Counteracting inflammation and insulin resistance with diet and exercise: A strategy for frailty prevention?

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EURGER-618; No. of Pages 12 European Geriatric Medicine xxx (2015) xxx–xxx

Available online at

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Research paper

Counteracting inflammation and insulin resistance with diet and exercise: A strategy for frailty prevention? G. Zuliani a,*, C. Soavi a, M. Maggio b, F. De Vita b, A. Cherubini c, S. Volpato a a

Department of Medical Sciences, Section of Internal and Cardiopulmonary Medicine, University of Ferrara, via Savonarola No. 9, 44100 Ferrara, Italy Department of Clinical and Experimental Medicine, Geriatric Rehabilitation Department, Section of Geriatrics, University of Parma, University Hospital of Parma, Italy c IRCCS-INRCA, Geriatrics and Geriatric Emergency Care, Ancona, Italy b

A R T I C L E I N F O

A B S T R A C T

Article history: Received 15 September 2014 Accepted 7 November 2014 Available online xxx

Frailty is a condition of increased vulnerability to cope with stressors, predisposing to the development of disability in basic and instrumental activities of daily living, falling, institutionalization and finally death. It is characterized by the loss of functional reserve in multiple domains resulting in a reduced tolerance to common external stresses. The pathogenetic steps conducting to frailty are not completely clear, but there is increasing evidence of a crucial role of insulin resistance and systemic inflammation in the development of frailty, disability, and related medical conditions. These two conditions may act directly, through a negative impact on homeostatic regulation and cross-systems compensation, or indirectly, by the effect of several diseases strongly related to frailty. Therefore, counteracting insulin resistance and systemic inflammation could be a powerful way to prevent the development of frailty and/or of its adverse outcomes. In this framework, diet and physical exercise may represent two important weapons in the prevention of frailty; indeed, current literature supports the effectiveness of a correct lifestyle based on a healthy diet (Mediterranean type diet) and regular physical exercise on frailty primary prevention. Studies on secondary prevention of frailty suggest that multi-component and resistance training, together with adequate energy and protein intake, might be helpful although data are still lacking. The efficacy of dietary supplementation in secondary prevention of frailty, albeit promising, remains to be confirmed in large clinical trials. ß 2015 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved.

Keywords: Frailty Inflammation Insulin resistance Exercise Diet Nutritional supplementation Physical activity

1. Introduction Although the concept of becoming frail with ageing is not a recent acquisition, there is no universal agreement on its definition. According to the majority of authors, frailty is characterized by increased vulnerability to cope with stressors; thus, it is more likely to occur when an individual, after challenges, has a diminished ability to return to an homeostatic status [1]. Frail individuals have an higher risk of developing disabilities in basic (BADLs) and instrumental (IADLs) activities of daily living, falling, institutionalization, and death. Although different definitions have been proposed, two themes seem to better depict the frailty concept:  loss of functional reserve in multiple areas/domains;

* Corresponding author. Tel.: +39 0532 247409; fax: +39 0532 210884. E-mail addresses: [email protected], [email protected] (G. Zuliani).

 existence at a level close to or past the threshold for failure, with reduced tolerance to common stresses. Frailty has been defined as a ‘‘geriatric syndrome’’, indicating the accumulated effect of impairments in multiple domains that all together result in a particular adverse outcome. Different frail ‘‘phenotypes’’ have been proposed [2–4]. Fried et al. suggested a phenotype characterized by at least three out of five clinical criteria including unintentional weight loss ( 4.5 kg in 1 year), self-reported exhaustion, reduced grip strength measure, slow walking speed, and low physical activity [2]. Most definitions of frailty involve decline in mobility, strength, endurance, nutrition, and physical activity as clinical components [2], while others include cognitive impairment and depression too [5]. Thus, there are several domains involved in frailty development including neurological control/cognition, mechanical performance/mobility (muscle/bone strength, joint function, balance, coordination, and motor processing), energy metabolism (nutrition and cardiopulmonary function), and physical activity [6,7]. Depression, pain, and

http://dx.doi.org/10.1016/j.eurger.2014.11.010 1878-7649/ß 2015 Elsevier Masson SAS and European Union Geriatric Medicine Society. All rights reserved.

Please cite this article in press as: Zuliani G, et al. Counteracting inflammation and insulin resistance with diet and exercise: A strategy for frailty prevention? Eur Geriatr Med (2015), http://dx.doi.org/10.1016/j.eurger.2014.11.010

