The role of zinc on nutritional status, sarcopenia, and frailty in older adults: a scoping review

Abstract Background Zinc (Zn) deficiency, malnutrition, sarcopenia, and frailty are prevalent among older adults and are prominent factors contributing to disability and mortality. Objective This scoping review was conducted to aid understanding of the extent and types of research addressing the role of Zn in nutritional status, sarcopenia, and frailty, among older individuals. Method A systematic search was performed in August 2022 of 3 electronic databases (PubMed, Web of Science, and ProQuest) using predefined search terms. The review was conducted referring to the Arksey and O’Malley framework and PRISMA-ScR. Results The search retrieved 16 018 records, and a total of 49 studies were included in this review after the screening. Of those, 30 were based on dietary Zn intake, 18 on tissue Zn levels, and 1 on both. Most studies were based on cross-sectional data from community-dwelling older adults. Studies addressing the associations between Zn status and individual anthropometric and sarcopenia-related variables reported inconsistent results. However, most studies reported inverse associations between malnutrition, frailty, and Zn status. Conclusion There was more consistent evidence of the relationship of Zn status with malnutrition, sarcopenia, and frailty rather than with individual nutritional parameters. Validated screening and assessment tools and criteria and prospective studies are required to elucidate the relationship of Zn with sarcopenia and frailty in the older population.


INTRODUCTION
With the accelerated pace of population aging globally, sarcopenia and frailty have become leading health problems among older adults.The World Health Organization (WHO) defines the concept of healthy aging as the "development and maintenance of the functional ability to enable well-being in older age." 1 Both sarcopenia and frailty are characterized by loss of muscle mass (MM) and function, making individuals susceptible to functional disability 2 and reducing the opportunity to experience healthy aging.
Increasing age is associated with changes in body composition, such as an increase in fat mass and abdominal fat accumulation and a decrease in fat-free mass.Sarcopenia is a muscle disorder commonly found in the geriatric population and characterized by low MM, low muscle strength, and/or decreased physical function. 3Frailty is a common geriatric syndrome caused by the multisystemic reduction of physiological capacities, which increases vulnerability to stress.Nutritional frailty refers to a sudden significant weight loss together with loss of MM and strength that makes older adults susceptible to disability. 4 The etiology of frailty is multifaceted and includes nutritional problems such as malnutrition and obesity.Recent studies have revealed the simultaneous presence of frailty and obesity among increasing numbers of older adults. 5he nutrient intake and nutritional status of older people are affected by several factors associated with increased age.First, age-associated physiologic changes, such as the reduced capacity to absorb and use nutrients, put older adults at risk of macro and micronutrient deficiencies.Second, older adults are required to consume micronutrients in greater densities due to lower energy requirements.Third, many older adults are suffering from chronic diseases that may be associated with their diet, making provision of optimal nutrition and maintaining adequate stores of essential vitamins and minerals problematic.Last, alterations in appetite, taste, and swallowing, resulting from the intrinsic changes associated with the aging process, the disease itself, and/or treatments a person is receiving, can affect the eating habits of elderly individuals. 6,7The decrease in appetite and/or food intake with aging, referred to as "anorexia of aging," increases the risk of protein-energy malnutrition, sarcopenia, and frailty in older people. 8inc (Zn) is an important nutrient that influences the nutritional intake and nutritional status of older people because it affects taste and appetite.Older adults are susceptible to Zn deficiency due to many factors, including lower consumption of Zn-rich foods, which can be caused by the decline in taste acuity, poor dentition, inadequate mastication of food; and also intake of foods that reduce the bioavailability of Zn, or the presence of non-communicable diseases. 9Zn deficiency is potentially associated with impaired taste acuity, because salivary Zn is linked with gustatory nerve activity. 10Particularly, a decline in salt taste acuity with advancing age is associated with Zn status. 11Zn deficiency can result in reduced appetite through interaction with leptin, 12 leading to or resulting from reduced intake of foods high in Zn by older adults.As such, Zn deficiency is both a cause and an effect of the loss of taste acuity with aging.Along with the poor appetite and dysphagia common among older people, impaired taste perception reduces the pleasure of eating and contributes to malnutrition.
In light of these facts, in this scoping review, we aimed to (1) identify the scope and nature of research related to the role of Zn and nutritional health of older adults; (2) examine potential relationships among Zn deficiency, nutritional status, sarcopenia, and frailty among older adults; and (3) identify gaps in the existing literature and research priorities that will better inform evidence-based practice and policies.

