The World Health Organization declared the years between 2020 and 2030 as the Decade of Healthy Ageing. By the end of 2020, the number of people aged over 60 years old will surpass the number of children under 5 years old. Elderly people will globally increase from 1 billion in 2019 to 1.4 billion in 2030 (about 34% increase rate). By 2050, the proportion of people aged 60 years among the population is expected to be one in five [1
]. Considering this demographic transition, the preservation of wellbeing is a crucial issue of ‘adding years to life’ [2
Since the beginning of 2000, ‘healthy ageing’ has been defined as “a lifelong process optimising opportunities for improving and preserving health and physical, social and mental wellness, independence, quality of life and enhancing successful life-course transitions” [3
An emerging condition affecting healthy aging is sarcopenia. In 2009, the International Sarcopenia Consensus Conference Working Group defined sarcopenia as “an age-related loss of skeletal muscle mass, with or without an increase in fat mass” [4
]. More recently, sarcopenia has been defined by a European Consensus as “a muscle disease (muscle failure) rooted in adverse muscle changes that accrue across a lifetime” [5
]. According to this new consensus, the key characteristics of sarcopenia are low muscle strength and reduced physical performance. Optimal care is crucial in the prevention and treatment of sarcopenia, because this condition is related to increased risk of fractures, impaired ability to perform activities of daily living, cardiovascular and respiratory diseases, cognitive impairment, loss of independence, and eventually death.
Scientific evidence suggests a central role of protein intake in preserving lean mass and preventing sarcopenia, but the definition of the best quantity and quality of protein sources is still an open issue [6
Ageing is a plastic process, and it may affect nutritional requirements [9
]. For example, basic science studies demonstrated that protein metabolism in the elderly is characterized by a high splanchnic extraction and a declining anabolic response to ingested proteins [11
]. Lifestyle factors, such as high-quality diet, physical activity, little or no alcohol consumption and smoking avoidance, can influence the quality of ageing, improving wellbeing throughout the life span [9
]. Taking into account these findings, the European Union Geriatric Medicine Society (EUGMS), in cooperation with other scientific organizations, appointed an international study group to review dietary protein needs with aging (PROT-AGE Study Group) [11
]. According to PROT-AGE position paper, recommendations for dietary protein intake in healthy older adults are as follows:
average protein intake for older people should range from 1.0 to 1.2 g/kg of body weight per day (while in young adults, the recommended intake is about 0.7–0.8 g/kg/day) [12
it must be taken into account that the feeding-associated anabolic threshold for dietary protein is higher in the elderly than in younger subjects, with the amount of protein required to reach it from a variety of foods being in the order of 25–30 g of protein per meal;
dietary recommendations for protein intake in the elderly should consider, beyond quantity, also quality, protein source and timing of intake;
best protein sources are rich in leucine;
oral supplementation should be considered when dietary protein intake does not reach recommended goals [11
Sources of animal proteins, such as meat, fish and poultry, are excellent for their essential amino-acid content, but their consumption may be impaired in the elderly, because of poor dentition, reduced appetite, or even anorexia, solid dysphagia, taste alteration, cost, and, when mobility is reduced, barriers in shopping and cooking [13
]. Legumes and pulses are even good protein sources, but may enhance gastrointestinal functional disorders, such as slow gastric emptying, bloating, abdominal distention and diarrhea [15
]. Dairy foods are rich in leucine, and they are available in many different forms, even soft and enriched with probiotics, but the weekly amount is usually restricted to 2–3 servings (excluding milk and yogurt), due to their fat content [16
There is a large variety of protein oral supplements, mainly based on soy or cow-milk sources [17
]. Among the latter, whey proteins (WP), a by-product of cheese making, should be regarded as one of the best sources for oral protein supplementation, for their high leucine content, fast digestibility and amino-acid availability (demonstrated in both young and old subjects) [18
With regard to these considerations, we performed a systematic literature review, to investigate the role of cow-milk proteins (hence forward generally called “milk proteins”) supplementation in the elderly, exploring its effects on several health outcomes particularly relevant to older people (e.g., muscle and bone mass preservation, cognitive performance, cardiovascular risk factors). Our aim was to map the scientific evidence currently available, in order to evaluate which outcomes have already been widely targeted, and to identify those which still have to be studied in depth with new trials. We also aimed to assess the presence of knowledge gaps yet to be addressed. We expected to include studies with a high level of heterogeneity, so we considered it to be more appropriate to present the results of the systematic literature review as a narrative synthesis.
2. Materials and Methods
The systematic literature review started in April 2019, and it has been performed according to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines [20
]. The review has been registered on PROSPERO—international prospective register of systematic reviews (CRD 42020137114).