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visual/auditory impairment might also be important determinants of frailty. Although frailty has been often considered a synonymous of disability and multimorbidity, and might overlap with these conditions, it has specific and distinct characteristics [2]. As suggested by Clegg et al. [8] frailty might be viewed as the result of an acceleration in the progressive decline of multi-systemic homeostatic reserve related to aging, genetic, epigenetic, and environmental factors. As a matter of fact, in the Women’s Health and Aging Study, Fried et al. found a significant non-linear positive relationship between the number of deregulated homeostatic systems and the prevalence of frailty [9]. A current pathogenetic hypothesis of frailty is based on interaction between aging and multiple chronic diseases. Aging itself is characterized by reduced reserve across different homeostatic systems; as a result, a multisystemic impairment related to the accumulation of cellular/ molecular damage, and loss of feed forward and feedback mechanisms among interacting systems is observed [8,10–12]. Multiple chronic diseases superimpose the weakened homeostatic systems by further reducing cross-system compensation, and favoring the onset of frailty. The importance of multimorbidity in the determinism of frailty has been underlined by Sanders et al. [13]. These authors used the ‘‘physiologic index of comorbidity’’ [14] to obtain a measure of ‘‘disease burden’’ (cardiovascular and kidney disease, diabetes, arthritis, depression and cognitive impairment). The finding of an association between frailty and disease burden, independent of diagnosed chronic conditions, emphasized the concept that unrecognized physiologic changes may contribute to frailty [13]. These and other data suggest that, although multimorbidity might not be a necessary condition for frailty, the presence of clinical/subclinical diseases might be really important for the development of frailty [2].

2. From pathogenesis to prevention of frailty Starting from current pathogenetic hypothesis, the prevention of physical frailty in the population should be aimed to contrasting/eliminating the conditions consistently associated with frailty development, including:

 the multi-systemic impairment related to aging itself;  the multi-systemic effects of multimorbidity and sub-clinical diseases.

The preventive approaches to frailty might be divided into primary and secondary prevention (Fig. 1). The first intervention should target robust or pre-frail adult-older individuals, with the aim to delay frailty onset by preventing chronic related diseases and by slowing down the decline in physiological reserve. Once the process of frailty has started, the targets of secondary prevention would focus on slowing down (reversing) its progression and delaying related adverse outcomes (i.e. falls, hospitalization, and disability) [15]. Interventions in secondary prevention of frailty may include correction of nutritional deficits, improvement of cognitive or depressive status, and promotion of physical activity. Actually, since we still do not have an accepted definition of the frail ‘‘phenotype’’, the distinction between primary and secondary prevention of frailty might be difficult in some cases. However, the key points of population-based primary prevention of frailty would be the identification of a pathogenetic background common to frailty phenotype and related chronic diseases. In this regard, Walston et al. [16] proposed a biological model in which different molecular mechanisms together with aging-related chronic diseases would lead to a condition of systemic inflammation (SI), insulin resistance (IR), and oxidative stress, which in turn would result in the development of frailty (Fig. 2). Genetics might influence this process; indeed, an association between frailty and several mitochondrial DNA variations has been reported [17]. Nevertheless, lifestyle seems to have a central role. Vita et al. found that smoking, elevated BMI, and poor physical exercise during adulthood predict disability and earlier mortality (two outcomes of frailty) in older age [18], while Bouillon et al. found that commonly used CVD risk scores in the adulthood similarly predict the risk of frailty [19]. Of interest, SI and IR (together with oxidative stress) have been consistently associated not only with frailty, but also with several frailty-related medical conditions including cardiovascular disease [20–24], heart failure [25–27], cognitive impairment/dementia [28–32], chronic kidney disease [33–36], sarcopenia [37–40], and

Fig. 1. Possible timing of primary and secondary prevention of frailty syndrome.

Please cite this article in press as: Zuliani G, et al. Counteracting inflammation and insulin resistance with diet and exercise: A strategy for frailty prevention? Eur Geriatr Med (2015), http://dx.doi.org/10.1016/j.eurger.2014.11.010

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3

AGEING PROCESS

Mitochondrial damage Shortened telomeres DNA damage Cell senescence

Systemic Inflammaon Insulin Resistance Oxidave Stress

Ageing Life style Enviroment Genecs

Reduced Cognion Sarcopenia Impaired Glucose metabolism Anorexia Reduced Immunity

FRAILTY phenotype

Coronary Heart Disease Congesve Hearth Failure Stroke Peripheral Arterial Disease Diabetes Obesity Demena Chronic kidney disease

AGEING PROCESS

Modified from Walston 2006

Fig. 2. Role of insulin resistance and systemic inflammation in the pathophysiology of frailty syndrome. Modified from Walston et al., 2006.

osteopenia [41,42]. Moreover, SI and IR have been shown to predict common adverse outcomes of frailty such as disability [43,44] and total mortality [45,46]. 2.1. Insulin resistance, systemic inflammation, and frailty Studies conducted on centenarians have shown that IR might be a marker of age-related ill health and reduced lifespan [43]. These authors hypothesized that excess adiposity and sarcopenia (ageassociated loss of skeletal muscle mass and function) may underline the age-related diseases, inducing alterations in adipokines secretion, skeletal myocyte mitochondrial function, and brown fat activity [43]. As a matter of fact, in older individuals metabolic syndrome is associated with SI, and this association is principally driven by abdominal fat accumulation [47]. Metabolic syndrome is also associated with increased soluble gp130 plasma levels (i.e. with IL-6 trans-signaling activation), and this condition, typical of several diseases associated with aging, is mediated by IR [48]. In the Cardiovascular Health Study (CHS), Walston et al. found that the pathophysiological basis of frailty was characterized by SI and elevated markers of blood clotting [49], even after exclusion of subjects with diabetes or CVD. Successively, Barzilay et al. demonstrated that IR, assessed by the homeostatic model assessment (HOMA), and SI were positively correlated with frailty incidence [50]. Interestingly, in the CHS study the principal characteristics of subjects becoming frail after 9-years follow-up included higher HOMA score, CRP, IL-6, white blood cell count, and higher probability to becoming diabetics [50]. Abbatecola et al. found that IR was independently associated with scores of low frontal cortex functions in older non-demented, non-diabetic people [51]. These authors hypothesized that cognitive decline might be associated with an increased risk of frailty, and this association might be mediated by IR [52]. Thus, IR can be considered a risk factor not only for many age-related diseases but also for most of the clinical features of frailty; indeed, by altering lipid metabolism, increasing inflammatory state, and

