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MULTICOMPONENT EXERCISE PROGRAM IN OLDER ADULTS WITH LUNG CANCER DURING ADJUVANT/PALLIATIVE TREATMENT: A SECONDARY ANALYSIS OF AN INTERVENTION STUDY

 

N. Martínez-Velilla1,2,3, M.L. Saez de Asteasu1,2, R. Ramírez-Vélez1, I.D. Rosero1, A. Cedeño-Veloz1,3, I. Morilla1,4, R.V. García1,4, F. Zambom-Ferraresi1,2, A. García-Hermoso1,5, M. Izquierdo1,2

1. Navarrabiomed, Complejo Hospitalario de Navarra (CHN)-Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain; 2. CIBER of Frailty and Healthy Aging (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain; 3. Department of Geriatric Medicine, Complejo Hospitalario de Navarra, Irunlarrea 3, Pamplona, Spain; 4. Department of Medical Oncology, Complejo Hospitalario de Navarra, Pamplona, Spain; 5. Laboratorio de Ciencias de la Actividad Física, el Deporte y la Salud, Facultad de Ciencias Médicas, Universidad de Santiago de Chile, USACH, Santiago, Chile.
Corresponding author: Mikel Izquierdo, PhD, Department of Health Sciences, Public University of Navarra, Av. De Barañain s/n 31008 Pamplona (Navarra) Spain, Tel + 34 948 417876, mikel.izquierdo@gmail.com

J Frailty Aging 2021;in press
Published online January 18, 2021, http://dx.doi.org/10.14283/jfa.2021.2

 


Abstract

Background: Lung cancer is the second most prevalent common cancer in the world and predominantly affects older adults. This study aimed to examine the impact of an exercise programme in the use of health resources in older adults and to assess their changes in frailty status. Design: This is a secondary analysis of a quasi-experimental study with a non-randomized control group. Setting: Oncogeriatrics Unit of the Complejo Hospitalario de Navarra, Spain. Participants: Newly diagnosed patients with NSCLC stage I–IV. Intervention: Multicomponent exercise programme that combined resistance, endurance, balance and flexibility exercises. Each session lasted 45–50 minutes, and the exercise protocol was performed twice a week over 10 weeks. Measurements: Mortality, readmissions and Visits to the Emergency Department. Change in frailty status according to Fried, VES-13 and G-8 scales. Results: 26 patients completed the 10-weeks intervention (IG). Mean age in the control group (CG) was 74.5 (3.6 SD) vs 79 (3 SD) in the IG, and 78,9% were male in the IG vs 71,4% in the CG. No major adverse events or health-related issues attributable to the testing or training sessions were noted. Significant between-group differences were obtained on visits to the emergency department during the year post-intervention (4 vs 1; p:0.034). No differences were found in mortality rate and readmissions, where an increasing trend was observed in the CG compared with the IG in the latter (2 vs 0; p 0.092). Fried scale was the unique indicator that seemed to be able to detect changes in frailty status after the intervention. Conclusions: A multicomponent exercise training programme seems to reduce the number of visits to the emergency department at one-year post-intervention in older adults with NSCLC during adjuvant therapy or palliative treatment, and is able to modify the frailty status when measured with the Fried scale.

Key words: Lung cancer, frailty, exercise, health-care resources.


 

