Dietary patterns and changes in frailty status: the Rotterdam study

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1 DOI /s ORIGINAL CONTRIBUTION Dietry ptterns nd chnges in frilty sttus: the Rotterdm study Sndr C. M. de Hs 1,2 Ester A. L. de Jonge 1,3 Trudy Voortmn 1 Jolien Steenweg de Grff 1 Oscr H. Frnco 1 M. Arfn Ikrm 1 Fernndo Rivdeneir 1,3 Jessic C. Kiefte de Jong 1,4 Josje D. Schoufour 1,3 Received: 20 Mrch 2017 / Accepted: 11 July 2017 The Author(s) This rticle is n open ccess publiction Abstrct Purpose To determine the ssocitions between priori nd posteriori derived dietry ptterns nd generl stte of helth, mesured s the ccumultion of deficits in frilty index. Methods Cross-sectionl nd longitudinl nlysis embedded in the popultion-bsed Rotterdm Study (n = 2632) ged 45 yers. Diet ws ssessed t bseline (yer 2006) using food frequency questionnires. Dietry ptterns were defined priori using n existing index reflecting dherence to ntionl dietry guidelines nd posteriori using principl component nlysis. A frilty index ws composed of 38 helth deficits nd mesured t bseline nd follow-up (4 yers lter). Liner regression nlyses were performed using dherence to ech of the Sndr C. M. de Hs nd Ester A. L. de Jonge contributed eqully to this mnuscript. Electronic supplementry mteril The online version of this rticle (doi: /s ) contins supplementry mteril, which is vilble to uthorized users. * Josje D. Schoufour j.schoufour@ersmusmc.nl 1 Deprtment of Epidemiology, University Medicl Centre, Ersmus MC, P.O. Box 2040, 3000 CA Rotterdm, The Netherlnds 2 VU University Amsterdm, Amsterdm, The Netherlnds 3 Deprtment of Internl Medicine, University Medicl Centre, Ersmus MC, P.O. Box 2040, 3000 CA Rotterdm, The Netherlnds 4 Deprtment of Globl Public Helth, Leiden University College The Hgue, P.O. Box 13228, 2501 EE The Hgue, The Netherlnds dietry ptterns s exposure nd the frilty index s outcome (ll in Z-scores). Results Adherence to the ntionl dietry guidelines ws ssocited with lower frilty t bseline (β 0.05, 95% CI 0.08, 0.02). Additionlly, high dherence ws ssocited with lower frilty scores over time (β 0.08, 95% CI 0.12, 0.04). The PCA reveled three dietry ptterns tht we nmed Trditionl pttern, high in legumes, eggs nd svory sncks; Crnivore pttern, high in met nd poultry; nd Helth Conscious pttern, high in whole grin products, vegetbles nd fruit. In the cross-sectionl nlyses dherence to these ptterns ws not ssocited with frilty. However, dherence to the Trditionl pttern ws ssocited with less frilty over time (β 0.09, 95% CI 0.14, 0.05). Conclusion No ssocitions were found for dherence to helthy pttern or Crnivore pttern. However, Even in popultion tht is reltively young nd helthy, dherence to dietry guidelines or dherence to the Trditionl pttern could help to prevent, dely or reverse frilty levels. Keywords Dietry ptterns Diet qulity Elderly Frilty Frilty index Introduction Although there is no complete consensus on the conceptuliztion of frilty, experts gree tht frilty is stte of incresed vulnerbility to dverse helth outcomes [1]. The frilty index, developed by Mitnitski nd Rockwood, pprises frilty s the ccumultion of helth-relted nd ge-relted deficits [2]. The included deficits cover brod rnge of helth spects including cognition, disbilities, lbortory bnormlities, nd comorbidities [3]. Severl Vol.:( )

2 studies, mong different ge-ctegories nd popultions, show tht high frilty index score is ssocited with n incresed risk for disbility, flls, hospitliztion, nd mortlity [4 7]. Prevention of frilty is importnt becuse it is difficult to recover from fril stte to non-fril stte [8]. One importnt modifible fctor tht might either positively or negtively influences frilty is diet. Most reserch on nutrition nd frilty or overll helth sttus hs focussed on single nutritionl components [9], such s mcronutrients nd micronutrients. Although these studies hve provided vluble knowledge towrds possible nutritionl strtegies to prevent frilty (e.g., high protein intke [10, 11], people do not et single nutritionl components but mels, combined into ptterns. Dietry pttern pproches tke into ccount the totlity of the diet nd llow for possible interctions nd synergetic effects of nutritionl components [12]. One wy to define person s dietry pttern is vi priori pproch, studying dherence to