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A Multicomponent Exercise Intervention that Reverses Frailty and Improves Cognition, Emotion, and Social Networking in the Community-Dwelling Frail Elderly: A Randomized Clinical Trial

      Abstract

      Background

      Frailty can be an important clinical target to reduce rates of disability.

      Objective

      To ascertain if a supervised-facility multicomponent exercise program (MEP) when performed by frail older persons can reverse frailty and improve functionality; cognitive, emotional, and social networking; as well as biological biomarkers of frailty, when compared with a controlled population that received no training.

      Design

      This is an interventional, controlled, simple randomized study. Researchers responsible for data gathering were blinded for this study.

      Setting

      Participants from 2 primary rural care centers (Sollana and Carcaixent) of the same health department in Spain were enrolled in the study between December 2013 and September 2014.

      Patients

      We randomized a volunteer sample of 100 men and women who were sedentary, with a gait speed lower than 0.8 meters per second and frail (met at least 3 of the frailty phenotype criteria).

      Interventions

      Participants were randomized to a supervised-facility MEP (n = 51, age = 79.5, SD 3.9) that included proprioception, aerobic, strength, and stretching exercises for 65 minutes, 5 days per week, 24 weeks, or to a control group (n = 49, age = 80.3, SD 3.7). The intervention was performed by 8 experienced physiotherapists or nurses. Protein-calorie and vitamin D supplementation were controlled in both groups.

      Results

      Our MEP reverses frailty (number needed to treat to recover robustness in subjects with attendance to ≥50% of the training sessions was 3.2) and improves functional measurements: Barthel (trained group 91.6 SD 8.0 vs 82.0 SD 11.0 control group), Lawton and Brody (trained group 6.9 SD 0.9 vs 5.7 SD 2.0 control group), Tinetti (trained group 24.5 SD 4.4 vs 21.7 SD 4.5 control group), Short Physical Performance Battery (trained group 9.5 SD 1.8 vs 7.1 SD 2.8 control group), and physical performance test (trained group 23.5 SD 5.9 vs 16.5 SD 5.1 control group) as well as cognitive, emotional, and social networking determinations: Mini-Mental State Examination (trained group 28.9 SD 3.9 vs 25.9 SD 7.3 control group), geriatric depression scale from Yesavage (trained group 2.3 SD 2.2 vs 3.2 SD 2.0 control group), EuroQol quality-of-life scale (trained group 8.2 SD 1.6 vs 7.6 SD 1.3 control group), and Duke social support (trained group 48.5 SD 9.3 vs 41.2 SD 8.5 control group). This program is unique in that it leads to a decrease in the number of visits to primary care physician (trained group 1.3 SD 1.4 vs 2.4 SD 2.9 control group) and to a significant improvement in frailty biomarkers.

      Conclusions

      We have designed a multicomponent exercise intervention that reverses frailty and improves cognition, emotional, and social networking in a controlled population of community-dwelling frail older adults.

      Trial Registration

      ClinicalTrials.gov. Identifier: NCT02331459.

      Keywords

      Prevention and treatment of age-associated frailty is a major concern in geriatrics because of its high prevalence (7.0%–16.3%) in older persons
      • Rodriguez-Manas L.
      • Fried L.P.
      Frailty in the clinical scenario.
      and because of its importance in the clinical setting.
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      • Young J.
      • Iliffe S.
      • et al.
      Frailty in elderly people.
      • Rodriguez-Manas L.
      • Feart C.
      • Mann G.
      • et al.
      Searching for an operational definition of frailty: A Delphi method based consensus statement: The frailty operative definition-consensus conference project.
      Frailty is an age-associated, biological syndrome characterized by decreased biological reserves, due to dysregulation of several physiological systems, which puts an individual at risk when facing minor stressors, and is associated with poor outcomes (ie, disability, hospitalization, and death).
      • Rodriguez-Manas L.
      • Feart C.
      • Mann G.
      • et al.
      Searching for an operational definition of frailty: A Delphi method based consensus statement: The frailty operative definition-consensus conference project.
      Frailty identifies a high-risk subgroup and offers a more predictive value than chronic disease for adverse outcomes at older ages.
      • Sourial N.
      • Bergman H.
      • Karunananthan S.
      • et al.
      Implementing frailty into clinical practice: A cautionary tale.
      Very importantly, frailty is reversible at early stages.
      • Rodriguez-Manas L.
      • Fried L.P.
      Frailty in the clinical scenario.
      • Fiatarone M.A.
      • O'Neill E.F.
      • Ryan N.D.
      • et al.
      Exercise training and nutritional supplementation for physical frailty in very elderly people.
      A frail individual can become nonfrail if frailty is detected and treated at the onset.
      There are studies exploring the benefits of exercise in frail older adults,
      • Fiatarone M.A.
      • O'Neill E.F.
      • Ryan N.D.
      • et al.
      Exercise training and nutritional supplementation for physical frailty in very elderly people.
      • Cadore E.L.
      • Rodriguez-Manas L.
      • Sinclair A.
      • Izquierdo M.
      Effects of different exercise interventions on risk of falls, gait ability, and balance in physically frail older adults: A systematic review.
      • Cadore E.L.
      • Moneo A.B.
      • Mensat M.M.
      • et al.
      Positive effects of resistance training in frail elderly patients with dementia after long-term physical restraint.
      • Theou O.
      • Stathokostas L.
      • Roland K.P.
      • et al.
      The effectiveness of exercise interventions for the management of frailty: A systematic review.
      • Gine-Garriga M.
      • Roque-Figuls M.
      • Coll-Planas L.
      • et al.
      Physical exercise interventions for improving performance-based measures of physical function in community-dwelling, frail older adults: A systematic review and meta-analysis.
      but recommendations on the appropriate design of an exercise protocol to maximize its beneficial effects in a population of frail individuals are still scarce.
      • Cadore E.L.
      • Rodriguez-Manas L.
      • Sinclair A.
      • Izquierdo M.
      Effects of different exercise interventions on risk of falls, gait ability, and balance in physically frail older adults: A systematic review.
      • Gine-Garriga M.
      • Roque-Figuls M.
      • Coll-Planas L.
      • et al.
      Physical exercise interventions for improving performance-based measures of physical function in community-dwelling, frail older adults: A systematic review and meta-analysis.
      As recently commented in The Lancet, the effects of the exercise interventions are not conclusive and do not show convincing evidence of effectiveness.
      • Rodriguez-Manas L.
      • Fried L.P.
      Frailty in the clinical scenario.
      One factor explaining this fact is the difference in the outcomes assessed (mainly physical determinants and functional abilities) between the studies. When compared with control interventions, physical exercise has shown to improve the score in the short physical performance battery (SPPB), including gait speed, in the frail elderly.
      • Gine-Garriga M.
      • Roque-Figuls M.
      • Coll-Planas L.
      • et al.
      Physical exercise interventions for improving performance-based measures of physical function in community-dwelling, frail older adults: A systematic review and meta-analysis.
      Results, however, are inconclusive for endurance outcomes, and no consistent effect has been observed on functional status, activities of daily living (ADLs), biochemical status, adverse health consequences, and psychosocial state.
      • Gine-Garriga M.
      • Roque-Figuls M.
      • Coll-Planas L.
      • et al.
      Physical exercise interventions for improving performance-based measures of physical function in community-dwelling, frail older adults: A systematic review and meta-analysis.
      Moreover, in most studies, frailty is not used as an outcome measure.
      • Theou O.
      • Stathokostas L.
      • Roland K.P.
      • et al.
      The effectiveness of exercise interventions for the management of frailty: A systematic review.
      Thus, the major aim of our study was to ascertain if a supervised-facility exercise program improves frailty, functionality, cognitive and emotional status, social networking, and biological markers of frailty, when compared with a controlled population that received no training. The intervention consisted of a multicomponent, exercise training program lasting 65 minutes per session, performed 5 days per week for 24 weeks.
      Nutritional supplementation has been associated with improvements in physical performance in frail older adults.
      • Abizanda P.
      • Lopez M.D.
      • Garcia V.P.
      • et al.
      Effects of an oral nutritional supplementation plus physical exercise intervention on the physical function, nutritional status, and quality of life in frail institutionalized older adults: The ACTIVNES study.
      To avoid its influence, protein-calorie and vitamin D supplementation were controlled in our study.