impairing endothelial function IR might exert a pivotal role in frailty development [53]. Similar conclusions were reached by Pasini et al. [54] who found that the ‘‘hypercatabolic syndrome’’ might be the common soil for several diseases and senescence. The crucial components of this syndrome were IR and increased circulating catabolic stimuli (i.e. inflammatory cytokines–SI, and hormones); the imbalance between anabolic action and catabolic thrust would induce skeletal/cardiac muscle protein breakdown leading to deficits in function and finally to sarcopenia. The latter has a crucial role in frailty determinism since it has been associated with reduction of muscle strength and tolerance to exertion, and quantitative/qualitative bone modifications. These conditions lead to disability [55] but also imply a reduction of basal metabolism resulting in overweight/obesity and IR [56]. The loss of muscle tissue is accompanied by infiltration with fat and connective tissue [57]; this condition might sustain sarcopenia by release of inflammatory cytokines from infiltrating macrophages, and of adipokines from adipocytes [58]. Since chronic inflammation is one of the mechanisms at the basis of IR and metabolic syndrome [59–61], the presence of sarcopenia, and especially of sarcopenic obesity (combination of reduced fat-free mass and increased fat mass) [62] likely starts a vicious circle resulting in further loss of muscle mass and mobility, IR, and risk of metabolic syndrome development [63]. Sarcopenic obesity has a strong impact on global health, worse than obesity or sarcopenia alone [64,65]; in post-menopausal women sarcopenic obesity was associated with lower gait speed and cardiopulmonary fitness [62]. Data from the New Mexico Elder Health Survey showed that sarcopenic obesity often precedes disability [66]; moreover, it has been shown that it is related to decline in functional ability [67], risk of frailty [68], poor quality of life [69], longer hospitalization [70], and greater mortality [71,72]. In conclusion, IR and SI not only are linked one to each other, but represent two major pathological conditions strongly related to frailty pathogenesis. Preventing or counteracting IR and SI in adult

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and older populations might contribute to prevention frailty and its consequence by:  reducing the impact of multi-systemic impairment related to ageing;  preventing several chronic diseases known to contribute to the loss of homeostasis and cross-system compensation. 3. The role of diet in the prevention and treatment of frailty Nutrition might have an important role in the prevention of both IR and SI, two essential pathways to frailty. When dealing with this topic, it is important to highlight that:  the expression of pro-inflammatory cytokines is associated with impaired insulin signaling in hepatocytes and muscle cells [73];  SI takes place acutely following meals, lasting for a few hours and recurring several times a day following eating. Recently, the importance of post-prandial inflammation in the generation of IR has been also appreciated [74]. 3.1. Evidence from dietary observational studies In general, the adherence to Mediterranean diet has been associated with lower SI [75]. Also, a ‘‘prudent’’ diet (higher intakes of fruit, vegetables, legumes, fish, poultry, and whole grains) is associated with lower CRP levels compared with Western diet [76]. On the other hand, a dietary pattern characterized by higher consumption of sugar-sweetened beverages, burgers and sausages, crisps, snacks, and white bread was been associated with IR and diabetes [77]. Instead, a higher consumption of whole grains and a lower consumption in soft drinks, white bread and refined grains, crisps and other snacks, and processed meat is protective against IR, metabolic syndrome, and diabetes [77]. Diet could have an important role in preventing frailty by different mechanisms. Odegaard et al. recently reviewed the molecular pattern relating over-nutrition to IR and inflammatory response [78]. Both macrophages infiltrating adipose tissue and adipocytes are responsible for the constitution of a pro-inflammatory micro-environment [79], by passing cellular stress responses and triggering SI. A central role in IR development is detained by nutrition and excessive caloric intake [79,80]. Healthy eating patterns have been associated with lower circulating concentrations of inflammatory markers. Whole grains, vegetables and fruits, fish, foods containing polyunsaturated fatty acid, vitamin C and E, and carotenoids have been associated with lower SI; on the contrary, saturated and trans-monounsaturated fatty acids (FA) are considered to be pro-inflammatory [79]. Several studies have investigated the eating habits involved in inflammation focusing on fatty acids, high glycemic index foods (e.g. sugar beverages, white bread, potatoes), and exceeding caloric intake [81]. The inflammatory effect of a high omega 6/omega-3 FA ratio has been demonstrated in humans [82,83]. Higher omega-3 FA intake, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), reduce the production of inflammatory cytokines; indeed, plasma polyunsaturated fatty acids have been associated with lower inflammatory markers in older adults [84]. Foods with high glycemic index are an important source of inflammation; they increase serum levels of CRP [85], IL-6, IL-7, IL-18 [86], and free radicals levels [87]. Moreover, consequent hyperinsulinemia induces an increase in IGF and androgens, and a reduction in GH serum levels, all conditions leading to inflammation [81]. There is strong evidence that over-nutrition in adulthood leads to SI, IR, and oxidative stress, and finally to increased risk of

