The phenomenon of reduced nutritional intake in older individuals (aged ≥65 years), known as the anorexia of aging, is considered a major contributor to DRM and muscle loss, which is believed to be mediated by the non-inflammatory mechanisms (20, 36–38). Particularly in advanced age and in the case of acute and chronic illness, a reduced dietary intake together with the effects of catabolic processes rapidly lead to malnutrition, which is noted in up to two thirds in hospitalized older patients (20, 38–40).

The rising prevalence of sarcopenia is also notable, reaching 36.4% in the hospitalized geriatric population (41, 42). The sarcopenia-related changes in the architecture of skeletal muscle involve a reduction in the number and size of muscle fibers, particularly type II (fast muscle fibers), in a single motor unit with a concurrent gradual infiltration of muscle fibers by adipose and connective tissue (33, 41, 43). Thus, the net change is from type II (fast muscle fibers) to type I (slow muscle fibers) fibers, with consequent alterations such as limited energy to perform daily tasks, predominance of oxidative metabolism, higher protein turnover with diminished ability to grow in size and the different responses to nutrient intake (33, 44, 45).

Overall, muscle loss and frailty are common in elderly populations (17). Muscle loss is associated with an 8% decline per decade between ages 40–70, and 15% decline per decade after age 70 at average (17, 46–48). Frailty is defined as the deterioration in the functioning of multiple physiological systems accompanied by an increased vulnerability to stressors (10% at 65 years and increases with aging) (17, 46–48). This leads to multiple adverse consequences (higher risk of falls, fractures, disability, morbidity, and mortality) in general, and the progression of the disease and poor responses to treatment and delayed recovery from illness specifically in patients with cancer and chronic disease (33, 46–50).

Cancer-related malnutrition (CRM) is a complex multifactorial process characterized by weight loss, metabolic and endocrine alterations, increased tissue protein turnover, and muscle loss (10, 19, 25). CRM is a common occurrence, affecting 50–80% of cancer patients. Its prevalence is notably higher and the condition more severe, especially among older patients and those with cancers of the upper gastrointestinal tract, head and neck, or lungs (10, 25, 51–54).

Muscle loss is especially relevant in CRM, given the adverse effects of both the tumor and the anti-cancer treatment on the patient’s nutritional status and muscle health (6, 22, 30). The progressive loss of skeletal muscle mass is recognized as the primary nutritional challenge in cancer patients. Low muscle mass is prevalent in patients with cancer, and it occurs independent of cancer site, disease stage, treatment phase or patients’ body weight. It serves as an independent indicator of several adverse outcomes, including diminished physical function, reduced QoL, increased surgical complications, accelerated cancer progression, and decreased survival rates (55–57).

Since the Cancer and Leukemia Group B trial 39,801 for unresectable stage III non-small cell lung cancer, pretreatment weight loss ≥ 5% has been a crucial survival prognostic factor to consider (58). Malnutrition and muscle loss can occur before diagnosis, as well as during or after treatment in the setting of cancer (25, 59). They are associated with reduced physical function and QoL, dose-limiting toxicities, reduced treatment response, increased risk for post-surgical complications, prolonged length of hospital stay (LOS) and reduced survival (25, 59–61). Indeed, pretreatment assessment based on nutritional evaluation appeared to be a robust prognostic factor even stratifying patients into survival groups (62, 63). Moreover, muscle depletion can hinder the administration of an optimal (dose-intense) regimen, thereby directly compromising the effectiveness and results of anticancer treatments (59, 64–66).

Nearly 20–40% of cancer patients die from malnutrition and related complications rather than the malignancy itself, highlighting the importance of assessing nutritional status early at the time of initial diagnosis (10, 22, 55, 67, 68).

Neurological diseases are frequently associated with malnutrition as numerous neurological diseases demonstrate a major impact on nutrition of affected patients, while the nutritional factors may also be involved in the pathogenesis of neurological diseases (69). Oropharyngeal dysphagia, paralysis, immobility, abnormal motor function, impaired consciousness, perception deficits, cognitive dysfunction, and increased needs are the main factors associated with development of malnutrition in patients with neurological diseases (69).

