Introduction
The rapid aging of our population is a major public health issue [
1]. A longer lifespan is often accompanied by an increased risk of disability and mortality, including the appearance of chronic diseases such as cardiovascular disorders, cancer, stroke, and dementia [
2]. In addition to the focus on chronic diseases, a high amount of research tries to capture overall health. Overall health is determined by the accumulation of a wide range of health problems, including symptoms, signs, diseases, and disabilities [
3], and not merely the absence of chronic diseases [
4].
One way to assess overall health is via frailty, generally described as a non-specific state of homeostatic dysregulation in multiple systems, and vulnerability to stressors, such as illness, injury, or psychological stress [
5,
6]. Frailty is a strong predictor for adverse events, including disability, institutionalization, hospitalization, and mortality [
7,
8]. There are two well-known operationalizations of frailty: physical frailty and multidimensional frailty. Physical frailty, based on the presence of at least three of the following five criteria: weight loss, weak grip strength, exhaustion, slow gait speed, and low physical activity, mainly focused on predefined physical variables [
5]. While multidimensional frailty covers a broad range of health domains, combining indicators on cognition, disabilities, biochemical abnormalities, and diseases [
3,
9]. Indicators on separate health domains have only small effects on health; their cumulative effect becomes significant [
10].
Multidimensional frailty focuses on a more holistic approach to treatment, rather single health deficits
For healthy aging, it is important to counteract the onset and progression of frailty. Different lifestyle factors play an important role in the prevention of frailty. One important modifiable factor is nutrition, by providing energy which is important for the overall homeostasis and by proving essential nutrients, necessary for the maintenance of bodily and organ functions [
11]. So far, a recent literature review showed that most studies have focused on the association between protein and physical frailty [
12]. High protein intake is shown to be beneficiary for physical frailty including muscle mass and muscle strength [
13]. Nonetheless, far too little attention has been put to the association between macronutrients in general and more holistic approaches such as the frailty index. Considering multidimensional frailty, macronutrients intake might be beneficiary for some health domains but harmful for other health domains. For example, on one hand, a high protein diet is associated with higher satiety and lower total caloric intake, and lower body weight, and less body adiposity [
14‐
17]. However, on the other hand, it is suggested that high protein intake might be harmful to kidney function [
18]. Also, two systematic reviews concluded that high protein intake but a low carbohydrate intake was associated with higher all-cause mortality risk [
19,
20]. Similar, a high carbohydrate or fat intake is associated with an increased coronary heart disease risk and a higher body mass index [
21]; on the other hand, overweight might have a lower all-cause-mortality compared to normal weight at an older age [
22].
To our knowledge, only a few studies investigated the association between diet and the frailty index, all focused on diet quality. These studies showed that better diet quality is associated with less frailty [
23‐
25]. No studies are available on macronutrient intake and multidimensional frailty. We hypothesize that the macronutrient composition of the diet is of influence on the frailty index. The aim of the current study is to examine the longitudinal association of macronutrient intake with the frailty index, taking total energy intake and the overall macronutrient composition of the diet into account.
Discussion
This study did not observe an association between total carbohydrates and total fats with frailty over time. A positive association between mono-unsaturated fatty acids intake and frailty in the total population was observed. Furthermore, an association between protein intake and more frailty over time was seen, but only among those with normal weight. This association was mainly driven by animal protein which was associated with a higher frailty index score over time. Moreover, higher protein intake at the expense of a concomitant lower intake of carbohydrates or fat was associated with more frailty over time.
Comparison of our results with published data is challenging, because data on the association between nutrition and frailty are scarce. A recent review also emphasized that most studies focused on the association between protein intake and the physical domain of frailty [
12]. Far less is known for other domains of frailty: cognition, mood, social health, and comorbidity. The frailty phenotype is physically orientated, and is distinct from disabilities, chronic diseases, cognition, and mental health, whereas the frailty index does include these health domains. Moreover, other studies used different definitions of frailty or overall health.
In our study, we did not find an association between carbohydrate intake and frailty after full adjustment. To our knowledge, no studies are known for assessing the association between carbohydrates and frailty. Furthermore, no association between overall total fat intake and frailty was seen in our study. Nevertheless, we did observe an association between mono-unsaturated fatty acids intake and more frailty over time in the total population. This result was unexpected as mono-unsaturated fatty acids are generally known to be beneficial for several components of frailty including cognition [
45]. However, important contributors to total mono-unsaturated fatty acids intake are meat products, added fats, and dairy products [
46]. In line with our results, Hodge et al. showed in a prospective cohort study that a dietary pattern, high meat, and fatty products were associated with worsening health [
47].