existing dietry guidelines or recommendtions in reltion to helth outcomes. Alterntively, n posteriori pproch llows the identifiction of nturlly occurring dietry ptterns of popultions [13]. The dvntge of n priori pproch is tht it llows for comprison between studies. The posteriori pproch hs the dvntge tht cn identify new dietry ptterns, which could led to improvements of current dietry guidelines. Tking into ccount both complementry pproches provides most insight into possible ssocition between dietry ptterns nd frilty. Although few previous studies evluted dietry ptterns nd frilty, the mjority of studies on frilty nd nutrition use the frilty phenotype s n outcome [9, 14 17]. The frilty phenotype defines frilty s the presence of three out of five physicl frilty symptoms (weight loss, wekness, exhustion, slowness nd low ctivity) [4]. Although this method hs gret dvntges for clinicl prctice, due to its physicl orienttion, it is less useful s mesure of overll helth [18]. A different, more holistic pproch to frilty is the frilty index [2]. Informtion on how dietry ptterns re ssocited with the frilty index is scrce. To our knowledge, only one previous study, by Woo et l., exmined dietry ptterns nd the frilty index nd found tht better diet qulity ws ssocited with lower frilty index [14]. Nevertheless, no longitudinl studies ssessing the ssocition between diet qulity nd chnges in frilty index over time hve been performed. To provide more insight into how diet qulity is ssocited with the frilty index nd chnges in frilty sttus over time we im to: (1) exmine the cross-sectionl ssocition between dherence to ntionl dietry guidelines ( priori defined dietry pttern) nd popultion-specific ( posteriori derived) dietry ptterns nd the frilty index in middle-ged nd elderly popultions nd (2) exmine if these priori nd posteriori defined dietry ptterns re ssocited with chnges in frilty over 4-yer follow-up period. Methods Study popultion nd design This study ws embedded in the Rotterdm Study (RS) n ongoing prospective cohort in the Netherlnds [19]. A more detiled description of the RS is provided elsewhere [19]. Briefly, the first bseline visits took plce between 1990 nd All residents ged 55 yers nd over in the Ommoord district of Rotterdm (n = 10,215), the Netherlnds, were invited to prticipte, of which 7983 (78%) took prt in the RS s first cohort (RS-I). The study ws extended in the yer 2000 (RS-II; n = 3011) nd in 2006, inviting ll residents ged 45 yers nd over (RS-III; n = 3932). In totl, 14,926 prticipnts were included in the RS, who visited the reserch center for detiled mesurements every 3 4 yers. During n extensive home interview, trined reserch ssistnts collected dt on brod rnge of helth vribles including, ctivities of dily living, current helth sttus, use of mediction, depression nd lifestyle. Subsequently, prticipnts visited the study center for detiled exmintions with n emphsis on imging, collection of body fluids, nd physicl functioning. The RS ws pproved by the Medicl Ethics Committee of the Ersmus Medicl Center nd by the review bord of The Netherlnds Ministry of Helth, Welfre nd Sports. All prticipnts signed n informed consent. This study dheres to the Declrtion of Helsinki for reserch involving humn subjects. For the current study, we included the first nd second visit of the third cohort of the RS (RS-III-1nd RS-III-2) comprising of 3932 prticipnts. For 2632 prticipnts, vlid dietry intke nd frilty index were vilble t bseline ( ) nd for 2253 prticipnts frilty index ws lso vilble t follow-up ( , Fig. 1). Dietry ssessment Dietry intke ws mesured with self-dministrted semi-quntittive food frequency questionnire (FFQ) developed by Wgeningen University nd Reserch centre, dpted for the Rotterdm Study. The bility of the FFQ to rnk people ccording to their intke ws previously shown in two vlidtion studies using 9-dy dietry record [20] nd 4-week dietry history [21]. The FFQ includes 389 items bout the frequency nd mount of consumed food items in dys, weeks nd months ccording to the previous yer nd ws filled out t home. For the estimtion of the portion sizes in grms stndrdized household mesures were pplied [22]. For clcultion of the nutritionl dt the