DRM occurs in the setting of neurological disorders, frequently as a consequence of oropharyngeal dysphagia, immobilizing disability or dementia/cognitive dysfunction (26, 70, 71). DRM and sarcopenia are highly prevalent in almost every neurodegenerative disease or disorder with immobilizing disability, particularly in the presence of stroke and dementia (71). Malnutrition precedes the clinical manifestation of sarcopenia and increases its severity, and their comorbid existence leads to decreased mobility, physical limitation and fragility, deterioration in respiratory functions, and a 3-fold increase in falls (71). Besides, there is a 3.5-fold increase in the risk of death in sarcopenic elderly people, in addition to increased risk of major complication rates of all medical procedures with more frequent and longer hospitalizations (71). Therefore, prevention of sarcopenia is of crucial importance (71) Moreover, the prevalence of sarcopenia increases with the advanced clinical stage of the neurological disorder, adversely affecting the physical performance and QoL via an additive interaction with the underlying neurological deficit or comorbid conditions (i.e., age, diabetes, COPD, cirrhosis, cancer, CKD) (71). Malnutrition is highly prevalent in hospitalized patients with stroke and is an independent predictor of high mortality and poor functional outcomes (72–75). There is a considerable degree of loss in the global muscle mass in acute ischemic stroke patients over a two-week period (76).

Recently, acute ischemic stroke setting is considered an additional arena where muscle health and systemic inflammatory response closely interact with each other, and muscle mass appeared to be a novel factor related to the level of post-stroke stress response (77).

In fact, given the interaction between nutrition and neurological status, malnutrition and nutritional imbalances are considered both as the cause and consequence of certain neurological pathologies (78). Excessive or inadequate levels of some nutrients with a vital role in the proper functioning of the nervous system due to malnutrition, illness, or drug intake may cause or exacerbate certain neurological symptoms and disorders (78). Also, certain neurological conditions (i.e., stroke, dementia, Parkinson’s disease, and autism spectrum disorders) may lead to a higher susceptibility to nutritional deficiencies, gastrointestinal disorders and feeding difficulties (78).

Muscle loss and malnutrition are also highly prevalent features of critical illness, as mediated by the inflammatory pathways (6, 79). Patients in the intensive care unit (ICU) display marked nutritional challenges and are nutritionally compromised with malnutrition rates of 38–78%, which is independently associated with poor clinical outcomes (26, 80–82).

Once in the ICU, these patients experience a rapid and profound loss of lean body mass (can be as high as 2% per day), and an early and rapid muscle loss during the first week of ICU stay due to overall net catabolic tendency (83). Accordingly, critically ill patients can lose over 20% of their skeletal muscle during the first 10 days of ICU stay (83, 84). The inactivity, malnutrition, inflammation, and dysregulation of protein metabolism secondary to critical illness are considered the main contributors for this early and rapid skeletal muscle loss (83, 84). Myosteatosis (fatty infiltration of muscle tissue), considered an important marker of muscle composition, is associated with death regardless of muscle mass (6, 85). Accordingly, muscle loss, myosteatosis, and malnutrition concomitantly impact the survival and long-term recovery of critically ill patients, while muscle loss itself is also considered an independent determinant of increased mortality and decreased ventilator-free and ICU-free days (6, 86).

Overall, 25–67% of ICU patients experience intensive care-acquired weakness (ICU-AW), which usually starts during the first week of ICU stay, reaching a 15–20% incidence within the first 10 days (81, 85). Muscle loss plays a major role in ICU-AW which is associated with prolonged duration of mechanical ventilation, prolonged ICU and hospital stay, and increased ICU and hospital mortality (79, 87, 88).

Notably, while more patients are currently surviving the hospitalization, ICU survivors frequently experience significant post-ICU morbidities including muscle weakness and impairments in physical functioning (26, 87, 89). These can persist for years resulting in significantly increased healthcare-associated costs (26, 87, 89). One major factor contributing to the “post-ICU syndrome” is also the muscle loss, emphasizing that adequate nutrition support is an integral component in the treatment of critically ill patients (26, 89).

Since protein is one of the most effective anabolic stimuli to support muscle health, high protein intake is crucial to delay or reverse the muscle loss (33, 100). High protein supplementation via ONS or enteral tube feeding has been the most researched nutrition intervention to prevent skeletal muscle loss in both the hospital and community healthcare settings (26). There is growing evidence that use of high-protein ONS (HP-ONS; ≥20% of total calories as protein) can help maintain and rebuild muscle mass and strength in different clinical populations (22, 24, 26, 33, 98). In a meta-analysis 29 randomized-controlled trials (RCTs) with a total of 7,166 patients, trials using high-protein strategies in medical inpatients at nutritional risk had significant positive effects on mortality compared to trials with low-protein interventions (92). Therefore, dietary interventions consisting of HP-ONS during sarcopenia and illness-associated muscle wasting have been currently proposed as potential nutritional strategies to mitigate muscle loss and related outcomes (1, 6, 24, 91–95, 101).