MATERIALS AND METHODS
This scoping review was conducted and reported referring to Arskey and O'Malley's 6-stage methodological framework (excluding the last and optional stage of consulting with stakeholders) 13 and the recommendations made by Levac et al 14 and Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement for Reporting Scoping Reviews (PRISMA-ScR; see Table S1 in the Supporting Information online). 15age 1: Develop the research question Levac et al 14 recommended developing the research question by clearly clarifying the concept, population, and outcomes of interest to establish the focus of the review and an effective search strategy.As such, the concept of this scoping review was defined as a type of review that aims to identify the key concepts, theories, sources of evidence, and research gaps by collating the available literature on a particular topic.
This review was guided by the broad question: what kind of evidence is available in the existing literature about the potential associations between nutritional status, sarcopenia, frailty, and Zn in older adults?Three specific questions were to be answered by the review.(1) Is there a relationship between Zn status and nutritional parameters?(2) Does such relationships influenced by the method of nutritional screening or evaluation of Zn status? (3) What are the existing research gaps?
The study population was clarified as older adults (!60 years; or specific definitions for older people).Health outcomes of interest were the relationship of Zn status with nutritional status, physical performance, sarcopenia, and frailty.Zn status, which was assessed in terms of dietary intake or concentrations in serum, hair, or nails, was considered.The nutritional status, which measured as body mass index (BMI), body composition (body fat % and body muscle %), body circumferences (hip, waist, calf, mid-upper arm, and middle arm), or physical fitness, and nutritional risk, sarcopenia, or frailty, screened using any definition, were included in the review.

Stage 2: Identify relevant studies
A comprehensive literature search was conducted in 3 electronic databases: PubMed (US National Library of Medicine), Web of Science (Thomson Reuters), and ProQuest (Clarivate) in August 2022.No filters or limits were applied to widen the search.The search strategy used for PubMed is provided in File S1 in the Supporting Information online.The references of the extracted studies and relevant reviews, and suggested articles by PubMed were used to identify additional studies.Records retrieved from database searches were imported into Endnote software, version 20.2 (Clarivate).The software was used to remove the duplicates.

Stage 3: Screening and study selection
The preliminary screening of the titles and abstracts of extracted reports was conducted by 1 reviewer (H.M.A.).Secondary review of titles, abstracts, and article content for inclusion was done by another reviewer (Y.K.) independently.After consensus was reached, the full text of the selected studies was reviewed by the first reviewer to confirm adherence to eligibility criteria.The population, interventions, comparators, outcomes, and study design (PICOS) criteria were applied to include and exclude studies during the screening process (Table 1).

Stage 4: Extract data
The following information was extracted from the articles selected after the full-text screening: author(s); year of publication; study location; methodology (design, living arrangement, inclusion and exclusion criteria); sample characteristics (sample size, age, sex, related nutritional data); assessment method of Zn (Zn intake or Zn levels in serum, hair, or nails); variables related to nutritional status, sarcopenia, or frailty; the definitions used to screen nutritional status, sarcopenia, or frailty; and findings related to the review question.Two reviewers (H.M.A. and Y.K.) independently extracted and then reviewed the data with the other authors.The data extracted are summarized  in Tables 2 and 3. [47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64] Stage 5: Collate, summarize, and report the results Extracted data were collated into an Excel spreadsheet (Microsoft) and summarized using thematic analysis. The fllowing 2 themes were identified: (1) the relationship of Zn intake (dietary with or without supplement) with nutritional status, sarcopenia, and frailty; and (2)      37 Tasmania, Australia Prospective study Follow-up in 2-3 y (2.6 6 0.4) 1. Zn intake by FFQ 2. Nutritional status determined by: ALM by DEXA Zn intake was associated with ALM at the baseline and ALM changes overtime.
(continued)   the relationships of serum, hair, or nail Zn concentrations with the aforementioned factors.