developing frailty. However, it has to be underlined that in older age the deficiency of nutrients, and not their excess, might increase the risk of becoming frail. The lack of fundamental components, such as certain amino acids, has been implicated in the development of sarcopenia [88,89], while macro-nutrient supplements have been shown to be helpful in maintaining muscular protein metabolism and cellular function [54,88]. Interestingly, in the InCHIANTI study the combination of low protein intake and SI significantly correlated with the decline in muscle strength [90], indicating their additive negative effect on sarcopenia. The onset of disability might also be linked to the nutritional pattern; indeed, it has been shown that among older frail nursing home residents, several markers of malnutrition predict the future worsening in functional status [91]. Crucially, it has been demonstrated that, in elderly women, higher protein consumption is associated with a strong, independent, dose-responsive lower risk of incident frailty; in particular, a 20% increase in calibrated protein intake was associated with a 32% decrease in the risk of frailty [92]. It is not just the lack of proteins, but a general lack of nutrients that might lead to an increased risk of frailty in older age. Frailty has been associated with low levels of micronutrients, including vitamin E and vitamin D [93,94]. Moreover, Bartali et al. found that a daily intake of 21 Kcal/kg or less was significantly associated with frailty [95], together with low protein and vitamin (D, E, C, and folate) intake. These findings seem to suggest the existence of a sort of ‘‘paradox of nutrition and frailty’’; while in middle adulthood overnutrition seems to acts as a major risk factor for developing frailty, in advanced age under-nutrition increases the risk of being frail. Actually, it is likely that under- and over-nutrition might have the same effects on young and older people; on this light, undernutrition would be a risk factor for developing frailty in young individuals too, with the difference that younger people, having more preserved homeostatic reserve, do not reach the threshold passed which frailty can be diagnosed. A similar phenomenon can be observed when referring to the relationship between nutritional status and neurodegenerative diseases, configuring a condition known as the ‘‘paradox of obesity and dementia’’ [96]. In midlife, over-nutrition and obesity are associated with an increased risk of developing dementia in older age [97,98]; in later life, individuals with Alzheimer’s disease often have lower body weight and BMI compared with non-demented individuals, and being underweight is rather common in the years preceding the development of dementia [99]. Once again, an important role might be played by omega-3 FA [100]. FA serve as both energy substrates and integral membrane components essential for proper neuronal and brain function. Polyunsaturated FA (PUFA) are incorporated into neuronal membranes; they increase membrane fluidity and are converted into phospholipids and second messengers modulating inflammation, oxidative stress, and neuronal health [100]. DHA seems to be involved in memory processes, since higher DHA levels have been shown to enhance hippocampal-dependent learning processes [101]; moreover, it has been linked to the phenomenon of hippocampal neurogenesis in the adult brain [102,103]. In the brain, DHA exerts a protective role against apoptosis and neural degeneration being cleaved by the enzyme 15-lipoxygenase in NPD1 (neuroprotectin D1) [100]. Data from in vitro assays, cell cultures, and transgenic animal models of Alzheimer’s disease support a direct association of omega-3 FA (especially DHA) with amyloid processing in the brain [104–107]. These molecules can alter the amyloidogenetic pathway through several complex mechanisms [100]. Several cell culture and transgenic animal studies have demonstrated a reduction in amyloid plaque formation after treatment with DHA [108,109].