While protein targets of at least 1.0 g/kg body weight have been recommended in the past, more recent and larger RCTs, such as the EFFORT trial performed in 2028 hospitalized polymorbid patients at malnutrition risk, support used a nutritional support with a higher daily protein target of 1.2–1.5 g/kg body weight (102, 103). The EFFORT trial demonstrated that an individualized high-protein nutritional intervention (10 grams more protein daily) effectively counteracted negative outcomes in hospitalized patients. This intervention increased caloric and protein intake, resulting in a significantly lower rate (23% vs. 27%) of composite unfavorable clinical outcomes (mortality, intensive care need, non-elective re-hospitalization, major complications, worsening functional status) by 30 days. Additionally, it significantly improved survival rates, with a 35% risk reduction in 30-day mortality compared to standard hospital food (103). Importantly, a secondary analysis of the EFFORT trial (n = 506) documented that individualized nutrition support significantly improved functional and QoL outcomes, and reduced mortality in cancer patients with increased nutritional risk (104).

A secondary analysis of EFFORT study in malnourished patients with aging-related vulnerability showed a > 50% reduction in the risk of 30-day mortality along with notable improvements in long-term mortality at 180 days, functional outcomes and QoL measures in patients receiving individualized nutritional support compared with those receiving routine hospital food (105).

Accordingly, based on the evidence regarding the benefits of protein intake in treating age-related decline in muscle mass, strength, and functional abilities, the ESPEN recently increased the protein recommendations to 1.0–1.2 g protein/kg body weight/day for healthy elderly and to 1.2–1.5 g protein/kg body weight/day for malnourished or at risk of malnutrition elderly with acute or chronic illnesses (20).

A recent RCT in older adults (aged ≥75 years) at risk of malnutrition, who were hospitalized for various conditions (including treatable cancer, pneumonia, fractures, and urinary tract infection), revealed that a protein intake of 1.5 g/kg/day compared to 1.0 g/kg/day was associated with a significant improvement in hand grip strength. There was also a tendency for improved skeletal muscle and activities of daily living (ADL) indices, as measured by the Barthel index and Lawton score. This emphasizes the potential effectiveness of high protein intake in ameliorating the loss of muscle strength in older hospitalized adults at risk of malnutrition (106).

More recently, β-hydroxy-β-methyl-butyrate (HMB), an active metabolite of the essential amino acid leucine, has attracted interest due to reported anabolic (a potent stimulator of protein synthesis) and anticatabolic (inhibitor of protein breakdown) effects on muscle metabolism (26, 33, 107, 108). Although HMB is found in certain foods (e.g., avocado, catfish, cauliflower, and grapefruit), achieving a therapeutic dose (3 g/day) is only possible through isolated supplements, either alone or in combination with amino acids such as arginine and glutamine (HMB/Arg/Gln), or HMB-enriched oral nutritional supplements (HMB-enriched ONS) (23, 24, 109).

A growing body of evidence suggests that high-protein, HMB-enriched ONS (HP-ONS + HMB) may slow or reverse muscle loss, aiding in the recovery of muscle mass, strength, and function in various clinical populations in both hospital and community settings. This includes older adults, individuals with sarcopenia, those experiencing hospitalization and bed rest, hypercatabolic diseases, cancer, sepsis, and endotoxemia (17, 22–24, 46, 88, 96, 99, 108, 110–113).

The NOURISH study was a multicenter RCT in 652 older adults (≥65 years) with malnutrition or malnutrition risk hospitalized for acute cardiopulmonary problems (congestive heart failure, acute myocardial infarction, pneumonia, or chronic obstructive pulmonary disease) (110). The trial showed that administration of a high-protein ONS containing HMB (HP-HMB; 2 times 20 g protein and 1.5 g calcium-HMB) improved nutritional status, body weight, and vitamin D levels (110). Moreover, it maintained muscle mass and reduced the risk of mortality by 50% (4.8% vs. 9.7%, p = 0.018; the number-needed-to-treat to prevent 1 death in 3 months was 20.3) through 90 days post-hospital discharge, as compared to standard nutritional care and placebo (110). The 90-day readmission rate, LOS and ADL remained similar between treatments (110).

