The nutritional pattern of frailty – Proceedings from the 5th Italian Congress of Endocrinology of Aging, Parma, Italy, 27–28 March 2009

Abstract

Frailty has become one of the ‘hot spots’ in geriatric research. Frailty has multifactorial origin, and is regarded as a fundamental risk factor for deteriorating health status and disability in elderly people and is highly prevalent in the population above the age 65. It is estimates that prevalence rates up to 27% and pre-frailty rates up to 50% qualify for the term “epidemic”. Although the role of nutritional deficiency in the development of age-related frailty was suggested long ago, research conducted in this area is relatively recent. The critical role of micronutrients in this context suggests the need to improve the quality of food eaten by elderly people whereas quantity of food appears to be less relevant. This review summarizes the recent literature on the nutritional pathways to frailty with particular focus on the effect of energy, protein and micronutrients.

Keywords:

• Frailty
• nutrition
• malnutrition
• functionality
• elderly
• micronutrients
• antioxidants

Introduction

The concept of frailty has become one of the ‘hot spots’ in geriatric research. Although the perception that some older persons were frail always existed (the ancient Egyptian symbol for ‘old man’ depicts a bent figure holding a walking stick) and frailty has been knowledged by physicians as a predictor of an old person's impending decline and aggravation of health status, the operationalization of the frailty syndrome (Fried et al. and Rockwood et al. [1–3]) is a ‘breakthrough’ as a scientific issue. Frailty is regarded a multi-system disorder and one of the pivotal geriatric syndromes which is induced by multiple pathophysiological processes ranging from malnutrition to hormonal dysbalances, chronic inflammation, multimorbidity and others. Frailty leads to adverse outcome such as deteriorating health status, immobilization, disability and ultimately death [4]. Frailty is particularly characterized by a reduced functional reserve and increased vulnerability to internal and external stressors. From a geriatric viewpoint, this aspect of frailty implies that frail elderly people are at a high risk of inadequate recovery from even minor events such as gastroenteritis or change of residence. An overview on the influencing factors on frailty or frailty-related parameters proposed are shown in Table I. Because of the diversity of parameters affecting the development of frailty, the term ‘frailty puzzle’ has been coined by Kinney [11]. Recognition and treatment of the causes for frailty and the frailty syndrome itself may, therefore, represent a key approach to improving the care provided for elderly people, particularly as frailty is highly prevalent in the elderly population [52,53]. A very recent publication by Santos-Eggimann et al. implementing Fried's criteria identified prevalence rates in ten European countries ranging from 5.8% to 27.3% for frailty and from 34.6% to 50.9% for pre-frailty in persons 65 years and older [54]. Such high prevalence rates qualify for the term ‘epidemic’. Nutritional influences and particularly low micronutrient intake have been identified as an essential risk factor for the development and severity progression of frailty in elderly people [12]. This review, therefore, aims at summarizing the recent literature on the nutritional links to frailty, frailty components and frailty-related parameters such as low muscle strength and low walking speed. Data on prevalence of poor nutritional intake among elderly people and its association with frailty will be examined. Moreover, the influence of energy and protein intake as well as the intake of micronutrients such as vitamins, antioxidants and trace elements will be discussed in light of the most recent and most relevant publications.

Table I.  Influencing factors on the development or aggravation of frailty or frailty-related parameters.

Parameter, literature reference	Description
Age [1,5–8]	Prevalence of frailty increases with age
Gender [1,9,10]	Frailty more prevalent in women
Malnutrition [5,8,11–20]	Loss of appetite, weight loss, sarcopenia. Low energy and protein intake. Low intake and blood levels of vitamins (B, C, D, E, folate), antioxidants (carotenoids) and trace elements (selenium, zinc).
Comorbidity, multimorbidity [1,8,21–25]	Simultaneous presence of one or multiple, mostly chronic diseases (e.g. cardiovascular disease, congestive heart failure, arthrosis, osteoporosis, chronic renal insufficiency). Polypharmacotherapy.
Hormonal dysbalances [17,26–34]	Low levels of testosterone, growth hormone, DHEAS, cortisol, IGF-1, leptin, sex hormone-binding globulin. Multiple hormonal deficiencies. Anti-androgen treatment. Increased insulin resistence, metabolic syndrome.
Cytokines, ‘oxidative stress’ [17,19,31,34–42]	Increased levels of CRP, IL-6, TNF-α and leukocytes. Activation of the coagulation system. (Anemia).
Body composition changes [43–46]	Changes of body composition: increase of fat mass, decrease of lean body mass (i.e. muscle mass). Sarcopenia. Decrease of bone density.
Neuropsychological disorders [47–49]	Parkinson's disease, Alzheimer's disease. Depression and other psychoses.
Socio-economic factors [1,8,9,50,51]	Lack of social involvement (relatives, friends, church, organizations). Low life satisfaction. Low income, low educational level, non-white-collar occupation.