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Being rich of fruits, vegetables, and omega-3 FA, and poor of high glycemic foods, Mediterranean diet has been studied thoroughly; on the whole these studies demonstrated a reduction in mortality among people adhering to Mediterranean diet over the course of studies focused on heart disease, cancer, and some other diseases [110]. Mediterranean diet was associated with reductions in systolic/diastolic blood pressure, peripheral artery disease, and obesity, while it was demonstrated to be beneficial in preventing osteoporosis, rheumatoid arthritis, several forms of dementia (including Alzheimer’s disease), and cancer [110]. These effects of Mediterranean diet have been attributed to micro-components with antioxidant properties, but also to some components of virgin oil and vegetables showing anti-proliferative and pro-apoptotic effects [110]. Among the components of Mediterranean diet, carotenoids demonstrated to quench free radicals, reduce damage from reactive oxygen species, and modulate redox-sensitive transcription factors implicated in IL-6 production. Since it has been shown that low serum carotenoids are independently associated with low skeletal muscle strength and development of walking disability [111], these mechanisms might explain the protection of carotenoids against sarcopenia. Interestingly, a longitudinal study on older subjects showed that adherence to Mediterranean diet was inversely associated with the development of frailty, the risk of low physical activity, and of low walking speed [112]. Similarly, a cross-sectional study demonstrated that among in older people the risk of being frail was significantly reduced in people with higher adherence to Mediterranean diet (O.R.: 0.26; 95%C.I.: 0.07–0.98) [113]. Dairy products (i.e. milk, cheese, yoghurt) might be also important for maintaining physical performance and avoiding sarcopenia; a recent study found that older women eating more dairy products had significantly greater whole body leanmass, appendicular skeletal muscle mass, and greater handgrip strength [114]. 3.2. Evidence from dietary intervention studies Apart from the dietary intake, several macro/micronutrient supplementations have been considered to exert a possible role in the primary/secondary prevention of frailty (Table 1). With regards to primary prevention, since a higher content of DHA in red blood cells was associated with less frailty among older individuals, omega-3 supplementation was considered for its possible role in preventing the loss of physical performance. A sixmonth DHA and EPA supplementation trial induced an improvement in walking speed compared to placebo, explaining more than 13% of the variance in the change in walking speed [115]. On the other hand, several authors demonstrated the effectiveness of Vitamin D supplementation in maintaining physical performance [116,117], suggesting its therapeutic role in improving neuromuscular function and reducing not only fractures after falls, but also the incidence of falls. Moreover, in a small study by Solerte et al. [118] oral supplementation of elderly sarcopenic people with amino acid mixtures resulted not only in increased lean mass, but also in significantly reduced TNF-alpha and increased IGF-1 levels. Nutritional interventions have been also considered in the secondary prevention of frailty, and incident disability, but the results were not really promising. For example, although vitamin D supplementation has been associated with improved balance and reduced risk of falls and fracture [119,120], other studies showed no benefit on muscle power and strength [121,122]. Latham et al. [123] found that vitamin D did not improve rehabilitation outcomes in frail older people, nor physical performance, even in vitamin D deficient patients. Both carotenoids and creatine, which have demonstrated a potential benefit in primary prevention of frailty [124], have not been studied yet in secondary prevention of frailty [125], and there

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are discordant data regarding beta-hydroxi-beta-metil-butyrate and amino acid supplementation in frail older subjects [126,127]. On the other hand, a RCT by Tieland et al. [128] found an increase in muscle strength and function (but not in muscle mass) after 24 weeks of protein supplementation in frail older individuals. Leucine and other branched chain amino acids were also considered, having a positive effect on the pathway involved in muscle protein synthesis [129], but results from studies in young men lack of consistence, while studies are still not available for elderly people [130]. Daniels et al. [131] reviewed the interventions aimed at preventing disability in frail community-dwelling older individuals; these authors found that both macro/micronutrient supplementation, in spite of being effective on total energy intake and weight gain, were not able to prevent the development of disability. Nevertheless, it must be kept in mind that, as stated by the Society for Sarcopenia, Cachexia, and Wasting Disease expert panel [132], nutrition/nutrient supplementation itself might be important, although not sufficient, to avoid frailty and related-conditions. It can be concluded that adequate protein supplementation alone might only slow down the loss of muscle mass, while exercise (resistance and aerobic) in combination with adequate protein and energy intake is needed to prevent and manage sarcopenia. Tieland et al. [133] demonstrated that the combination of protein supplementation and resistance training resulted in muscle hypertrophy, increased strength and performance in frail elderly patients. Kim et al. [134] showed that the combination of leucine supplementation and physical exercise was superior to either interventions alone in increasing muscle mass and performance in sarcopenic older women. On the basis of all these results, the Position Paper from the PROT-AGE Study Group [130] considers protein supplementation an important preventive-therapeutic intervention against functional decline, especially in frail elderly with malnutrition. It should be associated with physical exercise (both endurance- and resistance-type exercises). Protein supplementation should take place just after physical exercise, to take advantage of its sensitizing effect [135], and should contain at least 2–2.5 g of leucine [130]. 4. The role of physical exercise in the prevention of frailty Physical inactivity is known to be a risk factor for several frailtyrelated pathologies including type 2 diabetes [136], CVD [137], cancer [138,139], dementia [140,141], and depression [142]; moreover, it is known to increase all-cause mortality [143]. In 2009, Pedersen [144] proposed the existence of a ‘‘physical inactivity network’’, and identified a cluster of pathologies with the term ‘‘diseasome of physical inactivity’’; the condition linking physical inactivity to all these pathologies was hypothesized to be SI. It is well known that, if over-nutrition is responsible for increased inflammatory burden, physical inactivity contributes to enhance SI, even independently of obesity [145,146]. There are multiple mechanisms by which regular physical activity protects against chronic inflammation-related diseases:  regular exercise induces the reduction of visceral fat mass, which is known to be associated with SI and IR [147,148];  skeletal muscle produces cytokines and other peptides that suppress pro-inflammatory activity with paracrine or endocrine signaling [149,150]. On the other hand, aerobic and resistance exercise are responsible for the remodelling of myocites [151,152]; through this mechanism physical activity exerts its positive effects on

Please cite this article in press as: Zuliani G, et al. Counteracting inflammation and insulin resistance with diet and exercise: A strategy for frailty prevention? Eur Geriatr Med (2015), http://dx.doi.org/10.1016/j.eurger.2014.11.010

Sample

Hutchins-Wiese et al., J Nutr Health Aging (2013) Dhesi et al., Age Ageing (2004)

126 participants

Gender

Prevention

Intervention

Endpoint

Results

F

I

2.4 g N-3 PUFA/day for 6 months

Walking speed

Improvement in walking speed

139 participants

 65 years (mean 76.6)

Both

I

600 000 UI vitamin D i.m.