A post-hoc analysis of the NOURISH trial examined the impact of a specialized ONS on QoL in hospitalized older adults with cardiopulmonary diseases. Patients who received the specialized ONS (HP-HMB) during hospitalization and for 90 days post-discharge experienced improved QoL compared to those who received a placebo. The improvements were particularly notable in the mental health (at days 60 and 90, p = 0.043 and p = 0.007, respectively), vitality (at day 90, p = 0.049), social functioning (at day 90, p = 0.023) and general health (at hospital discharge and beyond: day 0 [p = 0.041], day 30 [p = 0.044], day 60 [p = 0.015] and day 90 [p = 0.005]) domains of SF-36 (114).

The SHIELD study was a RCT investigating the effectiveness of daily consumption of ONS containing HMB and Vit D for 6 months in 811 community-dwelling older adults aged ≥65 years at risk of malnutrition (111). The nutritional intervention was reported to s enable a higher proportion of patients to achieve the 180-day primary composite outcome (survival without hospital re-admission and with at least 5% weight gain) compared to placebo (33.4% vs. 8.7%, p < 0.001), largely driven by body weight component (36.2% vs. 9.4%, p < 0.001) (111). In addition, it was associated with a significantly improved nutritional (higher energy, protein, fat, and carbohydrate intakes, improved MUST score and Vit D status) and functional (greater leg strength at day 90 and greater hand grip strength for females at day 180) outcomes (111). Within the low appendicular skeletal muscle mass index (ASMI) subgroup, the ONS-HMB intervention group had significantly greater calf circumference at days 90 and 180 compared to placebo (111).

Other studies in community-dwelling older adults with sarcopenia also revealed the association of high-protein ONS with HMB (HP-HMB) with the amelioration of the intramuscular adiposity, and significantly increased Vit D serum levels, body weight and BMI, besides the improvements in muscle mass, muscle strength, and physical performance (94, 115). A metanalysis of 15 RCTs involving 2,137 patients with a variety of clinical conditions characterized by loss of skeletal muscle mass and weakness including aging and critical illness revealed some evidence to support a positive effect of HMB on increasing the skeletal muscle mass and strong evidence to support its effect on improving muscle strength (23).

Incremental biomarker changes (i.e., immunoglobulins, myoglobin, total protein, vitamin E and magnesium) and improved leg muscle strength and quality in response to ONS containing HMB (vs. ONS without HMB) among malnourished and sarcopenic adults are also considered to emphasize positive effect of HMB on the skeletal muscle health (12, 116).

The association of HMB supplementation with enhanced strength and muscle quality in elderly men and women seems to support its potential as a nutritional intervention to prevent sarcopenia and its associated functional decline (117). Nonetheless, although emerging number of studies are available with HMB in the elderly, there remains a controversy particularly in terms of improvements in lower body strength and the maintained effectiveness of a longer period of HMB supplementation on muscle strength or functionality (117–119). Obviously, further high-quality studies are needed to understand the exact role of HMB on muscle, strength and functionality in a variety of clinical conditions and in elderly, and thus to enable interpretation and translation into clinical practice (23, 117).

Vitamin D supports bone, muscle, and immune health, and a link between vitamin D deficiency and muscle dysfunction has been demonstrated in addition to evidence of a longitudinal association between low vitamin D status and sarcopenia (6, 120, 121). The age-dependent decline in vitamin D levels can be reversed by dietary intake of vitamin D which has been linked to improved muscle health and decreased risk of falls and fractures in the elderly (26, 111, 122).

Although, a high prevalence of vitamin D deficiency is indicated in both the general population and at-risk groups, it is often more severe in at-risk groups including patients with cancer, central nervous system diseases, musculoskeletal or systemic connective tissue diseases, chronic kidney disease, endocrine and metabolic conditions, malabsorption syndromes, obesity and corticosteroid use (123).