Lack of a uniform definition of frailty in cited publications.

Inadequate nutritional intake is frequent among elderly people

Although food intake generally declines with aging possibly because of lower caloric requirement to maintain reduced lean body mass, inadequately low nutritional intake is frequently observed among elderly people, particularly in those with increased care needs [55]. In free-living elderly, the U.S. National Health and Nutrition Examination Survey (NHANES III) identified low energy and nutrient intake in up to 21% of the elderly study population [56]. The InCHIANTI study (Invecchiare in Chianti/Aging in the Chianti area, Italy) examined nutritional status and nutrient intake in a sample of the general population including old and very old people and found a strong age-dependency of inadequate energy, protein and micronutrient intake [57]. Study participants above the age of 85 had the lowest dietary intake of any examined nutrient often below the official recommendations. With regard to protein, 29% of women and 38% of men above age 85 did not meet their recommended intake. This proportion was even higher for some vitamins and trace elements. Gariballa and Forster examined food diaries completed by community-living elderly people immediately following hospital discharge [58]. The mean energy intake in this population met only 67.7% of UK reference values, which was attributed to difficulties with shopping and cooking, isolation, depression and ill health. In the nursing home setting, the prevalence of inadequate nutrient intake is even higher. Two recent studies on nursing home residents found inadequate energy intake in 60% and inadequate micronutrient intake (vitamins E, B₆, folate, magnesium, zinc) in 70% of the examined population [59,60]. Although inadequate nutritional intake may be temporary and does not necessarily equal overt malnutrition or nutritional risk, similar findings were obtained when screening tools suitable for a geriatric population such as the Mini Nutritional Assessment® (MNA) were used in the nursing home setting. Kulnik and Elmadfa [61] found that 37.8% of nursing home residents were malnourished, while another 48.3% were assessed as ‘at risk’ of malnutrition. Wikby et al. [62] reported 20.0% of nursing home residents to be malnourished and 50.0% to be ‘at risk’.

Data on dietary intake in geriatric acute care patients are rather scarce, which may be due to the shorter length of stay in hospitals compared to long-term units and the time-consuming character of most of the established methods for measuring dietary intake [63]. A recent study from the UK revealed inadequate food consumption, which was defined as having eaten less than three-quarters of the served dishes, in 67% of geriatric acute care patients [64]. These findings should be interpreted considering the growing evidence that elderly people hospitalized for acute disease may require a higher protein intake to maintain a positive nitrogen balance than previously assumed and officially recommended in healthy elderly people [65].

Association of inadequate nutritional intake with frailty

As already mentioned, inadequate nutritional intake is frequently observed among free-living as well as institutionalized and hospitalized elderly people. If frailty in elderly people is promoted by poor nutritional intake then an association between these entities must be confirmed in observational studies. The majority of data on this topic have been derived from the aforementioned Italian InCHIANTI study and the US Women's Health and Aging Study (WHAS) which have systematically examined the relationship between nutritional status and frailty in large, longitudinal studies. Bartali et al. [12] established a link between deficient nutritional intake and the frailty syndrome based on InCHIANTI study data utilizing Fried's criteria. Twenty percent of the InCHIANTI population was frail and out of those who were frail more than 53% showed deficient intake of at least one out of nine examined nutrients. Nearly one third of the frail persons had an inadequate intake of more than three nutrients. An energy intake of less than 21 kcal/kg body weight/day was strongly associated with being frail. This observation was valid for some micronutrients, too, even independently from energy intake. The odds ratio for being frail associated with having three or more nutrient deficiencies compared with two deficiences or less was 2.12. Based on data from the WHAS, Semba et al. [5] identified low serum micronutrient concentrations to be predictive of becoming frail. At baseline, 32.6% of study participants were frail and those who were frail had significantly lower serum concentrations of numerous micronutrients (vitamins E, D, selenium and zinc) as compared to their non-frail peers. In the course of regular follow-up examinations, about one third of the non-frail study participants became frail. Low micronutrient concentrations in non-frail persons at baseline were identified as an independent risk factor for becoming frail during the follow-up period. Also the number of nutritional deficiencies was associated with an increased risk of becoming frail. Thus, as exemplified by the two mentioned studies, inadequate intake of energy and low serum concentrations of micronutrients have been associated with an increased prevalence of frailty and an increased risk of becoming frail in the future.