Postural sway, choice reaction time, aggregate functional performance time, muscle strength, falls

122 participants

Mean 85.3 years (range 63–99)

F

I

Meta-analysis of 5 studies (1237 people) 9605 participants

> 70 years

Both (most F) F

I

1200 mg calcium plus 800 IU cholecalciferol or 1200 mg calcium per day over 12 weeks Vitamin D supplementation

Falls, muscle strength, grip strength, and the timed up andgo test Falls

Improvement in postural sway, choice reaction time, aggregate functional performance time. No improvement in muscle strength or falls Improvement in falls and muscoloskeletal function

[117]

Bischoff et al., J Bone Miner Res (2003)

[119]

Bischoff et al., JAMA (2004)

Reduction in falls

[120]

Larsen et al.,. Aging Clin Exp Res 2005

I

Falls

Reduction in falls

Mean 76 years (range 65–87)

M

I

Daily supplement of 1000 mg calcium carbonate and 400 IU (10 mg) vitamin D3 Cholecalciferol (1000 IU/d) or placebo supplementation for 6 months

[121]

Kenny et al., J Am Geriatr Soc (2003)

65 participants

Muscle strength and power, physical performance and activity, health perception

Meta-analysis of 13 trials (2496 people)

Mean 60 years

Both

I

Vitamin D supplementation

Falls and physical function

Gotshalk et al., Med Sci Sports Exerc (2002)

20 participants

59–72 years

M

I

0,3 mg/kg creatine/day for 7 days

Fat-free mass, dynamic and isometric strength, lower limbs power, gait, balance

[126]

Vukovich et al., J Nutr (2001)

30 participants

70  1 year

Both

I

Fat-free mass, fat mass

[127]

Flakoll et al., Nutrition (2004)

50 participants

Mean 76.7 years

F

I

[128]

Tieland et al., J Am Med Dir Assoc (2012)

65 participants

 65 years

?

II

beta-OH-beta-methyl-butyrate 3 g/day for 8 weeks or placebo (both with physical activity) 2 g beta-OH-beta-methyl-butyrate, 5 g arginine, and 1.5 g lysine daily for 12 weeks 15 g protein at breakfast and lunch for 24 weeks

No significant difference in strength, power, physical performance, or health perception No reduction in risk of falling (only 3/13), positive effect of calcium + vitamin D (only 1 study) Improvements in fat-free mass, dynamic and isometric strength, lower limbs power, gait, balance Significant higher increase in fat-free mass and decrease in fat mass Improvement in handgrip, leg strength, limb circumference, ‘‘get-up-and-go’’ test Improvement in physical performance, not in muscle mass nor strength

[122]

Latham et al., J Am Geriatr Soc (2003)

[124]

[115]

Age

> 65 years

Handgrip, leg strength, limb circumference, ‘‘get-up-and-go’’ test Muscle mass, strength, and physical performance

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Study

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Reference [115]

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Table 1 Studies evaluating the effect of nutritional interventions on frailty prevention in the older population.

Study

Sample

Age

Gender

Prevention

Intervention

Endpoint

Results

[168]

Liu et al., Cochrane Database Syst Rev (2009) Fiatarone et al., JAMA (1990)

Metanalysis of 121 trials, 6700 participants 10 participants

?

Both

I

Progressive resistance training

90  1 year

?

II

Resistance training (8 weeks)

Physical ability, gait speed, getting out of a chair, muscle strength Muscle strength, size, and functional mobility

[166]

Serra-Rexach, J Am Geriatr Soc (2011)

40 participants

Range 90–97 years

Both

II

Resistance training (8 weeks)

Improvement in physical ability, gait speed, getting out of a chair, muscle strength Improvements in muscle strength, size and functional mobility Improvement in muscle strength and in falls

[167]

Chin et al., Sports Med (2008) Theou et al., J Aging Res (2011)

Systematic review of 20 studies Systematic review of 47 studies

?

Both

II

Mean 81.5 years

Both (F 74.5%)

II

Resistance training, Tai-Chi, multi-component training Multi-component exercise interventions, resistance training, other exercise interventions (walking, balance training, water exercises, TaiChi, whole body vibration exercise, exercise therapy using the Takizawa Program, and exercise using a horse-riding simulator)

Cadore et al., Rejuvenation Res (2013) Chou et al., Arch Phys Med Rehabil (2012)

Systematic review of 20 studies

Mean 78.2 years

Both

II

Meta-analysis of 8 trials (1068 people)

Range of mean ages 75.3–86.8 years

Both (most F)

II

[164]

[168]

[169]

[170]

Strength training, endurance training, balance training, and multi-component exercises Flexibility, low- or intensiveresistance, aerobic, coordination, balance, and TaiChi exercises; repetitive performance of ADLs; taskoriented or gait training

Muscle strength and functional capacity (handgrip strength, 8m walk test, 4-step stairs test, timed up-and-go test, and number of falls) Functional performance Body composition, nutritional status, cardiorespiratory function (VO2 max, heart rate, BP), muscle function, flexibility, neurological function (reaction time), cognitive function, depression, mobility (walking speed and endurance, timed up-and-go test, chair rising ability, stair climbing), balance, functional performance, ADL disability, quality of life, falls