3 Full cohort RS-3-1 N = 3932 Pr cipnts eligible for dietry intke ssessment n= 2692 Pr cipnts with relible FFQ dt n= 2644 Included in our crosssec onl nlysis n= 2632 Included in our followup nlysis n= 2253 Dutch Food Composition Tble (NEVO) of 2006 ws used [23]. Prticipnts with extremely high (>5000 kcl) or low (<500 kcl) dily energy intke were excluded s it ws ssumed tht their questionnire ws unrelible (Fig. 1). Dietry ptterns Not ended study center n = 275 FFQ not vilble n= 965 Extremely high or low dily energy intke n= 48 No frilty index t bseline n = 12 Lost to follow-up n = 373 No frilty index t follow-up n= 6 Fig. 1 Flowchrt of the study popultion. FFQ Food Frequency Questionnire Two different pproches to determine dietry ptterns were pplied: (1) n priori defined index for diet qulity nd (2) posteriori defined dietry ptterns using principl component nlysis (PCA). A priori defined ptterns nd ssignment of pttern dherence scores We pplied The Dutch Helthy Diet index (DHD-index), developed by vn Lee et l. [24]. The DHD-index is vlidted index, exmining dherence to the Dutch Guidelines for Helthy Diet of 2006 from the Dutch Helth Council [25, 26]. The originl DHD-index included ten guidelines bsed on the recommendtions of the Dutch Helth Council (Supplementry Tble I). Prticipnts received sub-score, using 10-point scle tht reflected their dherence to ech of these ten guidelines. These sub-scores were then summed to obtin single index for ech prticipnt. No informtion ws vilble on the use of fish oil cpsules, so only dietry intke of fish ws included. Due to limited informtion on cidic drinks nd foods in our cohort, nd becuse we were solely interested in the effect of diet, we creted n dpted version of this originl index excluding cidic drinks nd physicl ctivity, with theoreticl rnge of 0 till 80 points. A higher score represented higher dherence to the ntionl guidelines. A posteriori defined ptterns nd ssignment of pttern dherence scores All food items were ctegorized into 28 pre-defined food groups to reduce the complexity of dietry dt. An overview of these food groups, which were bsed on similrities in product composition (for exmple len versus ft diry products) or culinry use (for exmple redymde mels), is shown in Supplementry Tble II. Next, dietry ptterns were derived by PCA on intke of these food groups in grms per dy, undjusted for totl energy intke. We used vrimx rottion nd Kiser Normliztion to obtin ptterns with simpler structure [27] nd optiml interpretbility. Fctor lodings, which reflect the correltion between food group nd dietry pttern, were used to chrcterize nd lbel pttern using cut-off of 0.2. Food groups with fctor loding >0.2 indicte positive contribution nd < 0.2 negtive contribution to specific pttern [46, 47]. Adherence to ptterns with n Eigenvlue ( mesure of explined vrince) of >1.5 only ws studied in reltion to the frilty index. For ech prticipnt, pttern dherence scores (Z-scores) were constructed by summing up observed intkes of the pttern s food groups weighted by the corresponding fctor loding for ech of the three dietry ptterns seprtely. Frilty index Frilty ws mesured with frilty index, n instrument bsed on the ccumultion of helth deficits [2]. In generl, deficits cn be symptoms, signs, diseses, disbilities nd lbortory mesurements s long s they re ge-relted nd helth-relted nd re not too exceptionl or too common [3]. We used slightly dpted version of previous vlidted frilty index designed for the Rotterdm Study, consisting of 38 helth-relted vribles covering severl helth domins: functionl sttus (n = 13), helth conditions (n = 6), cognition (n = 6), diseses (n = 6), nutritionl sttus (n = 3) nd mood (n = 4) [28]. Deficits were dichotomized or ctegorized into score rnging from

4 0 (not present) till 1 (present). Per person, the number of present deficits ws divided by the totl number of deficits, providing continuous score rnging from 0 (no deficits present, lest fril) till 1 (ll deficits present, extremely fril). Missing vlues on the deficits were imputed using multiple imputtion by chined equtions [28]. Individuls with less thn 20 observed items were determined to hve insufficient informtion to considerbly contribute to vlid frilty index nd were excluded from the nlyses (Fig. 1). To be ble to evlute chnges over time we hd to remove seven items from the originl Rotterdm Study Frilty Index, nmely: vitmin D, sex hormone binding globulin, mobility, uric