostic assessments). These differ from previously published meta-analyses/systematic reviews.

In conclusion, nutritional supplementations seem to be useful in improving frailty, some muscle mass, muscle strength and physical performance, particularly if they are proteins. Other high-quality RCTs are needed to confirm our findings.

Acknowledgements

We would like to express our gratitude to all those who helped us during the writing of this manuscript.

  • Practical Application:What is already known on this topic: Malnutrition can increase the risk of frailty in the elderly. More and more scholars are paying attention to the relationship between dietary pattern and frailty. But what’s still missing is a meta-analysis of how dietary patterns affect frailty in older adults. What this study adds: Nutritional supplementations seem to be useful in improving frailty, some muscle mass, muscle strength and physical performance, particularly if they are proteins. How this study might affect research, practice or policy: Appropriate nutritional interventions may reduce the risk of frailty, delay or even reverse frailty.
  • #These authors contributed equally to this study
  • Availability of data and material

    All data generated or analyzed during this study are included in this published article.
  • Funding

    Key R & D projects in Ningxia Hui Autonomous Region (No.2021BEG03116); The General Hospital of Ningxia Medical University "new master training".

References

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Publication Dates

  • Publication in this collection
    02 Sept 2022
  • Date of issue
    2022

History

  • Received
    20 May 2022
  • Accepted
    30 July 2022
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