However, the effects of vitamin D supplementation on muscle health remains controversial with diverse findings of studies in different patient populations, such as both vitamin D deficient and community populations, as well as those with or without sarcopenia (26, 124). The mechanisms whereby vitamin D reduces the risk of cancer incidence (regulation of cellular differentiation, proliferation, and apoptosis) and mortality (reduced blood supply to tumors and reduced metastasis into surrounding tissues) share overlapping characteristics, while RCTs have only confirmed the role of vitamin D supplementation in reducing the risk of cancer mortality rates (123).

The studies that specifically investigated the effect of oral vitamin D supplementation for the prevention of sarcopenia and frailty in older patients also yielded heterogeneous results (41).

A number of epidemiological studies have suggested the potential role of vitamin D in order to maintain or improve muscle strength and function, physical performance and preserve independence in older people (125, 126) Older people with vitamin D deficiency might be at risk of sarcopenia, a geriatric syndrome characterized by the progressive loss of skeletal muscle mass and strength often complicated by adverse events, such as falls, disability hospitalization and death (41). The prevalence of sarcopenia was reported to be up to 29% in older persons in the community healthcare setting. Sarcopenia diagnosis is confirmed by the presence of low muscle mass plus low muscle strength or low physical performance. Cellular changes in sarcopenic muscle are characterized by size and number declines in type II muscle fiber together with intramuscular and intermuscular fat infiltration (127). Vitamin D affects the diameter and the number of type II (type IIA in particular) muscle cells which are responsible for inducing fast muscle contraction velocity and anaerobic maximal intensity short-burst activities (i.e., sprinting, jumping, change of direction, acceleration and deceleration) (41). Hence, vitamin D is considered likely to maintain or improve muscle strength and function, physical performance and to preserve independence in older people, since type II fibers are important, not only for young athletes, but also for the elderly in relation to their ability to reduce the risk of falling (41).

Daily oral supplementation of calcium and vitamin D in community-dwelling older (≥ 70 years) adults with vitamin D serum levels < 78 nmoL/L revealed an improvement in muscle strength and physical performance as well as reduction in fall rates after 12 months compared to placebo (128). Similarly, vitamin D supplementation (20 μg per day) for a 6-month period in post-menopausal women with a diagnosis of osteoporosis and/or vitamin D deficiency (<30 ng/mL) was significantly correlated to an increase of muscle strength (hand grip strength and knee extension strength) and physical performance with a parallel reduction in the risk of falls (129).

However, some studies in cohorts of community-dwelling older adults (≥ 75 years) did not demonstrate any relations of serum vitamin D levels with muscle strength and physical performance (130, 131), while findings from systematic reviews and a meta-analysis suggest beneficial effects of vitamin D supplementation on muscle strength and physical performance, but not on muscle mass in older adults (132, 133). Accordingly, while there are some promising data regarding the role of vitamin D and sarcopenia, it is unclear whether the dose, frequency of dose, or length of treatment impacts the efficacy of vitamin D on improving muscle mass or function (123, 134).

Also, SHIELD study showed significant improvements in vitamin D status in the intervention (ONS containing HMB and Vit D) group, as compared to worsening vitamin D status in the placebo group, emphasizing vitamin D deficiency in older people can be effectively addressed by ONS interventions, which is expected to help avert the adverse outcomes such as increased risk of functional impairment, frailty, falls, and mortality (111, 135). In another RCT, the potential of HMB and vitamin D3 supplementation to enhance muscle strength and physical functionality was reported in older adults, even in those not engaged in an exercise training program (136).

Implementation of individualized nutritional counseling and intervention, as endorsed by nutrition care guidelines, is critical in achieving nutritional intake goals in older adults and clinical populations (6, 20, 137). Nutrition interventions are most beneficial when they are proactive, initiated early, and continued through recovery, preferably as part of multimodal interventions that include structured exercise program (6). It should be considered that polymorbid medical inpatients are commonly malnourished and their nutritional status often does not improve but instead deteriorates during the hospital stay, increasing the risk for functional decline, loss of independence and greater morbidity post-discharge (102).

Given the significant contribution of poor nutritional status to the recently described ‘post-hospital syndrome,’ which refers to a 30-day period of generalized transient vulnerability following hospital discharge, ensuring adequate nutritional intake during the transition from hospital to home is crucial. This is particularly important for malnourished patients to reduce morbidity and the rate of unplanned readmissions during the post-discharge recovery period (102, 138). Hence, provision of individualized nutritional support, basically via targeted high protein ONS interventions, seems to be critical beyond the hospitalization period, given the evidence on benefits of continued nutritional intervention on improved body weight, protein intake and nutritional status (102, 139, 140).