      Methods

      Study Design and Participants

      This is an interventional, controlled, simple randomized study. Researchers responsible for data gathering were blinded for this study. Two primary care centers of the same health department in La Ribera (Valencia, Spain) were involved: Carcaixent and Sollana. The number of citizens in each center in 2014 were 20,613 (10.3% of the population ≥70 years) and 5041 (11.1% of the population ≥70 years), respectively.
      The protocol was approved by the Committee on Ethics in Research of the “Hospital Universitario de La Ribera.” The centers included rural communities. This study took place between December 1, 2013, and September 30, 2014. Informed consent was obtained from each participant who signed it after fully understanding the procedures (n = 100).
      A sample size of 38 individuals per group was calculated considering a difference of 5 points on the Barthel Index between the groups (SD = 6) and alpha and beta errors of 5%. We increased the sample size in an additional 15% (losts during follow-up) and 5% (mortality). The resultant sample size was 46 per group. To increase the estimated study power we enrolled 50 individuals per group with an estimated study power of 98.6% for detecting the difference.
      The eligibility criteria were the following: men and women aged 70 years or older who were (1) sedentary (less than 3 hours of weekly physical activity), (2) frail according to the frailty phenotype,
      • Fried L.P.
      • Tangen C.M.
      • Walston J.
      • et al.
      Frailty in older adults: Evidence for a phenotype.
      (3) with a gait speed slower than 0.8 m/s, (4) and were community dwellers (see Table 1). Exclusion criteria were (1) life expectancy less than 6 months by any cause, (2) a value of 7c-7d in the Global Disability Score (GGS-FAST) in cognitive impaired patients (score <24 in the Mini-Mental State Examination [MMSE]), (3) severe disability (score <15 points on the Barthel Scale or an E score or higher in the Katz scale), (4) ejection fraction left ventricle 20% or less, (5) hospital admission in the past 3 months for any reason, (6) oncologic patient with active treatment with chemotherapy or radiotherapy, (7) major nonambulatory surgery in the past 6 months before the beginning of the study, (8) family member centenarian in the previous 2 generations, (9) patient with a coronary event in the past 12 months, (10) institutionalized patients, or (11) impossibility of going to the primary care center when using their own means of transport.
      Table 1Baseline Characteristics of the Participants
      Intervention Group, n = 51Control Group, n = 49P
      Characteristic
       Gender, n (%)
      Male22 (43.1)24 (49.0).688
      Female29 (56.9)25 (51.0)
       Age79.7 (SD 3.6)80.3 (SD 3.7).302
       Marital status, n (%)
      Single3 (6.1)3 (6.1)
      Married19 (38.8)19 (38.8).984
      Widow27 (55.1)27 (55.1)
       Living with, n (%)
      Spouse16 (31.4)16 (32.7)
      Alone28 (54.9)27 (55.1).973
      Children7 (13.7)6 (12.2)
      Conditions, No./total (%)
       Hypertension44 (86.3)33 (67.3).033
       Hyperlipidemia28 (56.9)18 (36.7).048
       Diabetes mellitus19 (37.3)15 (30.6).619
       Chronic obstructive pulmonary disease7 (13.7)1 (2).112
       Smoking
      No39 (76.5)28 (57.1)
      Yes2 (4.1)2 (4.1).102
      Ex-smoker10 (19.6)19 (38.8)
       Fall syndrome8 (15.7)4 (8.2).329
       No. of falls 6 months previous to the study0.6 (SD 1.3)0.5 (SD 1.2).514
       No. of risk factors for falls6.3 (SD 3.4)5.9 (SD 2.3).384
       Hearing impairment28 (57.1)25 (54.3).540
       Parkinson disease2 (4.1)2 (4.1)1.000
       Previous stroke4 (7.8)4 (8.2).758
       Arthritis35 (68.6)23 (46.9).042
       Heart failure12 (23.5)7 (14.3).310
       Ischaemic heart disease4 (7.8)4 (8.2).953
       Renal failure7(13.7)2 (4.1).184
       Anxiety depressive disorder21 (41.2)14 (28.6).213
       Cancer previous7 (13.7)5 (10.2).760
       Charlson Index
      The values represent the score met by the patients.
      2.4 (2.2)1.9 (1.5).113
       Fried frailty criteria
      The values represent the score met by the patients.
      3.6 (0.8)3.8 (0.6).106
       Edmonton frailty scale
      The values represent the score met by the patients.
      8.6 (2.4)8.5 (1.9).876
      The values represent the score met by the patients.
      The listing of individuals was obtained from the Valencian Community health database (Abucasis). Targeted mass mailing was the primary recruitment strategy. All the volunteers received the study information in their health and sociocultural centers. Those interested in the study were contacted by phone and were invited for an interview to provide more details and to check the eligibility criteria. At enrollment, the intervention and control groups were similar. Sample characteristics at study entry are provided in Table 1.
      Both groups received nutritional information of the optimal energy intake, the requirement to ensure a minimal protein intake of 0.8 g/kg body weight, and hygienic and dietetic correcting measures of any geriatric syndrome observed. In both groups, we supplemented the participants with calciferol when blood plasma calcidiol levels were 30 ng/mL or lower. It was given with the following criteria: calcidiol 10 ng/mL or lower: 10,000 IU/wk of calciferol for 3 months; calcidiol between 11 and 20 ng/mL: 10,000 IU every 10 days during 3 months; calcidiol between 20 and 29 ng/mL: 10,000 IU every fortnight during 3 months. After that treatment, we gave a supplementary treatment with 1200 mg calcium and 800 IU calciferol daily.