2.1. Literature Search Strategy
Five electronic databases were systematically searched: PubMed, Web of Science, Embase, Cochrane Library, ClinicalTrials.gov. The strings used for the search in these databases were based on Medical Subject Heading (MeSH) terms, text keywords and Boolean operators, as follows:
PubMed: “Milk Proteins/administration and dosage” [MeSH] OR “Milk Proteins/adverse effects” [MeSH] OR “Milk Proteins/metabolism” [MeSH] OR “Milk Proteins/organization and administration” [MeSH] OR “Milk Proteins/pharmacokinetics” [MeSH] OR “Milk Proteins/pharmacology” [MeSH] OR “Milk Proteins/supply and distribution” [MeSH] OR “Milk Proteins/therapeutic use” [MeSH] OR “Milk Proteins/therapy” [MeSH] OR “Milk Proteins/toxicity” [MeSH]) AND “aged” [MeSH].
Web of Science: (“milk proteins” OR “whey proteins” OR “caseins”) AND (“older” OR “elderly”) in the categories Nutrition Dietetics, Endocrinology Metabolism, Medicine Research Experimental, Geriatrics Gerontology, Toxicology, Chemistry Medicinal, Gastroenterology Hepatology, Medicine General Internal, Pathology, Integrative Complementary Medicine, Gerontology, Rehabilitation.
Embase: (“milk proteins” OR “whey proteins” OR “caseins”) AND (“aged” OR “old” OR “elderly”) in titles, abstracts or keywords.
Cochrane Library: (“milk proteins” OR “whey proteins” OR “caseins”) AND (“aged” OR “old” OR “elderly”) in title, abstract or keywords.
ClinicalTrial.gov was checked for ongoing or unpublished trials: “ageing” as condition or disease, “milk proteins” as other terms.
A search in Google Scholar was also performed using the terms “milk proteins” AND “elderly”.
The whole literature search was limited to interventions on human beings, and the language restricted to English, whereas no restriction on publication year was applied.
The reference lists of the eligible studies were manually searched for additional articles.
2.2. Study Selection
Two investigators (B.Z. and M.Z.) independently selected the studies to be included in the review, on the basis of pre-defined eligibility criteria and screened titles and abstracts. One author (BZ) checked full texts for final inclusion. Any disagreement was resolved by discussion and re-examination of the studies by two investigators (B.Z. and M.Z.).
To be included in the review, studies had to consider: (i) subjects aged 60 years or more, or (ii) menopausal/postmenopausal women. We excluded studies whose target groups were children, adolescent, young or adults, or if an aged-based analysis in subjects over 60 years was not provided. In all included studies, at least one intervention arm had to include supplementation with cow-milk proteins, caseins, whey proteins or bioactive cow-milk peptides. We included randomized clinical trials (RCTs), observational, cross-sectional, cohort and case-control studies. We excluded opinion letters, editorials, case reports, conference abstracts, and comments. We also excluded systematic reviews and meta-analyses, after having manually searched their references lists to be sure that all relevant studies were already included in our review.
Studies are presented as a narrative synthesis, organized in sub-sections according to the different health outcomes. We reported the main features of each study, including information about participants, intervention and principal endpoints.
To our knowledge, this is the first systematic literature review targeting the role of milk protein supplementation in the elderly. The large majority of the studies included in our review showed a beneficial effect of milk protein supplementation, whey proteins in particular, in promoting improved health outcomes in a wide range of body systems. The variety of outcomes reflects the multidimensionality of diet-based support therapies. This review clearly reveals the lack of long-term studies and the need for further research on the persistency over time of the beneficial effects of milk proteins supplementation, as well as on the late onset of possible side effects.
As stated in the guidelines on clinical nutrition and hydration in geriatrics by the European Society of Clinical Nutrition and Metabolism (ESPEN), nutrition is a key factor in preserving health and wellbeing in old people [143
]. Dairy products provide not only proteins, but also a substantial amount of micronutrients (vitamins and minerals) relevant for healthy ageing, and according to some authors, reference national food patterns should consider their unique nutritional properties, especially for frail elderly people [144
]. Several studies included in this review were concordant in identifying WP as good nutritional sources in ageing population, especially because they are fast digested and well absorbed, rich in essential amino-acid and in leucine, and able to stimulate muscular protein synthesis without suppressing overall energy intake or increasing fat mass. These characteristics are very relevant to older people, taking into account that muscle loss (in mass and in strength), anorexia and sarcopenia, with and without obesity, are frequent among this population group.