The role of protein in frailty

It has been previously demonstrated that insufficient energy intake, but also protein intake, is related to frailty [12]. Several studies have established a link from insufficient dietary protein intake and low serum protein concentrations to frailty or frailty-related parameters of functionality in elderly people. In community-dwelling elderly people from the US Health, Aging and Body Composition Study (Health-ABC), Houston et al. [66] demonstrated that low dietary protein intake was associated with loss of lean body mass, i.e. muscle mass, as measured by dual energy X-ray absorptiometry (DEXA). Although all study participants lost muscle mass during the 3-year follow-up, those with lowest protein intake at baseline (0.7 g/kg body weight/day) lost more than 40% more muscle mass than those with highest protein intake (1.1 g/kg body weight/day). Continuing loss of muscle mass eventually leads to sarcopenia which has been termed ‘nutritional frailty’ to clarify the close interrelationship between poor nutritional status, loss of muscle mass and strength, and functional decline [13]. Similarly, using data from the Health-ABC study it was demonstrated that also lower serum albumin concentrations, even within the normal range, was associated with greater loss of muscle mass in a 5-year follow-up [67]. Unfortunately, no functional parameters were included in both aforementioned studies to examine the implication of muscle mass loss on physical function in older persons. Kwon and coworkers [68,69] examined serum albumin and vitamin D, which are physiologically interconnected in muscle function and metabolism, and their association with physical performance among community-dwelling elderly Japanese. Study participants with isolated deficiencies of either albumin or vitamin D had poor muscle strength as assessed by knee-extension power and hand-grip strength (one of Fried's criteria) and impaired balance capability as assessed by the timed up-and-go test and functional reach. Worse function, though, was found in participants with deficient serum concentrations of both albumin and vitamin D. These results illustrate the supposed synergistic effect of protein and vitamin D on muscle strength, which is of particular interest with regard to the high prevalence of vitamin D deficiency in the elderly population [70,71]. Serum albumin was found to be a predictor of future loss of muscle strength as proposed by Schalk et al. [72] from the Longitudinal Aging Study, Amsterdam. Even at baseline, lower albumin values (<43 g/l) were associated with decreased muscle strength as measured by hand-grip strength. In a 3-year follow-up examination, lower baseline serum albumin levels were significantly associated with an increased loss of muscle strength. Notably, such ‘lower’ albumin levels were still higher than commonly reported cut-off values between 35 and 38 g/l which might emphasize the role of serum albumin as an early marker of muscle strength decline [72].

The role of micronutrients in frailty

The association between frailty and micronutrients and among them particularly those with antioxidative capacity, has come into focus during the last few years. ‘Oxidative stress’ caused by free radicals is considered a major damaging influence on macromolecules (enzymes, lipids, DNA), a contributor to aging at the cellular level and an influencing factor on disability and mortality in elderly people [73–78]. A majority of vitamins hold antioxidative capacity, e.g. the vitamins A (retinol), C (ascorbate), D (cholecalciferol) and E (tocopherol group). Carotenoids constitute another group of antioxidants and comprise vitamin precursors like β-carotene and other vitamin-like substances such as α-carotene, lycopene, lutein and several more which are of utmost importance to scavenging free radicals [78]. The main food source for carotenoids is fresh fruits and vegetables and carotenoid serum concentrations are regarded the most valid markers of fruit and vegetable intake [79]. Some trace elements, too, like selenium bear antioxidative capacity after integration into proteins (selenoenzymes) where selenium constitutes the active centre. Zinc, another trace element, is involved in immune function and wound healing which are highly relevant attributes particularly at an advanced age [80].

Micronutrients in the Women's Health and Aging Study

Based on Fried's criteria, Semba et al. and Michelon et al. examined the relationship between serum micronutrients and frailty in community-dwelling women recruited in the WHAS [5,14]. In general, serum micronutrient concentrations in the group of frail study participants were found to be lower than in the non-frail and even the pre-frail group [14]. Frailty was significantly associated with lower serum levels of vitamin E, vitamin D, total carotenoids, selenium and zinc. Vitamin E and carotenoid status were even predictive for becoming frail in the future. A cumulative effect of micronutrient deficiencies was suggested by Semba et al. [5] and a 10% rise in the risk of becoming frail was estimated for each additional nutrient deficiency. Low serum levels of the vitamins B₆, B₁₂ and selenium were identified as predictors of disability, defined as having difficulty in two or more ADL functions, in community-dwelling older persons [12]. Another study by Semba et al. [76] examined the influence of carotenoids on the development of walking disability. Study participants in the lowest quartile of serum carotenoids were more than 1.5 times more likely to develop walking disability than those in the upper three quartiles. Although measurements of serum carotenoids were only available at baseline and not from the follow-up examinations, this study still is a landmark about the relationship between an important group of micronutrients and a subsequent worsening of functional status. A link between antioxidants, inflammation and mortality has been suggested by the findings that increased serum carotenoids and selenium were associated with lower levels of the inflammatory cytokine IL-6, which has been identified as a contributing factor to the frailty syndrome (Table I) [35]. There was an increased likelihood for having higher IL-6 levels after 2 years in study participants with low levels of vitamin A and carotenoids at baseline. Moreover, those with lower levels of selenium were more than 1.5 times more likely to die within 5 years after study inclusion as compared to those with higher selenium levels. A subsequent study by Ray et al. [81] identified serum selenium and total serum carotenoids as independent risk factors for all-cause mortality. The role of selenium on functionality has been studied more extensively by Beck et al. [82], who demonstrated that low serum selenium concentrations were independently associated with poor hand-grip strength. It was hypothesized that IL-6 takes the role of a mediator between selenium and muscle strength via the nuclear factor kappa-B (NF-κB). Therefore, higher selenium levels lead to a decreased concentration in NF-κB which then results in a downregulation of IL-6, which has been shown to be related to muscle weakness and sarcopenia [36,82]. A similar pathway has been suggested for carotenoids [78].