      Randomization

      The primary health center in which intervention and control was going to be performed was randomly assigned following simple randomization procedures performed by the Department of Research in the health department in La Ribera.
      To avoid bias due to contamination between the patients allocated to each branch of the study, the randomization units were the health centers instead of the patients. The control group received no training and they attended the regular primary care program established by their center.
      • Boshuizen H.C.
      • Stemmerik L.
      • Westhoff M.H.
      • Hopman-Rock M.
      The effects of physical therapists' guidance on improvement in a strength-training program for the frail elderly.
      A diagram outlining subject flow from first contact to study completion is provided in Figure 1.
      Figure thumbnail gr1
      Fig. 1Subjects flow diagram from initial contact through study completion.
      Intervention was performed by 4 physiotherapists and 4 nurses. All the group members had at least 10 years of experience. They had previously participated in 2 physical activity–related falls prevention programs.

      Multicomponent Exercise Program

      A multicomponent exercise program (MEP) is defined as a combined program of endurance, strength, coordination, balance, and flexibility exercises that have the potential to impact a variety of functional performance measures.
      • Marques E.
      • Carvalho J.
      • Soares J.M.
      • et al.
      Effects of resistance and multicomponent exercise on lipid profiles of older women.
      Those in the intervention group performed 65 minutes of daily activities, 5 days per week for 24 weeks at the “Hogar del Jubilado,” Valencia. The sessions were delivered in a group, were supervised, and involved a combination of the following activities: proprioception and balance exercises (10–15 minutes), aerobic training (initially at 40% of maximum heart rate increasing progressively to 65%),
      • Nelson M.E.
      • Rejeski W.J.
      • Blair S.N.
      • et al.
      Physical activity and public health in older adults: Recommendation from the American College of Sports Medicine and the American Heart Association.
      strength training (initially at 25% of 1 repetition maximum to 75%), and stretching. The details of time, intensities, and progression of the exercise training can be seen in Table 2A and B. The ratio of trainers to participants was 15. Patient exercise compliance was 47.3% (95% confidence interval [CI] 38.7%–55.7%).
      Table 2A. Multicomponent Exercise Program Characteristics. B. Representation of the Multicomponent Exercise program.
      Intervention Characteristics: 24 wk, 5 d/wk, 65-70 min/session
      Day 1Day 2Day 3Day 4Day 5
      10 min (warm-up)10 min (warm-up)10 min (warm-up)10 min (warm-up)10 min (warm-up)
      10 min
      Proprioception and balance exercises.
      15 min
      Proprioception and balance exercises.
      15 min
      Proprioception and balance exercises.
      15 min
      Proprioception and balance exercises.
      15 min
      Proprioception and balance exercises.
      40 min
      Aerobic training (initially at 40% of HRmax increasing progressively to 65%).
      40 min
      Strength training with resistance bands.
      40 min
      Aerobic training (initially at 40% of HRmax increasing progressively to 65%).
      40 min
      Strength training with resistance bands.
      40 min
      Aerobic training (initially at 40% of HRmax increasing progressively to 65%).
      5 min
      Stretching.
      5 min
      Stretching.
      5 min
      Stretching.
      5 min
      Stretching.
      5 min
      Stretching.
      Characteristics of the Strength Training
      Month 1Month 2Month 3Month 4Month 5Month 6
      Wk 1Wk 2Wk 3–Wk 4Wk 1–Wk 4Wk 1Wk 2Wk 3–Wk 4Wk 1–Wk 4Wk 1Wk 2Wk 3–Wk 4Wk 1–Wk 4
      25% 1-RM