Search results
The original search of the 2 peer-reviewed databases (PubMed and Web of Science) conducted in August 2022 resulted in 6018 potentially relevant articles.In addition, 10 000 records extracted from the ProQuest database (the maximum number of records displayed by the database to avoid duplications) and sorted according to their relevance were also included.Manual searching identified 2 articles.Duplicate articles (n ¼ 992) were removed using Endnote software, and the titles and abstracts of 15 028 studies were screened for eligibility.This resulted in 252 studies for full-text review using the inclusion and exclusion criteria.After excluding 203 articles, a total of 49 articles (including the 2 articles identified by the manual search) were included in the scoping review (Figure 1).Those articles Adjusted by age and body weight.Abbreviations: ALM, appendicular lean mass; AWGS, Asian Working Group for sarcopenia; BIA, bioelectrical impedance analysis; BMI, body mass index; CC, calf circumference; CI, confidence interval; CST, chair stand test; DEXA, dual-energy X-ray absorptiometry; EAR, estimated average requirement; EWGSOP, European Working Group on Sarcopenia in Older People; F, female; FFQ, food frequency questionnaire; FM, fat mass; FNIH, Foundation of the National Health Institutes of Health; GS, gait speed; HGS, hand-grip strength; HR, hazard ratio; HW, healthy weight; IQR, inter-quartile range; J-CHS, Japanese version of the Cardiovascular Health Study; KCL, Kihon checklist; LEF, lower extremity function; M, male; MM, muscle mass; MNA, mini nutritional assessment; NRV, nutrient reference values; OR, odds ratio; OW, overweight; PA, physical activity; PF, physical fitness; Q, quartile; RDA, recommended dietary allowance; SD, standard deviation; SE, standard error; SEM, standard error of the mean; SMI, skeletal muscle index; SMM, skeletal muscle mass; SMM r , relative skeletal muscle mass; SPPB, short physical performance battery; T1, tertile 1; T2, tertile 2; T3, tertile 3; TUG, timed up-and-go; WC, waist circumference; zCST, standardized chair-stand test; zHGS, standardized hand grip strength; Zn, zinc; zSMI, standardized skeletal muscle mass index; zSMM, standardized skeletal muscle mass.
Relationship of Zn intake with nutritional status, sarcopenia, and frailty Our review summarizes evidence from 31 studies that assessed the relationship of Zn intake with nutritional status, sarcopenia, or frailty (Table 2).One study reported that Zn intake in older women was negatively associated with both BMI and waist circumference. 31nother study reported a significant positive association between appendicular lean mass and Zn intake at baseline and over 2.6 years. 37Relationships between anthropometric parameters (calf circumference, skeletal MM, and BMI) reported in 5 other studies were nonsignificant. 19,25,29,30,46Two studies revealed that Zn intake was significantly lower among older adults who are malnourished or at risk of malnutrition, using Mini Nutritional Assessment as the screening tool, than those with normal nutritional status. 26,34ight studies assessed the relationship between Zn intake and sarcopenia, 16,21,23,28,35,36,41,43 whereas only 2 studies reported that higher Zn intake was associated with a lower risk of sarcopenia. 21,36Many studies assessed the relationships between Zn intake and different sarcopenia-related variables, including HGS, 18,32,46 lower extremity strength, 37,46 GS, 32,44 and physical fitness. 17,18,33,42Among those, 1 study revealed a significant positive association between Zn intake and Short Physical Performance Battery (SPPB) score. 42The study further showed that a higher intake of Zn and a lower intake of foods rich in phytate pointed to a reduced risk of impaired lower extremity function.Another study reported that older adults with slow GS were more likely to be in the lowest quartile of Zn intake. 4442,45 Kaimoto et al 27 revealed significantly lower Zn intake in older women with prefrailty, whereas contrasting findings were reported by Hayashi et al. 24 The study by Vega-Cabello et al 42 concluded that the risk of frailty is inversely associated with Zn intake, its bioavailability, and a lower intake of phytate-rich foods.Furthermore, they found that older women who adhered to the recommended Zn intake (by the Institute of Medicine) had a lower risk of frailty.Significant associations between Zn intake and frailty were reported in 4 other studies, 22,38,39,45 whereas 2 studies found that associations are significant only in men. 39,45Another study also reported a higher prevalence of inadequate Zn intake among prefrail older men. 40The other study did not find significant associations between Zn intake and incident prefrailty or frailty. 20lationship of Zn status with nutritional status, sarcopenia, and frailty Table 3 summarizes the findings, from 19 studies, related to the relationship of Zn concentrations with nutritional status, sarcopenia, or frailty.,64 Three studies reported positive associations 30,53,57 and three reported no 48,52,59 associations between BMI and serum Zn concentrations, whereas 2 studies reported positive associations. 49,61Another study reported an inverse association between serum Zn concentrations and risk of undernutrition assessed with BMI and weight loss over 6 months. 58Data related to the relationship of serum Zn concentration with calf circumference, mid-upper arm circumference, fat mass, MM, and triceps skinfold thickness were also reported in 4 studies. 49,51,61,64Among those, Peng et al 61 reported an inverse association with mid-upper arm circumference, whereas Gariballa et al 51 reported a positive association with the MM at baseline and 6-week follow-up.The prevalence of Zn deficiency was significantly higher in older men who were at medium and high risk of malnutrition per the Malnutrition Universal Screening Tool criteria. 56Another study reported a positive correlation of serum Zn with Mini Nutritional Assessment score. 65u et al 64 reported significant associations between serum Zn concentrations and sarcopenia and sarcopenia-related variables, skeletal muscle index, and HGS.Among the 2 studies that assessed timed up-andgo, 1 reported a negative association with serum Zn. 54 In contrast, the other revealed no association with hair and nail Zn concentrations. 55Another study assessed the physical performance of older women and reported a positive association. 50Takeuchi et al 63 found significant associations between serum Zn and low HGS among older women in bivariate analysis; however, the association was lost in multivariate analysis.Mocchegiani et al 60 found no associations between serum Zn and SPPB, GS, and HGS.Evidence of inverse associations between frailty and serum Zn concentrations was included in 2 studies. 47,62