Introduction

Lung cancer is the second most prevalent common cancer in the world and predominantly affects older adults; 50% of the diagnoses are in patients aged 70 or older, and about 14% in over 80 years old (1, 2). Overall, the survival rate at 5 years is lower in the very old, and patients aged 80 years or older are less likely to receive local therapy than younger patients (2). Additionally, the incidence and mortality from lung cancer have decreased among individuals aged 50 years and younger but have increased among those aged 70 years and older (3). However, geriatric patients may be undertreated, and are routinely underrepresented on clinical trials for many reasons including frailty, doubts about the usefulness of therapy, or lower patient willingness to pursue aggressive therapy (4, 5).
The standard-of-care therapy for patients with stage III Non-small cell lung cancer (NSCLC) is concurrent chemotherapy and radiotherapy (CRT), but there is a lack of data regarding the use of CRT in octogenarians and nonagenarians. The goal for the treatment of patients with stage IV NSCLC is palliation, both through improvement in their quality of life (QOL) and in prolongation of survival. Few comparative studies have been conducted that are limited to older patients, and even in very recent research of older adults with NSCLC, the cut-off age was 65 or 70 years (6), and in some studies, even 62.7% of patients aged ≥80 years with stage III NSCLC received no cancer-directed care (7). Patient selection is a key factor in order to administer some treatments in older adults because they are more likely to have a poor performance status with comorbidities, which can lead to little benefit (8).
There is a growing interest in non-invasive interventions for patients with lung cancer, with the goal of maximising physical performance. Physical exercise can be beneficial at any stage of the disease through increasing strength, endurance and decreasing emotional issues (9). Multicomponent exercise programmes have demonstrated to be well tolerated and safe in patients with lung cancer, but there is still a paucity of data to draw conclusive and precise exercise guidelines. A recent Cochrane review failed to establish any conclusive evidence regarding efficiency of exercise training on physical fitness in patients with advanced lung cancer (10–12), and there is little information on what kind of benefits an exercise intervention can provide in the use of health-related resources or the impact on the ability to reverse frailty in the older population. To date, the clinical effectiveness of physical exercise in advanced cancer remains inconclusive.
This study aimed to examine the impact of this exercise programme in the use of health resources and its ability to reduce the number of visits to an emergency department at one-year post-intervention and to assess the changes in frailty status.

 

Methods

Study design, setting and ethical considerations

This is a secondary analysis of a non-randomised, opportunistic control, longitudinal trial designed to examine the effects of a multicomponent exercise programme on surrogate measures of health status in patients with lung cancer in real-world settings (12). Patients were treated at the Oncogeriatrics Unit of the Complejo Hospitalario de Navarra (CHN), Pamplona, Spain. The study ran from May 2018 to November 2019 and was approved by the CHN Research Ethics Committee (25 April, 2018, reference number Pyto2018/5#214) according to the World Medical Association Declaration of Helsinki Declaration.

Patient population

Newly diagnosed patients with NSCLC stage I–IV (TNM classification) were enrolled after histologically confirmation and screening for eligibility by their oncologist. The study included an initial exam at the first visit (baseline) and a final exam after 10-weeks. The inclusion criteria were: aged 70 years or older, have a diagnosis of confirmed lung cancer, with a life expectancy exceeding 3 months (prognosis), with multimorbidity, a Barthel score ≥60 points, and to be able to communicate and collaborate with the research team. Exclusion criteria were clinically unstable patients defined medically as having received active treatment (chemotherapy or radiotherapy) before inclusion in the study, moderate–severe cognitive impairment considered as a score ≥5 in the Reisberg Global Deterioration Scale, and contraindications to exercise or already engaged in high levels of physical training.

Outcome assessment

The primary outcomes of this study were mortality rate, readmissions and visits to the emergency department during the year after the intervention. The secondary outcomes were the changes in the level of frailty measured with G8 (14, 15), Vulnerable Elders Survey-13 (VES-13) (16, 17) and Fried scales (17). The G8 is an eight-item screening tool, developed for older cancer patients. The tool covers multiple domains usually assessed by the geriatrician when performing the geriatric assessment. A score of ≤14 is considered abnormal. The VES-13 is a 13-item self-administered tool, developed for identifying older people at increased risk of health deterioration in the community. A score of ≥3 identifies individuals as “vulnerable”, which is defined as an increased risk of functional decline or death over 2 years. The Fried Frailty Criteria includes five items: weight loss, handgrip strength, gait speed, exhaustion and physical performance and a score of ≥3 indicates “frailty”.
Members of the research team were able to access the medical records of each patient. The same assessments were repeated at 10-weeks after intervention or usual care, and we checked the medical records in order to assess the mortality, number of readmissions and visits to the emergency department during the year posterior to the intervention.