We did not observe an association between total protein intake and frailty in the full population. The possible beneficial effect of high protein intake on muscle function may be omitted by a possible negative association between protein and other health domains including digestive, renal, and vascular domains [
48]. Also, high dietary protein intake is often associated with a low diet quality, which might have a negative effect on the frailty status [
23‐
25,
49]. In our study, we did observe an association between high intake of protein at the expense of carbohydrates and more frailty over time. This is in line with two systematic reviews which concluded that high protein intake but a low carbohydrate intake was associated with higher all-cause mortality risk [
19,
20]. Also, we did observe an association between higher protein intake and increased frailty scores among participants with a normal weight, but not in participants who were overweighed or obese. High protein diet is associated with lower food intake, lower body weight, and body adiposity [
14‐
17]; this might explain that we did observe an association in normal weight participants, but not in overweight or obese. Persons with overweight or obesity have in general a high nutritional intake and, therefore, comply with dietary guidelines; however, the macronutrient composition might be less important for older adults suffering from overweight or obesity as an overall unhealthy diet mediates the association between the macronutrient composition and frailty. In our study, the association between protein and higher frailty status over time is mainly driven by higher intake of animal protein. A diet high in animal protein intake (such as meat) contributes to a higher dietary acid load. Because a high dietary acid load is associated with different chronic diseases, this might contribute to a higher frailty index score [
50,
51]. Whereas high intake of plant protein is associated with a healthy dietary pattern which is, in turn, associated with a lower frailty status [
24,
25,
27,
52].
This study has numerous strengths. To the best of our knowledge, this is the first study investigating the longitudinal association between macronutrient intake and the frailty index. Additionally, the comprehensive data collection allowed us to control for many confounders. Furthermore, the large sample size and multiple imputation procedure contributed to a more precise estimate of the association. Most studies on protein did not take into account the role of energy intake and other macronutrients in the diet and it is, therefore, unclear whether the onset and progression of frailty is affected by higher absolute or relative intake of protein, and for relative measure, if this is explained by lower intake of carbohydrates or fat. By taking total energy intake into account, the interpretation of the role of specific macronutrients will improve [
40]. The present study used different statistical methods to take the possible modifying and confounding effect of total energy into account, giving us more insight into the association between macronutrient intakes and frailty.
Despite these strengths, there are several limitations to consider. First, since there is no consensus on the definition of frailty, there are a variety of instruments to assess frailty and overall health which limits the comparability of our results. Measures of frailty show important differences with the frailty index, making a direct comparison with previous literature complex. Second, participants had relatively low frailty indices, and in many participants (37%), the frailty index became lower over time, whereas it was expected to increase. This might be explained, because a relatively healthy population participated in this study, which might have been expected as older adults who are frail or more vulnerable are less likely to participate in the study [
53‐
55]. This may have led to less strong associations. This limits the generalizability of our study results in more vulnerable populations. Third, because this study included multiple waves of the Rotterdam Study, different FFQs were used to measure dietary intake. Nevertheless, the use of an up-to-date FFQ to assess dietary intake has been advised to take into account the availability of new foods and new food composition [
56]. Finally, results may have been influenced by report bias as persons may give more socially desirable answers and exaggerate the consumption of healthy foods which might increase our estimate of the effect [
57].
In conclusion, our study contributed to the knowledge on the association between macronutrients and frailty over time. The intake of fat and carbohydrates did not contribute to the association between the macronutrient composition of the diet and overall health, measured by the frailty index. High protein intake, specifically animal protein intake, is associated with more frailty in a relatively healthy older adult population. Further research is needed on the association between protein intake and multidimensional frailty, focused on the source of protein, and on more vulnerable populations.
Acknowledgements
The authors are grateful to the study participants, the staff from the Rotterdam Study, and the participating general practitioners and pharmacists. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. Fernando Rivadeneira received a grant from the Netherlands Organization for Health Research and Development ZonMw VIDI 016.136.367. The funders played no role in the study design or in data collection and analysis.