An adequate supply of protein is necessary for maintenance or gain of muscle tissue, and any intervention without an adequate quantity and quality of protein utilization may fail to reverse muscle loss in cancer (55). Importantly, when cancer is associated with muscle loss, inadequate protein intake limits the effectiveness of other nutritional interventions (141). Nutrition guidelines in cancer patients recommend the protein intake of >1 g/kg/day, or, if possible, up to 1.5 g/kg/day or about 20% of total energy intake to prevent muscle loss and optimize motor function (19, 68, 137). However, it is still unknown whether 1.5 g/kg/day is sufficient enough to positively modulate body composition and prevent muscle loss in cancer patients (55).

In a systematic review of 8 studies in 554 patients with various cancer types (head and neck, lung and esophageal cancer) and a high prevalence of sarcopenia during treatment, patients with mean protein intake below 1.2 g/kg presented muscle wasting, while those with mean intake above 1.4 g/kg have maintained muscle during treatment (141). Hence, protein intakes below 1.2 g/kg, even when within the recommendations, have been associated with muscle wasting during treatment (141). Moreover, many cancer patients fail to meet this standard or even the protein intake levels recommended for healthy individuals (0.8 g/kg) (55). The reported intakes range widely from 0.2 to 2.7 g/kg, possibly due to variability of symptoms affecting nutrition (i.e., anorexia, taste/smell alterations, dysphagia, nausea, vomiting) prevalent in some cancer types (55, 142, 143).

A combination therapy of HMB, arginine, and glutamine was reported to be associated with an increase in lean body mass after 4 weeks in patients with advanced solid tumors, whereas it had no apparent benefit on lean body mass in a large sample of patients with advanced lung cancer and other cancers after 8 weeks (144–146). Hence, in addition to the fact that the optimal amounts of protein for preventing or treating muscle loss in cancer are undefined, the definition of ‘adequate protein’ may also differ with respect to cancer types (10, 55).

Moreover, cancer patients may deliberately alter their diet (i.e., avoid sugar or red meat) within the context of making lifestyle changes following the diagnosis (55, 143). This seems particularly concerning given that increased muscle anabolism is not unreasonable in cancer and these patients have anabolic potential despite their older age, inactivity, systemic inflammation, or insulin resistance (55, 143, 147, 148).

Also, protein intake is adjusted based on body weight, instead of body composition and lean mass, in the current guidelines, despite the large variability of body composition in populations (55). Hence, adjusting protein intake based on muscle health (e.g., mass) status may be a targeted approach to optimizing individual protein requirements (55).

Muscle mass loss may decrease the tolerance to drug and surgical treatments and directly compromise the efficacy and tolerability of anticancer treatments by preventing the delivery of an optimal (dose-intense) regimen (59, 64, 65, 109, 149, 150). Provision of early and prospective nutritional intervention may reduce the possibility of therapy-threatening adverse events and postoperative complications, optimizing the likelihood of treatment success, a better QoL and long-term survival (10, 25, 55, 59, 104). Accordingly, initiation of early support for an adequate intake before anti-cancer treatment is critical in cancer patients (10, 25, 55).

ESPEN recommends nutritional status screening to be performed regularly, beginning at the time of initial cancer diagnosis besides a worldwide consensus on the provision of nutritional support to malnourished or at-risk cancer patients at the time of initial diagnosis, rather than as a routine support adjunct to chemotherapy or irradiation (10, 19, 55, 151). However, weight loss and muscle loss sometimes can be considered as an inevitable consequence of progressive tumor growth and thus proactive nutritional intervention can be delayed (10). Hence, there is a need for oncology practitioners to have a better awareness of advances in the nutritional aspects of cancer care and the great potential of early nutritional intervention to reverse the muscle loss and to improve cancer therapy outcomes, morbidities, and, ultimately, mortality (10, 19, 25, 55, 152).

HMB has been recognized in ESPEN guidelines as an important functional ingredient to maintain muscle mass in cancer patients, as suggested to act on key regulatory events driving CRM leading to improved muscle growth/preservation (10, 19). In patients with cancer, a number of high-quality studies also support a beneficial effect of HMB supplementation on improving muscle mass and function, decreasing hospitalization, and improving survival (6, 86, 109, 141, 143, 153). Besides, HMB supplementation is suggested to have beneficial effects not only on muscle mass but also on tumor response, cancer therapy-related toxicity, surgical complications and hospitalization outcomes in patients with cancer (55, 109, 153–155).