Intervention

The intervention is described elsewhere (12). Briefly, the control group (CG) did not perform any kind of supervised physical exercises/activities during the intervention period but received habitual outpatient care, including comprehensive geriatric assessment and physical rehabilitation when needed.
The intervention group (IG) received a multicomponent exercise programme that combined resistance, endurance, balance and flexibility exercises. Each session lasted 45–50 minutes, and the exercise protocol was performed twice a week over 10 weeks (Table 1). EGYM Smart strength machines (eGym® GmbH, München, Germany) were used for both resistance training and maximum strength measurements of the lower and upper extremity muscles. Muscle power training including motivational gamification and maximum acceleration of constant weight from 30% to 60% of the maximun strength measurements were used during training (Explonic eGym® intelligent training program). The exercise programme was individualised and included measurements of vital signs at the beginning and end of each session. Patients were advised to carry out the «Vivifrail» programme (18) at home during the entire study period. The control group received the usual medical treatment and was advised to continue their usual activities without restriction in physical activity throughout the study period.

Table 1
Multi-component exercise program

Abbreviations: HR: Heart Rate; RM: Repetition Maximum.

 

Statistical analyses

All analyses were performed by a researcher who was not involved in the study’s participant assessments and interventions. The statistical data analysis was performed with the commercial software SPSS Statistics version 25.0 (IBM Corp., Chicago, IL, USA). The Shapiro–Wilk test was used to determine whether parametric tests were appropriate, and the normality of data was checked graphically. In the present study, descriptive data, including frequencies for categorical variables and means and standard deviation (SD) for continuous variables, were reported. Baseline differences and use of health resources (readmission and visits to the emergency department) were analysed using the chi-squared test and Mann–Whitney U test for nominal data and the Kruskal–Wallis test for ordinal data. A significance level of 5% (p <0.05) was adopted for all statistical analyses.

 

Results

Characteristics of participants

Of the 42 volunteers, 34 attended the oncologic and geriatric clinics screening. Of these, 26 completed the 10-weeks intervention. Two patients from the IG did not complete the programme due to death or oesophagal surgery. Data from the 19 remaining patients from the IG were analysed. A total of 6 of the 13 CG subjects dropped out of the study and did not take the final exam due to the progression of the disease (n = 3) or death (n = 3). Data from the 7 remaining CG participants were analysed. A total of 19 participants (4 females, 15 males) were eligible for analysis in the IG and 7 participants (2 females, 5 males) in the CG (Figure 1). All subjects in the IG completed at least 86% of the planned training sessions. No major adverse events or health-related issues attributable to the testing or training sessions were noted.
Table 2 displays the baseline characteristics by group. No significant differences were found between the two groups, except for age. Patients in the IG had a mean (SD) age of 74.5 (3.6) years, range 70–81 years (78.9% males) and BMI 26.8 (4.5) kg/m2. In total, 41% underwent surgery, and 78.9% received adjuvant chemotherapy alone or in combination with other therapies. Participants in the CG had a mean (SD) age of 79.0 (3.0) years, range 75–83 years (71.4% males), and BMI 25.5 (2.5) kg/m2. Within this group, 14% were submitted to surgery, and 85.7% were receiving adjuvant chemotherapy alone or in combination with other therapies.

Figure 1
CONSORT Flow Diagram – modified for non-randomized
trial design

Table 2
Baseline characteristics of the participants

Abbreviations: BMI, body mass index; COPD, chronic obstructive pulmonary disease; TNM, tumor node metastasis; VATS, video-assisted thoracic surgery; VES-13, Vulnerable Elders Survey-13. aData are reported as mean ± standard deviation or number (%).