      1 × 30R
      25% 1-RM

      2 × 30R
      25% 1-RM

      3 × 30R
      25% 1-RM

      3 × 30R
      50% 1-RM

      1 × 15R
      50% 1-RM

      2 × 10R
      50% 1-RM

      3 × 8R
      50% 1-RM

      3 × 8R
      75% 1-RM

      1 × 15R
      75% 1-RM

      2 × 10R
      75% 1-RM

      3 × 8R
      75% 1-RM

      3 × 8R
      HRmax, maximal heart rate; 1-RM, 1-repetition maximum; R, repetitions.
      Proprioception and balance exercises.
      Aerobic training (initially at 40% of HRmax increasing progressively to 65%).
      Strength training with resistance bands.
      § Stretching.
      The proprioception exercises included postural sway and dynamic balance, coordination, and flexibility of the lumbo-pelvic area. The aerobic training included walking around a circuit and climbing stairs. The strength training was performed with resistance bands and included isometric, concentric, and eccentric exercises with arms, hands, and legs. The stretching exercises included arms, legs, and neck (see Table 2B).
      Serious adverse events such as death or hospitalization were monitored during the study follow-up. To guarantee the clinical safety of the intervention, the eligibility criteria excluded patients at risk of instability of their comorbidities. Pulse oximetry was used to detect respiratory problems, %SpO2 lower than 90 was used as a criterion to stop the intervention. Moreover, a heart rate higher than that designed for the aerobic exercise, dizziness symptoms, and muscle or joint pain were also criteria to stop the intervention.

      Measurements

      The following parameters were recorded: age, gender, social situation, marital status. Anthropometric data: body mass index (BMI); abdominal, brachial, and leg girths; lean mass; and fat mass percentages were determined by bioelectrical impedance analysis (Tanita BC-601; TANITA Corporation, Maeno-Cho, Itabashi-ku, Tokyo, Japan). Functional assessment included the following: Barthel Index, Lawton and Brody, Tinetti, Timed-up-and-go (TUG), 6-minute-walk test, SPPB, physical performance test (PPT), Functional Ambulation Categories (FAC), Crichton, and handgrip strength. Cognitive, emotional, and social determinations were assessed using the MMSE, Duke social support, EuroQol quality-of-life scale (EQ-5D), and geriatric depression scale from Yesavage. Clinical measurements included comorbidities according to the Charlson Index,
      • D'Hoore W.
      • Sicotte C.
      • Tilquin C.
      Risk adjustment in outcome assessment: The Charlson comorbidity index.
      cardiac insufficiency according to the Framingham criteria,
      • McKee P.A.
      • Castelli W.P.
      • McNamara P.M.
      • Kannel W.B.
      The natural history of congestive heart failure: The Framingham study.
      ischemic cardiopathy, previous stroke event, chronic obstructive pulmonary disease, renal insufficiency, osteoporosis, and number of fractures. We also determined frailty (classical Fried frailty criteria and Edmonton frailty scale),
      • Fried L.P.
      • Tangen C.M.
      • Walston J.
      • et al.
      Frailty in older adults: Evidence for a phenotype.
      • Rolfson D.B.
      • Majumdar S.R.
      • Tsuyuki R.T.
      • et al.
      Validity and reliability of the Edmonton Frail Scale.
      the prevalence of other geriatric syndromes, number and risk of falls, number of voluntary hospital admissions, visits to the emergency service, and visits to the primary care center in the previous 6 months.

      D-Dimer and Calcidiol Assay

      Blood samples were obtained in fasting conditions. Serum and plasma were stored at −80°C. D-dimer and calcidiol were measured according to standard laboratory protocols at the central laboratory hospital. Other biochemical assays were performed (white blood cells, hemoglobin, glucose, creatinine, total protein, cholesterol, thyroid-stimulating hormone, transaminases, alkaline phosphatase, albumin, fibrinogen, factor VIII, triglycerides) but no differences were found between the experimental groups (data not shown).

      Protein Carbonylation

      The carbonyl groups in the protein side chains were detected by Western blotting using specific antibodies (OxyBlot Protein Oxidation Detection kit; Millipore, Billerica, MA), as previously described.
      • Ingles M.
      • Gambini J.
      • Carnicero J.A.
      • et al.
      Oxidative stress is related to frailty, not to age or sex, in a geriatric population: Lipid and protein oxidation as biomarkers of frailty.

      Brain-Derived Neurotrophic Factor Serum Levels

      Brain-derived neurotrophic factor (BDNF) was measured using an ELISA kit (ChemiKine TM; Millipore, Temecula, CA; Ref. CYT306), following the manufacturer's instructions.

      Statistical Considerations

      Statistical analysis was performed using SPSS 19.0 (SPSS, Inc., Chicago, IL). Categorical variables were expressed as percentages and continuous variables with mean value and SD. The t test was used to compare means and Pearson χ2 and Mantel-Haenszel linear tendency test for comparison of proportions. Threshold for statistical significance was considered with a P value of less than .05.

      Results

      Study Participants

      We screened 126 potential participants; of these, 100 were eligible and randomized (51 to the intervention and 49 to the control group; Figure 1). Table 1 shows that baseline characteristics were very similar between the 2 groups.
      The intervention group showed a greater prevalence of arthrosis at the beginning of the study. We did not find any other significant difference between the groups in the main conditions studied or in the prevalence of geriatric syndromes.

      Multicomponent Exercise Reverses Functional, Cognitive, Emotional, and Social Losses in Community-Dwelling Frail Individuals