One of the distinctive features of sarcopenia in elderly subjects is the anabolic resistance of aged muscle leading to a decreased ability to increase muscle protein synthesis in response to anabolic signals (i.e., nutrient intake and resistance exercise) (17, 101, 156). The anabolic resistance is considered likely to develop due to oxidative stress and low-grade inflammation and to be primarily regulated by the mechanistic target of the rapamycin (mTOR) signaling pathway (17, 101, 156).

Hence, older individuals need a greater quantity of high-quality protein intake to maintain muscle health and function, and HMB as the metabolite of leucine (a master dietary regulator of muscle protein turnover) is considered to offer the additional benefit in terms of maintaining muscle mass and function (101). Besides, HMB stimulates muscle protein synthesis by activating the mTOR system and an age-related decline in the endogenous plasma HMB levels in older adults is negatively correlated with a lean mass and muscle grip strength, further favoring HMB supplementation in older adults with or at risk of muscle loss (26, 109, 157, 158). In a meta-analysis of seven RCTs, HMB supplementation was reported to prevent the loss of lean body mass in older adults without causing a significant increase in fat mass (46).

The muscle wasting, due to accelerated protein breakdown and blunted protein synthesis (60% less in ICU patients vs. healthy subjects), starts upon admission to ICU and deteriorates life quality and increases mortality (86, 159). However, critically ill patients often receive less than the minimum recommended dose of 1.2/g/kg of protein, leading to worse clinical outcomes (84, 89).

Although switching from the historical hourly rate-based feeding (RBF) to the volume-based feeding (VBF) protocol, enabled a 20% increase in the amount of protein and calories received by the ICU patient, still not all patients receive the optimal protein intake (> 80%) of the aimed targe (89, 160). Therefore, enteral protein supplementation is considered a valuable strategy to increase protein intake in critically ill patients, which enables reaching 2 g/kg/day of protein intake per day (89, 160, 161). A recent meta-analysis of five small studies reported that higher doses of protein (with similar energy delivery) reduced muscle loss in critically ill patients (162), while an association between higher protein intake and lower mortality was also reported in a heterogeneous ICU population (163, 164).

However, optimal nutritional support for critically ill patients, particularly the effectiveness and safety of the early or overall high-dose protein application, remains a topic of debate with controversial results of the related studies (89, 164–166).

In addition, the studies specifically reporting the early protein intake revealed the lower mortality rates with a protein intake of >0.7 g/kg/day during the first 3 days of ICU admission (167) and with a day 4 protein intake of ≥1.2 g/kg/day (168), as well as the benefit of high protein intake only in certain subgroups, such as patient with normal kidney function (169), patients with a high NUTRIC score (170) and those with low skeletal muscle area (SMA) and low skeletal muscle density (SMD) (164).

The seemingly controversial findings suggest that “one size does not fit all” in the setting of ICU and optimal nutritional strategies may differ between individual patients (159, 164). This highlights a major drawback in the current nutritional care of ICU patients; that is, the impossibility of identifying specific patients who benefit from early high protein intake or to predict these patients will be high-risk patients for needing prolonged mechanical ventilation and becoming long-term stayers (159, 164).

Nonetheless, maintaining lean body mass and recovering muscle loss and function after critical illness cannot be achieved without optimal protein and energy delivery; a significant challenge is the insufficient protein content of most commercial enteral nutrition feeds, which hampers the delivery of adequate protein (159). HMB supplementation seems to be a valuable alternative in this regard, enabling improved amino acid metabolism and reduced net protein breakdown, despite it may not reveal an early improvement in muscle volume and strength (88, 171–174). In a RCT the impact of HMB (3 g/day) vs. placebo (maltodextrin) on muscle loss and protein metabolism was investigated in critically ill patients from day 4 in ICU (88). HMB treatment did not significantly reduce muscle wasting over 10 days of observation (primary endpoint), but resulted in significantly improved amino acid metabolism, reduced net protein breakdown, a higher phase angle (reflecting cell viability) and better global health scores on SF-36 (88). The loss of total SMA was 11% between days 4 and 15, similarly between the groups, confirming the important loss of muscle volume and mass in critically ill patients during the first 2 weeks of their ICU stay (83, 88, 159). Ten days later, HMB group had greater reduction in the net protein breakdown and turnover of several amino acids, reflecting the impact of HMB on metabolism (88).

