Effects of β-hydroxy-β-methylbutyrate (HMB) supplementation in addition to multicomponent exercise in adults older than 70 years living in nursing homes, a cluster randomized placebo-controlled trial: the HEAL study protocol

To date, people are living more years than ever before in history and the world’s aging is rising at a staggering rate [1]. Thus, strategies focused on health maintenance for aging people through exercise and proper nutrition are required to contribute to lifelong wellbeing and prevent ageing diseases and chronic illness. Frailty, sarcopenia, dynapenia and sarcopenic obesity states are the main metabolic complications in older people and represent a major public health challenge [2‐4]. A recent estimation from the Eurostat online database (28 European countries) suggests increments from 60 to 70% of individuals with sarcopenia in 2045 affecting 12.9 to 22.3% of people over 65 years old [5]. These diseases are caused by a degenerative loss of muscle mass (muscle wasting), strength and mobility. The combination of exercise with protein dietary supplementation is proven to be highly effective to increase muscle mass and strength in older adults [6‐8].

Evidence states that exercise in older people is a main component in frailty prevention (increases strength and decreases falls incidence) and functional capacity preservation (increases mobility and autonomy) [8‐10]. In turn, weak elders have greater risk of disability, hospitalization, morbidity and death [3, 11]. In addition to a better physical condition, exercise has a clear impact on psychological well-being in older people [12]. Although much remains to be done, the possibility of physical exercise as the new medication for the twenty-first century is truly inspiring. The first step of this revolution is that the question is turning from “may I prescribe physical activity for older people?” to “what kind of exercise must I prescribe?” [13]. Reducing sedentary behaviours and promoting exercise training in older adults living in nursing homes stands as a main global challenge [14, 15].

Very recently, the ERAMUS+ co-funding VIVIFRAIL project (http://​www.​vivifrail.​com) has developed a multicomponent exercise program (strength, balance and cardiovascular exercises), carefully adapted, for improving functional capacity for older people above 70 years [16]. The program includes a practical guide for testing and prescribing the physical training according to each specific condition (serious, moderate, slight or no limitation, and with or without risk of falling). Furthermore, the VIVIFRAIL App allows individuals’ monitoring and provides clear instructions to effectively complete the program within the everyday environment. Now that long-term exercise interventions in older adults are more possible than ever [17], what is now required is to examine the effectiveness of this program on relevant health and functional outcomes for older adults and nursing homes residents [15].

The β-hydroxy-β-methylbutyrate (HMB) dietary is a bioactive metabolite formed from the decomposition of leucine, an essential branched-chain amino acid. The importance of leucine has anti-catabolic properties and plays an important role in protein metabolism, glucose homeostasis, insulin action and recovery from exercise [18‐20]. A dose of 3 g of HMB dietary supplementation provides 60 g of leucine, which otherwise would imply 600 g of high biological value protein [21]. The HMB supplementation is affordable (around 50€/kg) and its consumption is safe with no adverse effects [22, 23]. In older adults > 60 years old, HMB is demonstrated to have anti-catabolic effect, enhance protein synthesis, attenuate proteolysis, increase muscle mass and decrease muscle damage [24‐26]. Despite the fact that HMB efficacy varies [25], a meta-analysis concluded that HMB supplements contribute to the preservation of muscle mass in old age [27]. Based on these findings, the supplementation of HMB appears to be an effective strategy to prevent metabolic and physical complications in ageing (frailty, dynapenia, sarcopenia and sarcopenic obesity) and preserve health, functional capacity and strength in older people.

A recent investigation [28] reported for the first time a significant reduction of 50% in whole body plasma concentration of HMB and reductions of 25% on the conversion of leucine to HMB in older adults (~ 65 y-old). At the moment, there is limited understanding why this happens, but it seems clear than reductions in HMB conversion are associated with age [29]. These decrements on high quality protein synthesis importantly accounted for a decline in muscle weakness in older people [30]. Hence, the possibility of palliating muscle and functional losses in the ageing by HMB supplementation is truly inspiring and encourages further studies [26, 27].

To date, only five Randomized Control Trial (RCT) studies have examined the effectiveness of exercise training combined with HMB dietary supplementation in older adults > 60 years old [31‐35]. Whereas it seems clear that HMB supplements contribute to the preservation of muscle mass in old age, contradictory evidence on its effects on strength increments [31‐34] and functional performance [33‐35] in older adults exists. These equivocal outcomes may be attributed to the protocols applied, with discrepancies in the training volume (number of sessions, time per session, number of reps), intensity (load monitoring and progression) and exercises. Besides, sample sizes explored are reduced (n < 32) and only one RCT [32] conducted an exercise intervention > 8 weeks. Consequently, there is a need for longer and larger studies to fully determine the potential effects of HMB supplementation on physical performance, translating to a functional benefit [34]. In this sense, the HEAL (HMB + Exercise = Adults Living longer) study will be the first RCT conducting a specific, individualized, multicomponent exercise intervention for the older adult population such as the VIVIFRAIL [16]. Because this evidence-based program has been proven as effective and safe in adults aged 65 years or over [17], it represents an excellent opportunity to determine the true effects of HMB supplementation in enhancing training performance. Furthermore, the promising results of HMB supplementation to mitigate age-related cognitive deficits [36, 37] and the lack of studies exploring its impact on people with very limited or no mobility [25, 38] encourage adopting this strategy in vulnerable people such as older nursing homes patients. Therefore, the aim of the HEAL study is to assess the effects of the combination of a daily multicomponent exercise and resistance training (VIVIFRAIL program) in addition to HMB supplementation on older adults’ health.

This paper outlines the protocol for a randomized, placebo-controlled study to determine the efficacy of HMB supplementation in addition to 24-weeks of multicomponent exercise and resistance training in adults ≥70 years old. At the time of writing, the study was ongoing (recruitment status). Baseline assessment is planned to started in March 2019.

Maintaining old people’s health and protecting them from frailty, muscle waist and cardiovascular diseases will save billions in public care costs by lengthening people’s healthy life, reducing the loss of income due to premature death and reducing nursing dependency [60]. Evidence supports that multicomponent exercise [8‐10, 17, 61] and HMB supplementation [24‐26] are effective in improving older adult’s health and palliating functional metabolic diseases in older people. However, the true effect of HMB supplementation combined with a tailored exercise program is still unknown. Just a few trials have investigated the combination of both [31‐33], showing promising results. Moreover, the implementation of the new VIVIFRAIL multicomponent exercise program for frail old people in addition to HMB supplementation is still to be done.

The study results will be of high relevance to old people living in nursing homes and their health care providers. If the benefits of the combined VIVIFRAIL and HMB are proven, this could be an alternative management strategy to consider in nursing homes with older adults and people with functional metabolic diseases and muscle-wasting conditions. In addition, the current exercise intervention is inexpensive and freely available (http://​www.​vivifrail.​com/​), which permits its replication. The findings of the HEAL study will help professionals from public health systems to identify cost-effective and innovative actions to improve older people’s health and quality of life, and endorse exercise practice in older adults living in nursing homes.