DISCUSSION
Zn deficiency, undernutrition, sarcopenia, and frailty are commonly found among the older population.A recent report, based on the discussions of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases working group (8 September 2016), has stated that it is important to have "healthier" dietary patterns in older age with adequate intakes of protein, longchain polyunsaturated fatty acids, vitamin D, and antioxidant nutrients 66 ; however, little was mentioned about the role of Zn in prevention and management of frailty and sarcopenia.Therefore, in this review, we went beyond the prevalence of these nutritional problems, aiming to explore their relationship.The information collated in this scoping review highlights the gaps in the current literature and provides the necessary basis for future studies focused on the potential use of Zn in the prevention and management of malnutrition, sarcopenia, and frailty in older adults.
Studies addressing the associations between Zn status and individual anthropometric and sarcopeniarelated variables, including BMI, waist circumference, calf circumference, MM, fat mass, GS, and HGS, have shown inconsistent results.Antioxidant nutrients have been suggested to prevent the loss of MM and muscle function by decreasing muscle fiber oxidation and inactivating the reactive oxygen species.As such, antioxidant-rich diets are proposed to be important in ameliorating sarcopenia progression.However, the existing evidence shows inconsistent associations among Zn status, sarcopenia, and muscle parameters.A recent meta-analysis conducted using 4 studies did not observe significant differences in Zn intake between older adults with and without sarcopenia (pooled standardized mean difference, À0.60 mg; 95%CI, À1.31 to 0.12 mg; I 2 ¼ 0%). 67Besides variations in the measurement methods and equipment used (eg, MM measured by skinfold thickness, bioelectrical impedance analysis, or dual-energy X-ray absorptiometry), inconsistencies may lie in the methodological differences of the studies.On the other hand, strong associations were found between Zn status and malnutrition or risk of malnutrition assessed using screening tools such as Mini Nutritional Assessment 26,34,65 and Malnutrition Universal Screening Tool, 56 suggesting the consideration of multiple factors associated with the nutritional status rather than focusing on 1 measurement.
Our review shows positive and negative associations, as well as no associations, between serum Zn concentrations and BMI.Several explanations have been proposed for the underlying mechanisms for serum Zn levels and overweight or obesity.One theory suggests that obesity-associated chronic inflammation and stress promote Zn absorption by adipocytes as a result of enhanced expression of metallothionein and Zn transporters. 68Conversely, Zn deficiency can induce the release of reactive oxygen species and cause oxidative stress in tissues, leading to obesity-related complications.Low dietary intake of Zn in older individuals can make them highly vulnerable to oxidative stress and inflammation, resulting in sarcopenic obesity.Another theory proposes that low serum Zn concentrations impair the leptin-signaling pathway and elevated levels of circulating leptin, causing leptin resistance.In addition, increased Zn excretion was observed in obesity. 69n the other hand, the positive associations observed may be because overweight and obese individuals are more likely to consume Zn-rich foods such as meats, seafood, and nuts than people of normal and low weight. 57cquired Zn deficiency is a potentially undiagnosed disorder, and the only clearly demonstrated sign among older adults is impaired immune defense, whereas other signs, such as impaired taste and wound healing, are less frequently observed. 70Serum Zn concentrations can be affected by various factors, including dietary intake; the status of Zn-binding proteins such as albumin, transferrin, and a-2-macroglobulin, diabetes mellitus, gastrointestinal disorders leading to malabsorption, heavy alcohol use, medications and various medical conditions that result in Zn depletion, and foods high in phytate content. 