Micronutrients in the InCHIANTI study

From the InCHIANTI study, including both male and female participants, Ble et al. [15] reported a distinct association between a single vitamin deficiency and the frailty syndrome. Low plasma levels of vitamin E were associated with frailty independently from confounders like general dietary intake, inflammation and body composition. Moreover, a subsequent study related low serum vitamin E levels to decline in physical function as assessed by the Short Physical Performance Battery (SPPB) [83]. Although the SPPB does not explicitly measure frailty, it contains walking speed which is also one of Fried's criteria, and the related parameters chair rise and balance test. Cesari et al. [16] reported that higher dietary intake and serum concentrations of vitamin C, α-tocopherol, γ-tocopherol and β-carotene were linked to better lower extremity performance, such as knee extension power and the SPPB. Particularly, higher dietary intake of vitamin C, probably the most well-known antioxidant, was positively associated to all of the examined physical performance parameters. Lauretani et al. [84] reported that low carotenoid concentrations were associated with accelerated decline in muscle strength in a 6-year follow-up examination. Study participants in the lowest quartile of plasma carotenoids showed poorer results in hip flexion power, knee extension power and hand-grip strength than those in the upper three quartiles 6 years after baseline. On the other hand, higher serum concentrations of carotenoids were associated with lower risk of developing severe walking disability [79]. Carotenoids were also found to be independent predictors of mortality [85]. In analogy to the results from the WHAS, also selenium was found to be related to muscle strength and mortality. Study participants within the lowest quartile of serum selenium showed an increased risk for poor hand-grip strength, knee extension power, hip flexion power at baseline and an increased risk for all-cause mortality in the following 6 years compared to study participants within the highest quartile of selenium [86,87].

In summary, although the WHAS lacks data on men and some of the aforementioned publications did not examine frailty per se but more or less isolated performance parameters or even disability, which may be regarded the state ‘beyond’ frailty, these findings give an articulated hint towards the impact of micronutrient deficiencies on physical well-being, functionality and even mortality in elderly people, even if pathophysiological pathways leading from micronutrient deficiencies to frailty and further on to disability and death are often not yet fully explained. Nevertheless, there is by now a considerable amout of publications suggesting that antioxidants might play an important role in reducing oxidative stress which otherwise promotes functional decline.

Other nutrition-related causes for frailty

From the WHAS it was shown that chewing and swallowing problems and use of dentures influence dietary intake and represented a risk factor for malnutrition, frailty and mortality [88]. Denture users had significantly lower serum levels of carotenoids and vitamin D. Denture use was particularly high among frail study participants and an increased 5-year mortality risk was observed for those denture users who complained about swallowing and chewing difficulties. Given the high prevalence of denture use among elderly people, the maintenance of masticatory function and oral health, therefore, seems vital to uphold the ability to adequate and satisfactory nutrition.

Conclusion

Inadequate nutrient intake is frequent among elderly people and related to increasing dependence and care needs. An association between poor nutritional intake and the frailty syndrome was demonstrated in numerous recent studies. Not only energy and protein intake have been linked to frailty and frailty-related parameters. Particularly, the role of micronutrients with antioxidative capacity in the development of frailty has been highlighted in recent publications. Intake of micronutrients was associated with frailty or related parameters of physical functioning, sometimes even independent from energy intake. Thus, macro- as well as micromalnutrition may be regarded one of the key factors contributing to the development and aggravation of frailty. Particularly, uncovering the role of micronutrients in this context may lead to an increased perception of the need to improve the quality of food eaten by elderly people – not just the quantity. In clinical practice, it should therefore be recommended to use a screening tool such as the MNA for routine screening as part of the management of aging [89,90]. If the screened subject shows low scores, it may be assumed that along with deficient macronutrients the subject will have low micronutrient intake as well. Consequently, the goal will be to raise general dietary intake of high-quality food to provide both kinds of nutrients.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.