Post-ICU syndrome of catabolic/hypermetabolic state can persist for up to 2 years following discharge and markedly impede the recovery in lean body mass and function (26, 87, 89). Hence, the improved ICU survival is not enough without addressing the post-ICU syndrome and optimizing post-ICU QoL a priority from the moment of ICU admission, which may require not only optimal nutrition, but perhaps pharmacologic intervention to overcome (26, 87, 89, 159).

There is convincing scientific evidence that the use of ONS is advantageous in patients with disabling neurologic diseases such as stroke, dementia, amyotrophic lateral sclerosis, multiple sclerosis or Parkinson’s disease (71). The use of a high-energy high-protein ONS is particularly valuable in case of increased risk of malnutrition (older patients, sarcopenia, infection, trauma or hospitalization) (71).

Using a high-energy high-protein ONS (2 kcaL/mL, 9 g protein/100 mL) vs. a standard energy and protein ONS (1 kcaL/mL, 4 g protein/100 mL) was associated with better functional independence measure motor score and 6-min walking test in stroke patients (175).

Apart from the benefits to muscle health, the experimental studies indicated the likelihood of other beneficial effects of HMB in neurology patients, such as improvement in the working memory and cognitive flexibility (via ameliorating the effects of aging in the dendritic tree of the pyramidal neurons in the medial prefrontal cortex) and spatial reference learning and memory (via stimulating hippocampal plasticity) (176–179). In the basis of early promising evidence in animal studies regarding its positive influences on cognition, spatial learning and memory, HMB supplement seems to have a potential to be beneficial for Alzheimer disease and other cognitive disorders (176, 177). This may also offer insights regarding the improved mental health/cognition QoL domain observed in malnourished older adults after receiving the specialized nutritional intervention with HP-ONS containing HMB (114).

The pivotal trials including the EFFORT trial in hospitalized polymorbid patients at malnutrition risk (103), the NOURISH trials in elderly hospitalized malnourished patients with cardiopulmonary diseases (110, 114) and the SHIELD study in community-dwelling older adults at risk of malnutrition (111) demonstrated evidence on significantly improved nutritional and functional outcomes and reduced adverse health outcomes with use of the high-protein ONS, the high-protein ONS containing HMB and the high-protein ONS containing HMB plus vitamin D, respectively. Also, there is an evolving literature pointing to the benefits of supplementing with HP-ONS containing HMB to address both nutritional status and muscle-related problems in older adults and in chronic or catabolizing conditions (6, 17, 22–24, 46, 88, 96, 99, 108, 109, 112, 113, 144, 146, 157, 171, 172, 174).

Besides the high-quality protein and HMB, the HP-ONS plus HMB formula may also contain vitamin D as another key ingredient with potentially positive effects on muscle health, especially when combined with protein (12, 24, 116, 136). Notably, a 24-week intervention compared two high quality nutritional supplements including control ONS (CONS; 14 g protein; 147 IU vitamin D3) and experimental ONS (EONS, 20 g protein; 499 IU vitamin D3; 1.5 g HMB) in malnourished older adults with sarcopenia (116). Both ONS were found to be capable of eliciting clinical benefits in simple field measurements (grip strength and gait speed) of sarcopenia (116). However, the EONS resulted in significant improvements in leg strength and muscle quality compared to CONS, indicating additional benefits of receiving higher protein, HMB and higher vitamin D in patients with mild-to-moderate sarcopenia (116).

Hence, HP-ONS enriched with “HMB and vitamin D” seems to be a promising nutritional intervention to improve recovery of muscle mass and function in patients at risk of malnutrition and muscle loss (24). Accordingly, a composite individualized nutritional intervention using a high protein-ONS (well-established effectiveness) containing HMB and vitamin D (as potentially beneficial contributors) may be a convenient and compliant nutritional strategy for the attenuation of both malnutrition and sarcopenia in geriatric population, cancer patients, critically ill patients and patients with neurological disorders, offering an up-to-date standard in clinical nutrition with beneficial effects beyond providing nutritional requirements (Figure 2).