cid, probnp, CRP nd homocysteine. Becuse, unfortuntely, these biomrkers were not ssessed t follow-up. Chrcteristics of the originl Rotterdm Study frilty index nd the dpted version re provided in Supplementry Tble III, no mjor differences in the men or medin were observed. Furthermore, the two scles hd high mutul correltion (r = 0.98) nd similr ssocitions with ge nd mortlity (Supplementry Tble III). Covrites Height (cm) nd body weight (kg) were mesured t the reserch center using stdiometer wering light clothing. Body mss index (BMI) ws clculted s body weight (kg) divided by height (m) 2. Smoking sttus ws clssified s never, former or current smoker. Level of eduction ws determined by the highest ttined eduction nd clssified s low (primry eduction nd lower voctionl eduction), middle (secondry generl eduction nd secondry voctionl eduction), middle-high (higher generl eduction) or high (higher voctionl eduction or university eduction). Monthly household income ws clssified s low (< 1.500), middle ( ) or high (> 2.900). Physicl ctivity ws ssessed with the LASA physicl ctivity Questionnire (LAPAQ) nd metbolic equivlents (MET) scores were clculted s the sum of hours week spent in light, moderte or vigorous ctivity (wlking, cycling, grdening, sports, nd hobbies), expressed in metbolic equivlent of tsk (MET) score [29]. MET scores represent the energy tht is required for n ctivity divided by the energy necessry t rest [30]. Totl energy intke in kiloclories per dy nd use of dietry supplements (yes/ no) were ll retrieved from the FFQ. Sttisticl nlysis First, bseline chrcteristics of the study popultion were shown in strt of frilty, dichotomized t the medin. A p vlue for the observed vlues ws provided using independent smple t tests for continuous vribles nd X 2 for ctegoricl vribles. Second, liner regression nlyses were performed to exmine the cross-sectionl ssocitions between dherence to ech dietry pttern nd the frilty index t bseline (ll in Z-scores). Anlyses were performed s bsic model, djusted for ge nd sex (model 1), followed by model tht ws dditionlly djusted for smoking, level of eduction nd income, physicl ctivity, dietry supplement use (model 2), nd model dditionlly djusted for energy intke (model 3). Confounders were tested bsed on previous studies [31, 31] nd included in the models if they substntil chnge in effect-estimte on t lest one of the dietry ptterns (>10%). Additionlly, the three posteriori derived dietry ptterns were djusted for ech other. The third models were djusted for totl energy intke becuse by design of the DHD-index, it might be esier to dhere to the guidelines t higher levels of energy intke. Third, we evluted the ssocition between the dietry ptterns nd chnges in frilty index over time. To test if the frilty index chnged significntly over time we pplied pired t test. Therefter, in line with the cross-sectionl results we creted bsic model nd n djusted model, using the frilty index t follow-up s n outcome, dditionlly djusting for the bseline frilty index. The coefficients of this model cn be interpreted s the difference between the men chnge frilty index score for ech unit increse in exposure [32]. For the posteriori defined dietry ptterns we clculted the food group intkes corresponding to 1SD difference in dietry pttern dherence to increse the interpretbility of the results. To exclude the possibility tht results were driven by nutrition-ssocited deficits in the frilty index, we creted frilty index without BMI, HDL nd totl cholesterol nd rern the nlyses. Additionlly, we performed severl sensitivity nlyses using the cross-sectionl dt. To test potentil selection bis, we clculted nd compred the frilty index score for prticipnts included nd excluded in the min nlyses. We tested for potentil interction by dding the product term of dherence to ech of the dietry ptterns with totl energy intke to model 3. A similr pproch ws used to study interction with sex, ge nd BMI. Strtified nlyses were performed if the p for interction ws <0.05. Lst, we performed the nlyses in subgroups fter excluding (1) prticipnts with incomplete dietry intke dt (>1% missing items in the FFQ), nd (2) prticipnts who decesed within 3 yers fter bseline. Anlyses were performed using SPSS sttisticl softwre (IBM, version 23). A p vlue <0.05 ws considered sttisticlly significnt.