 

Mortality, readmissions and Visits to the Emergency Department

Significant between-group differences were obtained on visits to the emergency department during the year post-intervention (4 vs 1; p:0.034). Furthermore, no differences were found in mortality rate and readmissions, where an increasing trend was observed in the CG compared with the IG in the latter (2 vs 0; p 0.092) (Table 3).

Table 3
Mortality rate, readmissions and visits to the Emergency Department at one year post-intervention

Abbreviations: ED, Emergency Department; IQR, interquartile range.

 

Change in frailty status according to Fried, VES-13 and G-8

Although no significant between-group differences were obtained on frailty status changes assessed with the G-8, VES-13 and Fried scale, the unique indicator that seems to be able to detect changes in frailty status is the Fried Index after the intervention (Table 4).

Table 4
Changes in frailty status according to G-8, VES-13
and Frailty Index after the intervention

Abbreviations: VES, Vulnerable Elders Survey.

 

Discussion

The main finding of this study was that supervised multicomponent exercise training can be beneficial for patients with lung cancer, by decreasing the number of visits to the emergency department. Previously, we showed that a multicomponent exercise programme in older patients with NSCLC under adjuvant therapy or palliative treatment positively affected measures of functional performance and quality of life (i.e., pain symptoms and dyspnea) (12), but this secondary analysis goes a step further, and analyses additional outcomes that may help when making decisions in relation to the use of healthcare resources.
Non-oncologic causes of readmission and death predominate in the first 90 days after pneumonectomy, after which oncologic causes prevail (19). Most previous studies have been related to readmissions after pulmonary resection (21, 22), but there is hardly any data on the influence of exercise programmes on the number of visits to the emergency department or on the influence of frailty in the use of health resources in cancer patients (17, 23). Older adults have been traditionally excluded from clinical trials, and clinical data obtained in a younger population cannot be automatically extrapolated to older patients with lung cancer (23). Older patients have more comorbidities and tend to tolerate aggressive chemotherapy and radiotherapy worse than younger patients. Much of the data available currently is based on retrospective studies of trials that included patients with good performance status and patients of all ages. Nonetheless, retrospective analyses of ordinary trials without age-specific entry criteria are potentially biased by the intrinsic selection that governs enrollment. In the present study, we did not find differences in the mortality rate, but this factor is very difficult to modify, especially in an older population as complex and frail as the one that participated in the study. However, we found that the IG had a non-significant lower number of readmissions (p = 0.09) and a lower number of visits to the emergency department (p = 0.034) at one-year post-intervention, which had at least a moderate impact on aspects related to the quality of life and use of health resources.
Chronological age alone should not be the only factor in the cancer treatment plan. Other factors should be taken into account and frailty assessment in older patients with primary lung cancer is increasingly being recognised as a very important tool (24), and it could be used even to prevent under- or overtreatment (25). In fact, a comprehensive geriatric assessment should be used together with an evaluation of the toxicity profile of each drug to guide the choice of the best treatment (26).
There is a big dilemma regarding the scales and the models to select the patients who most benefit of specific oncogeriatric approaches (15). Some studies suggest the VES-13 scale or G-8 scale, nevertheless, the only scale in our study that identified a possible reversal of the frailty status was the Fried Index. This could be because physical exercise modifies more parameters that are taken into account in Fried model of frailty (physical activity, grip strength and gait speed) compared to the G8 model (which has a vague and generic question about mobility), or the VES-13 (which has questions related more to basic activity rather than functional capacity). This has implications for future studies and helps to clarify which indices we should use in this population sector. In our study, a supervised exercise training programme was able to reverse frailty in 21.1% of patients (vs 0% in CG) using the Fried scale. This scale includes many functional aspects such as handgrip strength and gait velocity that could benefit from a physical exercise programme in comparison with G-8 and VES-13 scales.
The management of the older person with cancer should be based on the risk/benefit assessment, and in the multidisciplinary interventions (medical, psychological and social) it may improve the tolerance of the treatments (27). Exercise should be part of this multidisciplinary approach because it provides physiological and psychological benefits for cancer survivors Cancer rehabilitation as a part of clinical management is still underutilised, but older adults with lung cancer would welcome a proactive intervention. There are some barriers due to the psychosocial impact of diagnosis and the effects of cancer treatment, but the intervention must be tailored to individual need and address physical limitations, psychological and social welfare in addition to physical activity and nutritional advice (28). In this regard, the present study shows that these kind of programmes are feasible and may improve the quality of life of older patients with NSCLC.
This study had several limitations that should be considered. The most important was that the number of participants in our study was relatively small, but there are not many related studies with more patients, and so more extensive multicentre studies are encouraged to reinforce our findings. However, our study based on a supervised and individualized multicomponent physical exercise intervention including muscle power training and motivational gamification was beneficial and safe for patients with advanced NSCLC, under adjuvant therapy or palliative treatment. To our knowledge, none of the previous studies that have evaluated physical training in older adults with lung cancer reported serious adverse events, which is consistent with the findings of our study. We believe that the present study represents an important addition to the current body of knowledge on the safety of exercise interventions, particularly in the elderly with NSCLC under adjuvant therapy or palliative treatment. Well-designed randomized clinical trials should be performed to corroborate the current findings, with a larger sample size to detect a significant difference in the components studied.
In conclusion, a multicomponent exercise training programme seems to reduce the number of visits to the emergency department at one-year post-intervention in older adults with NSCLC during adjuvant therapy or palliative treatment for their disease, and is able to modify the frailty status measured with the Fried scale.