      Table 3 shows the functional, cognitive, psychological, and social variables studied. We did not observe differences between groups at the beginning of the study.
      Table 3Geriatric Scales, Functional, Cognitive, and Social Tests: Effect of the Multicomponent Exercise Program
      Intervention Group Before, n = 51Control Group Before, n = 49PIntervention Group After, n = 40Control Group After, n = 42P
      Falls
       No. of falls (6 mo)0.6 (SD 1.1)0.5 (SD 1.2).6540.3 (SD 1.1)0.5 (SD 0.7).488
       No. risk factors for falls6.5 (SD 3.3)5.9 (SD 2.3).3555.7 (SD 2.2)5.7 (SD 2.1).985
      Hospital visits
       No. of visits to PCP3.4 (SD 3.8)2.4 (SD 2.8).1031.3 (SD 1.4)2.4 (SD 2.9).021
       No. of emergency visits0.4 (SD 1.0)0.5 (SD 0.7).8920.6 (SD 1.1)0.9 (SD 1.5).237
      Functional Measurements
       SPPB8.6 (SD 2.0)8.6 (SD 1.7).9839.5 (SD 1.8)7.1 (SD 2.8).007
       PPT19.3 (SD 5.3)18.7 (SD 6.0).60123.5 (SD 5.9)16.5 (SD 5.1)<.001
       Barthel88.2 (SD 10.9)88.3 (SD 10.5).98491.6 (SD 8.0)82.0 (SD 11.0)<.001
       Lawton6.7 (SD 1.1)6.8 (SD 1.8).6096.9 (SD 0.9)5.7 (SD 2.0).001
       Tinetti23.5 (SD 4.4)24.7 (SD 3.4).19724.5 (SD 4.4)21.7 (SD 4.5).007
       Tinetti gait test10.7 (SD 2.0)10.9 (SD 1.8).51810.8 (SD 1.8)9.4 (SD 2.2).002
       Tinetti balance index13.1 (SD 3.1)13.6 (SD 2.7).44113.7 (SD 2.9)12.5 (SD 2.7).067
       FAC4.3 (SD 1.1)4.1 (SD 1.3).4403.8 (SD 1.4)3.9 (SD 1.0).694
       PAEE268.7 (SD 55.5)265.2 (SD 45.6).734485.6 (SD 98.1)265.8 (SD 46.1)<.001
      Frailty
       Fried frailty criteria3.6 (SD 0.8)3.8 (SD 0.6).1061.6 (SD 0.9)3.8 (SD 0.3)<.001
       Edmonton frailty scale8.7 (SD 2.5)8.5 (SD 2.1).7497.7 (SD 2.0)9.3 (SD 2.3)<.001
      Cognitive, emotional, and social tests
       MMSE26.5 (SD 5.3)27.3 (SD 5.8).46928.9 (SD 3.9)25.9 (SD 7.3).025
       Duke social support47.9 (SD 8.6)49.0 (SD 6.8).47448.5 (SD 9.3)41.2 (SD 8.5)<.001
       Yesavage2.9 (SD 2.4)2.4 (SD 2.7).3892.3 (SD 2.2)3.2 (SD 2.5).043
       EQ-5D7.4 (SD 2.0)7.7 (SD 1.8).4418.2 (SD 1.6)7.6 (SD 1.3).045
      EQ-5D, EuroQol quality-of-life scale; FAC, Functional Ambulation Categories; MMSE, Mini-Mental State Examination; PAEE, Physical Activity Energetic Expenditure; PCP, primary care physician; PPT, Physical Performance Test; SPPB, Short Physical Performance Test.
      P value indicates statistical difference between the control and intervention groups.
      Before the onset of the study, the physical activity performed by the individuals enrolled in the 2 groups was very low in all cases. At the end of the study, 77.5% of the intervention group performed 3 to 6 hours per week of exercise, whereas in the control group, 90% of the individuals performed 3 hours or less per week of exercise. This resulted in a significant increase in the energy consumption associated with physical exercise (PAEE) in the exercise group (P < .001) (see Table 3).
      The MEP was very effective in improving the PPT (P < .001), SPPB (P = .007), and in lowering of the frailty score assessed by Linda Fried's criteria (P < .001) and Edmonton (P < .001).
      • Fried L.P.
      • Tangen C.M.
      • Walston J.
      • et al.
      Frailty in older adults: Evidence for a phenotype.
      The statistical analysis showed that in 31.4% (95% CI 20.3–45.0) of the intervention group, frailty was reversed after the exercise training program. No participant in the control group reversed frailty after the 6-month period. The relative risk to reverse frailty to robustness was 2.4 higher in the intervention group when compared with the control group. After completing the analysis by intention to treat with binary logistic regression (adjusting for hypertension, hyperlipidemia, gender, age, and arthrosis) the variable associated with the recovery of robustness is the attendance at 50% of the programmed sessions with an odds ratio of 4.4 (95% CI 1.2–16.0) (P = .023). The number needed to treat to recover robustness was 3.2 (95% CI 2.0–4.5).
      We found a statistically significant improvement in performance in ADLs (Barthel Index) (P < .001) as well as in instrumental ADLs (Lawton Scale) (P = .001) after the MEP. People in the control group, but not those in the intervention group, decreased their performance in these functional measurements after the 6-month period. Gait and balance, assessed with the Tinetti scores, were also significantly improved after the MEP, whereas the control group showed deterioration in this parameter after the intervention period (see Table 3).
      The exercise intervention also improved cognition. A 9% increase in the MMSE score was found in the exercise group, whereas the sedentary group maintained or even slightly lost global cognitive function (P = .025). Moreover, exercise also resulted in an increase in emotional and social state of the individuals. The Duke social support (P < .001), Yesavage (P = .043), and EQ-5D tests (P = .045)
      • Landerman R.
      • George L.K.
      • Campbell R.T.
      • Blazer D.G.
      Alternative models of the stress buffering hypothesis.
      • Brooks R.
      EuroQol: The current state of play.
       showed that exercise causes a significant improvement in these parameters when compared with the sedentary group (Table 3). The EQ-5D was assayed using different nonparametric tests because the distribution of the values obtained was not normal.
      Finally, the number of visits to the primary care physician was significantly reduced in the exercise group (P = .021) (see Table 3).