5 Results Subject chrcteristics The medin (interqurtile rnge) frilty index of our popultion (n = 2632) ws 0.14 (0.09, 0.19). Chrcteristics of our study popultion in strt of the frilty index bove nd below the medin re shown in Tble 1. On verge, prticipnts were 57 yers (SD = 7.2) nd the men DHD-index for the full popultion ws 56.2 (SD 9.28). Dietry ptterns derived by principl component nlysis A posteriori, we derived three popultion-specific dietry ptterns tht we lbeled: (1) Trditionl pttern, chrcterized by high intke of svory sncks, legumes, eggs, fried pottoes, lcohol, processed met nd soup; (2) Crnivore pttern, chrcterized by high intke of red met nd poultry with low intke of met replcements; nd (3) Helth Conscious pttern, chrcterized by high intke of whole grins, vegetbles, fruit nd nuts. The fctor lodings of the food groups re presented in Tble 2. The Trditionl ptternexplined 10.0%, the Crnivore pttern 7.7% nd the Helth Conscious pttern 5.4% of the totl vrince in food group intke (Tble 2). The DHDindex ws positively ssocited with the Trditionl pttern (Person s r = 0.37) nd with the Helth Conscious pttern (Person s r = 0.13), nd negtively ssocited with the Crnivore pttern (Person s r = 0.25). Tble 1 Bseline chrcteristics of the study smple Low frilty index ( the medin ) High frilty index (>the medin) p vlue c n Bseline chrcteristics Sex (% men) 565 (42%) 534 (42%) 0.48 Age (yers) b 55.9 (5.2) 58.1 (7.1) <0.001 Smoking (%) 0.07 Never 447 (33%) 375 (29%) Former 575 (42%) 595 (46%) Current 328 (24%) 312 (24%) Income (%) <0.001 Low 169 (13%) 296 (23%) Middle 543 (40%) 604 (47%) High 638 (37%) 382 (30%) Level of eduction (%) <0.001 Low 257 (19%) 411 (32%) Middle 565 (42%) 506 (40%) High 525 (39%) 357 (28%) Alcohol use (glsses per dy) 1.36 (1.47) 1.26 (1.68) 0.09 Supplement use (% yes) 646 (48%) 677 (53%) 0.01 Frilty index score 0.09 (0.03) 0.21 (0.03) <0.001 Dutch Hethy Diet Index 56.6 (9.10) 55.9 (9.46) Adherence to Trditionl pttern (Z-scores) 0.06 (0.96) 0.06 (0.95) Adherence to Crnivore pttern (Z-scores) 0.04 (0.89) 0.03 (0.96) Adherence to Helth Conscious pttern (Z-scores) 0.03 (1.00) 0.05 (0.96) BMI (kg/m 2 ) 26.2 (3.65) 28.9 (4.98) <0.001 Energy intke (kcl) 2334 (696) 2250 (737) Physicl ctivity: METh/week 61.6 (55.1) 53.9 (62.2) <0.001 BMI body mss index, METh metbolic equivlent of tsk in hours Our popultion- specific medin is 0.14 b Men + SD c p vlue clculted using independent smple t-tests for continuous vribles nd X 2 for ctegoricl vribles

6 Tble 2 A posteriori defined dietry derived from principl component nlysis Food groups Trditionl pttern Crnivore pttern Helth Conscious pttern Whole grin products 0.76 Refined grin products Len diry products 0.27 Ft diry products Fruit Vegetbles 0.50 Legumes 0.51 Pottoes Fried pottoes 0.45 Poultry 0.48 Unprocessed red met 0.65 Processed met Met lterntives Eggs 0.47 Len fish Ftty fish Redymde mels Te 0.28 Coffee Wter nd diet sod Sugr sweetened beverges Alcohol 0.41 Sweet sncks Svory sncks Nuts Vegetble oils nd spreds 0.20 Animl fts Soup, suce, grvy nd dressing Eigenvlue Explined vrince (%) Food groups with fctor loding between 0.20 nd 0.20 were not shown Cross sectionl results: ssocitions between dietry pttern dherence nd the frilty index In the fully djusted models, priori defined dherence to the DHD-index ws ssocited with lower frilty index scores (β (95% CI) = 0.07 ( 0.10, 0.03), Tble 3, model 3. This implies tht with every SD increse in DHD-index (1 SD = 9.28) the frilty index ws on verge 0.05 SD lower (1 SD = 0.08). More specificlly, ny of the following ws ssocited with 0.08 lower frilty index score: 200 g of vegetbles, 14 g fibers per 100 kcl dy or <1 energy % trns ftty cids (supplementry dt Tble 1). After djustment for ll covrites nd energy intke, of the posteriori pttern only the Crnivore pttern ws ssocited with frilty (Tble 3). The interprettion of the Z-scores (one SD difference) for ech dietry pttern is provided in Supplementry Tble V. Longitudinl results: ssocitions between dietry pttern dherence nd chnges in the frilty index In totl, 2253 prticipnts were included in the longitudinl nlyses. For these prticipnts, the medin frilty index t follow-up ws 0.14 (SD = 0.08) nd frilty index ws lower t follow-up thn t bseline (SD = 0.06, p vlue <0.001). Higher dherence to the priori defined DHD-index nd the posteriori Trditionl pttern t bseline were ssocited with reduced frilty indices overtime in ll models, β (95% CI) = 0.07 ( 0.10, 0.04) nd β (95% CI) = 0.07 ( 0.11, 0.04), respectively, Tble 4, model 3. These results imply tht with ny of the following the