 

Funding: M.I. is funded in part by a research grant PI17/01814 from the Ministerio de Economía, Industria, y Competitividad (ISCIII, FEDER). R.R.-V. is funded in part by a Postdoctotal fellowship grant ID 420/2019 of the Universidad Pública de Navarra, Spain. N.M.-V. is funded in part by a research grant from Gobierno de Navarra: «Project prevención de deterioro funcional del anciano frágil con cáncer de pulmón mediante un programa de ejercicio tras valoración geriátrica integral” (Expediente 43/18), promovido por el Departamento de Salud.
Acknowledgments: We thank Fundacion Miguel Servet (Navarrabiomed) for its support during the implementation of the study, as well as Fundacion Caja Navarra and Fundacion La Caixa. Finally, we thank our patients and their families for their confidence in the research team.
Conflicts of Interest: The authors declare no conflicts of interest.
Ethical Standards: The study was approved by the CHN Research Ethics Committee (25 April, 2018, reference number Pyto2018/5#214) according to the World Medical Association Declaration of Helsinki Declaration.

 

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EFFECT OF A COMBINED TAI CHI, RESISTANCE TRAINING AND DIETARY INTERVENTION ON COGNITIVE FUNCTION IN OBESE OLDER WOMEN

 

F. XU1, M.J. DELMONICO1, I.E. LOFGREN2, K.M. UY1, S.A. MARIS1, D. QUINTANILLA1, A.G. TAETZSCH2, J. LETENDRE1, L. MAHLER3

 

1. Department of Kinesiology, University of Rhode Island, Independence Square II, Kingston, RI 02881, United States; 2. Department of Nutrition and Food Sciences, University of Rhode Island, Fogarty Hall, Kingston, RI 02881, United States; 3. Department of Communicative Disorders, University of Rhode Island, Independence Square II Kingston, RI 02881, United States.
Corresponding author: Furong Xu, Department of Kinesiology, The University of Rhode Island, 25 West Independence Way, Suite P, Kingston, RI 02881, (401)874-2412 (office), (401)874-4215 (fax), fxu2007@uri.edu

J Frailty Aging 2017;6(3):167-171
Published online May 24, 2017, http://dx.doi.org/10.14283/jfa.2017.16

 