      Anthropometric Variables and Analytical Results

      The anthropometric characteristics of the participants are shown in Table 4. We found a significant decrease in the value of the fat mass (P = .019) in frail individuals who followed the MEP. No differences in the rest of the variables measured were found between the groups.
      Table 4Anthropometric Characteristics of the Participants: Effect of the Multicomponent Exercise Program
      Intervention Group Before, n = 51Control Group Before, n = 49P valueIntervention Group After, n = 40Control Group After, n = 42P value
      Weight, kg75.0 (SD 14.0)74.2 (SD 12.6).75173.4 (SD 13.0)74.5 (SD 13.8).733
      BMI, kg/m229.9 (SD 5.6)30.0 (SD 4.2).90629.3 (SD 5.5)29.8 (SD 4.5).654
      Abdominal girth, mm105.9 (SD 13.1)106.2 (SD 9.7).983101.9 (SD 13.9)106.2 (SD 9.6).112
      Leg girth, mm47.2 (SD 5.3)45.6 (SD4.2).14846.0 (SD 5.0)45.3 (SD 5.6).567
      Arm girth, mm29.8 (SD 5.7)29.9 (SD 4.2).55829.4 (SD 3.6)29.8 (SD 3.5).453
      Lean mass, %44.9 (SD 9.2)45.7 (SD 12.1).74849.2 (SD 12.4)45.6 (SD 9.2).194
      Fat mass, %35.0 (SD 11.3)34.5 (SD 11.2).83528.7 (SD 8.8)34.1 (SD 8.9).019
      P value indicates statistical difference between the control and intervention groups.
      At the beginning of the study, the mean values for calcidiol were lower than those established as adequate for both the sedentary 15.6 (SD 9.5) and the intervention groups 23.3 (SD 8.6). Deficiency of vitamin D is an important factor in the development of frailty.
      • Smit E.
      • Crespo C.J.
      • Michael Y.
      • et al.
      The effect of vitamin D and frailty on mortality among non-institutionalized US older adults.
      • Shardell M.
      • D'Adamo C.
      • Alley D.E.
      • et al.
      Serum 25-hydroxyvitamin D, transitions between frailty states, and mortality in older adults: The Invecchiare in Chianti Study.
      We supplemented the participants with calciferol with the aim of bringing its plasma levels to normality in both groups, so as to prevent the deficit of calcidiol as a confounding factor in the interpretation of the results (see Material and Methods section). At the end of the study, no differences were observed between the values found in both groups: sedentary 35.4 (SD 16.6) and trained 32.6 (SD 14.0). They were within the range considered optimal.
      Two biomarkers of frailty were improved significantly with the exercise intervention. We found a significant (P = .02) decrease in D-dimer, a marker of ongoing clotting,
      • Walston J.
      • McBurnie M.A.
      • Newman A.
      • et al.
      Frailty and activation of the inflammation and coagulation systems with and without clinical comorbidities: Results from the Cardiovascular Health Study.
      after the MEP. At the beginning of the study, the mean values for D-dimer (mg/L) were 1.2 (SD 1.1) in the intervention group and 0.8 (SD 0.8) in the control group. At the end of the study, a decrease in D-dimer was found in the trained group 0.8 (SD 0.7) but no changes were registered in the control group 0.8 (SD 0.8).
      Plasma protein oxidation was significantly prevented after the MEP. The increment in plasma protein carbonyls after 6 months, expressed in arbitrary units, was 0.68 (SD 0.29) for the control group compared with a value of 0.05 (SD 0.99) in the intervention group (P = .05).
      Finally, we determined the serum levels of BDNF. At the beginning of the study the mean values for BDNF (ng/mL) were similar between the sedentary (90.5, SD 40.9) and the intervention groups (89.9, SD 36.7). At the end of the study, an increase in the BDNF serum levels was found in the group that followed the MEP (97.1, SD 38.1). The control group did not show any change in this parameter (90.7, SD 38.5). However, no statistical differences were observed between the values found in both groups.