Gait ability, balance, muscle strength, falls Timed up-and-go test, gait speed, Balance, performance in ADLs, quality of life

Improvement in 14/20 studies Improvement in: weight (2/8), muscle mass (4/10), fat mass (1/5), dietary intake (6/12), cardiorespiratory function (9/ 11), muscle function (20/40), flexibility (12/15), neurological function (3/8), cognitive function (1/3), depression (2/4), mobility (41/58), balance (28/ 41), functional performance (15/15), ADL disability (7/16), quality of life (4/10), falls (6/7). No improvement in BMI, bone mass, calf and arm circumference, muscle fiber distribution Improvement in: falls (7/10), gait ability (6/11), balance (8/ 10), muscle strength (9/13) Improvement in balance, gait speed, ADL performance. No improvement in timed up-andgo test and quality of life.

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Reference

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Please cite this article in press as: Zuliani G, et al. Counteracting inflammation and insulin resistance with diet and exercise: A strategy for frailty prevention? Eur Geriatr Med (2015), http://dx.doi.org/10.1016/j.eurger.2014.11.010

Table 2 Studies evaluating the effect of physical activity interventions on frailty prevention in older populations.

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muscle, increasing its strength and other parameters such as balance and reaction time [153,154]. The anabolic action of physical exercise on muscle protects against the development of sarcopenia, and maintains mineral bone density, preventing the development of osteoporosis. Together with these effects, the decrease in fat mass, increase in insulin sensitivity, and the reduction of blood pressure induced by resistance training protect against the development of metabolic syndrome. It’s principally based on these considerations that Sundell, in an interesting review [155], reached the sharable conclusion that resistance training might have a pivotal role in the prevention of both metabolic and frailty syndromes. In the Health Aging and Body Composition study, Peterson et al. evaluated the effects of different ‘‘degrees’’ of physical exercise on the development/worsening of frailty (five years follow-up) [156]. The authors distinguished between sedentary lifestyle, active lifestyle, and active exercise. Among non-frail subjects, both active lifestyle and exercise groups displayed a lower risk of developing frailty compared with sedentary patients, while among frail people active exercise, but not active lifestyle, prevented the worsening of frailty. Vermeulen et al. [157] evaluated several indicators of frailty, and found that gait speed was the most powerful predictor of future disability development. A recent Japanese study demonstrated that aerobic exercise was effective in preventing the progression of frailty and further disability in older adults [158]. Another key component of physical frail phenotype is cognitive decline; a low cognitive function has been associated with an increased risk of developing frailty over ten year-period [159]. Interestingly, the accumulation of amyloid in the brain might be a crucial step [160]; indeed, Alzheimer’s disease pathology, with or without clinical dementia, has been associated with frailty syndrome. Cognition is modulated by physical activity, as demonstrated by several studies [161,162]. The real mechanisms through which physical exercise protects against dementia are not clear, but higher testosterone levels (in men) and increased cerebral blood flow and decreased IR (in both sexes) have been

proposed as potential mechanisms leading to decreased amyloid accumulation and increased hippocampal neurogenesis and synaptic plasticity [162]. 5. Evidence from exercise intervention studies A large number of studies evaluated the possible effect of physical exercise on frailty and disability (Table 2); nevertheless, they are characterized by a very large variability as regards sample size, definition of frailty and its severity, type of exercise/exercise program, measurements and outcomes; thus, it is really difficult to obtain an overall picture and draw firm conclusions. Primary prevention of frailty by progressive resistance strength training (PRT) was evaluated in a Cochrane meta-analysis [163]. This study evaluated the results of 121 trials with a total of 6700 participants, and found that PRT improved physical ability, gait speed, capacity of getting out of a chair, and muscle strength; moreover, patients with osteoarthritis reported a reduction in chronic pain. The authors concluded that physical activity might be an effective intervention in improving physical functioning in older people, including improving strength and the performance in some simple and complex activities. As regards secondary prevention of frailty, several works appeared in current literature, giving different results. Works by Fiatarone et al. [164,165] and Serra-Rexach et al. [166] showed a positive effect of physical exercise on muscle strength and function in frail elderly people. Positive effects of exercise on ADLs were found also in the two meta-analysis [167,168]. The first included 20 studies focused on the effect of 23 different physical exercise programmes (comprising resistance training, Tai-Chi training, and multi-component training). The authors concluded that frail older adults with different levels of ability can improve their functional performance by regular exercise training, but underlined that more high-quality trials are needed to determine the most appropriate design of the exercise programme (notably, six of the trials included into this meta-analysis showed no effect of exercise training on functional performance, and this result might depend

Fig. 3. Possible approach to primary and secondary prevention of frailty syndrome based on diet and physical exercise.