70,71Noteworthy, the study by Vega-Cabello et al 42 included in this review reported that older adults with lower intake of highphytate foods have a reduced risk of impaired lower extremity function and frailty compared with those with high intake even if their dietary Zn intake is similar.Nevertheless, available evidence also indicates that there is no clear relationship between serum Zn concentrations and Zn intake. 72,73According to the estimations of a recent dose-response meta-analysis, only a 6% change in plasma or serum Zn concentrations was resulted by doubling the Zn intake. 74he recent report on European Society for Clinical Nutrition and Metabolism micronutrient guidelines states that it is essential to interpret plasma Zn concentrations together with changes in serum albumin levels and the effect of inflammation. 70Plasma Zn concentration decreased with the magnitude of the inflammatory response; therefore, to make a reliable clinical interpretation, the C-reactive protein level should be <20 mg/ L. 75 Moreover, circulating zinc negatively correlates with interleukin-6, interleukin-8, and tumor necrosis factor-a levels. 70However, few studies included in this review took these factors into consideration.The study conducted by Mocchegiani et al 60 reported that significant associations observed between serum Zn level, GS, and SPPB in the unadjusted model and the model adjusted for serum albumin were lost when adjusted for inflammatory biomarkers (C-reactive protein and interleukin-6).
The studies included in this review showed that older adults with sarcopenia had poor Zn status related to loss of MM and function.Zn is an essential micronutrient for MM synthesis; thus, the presence of Zn deficiency can cause a reduction in MM, leading to physical and functional impairment. 69Zn deficiency may further promote sarcopenia by interfering with antioxidant responses and autophagy.The characteristic features of frailty include low physical activity levels, slow motor performance, and weakness, which may be caused by the decline in MM and strength.Many studies that assessed the relationship between frailty and Zn status reported inverse associations, 27,40,42,47,62 despite the diversity of study designs, population characteristics, and frailty diagnostic criteria.The importance of antioxidants in frailty has been reported in previous studies.An inverse association was reported by Kobayashi et al 76 between frailty and dietary total antioxidant capacity (assessed by oxygen radical absorbance capacity, ferric-reducing ability of plasma, Trolox [a vitamin E analog] equivalent antioxidant capacity, and total radical-trapping antioxidant parameter) among older Japanese women. 76he prevention of sarcopenia and frailty remains a major challenge in medicine and public health, requiring urgent attention.Furthermore, the prevention of micronutrient and antioxidant deficiencies has been suggested as a potential intervention to reduce the risk of frailty and sarcopenia.The role of Zn in the prevention of sarcopenia and frailty is yet to be determined due to the conflicting findings reported in the studies included in this review.Alternative approaches to analyzing the Zn status, such as the ratio of serum Cu to Zn levels (CZr), has used in some studies.Gaier et al 77 found significant correlations between CZr and MM, muscle strength and power, lower extremity function, and SPPB decline.However, individual Cu and Zn levels were not correlated with decline in physical function.Another study has also concluded that CZr is a more reliable parameter than serum Cu and Zn concentrations to discriminate patients with physical disabilities from healthy persons. 78urthermore, some studies have assessed associations between sarcopenia and dietary and nutrient patterns rather than evaluating individual dietary intake.The better dietary pattern with a mean (SD) Zn intake of 6.97 (1.52) mg was a significant predictor of sarcopenia (Odds ratio ¼ 2.790; 95%CI, 1.394-5.58;P ¼ 0.004) than the poorer dietary pattern in which the mean Zn intake was 4.84 (1.14) mg among long-term-care residents. 79In contrast, a nutrient pattern that was high in vitamins and Zn, among others, did not show a significant association with sarcopenia. 