Abstract

Cognitive decline in older adults is a major public health problem and can compromise independence and quality of life. Exercise and diet have been studied independently and have shown to be beneficial for cognitive function, however, a combined Tai Chi, resistance training, and diet intervention and its influence on cognitive function has not been undertaken. The current study used a 12-week non-randomized research design with experiment and control groups to examine the effect of a combined Tai Chi, resistance training, and diet intervention on cognitive function in 25 older obese women. Results revealed improvements in domain specific cognitive function in our sample. Baseline cognitive function was correlated with changes in dietary quality. These findings suggest that Tai Chi and resistance training combined with diet intervention might be beneficial for community-based programs aiming to improve cognitive function.

Key words: Older adult, frailty, cognitive function, Tai Chi, exercise.


 

Introduction

Cognitive decline in older adults is a major public health problem as Alzheimer’s disease is the 6th leading cause of death in the United States and almost two-thirds of seniors with the disease are women (1). Tai Chi and resistance training (RT) have been linked individually to increased cognitive function or to the reduced the rate of cognitive decline (2, 3). Although Tai Chi is not a high intensity exercise, it may potentially slow the rate of cognitive decline or improve cognitive function and memories function in elderly individuals with or without cognitive impairment (2, 3). Studies of the effects of RT on cognitive function also showed positive results such as improvement in immediate memory and attention, but findings were not consistent due to various dosage and type of RT (2). Though both exercise modalities are suitable for the elderly (2, 3), the effects of Tai Chi and RT combined on cognitive function is still in its infancy. Furthermore, studies have determined that healthy dietary patterns were beneficial to cognitive health and associated with better cognitive function (4). However, little is known about the combined effects of Tai Chi and RT with dietary intervention on cognitive function in obese older women. The purpose of this study was to examine the effect of a combined Tai Chi, RT, and diet intervention on cognitive function assessed with the Repeatable Battery Assessment of the Neuropsychological Status (5; RBANS). It was hypothesized that the combined interdisciplinary intervention would result in improvements in cognitive function.

 

Methods

Study Design

A non-equivalent groups design with experiment (EXD) and control (CON) groups was used. Individuals were assigned to either the EXD or CON groups on a “first-come, first-served” basis. The EXD group participated in a 12-week intervention while the CON group was asked to maintain their normal lifestyle. The study took place at an inner-city senior center. The study was approved by the Institutional Review Board of the University of Rhode Island.

Participants

Eligible participants were women between the ages of 50-80 years with a body mass index ≥ 30kg/m2 who were not engaged in a regular exercise program. Individuals who expressed an interest in participating in the study were contacted by phone and screened for inclusion and exclusion criteria used in our previous studies (6). Thirty-three out of 92 elderly women who initially expressed interest in the study were eligible to enroll. The baseline characteristics of the participants are represented in Table 1.

Table 1 Baseline characteristics of the intervention (EXD) and control (CON) groups

Table 1
Baseline characteristics of the intervention (EXD) and control (CON) groups

Continuous data are expressed as mean ± standard deviation. Categorical data are expressed as counts (percentage).  P-values were obtained by performing t-test or Fisher’s exact test (category variables). SPPB = Short physical performance battery test. RBANS = Repeatable Battery for the Assessment of Neuropsychological Status index.

 

Outcome Measures

All testing procedures were performed at a senior center before and after the intervention under standardized conditions. Cognitive function was measured with the RBANS which has been widely used to identify and characterize cognitive decline in older adults (5). The test examined five domains: immediate memory, visuospatial/constructional, language, attention, and delayed memory (5). Physical function was measured using the short physical performance battery test (7). Individuals’ height and weight were recorded using a scale with stadiometer (Webb City, MO, USA). Body composition was measured using a foot-to-foot bioelectrical impedance device (Tanita BF-556, Arlington Heights, IL, USA) (8). In addition, the Yale Physical Activity Survey was used to examine participants’ physical activity (9). Diet quality and nutrition risk were assessed by the Dietary Screening Tool with a higher score indicated healthier dietary patterns (10).