Please cite this article in press as: Zuliani G, et al. Counteracting inflammation and insulin resistance with diet and exercise: A strategy for frailty prevention? Eur Geriatr Med (2015), http://dx.doi.org/10.1016/j.eurger.2014.11.010

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Positive effect on physical measures without effect on disability (improvement in only 3/10)

Disability and physical measures (weight gain, strength, mobility, oxygenuptake, physical fitness, physical activity and balance) Lean body mass, strength and physical performance

Muscle strength, gait velocity, stair climbing, spontaneous physical activity, muscle area Resistance training, multinutrient supplementation or both (10 weeks) II Both (F 63%) Fiatarone et al., N Engl J Med (1994) [165]

100 participants

Mean 87.1 years (range 73–98)

3 g/day of leucine-rich amino acid mixture for 3 months or multi-component physical activity or both interventions II F  75 years Kim et al., J Am Geriatr Soc (2012) [134]

155 participants

Both Tieland et al., J Am Med Dir Assoc (2012) [133]

62 participants

78  1 year

II

Muscle mass, walking speed, knee extension

Improvements of strength and physical performance in both groups, increase of lean body mass only in protein supplementation group Increase in walking speed in all 3 intervention groups, of muscle mass in exercise and exercise + supplementation group, of knee extension only in exercise + supplementaion group. Increase in muscle strength, gait velocity, stair climbing, spontaneous physical activity, muscle area (only in physical activity group)

Results Endpoint Intervention

Macro- or micronutrient supplementation, single component physical activity (lower limb strength) or multicomponent Protein (2  15 g/day) or placebo, both with resistance training program for 24 weeks II Both  65

Prevention Gender Age

Systematic review of 10 studies Daniels et al., BMC Health Serv Res (2008)

Sample Study Reference

[131]

Table 3 Studies evaluating the combined effect of nutritional and physical activity interventions on frailty prevention in older populations.

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on the type of exercise programme. Theou et al. [168] found that exercise had a positive impact on functional ability outcomes in frail people, but concluded that the exercise programmes that optimize the health of frail older adults seemed to be different from those recommended for healthy older adults. Despite there was paucity of evidence to characterise the most beneficial exercise programme in this population, multi-component training interventions of long duration [156], Tai-Chi, and cobblestone walking [125] generally gave the best outcomes. The recent meta-analysis by Cadore et al. [169] showed similar results, reaching the conclusion that the multi-component exercise intervention composed by strength, endurance, and balance training seems to be the best strategy to improve rate of falls, gait ability, balance, and strength performance in physically frail older adults. Worse conclusions were drawn from two other meta-analyses. Chou et al. [170] found that in frail older individuals exercise just induced a slight improvement in gait speed, balance, and functional performance, but these improvement had no effect on the quality of life. Daniels et al. [131] found that despite its positive effect on strength and walking function, a single lower extremity strength training was not able to prevent disability development in frail people. However, the authors concluded that long-lasting and high-intensive exercise programs for moderately frail older people might be effective on disability outcomes. Thus, physical exercise might be important in primary prevention of frailty while, among frail older people, it may be useful in the prevention of disability, but evidences are less strong. Probably, the best results in terms of primary and secondary prevention of frailty can be obtained joining dietary and physical interventions (Fig. 3). The results of studies evaluating the effectiveness of joined dietary/exercise interventions are resumed in Table 3. Since one of the most important outcomes of frailty is increased mortality, we finally report the results of the HALE project [171]. This longitudinal European study evaluated the effect of different lifestyle patterns on all-cause ten-year mortality in a cohort of over 2300 older individuals aged 70 to 90 years. The study clearly showed that adhering to the Mediterranean diet (HR: 0.77; 95%CI: 0.68–0.88) and regular physical activity (HR: 0.63; 95% CI: 0.55–0.72), together with moderate alcohol intake (HR: 0.78; 95% CI: 0.67–0.91), and non smoking (HR: 0.65; 95% CI: 0.57–0.75) were associated with a lower all-cause mortality. On the whole, lack of adherence to this ‘‘low-risk lifestyle pattern’’ was associated with a population attributable risk of 60% of all deaths.

6. Conclusions The existence of a strong relationship between IR, SI and frailty syndrome in the elderly is convincing. The effect of these pathological conditions on the pathogenesis of frailty might be either direct, through a negative impact on homeostatic regulation and cross-systems compensation, or mediated by the effect of several diseases strongly related to frailty, above all sarcopenia and cognitive decline. Diet and physical exercise may represent two important weapons in the prevention of physical frailty. Current literature provides support to the notion that a correct life style based on healthy diet (avoiding over-nutrition, Mediterranean type diet) and regular physical exercise might be two cornerstones of frailty primary prevention. Studies on secondary prevention of frailty suggest that multicomponent and resistance training together with adequate energy and protein intake might be helpful, although data are less strong; moreover, the efficacy of dietary supplementation in secondary

Please cite this article in press as: Zuliani G, et al. Counteracting inflammation and insulin resistance with diet and exercise: A strategy for frailty prevention? Eur Geriatr Med (2015), http://dx.doi.org/10.1016/j.eurger.2014.11.010

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prevention of frailty, albeit promising, remains to be confirmed in large clinical trials. Future research on frailty prevention should focus on:  identification of a standard definition of frailty, essential for evaluating the possible effect of interventions at earlier stages or along the continuum of the syndrome;  standardization of the outcomes measured in intervention studies;  realization of randomized multifactorial trials based on different combinations of dietary (supplementations) and physical exercise intervention;  comparison of cost-effectiveness analysis for different preventive approaches.

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