The main finding of this review is the evidence of the role of milk protein supplementation in the maintenance of skeletal muscle mass in ageing. Studies carried on up to 24 weeks showed that milk protein supplementation increased serum level of amino acids and leucine during the post-prandial period, resulting in leucine uptake by muscle cells, myofibrillary protein and mitochondria protein synthesis in both resting and active muscles. The increased MPS was demonstrated in the elderly, with and without adequate dietary protein intake. Most studies demonstrated the superiority of WP (fast proteins) to casein (slow proteins), soy or wheat proteins. It should be noted that the only long-period study (two years) included in this review, about this research area, did not show impact on muscle mass of WP supplementation in well-fed postmenopausal women [64
]. Further long-term studies are mandatory, because there are still concerns about excessive protein load and related negative effects on kidney and ageing process [145
Strictly linked to muscle loss, the role of milk protein in sarcopenia, “one of the most meaningful geriatric syndromes” [146
], was addressed by several studies included in this review. There is consensus on three fundamental factors in the prevention of sarcopenia: exercise (‘use it or lose it!
’), quantity of protein in the diet (20–30 g of proteins per main meal) and quality of proteins (preferring high leucine content, 4 g per meal) [147
]. The ideal moment of protein intake could be after exercise, since physical exercise boosts blood circulation, which increases the absorption of leucine. Protein supplementation in patients with sarcopenia is strongly recommended in the absence of other medical contraindications, especially when reaching protein needs through diet modifications alone are unsuccessful [6
]. There is an urgent need of evidence-based strategies aimed to improve recovery after hospital discharge in older adults. Exercise, probably the best way to recover muscle mass, is not always applicable, so efforts towards finding efficient nutritional strategies are expected. Preliminary findings [74
] reported that 24 g of WP supplementation during a daily rehabilitation program have an impact in promoting better health outcomes. Future studies designed to incorporate longer-term intervention, or post-hospitalization lifestyle modifications, are warranted.
Most studies included in this review focused on the effects of milk protein supplementation on bone metabolism are gender specific, enrolling mainly postmenopausal women. In intervention studies, milk proteins have proven to be superior to soy proteins in reducing bone resorption. Promising results indicate that the increase in serum IGF-1 levels induced by milk protein supplements was accelerated, with a significant difference, by zinc addition [148
The only long-term trial investigating the effect on blood pressure of two-year daily supplementation of a WP-based beverage among older women did not provide evidence of a hypotensive property of dairy proteins [100
], as suggested by short term RCTs.
The protective role of milk protein supplementation on serum markers of inflammation is still under investigation: the RCTs included in this review are not concordant. According to a study by Ticinesi and colleagues, further large studies assessing the anti-inflammatory effect of combined dietary supplements, including n-3 PUFA, vitamin D and WP, are needed [149
Milk protein supplementation for old COPD patients may have multiple positive therapeutic outcomes, thanks to their role in enhancing anabolic response [117
] and attenuating perceived exertion during exercise [110
]. Better results may be obtained, combining nutritional intervention with supervised exercise training, as part of a formal pulmonary rehabilitation program [150
Results of milk protein supplementation to prevent or ameliorate ARCD and dementia are still contradictory. Limited evidence showed some improvements in reaction time [122
], but no significant effects have been recorded on other cognitive functions. These results are probably due to the wide spectrum of neurocognitive manifestations with different underlying physiopathology mechanisms, which makes it difficult to standardize intervention protocols. As stated in a systematic review published in 2011, several research projects were involved in finding effective dietary interventions, which aimed to prevent or ameliorate ARCD [151
]. The main conclusion of the review is that low-fat dairy products, together with an adequate diet, may play a beneficial role in neurocognitive function during aging.
Milk protein supplementation is a promising nutritional intervention to stimulate immune response [136
]. Further studies are advocated, to investigate its role in counteracting immune-senescence, in reducing inflamm-aging and in stimulating response to infections and vaccination. The role of fermented dairy products, with and without milk protein supplementation, could represent an interesting starting point for further investigation, given the high compliance reported in this type of intervention [132
One of the major strengths of this review is the wide overview on several health topics related to ageing. A narrative synthesis of 103 articles gave the opportunity to (i) discuss the evidence on key research areas as well as on poorly investigated ones, (ii) map different target population, mainly healthy subjects, but also frail, sarcopenic, hospitalized and chronically ill patients, (iii) include gender medicine studies, and (iv) underline some knowledge gap.
Other key strengths of our work are the robust methodology adopted according to PRISMA criteria, the approved registration on PROSPERO, the extensive research through five electronic databases, including Clinicaltrials.gov to overcome publication bias, and a further search in Google Scholar. Moreover, two independent investigators (BZ and MZ) screened titles and abstracts to select included studies.
We acknowledge some limitations. We did not provide any meta-analysis, the heterogeneity of the included studies was explored descriptively. We did not conduct an a priori quality assessment of the studies, because we preferred including all studies selected according to the pre-defined objective criteria, without introducing any subjective judgements.