80Many studies have revealed the associations between self-reported physical activity, activities of daily living (ADL), and Zn status.One study reported that those who met the recommended exercise intensity and frequency for older adults had lower Zn intake (Male-11.1 mg, Female-8.4mg) than those who did not (Male-13.6mg, Female-9.2mg). 81Another study reported significantly lower serum Zn levels in physically disabled older adults (67.2 lg/dL) than healthy (128.1 lg/dL) controls and a positive correlation between serum Zn and activities of daily living score (r ¼ 0.449; P < 0.01). 78In contrast, studies that assessed the associations of serum Zn with ADL 82,83 and instrumental activities of daily living did not report significant findings. 83Davis et al 84 reported a low Zn intake in older adults with high perceived physical fatigability.
Strengths of this scoping review include the comprehensive search of 3 large and reliable databases (PubMed, Web of Science, ProQuest) without using limitations in publication years and study design.In combination with the manual search we conducted, it is possible that all the pertinent articles were identified.However, there are limitations to this scoping review.First, we did not evaluate the quality of evidence included in the review, which is an inherent feature of scoping reviews.Second, the findings cannot be generalized, because of the differences in study samples, designs, diagnostic criteria, and assessment methods used in the studies.The diversity of results also limited the extent of the analysis.Third, we included articles that were published only in English.Finally, associations, rather than causation, have been reported in studies.Nevertheless, future studies should focus on longitudinal, prospective aspects to investigate the potential relationships between Zn status and sarcopenia and frailty.
Studies that explored the differences in the above relationships with population characteristics (eg, male and female, community-dwelling and institutionalized elderly) are scarce, suggesting the need for such future studies.In addition, we noted gaps in pertinent literature from low-and middle-income countries, although these countries are experiencing rapid population aging.A major reason for this might be the lack of infrastructure and financial support to enable comprehensive studies in this context.Only 1 study included in this review assessed both Zn intake and concentrations, making it difficult to compare Zn screening methods.However, associations of sarcopenia and frailty were more evident for serum Zn concentrations than Zn intake.Zn and nutritional status are complex phenomena with myriad physical and social influences.Therefore, the use of comprehensive and validated tools and criteria to screen and assess the nutritional status of older adults is recommended because individual measures are not reliable in isolation.Moreover, using international consensus definitions in sarcopenia and frailty screening will delineate the associations.

CONCLUSIONS
In this scoping review, we found inconsistent results in the relationship of Zn intake and tissue Zn levels with individual nutritional measurements.The associations were more evident for serum Zn levels with malnutrition, sarcopenia, and frailty.Sufficient data are missing to compare population characteristics and clarify causative relationships, indicating the need for well-designed prospective studies.There is a need for studies from low-and middle-income countries to fill the gaps in the current literature.

Figure 1
Figure 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram of the selection and inclusion of studies in this scoping review.

Table 1
PICOS criteria for inclusion of studies Non-data-driven articles such as editorials, commentaries, letters to the editor, expert opinion, case reports, reviews Animal studies

Table 2
Characteristics and main findings of studies that reported relationships of Zn intake with nutritional status, sarcopenia, and frailty Nutrition Reviews V R Vol. 82(7):988-1011

Table 2 Continued
a Detailed definitions are available in Table S2 in the Supporting Information online.bSex-specific z scores (standardized).c

Table 3
Characteristics and main findings of studies that reported relationships of tissue Zn concentration with nutritional status, sarcopenia, and frailty Nutrition Reviews V R Vol. 82(7):988-1011