Intervention

Participants assigned to the EXD group received a 50-minute exercise intervention on three non-consecutive days each week for 12 weeks. The intervention included a modified 24-movement Yang style Tai Chi and RT (11).The behaviorally-based diet education occurred once a week for 45 minutes and was led by a registered dietitian (6).

Statistical Analysis

Normality of the data was assessed using the Shapiro-Wilk test. A paired sample t-test or Fisher’s exact test was performed to assess baseline group differences and compare post- and pre-intervention results. Between group differences were determined by an analysis of covariance using the changed score adjusted for baseline values. Intervention effect was determined by Cohen’s d. The Pearson correlation coefficient was used to determine the relationship between baseline RBANS total scale index and changes in outcomes measures. Statistical analyses were performed using SAS statistical software and significance was set at p < 0.05 (Version 9.3, SAS Institute, Cary, NC).

 

Results

Twenty-five participants completed the study with eight who dropped out due to personal reasons. Participant baseline characteristics for EXD and CON group comparisons are shown in Table 1. There were no significant differences between groups in any baseline variables. All participants’ RBANS index and subtest scores were below the average scores specified in the standardized 60-79 year-old sample (12). Nine of 16 participants in EXD and 4 of 9 in CON group had an RBANS total scale index below the average score of 90 for normative samples in the same age group (12).

 

Figure 1 Study flow chart

Figure 1
Study flow chart

 

The EXD group demonstrated significant changes in six subtests: story memory (p=0.031), figure copy (p=0.043), line orientation (p=0.025), digit figures (p=0.029), story recall (p<0.001) and figure recall (p=0.026). The CON group showed changes in three subtests: story memory (p=0.014), list learning (p=0.017), and figure copy (p=0.038). A comparison of the RBANS total scale index scores changes from baseline to post-intervention between groups showed significant differences in two domains: visuospatial/constructional (9.8±15.5 vs. -5.4±11.8, p=0.038, d = 1.10) and attention (-4.1±9.1 vs. 3.6±6.7, p=0.047, d = 0.96). No significant differences were observed between the EXD and CON groups in subtest scores (See Table 2). The baseline RBANS total index score correlated positively with dietary quality change (r=0.49, p=0.030). However, neither EXD nor CON group showed a significant linear relationship between baseline RBANS total index score and change in their dietary quality.

Table 2 The post-pre changes in RBANS scores between and within intervention (EXD) and control (CON) groups

Table 2
The post-pre changes in RBANS scores between and within intervention (EXD) and control (CON) groups

Data are expressed as means ± standard deviations; a. P-values were obtained by performing paired t-test or Wilcoxon signed rank test; b. P-values were obtained by performing analysis of covariance using the change score adjusted for baseline values; * Significant post-pre changes within groups (p < 0.05); † Significant post-pre changes between groups
(p < 0.05); RBANS = Repeatable Battery for the Assessment of Neuropsychological Status index.

 