frilty index t follow-up ws lower: 21 g/dy increse in refined grin products, 13 g/ dy increse in pottoes or 18 g/dy increse in svory sncks (supplementl tble V). Adherence to the posteriori derived Crnivore pttern ws ssocited with n incresed frilty index overtime in model 2, β (95% CI) = 0.03 (0.00, 0.07), but these results were no longer significnt if djusted for energy intke. The posteriori defined Helth conscious pttern ws not ssocited with chnges in frilty. Sensitivity nlyses We observed tht excluded prticipnts hd on verge higher frilty index score (men 0.18) thn the included prticipnts (men 0.14, p vlue <0.001). Additionl djustment by BMI did not highly influence the results. However, the cross-sectionl nlyses between dherence to the Crnivore pttern with frilty ws no longer significnt. We did not observe significnt interction terms between ny of the dietry ptterns nd gender (p vlue rnge ), totl energy intke (p vlue rnge ) or BMI (p vlue rnge ) on frilty. Supplementry Tble IV shows the sensitivity nlyses for the cross-sectionl results. Using the originl 45-item frilty index did not influence the ssocition between the priori derived DHD-index nd frilty (Supplementry Tble IV). Excluding prticipnts tht decesed within 3 yers (n = 38) or prticipnts with incomplete FFQ dt (n = 867) provided similr results for the priori derived DHD-index, wheres the posteriori derived Crnivore pttern ws significntly ssocited with higher frilty scores when excluding prticipnts who died within 3

7 Tble 3 Cross-sectionl ssocitions between dherence to dietry ptterns nd the frilty index t bseline (n = 2632) Dietry pttern Model 1 Model 2 Model 3 β (95% CI) β (95% CI) β (95% CI) A priori defined Reflection of dherence to ntionl dietry guidelines Dutch helthy diet index (DHDI) 0.08 ( 0.12, 0.05) 0.07 ( 0.10, 0.03) 0.07 ( 0.10, 0.03) A posteriori defined Reflection of popultion-specific dietry ptterns Trditionl pttern 0.04 ( 0.08, 0.05) 0.00 ( 0.04, 0.03) 0.01 ( 0.03, 0.05) Crnivore pttern 0.05 (0.01, 0.09) 0.04 ( 0.00, 0.08) 0.05 (0.01, 0.07) Helth conscious pttern 0.02 ( 0.01, 0.06) 0.03 ( 0.01, 0.06) 0.03 ( 0.01, 0.07) Model 1: djusted for ge nd sex Model 2: djusted for ge, sex, smoking, level of eduction, income, physicl ctivity, nd supplement use Model 3: djusted for ge, sex, smoking, level of eduction, income, physicl ctivity, supplement use nd totl energy intke Adherences to posteriori defined ptterns were dditionlly djusted for ech other Regression coefficients represent the differences in frilty index t bseline (in Z-scores, one Z-score represent frilty index score of 0.08) per Z-score increse in dietry pttern dherence Bold vlues indicte the significnce bsed on p vlue of <0.05 Tble 4 Longitudinl ssocitions between dherence to dietry ptterns nd chnges in the frilty index between follow-up nd bseline (n = 2253) Dietry pttern Model 1 Model 2 Model 3 β (95% CI) β (95% CI) β (95% CI) A priori defined Dutch Helthy Diet Index (DHDI) A posteriori defined Trditionl pttern Crnivore pttern Helth conscious pttern Reflection of dherence to ntionl dietry guidelines 0.07 ( 0.10, 0.04) 0.07 ( 0.10, 0.03) 0.07 ( 0.10, 0.04) Reflection of popultion-specific dietry ptterns 0.08 ( 0.11, 0.05) 0.07 ( 0.11, 0.04) 0.07 ( 0.11, 0.04) 0.04 (0.01, 0.08) 0.03 (0.00, 0.07) 0.04 ( 0.01, 0.07) 0.01 ( 0.03, 0.03) 0.01 ( 0.03, 0.04) 0.01 ( 0.03, 0.04) Model 1: djusted for ge, sex nd bseline frilty index (in z-scores) Model 2: djusted for ge, sex, bseline frilty index (in z-scores), smoking, level of eduction, income, physicl ctivity, nd supplement use Model 3: djusted for ge, sex, bseline frilty index (in z-scores), smoking, level of eduction, income, physicl ctivity, supplement use, nd totl energy intke Adherences to posteriori defined ptterns were dditionlly djusted for ech other Regression coefficients represent the differences in frilty index over the follow-up period (in Z-scores, one Z-score represent frilty index score of 0.06) per Z-score increse in dietry pttern dherence Bold vlues indicte the significnce bsed on p vlue of <0.05 yers nd prticipnts without fully complete FFQs (Supplementry Tble IV). Lst, lthough effect estimtes were similr, we observed slightly stronger ssocition between the DHDI index nd frilty in prticipnts ged bove the medin (57 yers) thn in those below the medin ge (Supplementry Tble IV). Discussion In this popultion-bsed cohort of middle ged nd elderly persons, we observed tht higher dherence to n priori defined helthy dietry pttern ws ssocited with lower frilty index t bseline, nd with beneficil chnges in