      Discussion

      Frailty is a major concern in clinical medicine because it is the main determinant of longevity and quality of life in the elderly population.
      • Gill T.M.
      • Gahbauer E.A.
      • Han L.
      • Allore H.G.
      Trajectories of disability in the last year of life.
      Importantly, frailty is reversible, especially if diagnosed early in the process.
      • Rodriguez-Manas L.
      • Fried L.P.
      Frailty in the clinical scenario.
      There are 6 systematic reviews
      • Cadore E.L.
      • Rodriguez-Manas L.
      • Sinclair A.
      • Izquierdo M.
      Effects of different exercise interventions on risk of falls, gait ability, and balance in physically frail older adults: A systematic review.
      • Theou O.
      • Stathokostas L.
      • Roland K.P.
      • et al.
      The effectiveness of exercise interventions for the management of frailty: A systematic review.
      • Chin A.P.
      • van Uffelen J.G.
      • Riphagen I.
      • van Mechelen W.
      The functional effects of physical exercise training in frail older people: A systematic review.
      • Daniels R.
      • van Rossum E.
      • de Witte L.
      • et al.
      Interventions to prevent disability in frail community-dwelling elderly: A systematic review.
      • Chou C.H.
      • Hwang C.L.
      • Wu Y.T.
      Effect of exercise on physical function, daily living activities, and quality of life in the frail older adults: A meta-analysis.
      • de Vries N.M.
      • van Ravensberg C.D.
      • Hobbelen J.S.
      • et al.
      Effects of physical exercise therapy on mobility, physical functioning, physical activity and quality of life in community-dwelling older adults with impaired mobility, physical disability and/or multi-morbidity: A meta-analysis.
      published specifically on the benefits of exercise in frail older adults. In some cases, clinical trials did not show convincing evidence of effectiveness,
      • Rodriguez-Manas L.
      • Fried L.P.
      Frailty in the clinical scenario.
      • Gine-Garriga M.
      • Roque-Figuls M.
      • Coll-Planas L.
      • et al.
      Physical exercise interventions for improving performance-based measures of physical function in community-dwelling, frail older adults: A systematic review and meta-analysis.
      • Laosa O.
      • Alonso C.
      • Castro M.
      • Rodriguez-Manas L.
      Pharmaceutical interventions for frailty and sarcopenia.
      whereas in others the main conclusion is that exercise can improve partial aspects of functional outcomes in the frail population, such as sit-to-stand performance, balance, agility, and ambulation.
      • Fiatarone M.A.
      • O'Neill E.F.
      • Ryan N.D.
      • et al.
      Exercise training and nutritional supplementation for physical frailty in very elderly people.
      • Gine-Garriga M.
      • Roque-Figuls M.
      • Coll-Planas L.
      • et al.
      Physical exercise interventions for improving performance-based measures of physical function in community-dwelling, frail older adults: A systematic review and meta-analysis.
      • Pahor M.
      • Guralnik J.M.
      • Ambrosius W.T.
      • et al.
      Effect of structured physical activity on prevention of major mobility disability in older adults: The LIFE study randomized clinical trial.
      The lack of consistency among the studies is due to the differences in the definition of frailty, training protocols, characteristics of the inactive groups, and in the main outcomes assessed.
      • Gine-Garriga M.
      • Roque-Figuls M.
      • Coll-Planas L.
      • et al.
      Physical exercise interventions for improving performance-based measures of physical function in community-dwelling, frail older adults: A systematic review and meta-analysis.
      Thus, a definite conclusion has not yet been reached.
      • Gine-Garriga M.
      • Roque-Figuls M.
      • Coll-Planas L.
      • et al.
      Physical exercise interventions for improving performance-based measures of physical function in community-dwelling, frail older adults: A systematic review and meta-analysis.
      Our previous work shows that exercise acts as a drug
      • Vina J.
      • Sanchis-Gomar F.
      • Martinez-Bello V.
      • Gomez-Cabrera M.C.
      Exercise acts as a drug; the pharmacological benefits of exercise.
      and that tailored exercise programs are needed, especially in the elderly.
      • Vina J.
      • Borras C.
      • Sanchis-Gomar F.
      • et al.
      Pharmacological properties of physical exercise in the elderly.
      We have reviewed the continuous debate on how much, what type, how often, what intensity, and how lengthy physical activity should be to prevent and/or treat diseases or a complex geriatric syndrome such as frailty.
      • Vina J.
      • Sanchis-Gomar F.
      • Martinez-Bello V.
      • Gomez-Cabrera M.C.
      Exercise acts as a drug; the pharmacological benefits of exercise.
      • Vina J.
      • Borras C.
      • Sanchis-Gomar F.
      • et al.
      Pharmacological properties of physical exercise in the elderly.
      There is no evidence available in the literature to pinpoint which kind of exercise is more effective for frail individuals.
      • Gine-Garriga M.
      • Roque-Figuls M.
      • Coll-Planas L.
      • et al.
      Physical exercise interventions for improving performance-based measures of physical function in community-dwelling, frail older adults: A systematic review and meta-analysis.
      Thus, the aim of this work was to ascertain if an MEP (including aerobic, anaerobic, proprioceptive, and stretching exercises) when performed by frail older persons can improve frailty, functionality, and social, affective, and cognitive functions, as well as anthropometric characteristics and biological markers of frailty, when compared with a controlled population that received no training.
      We found that in 31.4% (95% CI 20.3–45.0) of the intervention group, frailty was reversed after the exercise training program, whereas no one in the control group reversed frailty after the 6-month period.
      It has been reported that there is a significant improvement in the gait velocity and SPPB score after a training period.
      • Gine-Garriga M.
      • Roque-Figuls M.
      • Coll-Planas L.
      • et al.
      Physical exercise interventions for improving performance-based measures of physical function in community-dwelling, frail older adults: A systematic review and meta-analysis.
      • Manor B.
      • Lough M.
      • Gagnon M.M.
      • et al.
      Functional benefits of tai chi training in senior housing facilities.
      However, no effects have been observed in resistance, equilibrium, or ADLs.
      • Gine-Garriga M.
      • Roque-Figuls M.
      • Coll-Planas L.
      • et al.
      Physical exercise interventions for improving performance-based measures of physical function in community-dwelling, frail older adults: A systematic review and meta-analysis.
      These results coincide with those published by Fiatarone et al
      • Fiatarone M.A.
      • Marks E.C.
      • Ryan N.D.
      • et al.
      High-intensity strength training in nonagenarians. Effects on skeletal muscle.
      and Fairhall et al
      • Fairhall N.
      • Sherrington C.
      • Lord S.R.
      • et al.
      Effect of a multifactorial, interdisciplinary intervention on risk factors for falls and fall rate in frail older people: A randomised controlled trial.
      and with the data reported in the LIFE study in which a reduction in the incidence of major mobility disability was found after an exercise program, yet without improvement in ADLs.
      • Pahor M.
      • Guralnik J.M.
      • Ambrosius W.T.
      • et al.
      Effect of structured physical activity on prevention of major mobility disability in older adults: The LIFE study randomized clinical trial.
      Our MEP resulted in a significant improvement in performance in ADLs (Barthel Index) as well as in instrumental ADLs (Lawton Scale). The performance of the sedentary group decreased significantly in these functional measurements after the 6-month period. The gait and balance, assessed with the Tinetti scores, was also significantly improved after the MEP,
      • Binder E.F.
      • Schechtman K.B.
      • Ehsani A.A.
      • et al.
      Effects of exercise training on frailty in community-dwelling older adults: Results of a randomized, controlled trial.
      whereas the sedentary group showed deterioration in this parameter after the intervention period. The MEP was also effective in improving the PPT, SPPB, and in lowering of frailty.
      • Fried L.P.
      • Tangen C.M.
      • Walston J.
      • et al.
      Frailty in older adults: Evidence for a phenotype.
      • Rolfson D.B.
      • Majumdar S.R.
      • Tsuyuki R.T.
      • et al.
      Validity and reliability of the Edmonton Frail Scale.
      Patients’ exercise compliance was 47.3% (95% CI 38.7–55.7). The variable associated with the recovery of robustness (adjusting for hypertension, hyperlipidemia, gender, age, and arthrosis) is the attendance at 50% of the programmed sessions with an odds ratio of 4.4 (95% CI 1.2–16.0) (P = .023). The number needed to treat to recover robustness was 3.2 (95% CI 2.0–4.5).
      Our results support a recent study showing that there is a reduction in the prevalence of frailty at the end of a physical activity program.
      • Cesari M.
      • Vellas B.
      • Hsu F.C.
      • et al.
      A physical activity intervention to treat the frailty syndrome in older persons: Results from the LIFE-P study.
      Previous studies have highlighted the importance of the adherence to the exercise program to improve the scores in functional scales as well as in gait speed.
      • Fairhall N.
      • Sherrington C.
      • Kurrle S.E.
      • et al.
      Effect of a multifactorial interdisciplinary intervention on mobility-related disability in frail older people: Randomised controlled trial.
      Moreover, it has been shown that the characteristics of exercise programs that seem to result in better outcomes are as follows: multicomponent training with a duration of 5 months or longer
      • Smith K.
      • Winegard K.
      • Hicks A.L.
      • McCartney N.
      Two years of resistance training in older men and women: The effects of three years of detraining on the retention of dynamic strength.
      and performed 3 days per week for 30 to 45 minutes per session.
      • Theou O.
      • Stathokostas L.
      • Roland K.P.
      • et al.
      The effectiveness of exercise interventions for the management of frailty: A systematic review.
      In our study, the intervention characteristics were as follows: 24 weeks, 5 days per week, and 65 minutes per session. It has been shown that facility-supervised exercise programs, like ours, are more effective than home-based interventions for older adults.
      • Gine-Garriga M.
      • Roque-Figuls M.
      • Coll-Planas L.
      • et al.
      Physical exercise interventions for improving performance-based measures of physical function in community-dwelling, frail older adults: A systematic review and meta-analysis.
      We also found a reduction in the Yesavage Geriatric Depression Index, an increase in the MMSE score, and an improvement in the score relating to the objective part of the quality-of-life scale EQ-5D. It has been previously reported that an exercise intervention could improve individually the mood state,
      • Timonen L.
      • Rantanen T.
      • Timonen T.E.
      • Sulkava R.
      Effects of a group-based exercise program on the mood state of frail older women after discharge from hospital.
      the cognitive function,
      • Colcombe S.
      • Kramer A.F.
      Fitness effects on the cognitive function of older adults: A meta-analytic study.
      and the quality of life
      • Langlois F.
      • Vu T.T.
      • Chasse K.
      • et al.
      Benefits of physical exercise training on cognition and quality of life in frail older adults.
      in frail individuals. Our MEP leads to an improvement in all of these parameters. Social networking is a target of our intervention because it has been shown that frailty is associated with poor social functioning and with an increase in loneliness over time.
      • Hoogendijk E.O.
      • Suanet B.
      • Dent E.
      • et al.
      Adverse effects of frailty on social functioning in older adults: Results from the Longitudinal Aging Study Amsterdam.
      Social vulnerability of physically frail older adults should be taken into account in the care provision for frail older adults.
      Our exercise program resulted in significant lowering in fat mass. We have recently found that frailty, and not age, is related to oxidative stress.
      • Ingles M.
      • Gambini J.
      • Carnicero J.A.
      • et al.
      Oxidative stress is related to frailty, not to age or sex, in a geriatric population: Lipid and protein oxidation as biomarkers of frailty.
      Accordingly, now we find that protein oxidation is lowered by exercise. Finally, frailty has been associated with greater mean levels of D-dimer.
      • Walston J.
      • McBurnie M.A.
      • Newman A.
      • et al.
      Frailty and activation of the inflammation and coagulation systems with and without clinical comorbidities: Results from the Cardiovascular Health Study.
      We found a significant decrease in this frailty biomarker after the training program. Thus, all parameters used indicate that our exercise program is very effective in treating frailty.
      Physical frailty can potentially be treated with protein-calorie and vitamin D supplementation.
      • Morley J.E.
      • Vellas B.
      • van Kan G.A.
      • et al.
      Frailty consensus: A call to action.
      These nutritional interventions were controlled in our study. In both groups, we supplemented the participants with calciferol when blood plasma calcidiol levels were 30 ng/mL or lower. At the end of the study, all participants reported optimal levels of vitamin D. Moreover, we established a lower limit in the protein intake recommendation of 0.8 g/kg per day. Although experts propose a protein intake of up to 1.5 g/kg per day comprising 15% to 20% of the total caloric intake for sarcopenic elderly,
      • Morley J.E.
      • Argiles J.M.
      • Evans W.J.
      • et al.
      Nutritional recommendations for the management of sarcopenia.
      this is difficult to achieve in certain scenarios. It is considered that 40% of the elderly do not meet the recommended 0.8 g/kg per day of protein intake requirement in their diet. Thus, we believe that the lower limit established in our study is appropriate.