8 frilty during follow-up. Furthermore, dherence to the posteriori defined Trditionl pttern ws ssocited with lower frilty index over time. Dt on the ssocition between nutrition nd frilty re scrce nd direct comprison of our results with published dt is chllenging for severl resons. First, other studies used different definitions of frilty or overll helth. For exmple, socil helth, self-perceived helth nd resilience re identified to be importnt for helthy ging nd re, therefore, included in severl helthy ging instruments, but re not prt of the frilty index [33]. Additionlly, studies regrding frilty nd dietry ptterns use the frilty phenotype, defined s the presence of three out of five physicl frilty symptoms: weight loss, self-reported exhustion, wekness, slow wlking speed, nd low physicl ctivity [4]. The frilty phenotype is physiclly orientted nd is distinct from disbilities, chronic diseses, cognition nd mentl helth, wheres the frilty index does includes these helth domins. Second, ntionl dietry guidelines nd popultion-specific dietry ptterns differ per country nd per study popultion, s they re shped by locl or culturl hbits nd vilbility of food products [13]. Overll, previous studies found inconsistent results regrding the ssocition between priori defined dietry ptterns nd frilty, or spects of frilty. To our knowledge, Woo et l. [14] re the only ones to report on the ssocition between the frilty index nd n priori defined dietry pttern. They found tht dherence to the Diet Qulity Index Interntionl (DQI-I), n index bsed on (1) overll food group vriety, (2) dequcy of vegetbles, fruit, grins, fiber, protein, iron, clcium nd vitmin C, (3) modertion of totl ft, sturted ft, cholesterol, sodium nd empty clorie foods, nd (4) overll blnce in mcronutrient intke nd ftty cid rtio [34] ws ssocited with lower frilty index. However, they did not djust for other lifestyle fctors or totl energy intke. In line with our results, severl, but not ll, studies indicte tht dherence to ntionl or interntionl dietry guidelines might beneficilly ffect (physicl) frilty [9]. Smieri et l., found positive ssocition between diet qulity nd overll helth [35], wheres Akbrly et l., did not identify positive ssocition between diet qulity nd overll helth [36]. Furthermore, severl ppers report tht dherence to helthy diet (defined by different dietry guidelines) is generlly ssocited with better cognitive functioning, less depressive symptoms nd better physicl functioning [9], ll components of the frilty index. In ddition to dherence to dietry guidelines, dherence to the Mediterrnen diet hs been observed to hve severl beneficil effects on helth outcomes [37]. Previous efforts observed tht the Mediterrnen diet score ws inversely ssocited with the prevlence of physicl frilty [15], nd lower incidence of physicl frilty [16, 17]. Recently, Assmnn et l. studied overll helth nd its ssocition with posteriori defined dietry ptterns in French elderly popultion. They defined helthy ging s: not developing ny mjor chronic diseses, good physicl, nd cognitive function, no limittions in IADL, no depressive symptoms, no helth-relted limittions in socil life, good overll self-perceived helth, nd no function-limiting pin in 13-yer follow-up period. They found tht helthy dietry pttern (chrcterized by high intke of micronutrients, fibers nd ntioxidnts) ws ssocited with better helth, but only mong subjects with low energy intke [38]. In ddition, Helth Conscious or Prudent ptterns did show ssocitions with different spects of helthy ging including self-perceived helth, cognition nd depression [9, 40 43]. Contrry to our expecttions, we did not find n ssocition between the Helth Conscious pttern nd the frilty index. This non-significnt ssocition could be explined by the reltively low explined vrince of our Helth Conscious pttern (5.4%). Previously, n posteriori defined dietry pttern high in met nd ftty foods showed n inverse ssocition with overll helth, defined s mintining good mentl helth with the bsence of mjor chronic diseses nd limittions in physicl functioning [43]. This pttern shows similrities with the Crnivore pttern in our popultion. Nevertheless, we did not find n ssocition between this pttern nd frilty when models were djusted for socio-economic fctors nd lifestyle. Our sensitivity nlysis showed tht dherence to the dietry guidelines (DHD-index) ws ssocited with less frilty independent of BMI, HDL nd totl cholesterol, which re estblished intermedite helth fctors ssocited with dietry intke. We could speculte tht n overll helthy diet cn influence frilty vi severl mechnisms nd pthwys (e.g., diseses, cognition), not only vi deficits directly ssocited with nutrition. The effect estimtes observed in our study were rther smll. For exmple, the (undjusted) ssocition between dherence to the Crnivore pttern nd frilty implies tht the frilty index is points higher with every SD increse in dietry pttern dherence, which cn be ny of the following: 8 grms more poultry, 16 g more unprocessed red met or 19 g more processed met (Supplementry Tble IV). Nevertheless our results show tht dherence to helthy diet cn contribute to better overll helth sttus nd better potentil to preserve this helth sttus during 4-yer follow-up period, which cn hve importnt implictions on popultion level. Our study hs severl strengths. First, our combined use of priori nd posteriori defined dietry ptterns provided n opportunity to study both dherence to existing guidelines nd popultion-specific ptterns, in reltion to frilty. Wheres the first pproch provided us

9 insight into the potentil of current dietry guidelines to prevent frilty, the ltter could provide dditionl insight to improve these guidelines in the future. Both methods hve their own strengths. Wheres the PCA-derived dietry ptterns re dt driven nd consider the correltion structure between food groups, the pre-defined index could be used to quntify prticipnt s dietry qulity, regrdless of its source popultion. The ltter fcilittes comprisons between popultions [48]. Furthermore, we were ble to estblish longitudinl ssocitions between dietry pttern dherence nd chnges in frilty. This is strength, becuse in cross-sectionl design it is not possible to stte if prticipnts becme more fril s consequence of their dietry pttern or if they dpted their dietry pttern due to their frilty sttus [44]. Additionlly, we excluded prticipnts tht decesed within the first 3 yers of follow-up in sensitivity nlyses. Together, this implies tht the found results re true ssocitions nd not result of reversed custion. Nevertheless, we lso recognize some limittions. Prticipnts hd reltively low frilty indices (e.g., low vrition), which could result in less pronounced ssocitions. We observed tht on verge the frilty index becme lower over time, wheres it ws expected to increse. Similrly, weker or friler elderly people my be less ble or willing to come to the study center nd/or fill in the extensive FFQ [44, 45], which might hve led to selection bis. Indeed, we observed higher frilty index score for excluded prticipnts thn for included prticipnts. Furthermore, definition nd lbeling of the posteriori defined ptterns involved some rbitrry choices, including the definition of food groups, nd the cut-off vlues of fctor lodings nd Eigenvlues. Additionlly, the dietry ptterns identified only explined 20% of the vrince of the totl diet, reflecting the complexity of reducing the vrition in dietry intke dt into single components. Lst, the interprettion of posteriori defined dietry ptterns cn be difficult. To increse comprbility between the priori defined dietry pttern nd the posteriori defined dietry ptterns we provided ll estimtes in z-scores. To improve the interprettion of the estimtes we clculted the food group intkes corresponding to 1SD difference in dietry pttern dherence (supplementl Tble V). In conclusion, in this popultion of middle-ged nd elderly prticipnts, we observed tht popultion-specific dietry ptterns were not consistently ssocited with frilty or chnges in frilty sttus over time. Adherence to dietry guidelines ws consistently ssocited with less frilty nd reduction of frilty over time. These results suggest tht dherence to the Dutch dietry guidelines cn help to prevent frilty in older dults nd elderly people. Acknowledgements We grtefully cknowledge the contribution of the prticipnts of the Rotterdm Study, reserch ssistnts, the generl prctitioners, hospitls nd phrmcies in Rotterdm. Complince with ethicl stndrds Finncil support The Rotterdm Study is supported by Ersmus University Medicl Center nd Ersmus University, Rotterdm, the NWO; the Netherlnds Orgniztion for Helth Reserch nd Development; the Reserch Institute for Diseses in the Elderly; the Netherlnds Genomics Inititive; the Ministry of Eduction, Culture nd Science; the Ministry of Helth, Welfre nd Sports; the Europen Commission (DG XII); nd the Municiplity of Rotterdm. The funders plyed no role in the study design or in dt collection nd nlysis. JDS, EALJ, JCK, TV nd OHF work in ErsmusAGE, center for ging reserch cross the life course funded by Nestlé Nutrition (Nestec Ltd.), nd Metgenics Inc. 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