      Conclusion

      We report here a tailored multicomponent exercise training intervention for reversing frailty and improving physical function and cognitive, emotional, and social network determinations in frail older adults. We also report improvements in anthropometric and analytical variables; some of them considered good biomarkers of frailty. This results in a significant decrease in the number of visits to the primary care physician after the training program. This is of the utmost importance to lower health care costs.
      We allocated persons to both groups in an aleatory fashion. However, the intervention group showed a significantly higher prevalence of arthrosis than the control group. The limited follow-up period may have led to a lack of change in the incidence of falls, fractures, and hospital admissions. It is mandatory to design studies with longer follow-up periods on completion of the intervention program.

      Acknowledgments

      We thank the medical doctors, nurses, and physical therapists Cayetano Gómez, Ignacio Roca, Federico Vendrell, Amparo Ridaura, Rosa Ribes, Carla Borrás, Chabela Cuquerella, Nerea García, Arantzazu López, Alba Martínez, Arancha Martínez, Sandra Mas, Maria Carmen Oltra, Leydi Estefany Pechene, Jessica Pires, Alexander Blanquer, Julia Sabater, and Immaculada Tormos, involved in patient recruitment in the primary care centers of Sollana and Carcaixent. We thank Luis Pascual Gonzalez and Cecilia Maldonado Gallego for their help in the preparation of Table 2B. We also thank Mrs Marilyn Noyes for her kind help in reviewing the manuscript and to all the patients that have participated in the study.

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