Discussions

This study showed, for the first time, that a combined Tai Chi, RT and dietary intervention resulted in a significant improvement in cognitive function which was identified in visuospatial/constructional index, immediate story memory and delayed story recall from the RBANS. Participants’ initial cognitive function, on the other hand, was associated with changes in dietary quality.
The observed difference between the EXD and CON groups was performance on the visuospatial/constructional index and its effect size value suggested a high practice significance. This result was supported by the observation that the EXD group improved in both line orientation and figure copy subtests. Figure copy, as the part of visuospatial/constructional index, served as learning trial for figure recall (13) which also showed significant improvement in the EXD group. In contrast, the CON group showed decreases in the visuospatial construction index at the post-intervention evaluation. These findings suggest that the present study might be effective on visuospatial abilities thus has the potential to improve healthy aging as visuospatial construction is important for one’s ability to function in daily life (14).
Our findings demonstrated immediate story memory was improved for both groups, but delayed story recall was improved only for the EXD group. Prior studies with either Tai Chi or RT have reported improvement in immediate memory and/or delayed memory (3), which is consistent with the findings in the current study. However, when compared to a previous study of elderly people with mild cognitive impairment (12), participants in the present study had much lower baseline scores on the total RBANS scale and immediate memory, and had comparable scores in delayed memory indices. Nine of 16 participants in EXD had RBANS total scale scores below the average score of 90 specified in same age group normative data (12). These lower scores may indicate mild cognitive impairment in our study sample especially participants in EXD group who might have had pre-existing cognitive decline. Cognitive skills for story memory and delayed story recall may be related to methods of education/teaching instructions and delayed story recall is a sensitive measure of mild cognitive impairment (15). Therefore, group differences in delayed story recall may have important implications to inform us about how to plan and deliver exercise programs such as learning Tai Chi movements to deliver educational level appropriate instruction for participants to ensure compliance with exercise and dietary interventions.
The present study revealed significant correlations between initial RBANS total scale scores and changes in dietary quality. This is consistent with previous studies that showed older adults’ individual cognitive function influences the effectiveness of interventions (4). This suggests that individuals with higher RBANS total scale score might be more responsive to the beneficial impact of diet quality and could be more willing to accommodate dietary behavior change (4).
The present study has limitations including non-random sampling, participants’ dropout rate and small sample size which might led to sample bias and could have compromised statistical power of this study. Additionally, no correction has been made for this study due to its exploratory nature. These limited our findings interpretation and it warrants further investigation.
In summary, Tai Chi, RT and diet might have beneficial effect on cognitive function in older, inner city obese women, and initial cognitive function might be related to changes in diet quality. Although generalizability is limited by sample size, our findings suggest new approaches for future study, which may lead to interventions that improve cognitive function in elderly.

 

Funding: Funded by the College of Environment and Life Sciences Community Access to Research and Extension Services (CELS CARES) grant, USDA, #RH05236.
Conflicts of interest: None.

 

References

1. Alzheimer’s Association. 2014 Alzheimer’s Disease Facts and Figures. Alzheimer’s Dement. 2014;10:1–80.
2. Lam LCW, Chau RCM, Wong BML, et al. Interim follow-up of a randomized controlled trial comparing Chinese style mind body (Tai Chi) and stretching exercises on cognitive function in subjects at risk of progressive cognitive decline. Int J Geriatr Psychiatry. 2011;26:733–40.
3. Cassilhas RC, Viana VAR, Grassmann V, et al. The impact of resistance exercise on the cognitive function of the elderly. Med Sci Sports Exerc. 2007;39:1401–7.
4. Wengreen H, Neilson C. Diet quality is associated with better cognitive test performance among aging men and women. J Nutr [Internet]. 2009;139:1944–9.
5. Randolph C. Repeatable Battery for the Assessment of Neuropsychological Status. Bloomington: MN: Psych Corp; 2012.
6. Taetzsch A, Quintanilla D, Maris S, et al. Impact on diet quality and resilience in urban community dwelling obese women with a nutrition and physical activity intervention. 2015;4:102–8.
7. Gill TM. Assessmetn of function and disability in longitudinal studies. J Am Geriatr Soc. 2010;58:S308–12.
8. Ritchie JD, Miller CK, Smiciklas-Wright H. Tanita foot-to-foot bioelectrical impedance analysis system validated in older adults. J Am Diet Assoc. 2005;105:1617–9.
9. Young DR, Jee SH, Appel LJ. A comparison of the Yale Physical Activity Survey with other physical activity measures. Med Sci Sports Exerc. 2001;33:955–61.
10. Bailey R, Mitchell D, Miller C, et al. A dietary screening questionnaire identifies dietary patterns in older adults. J Nutr. 2007;137:421–6.
11. Maris SA, Quintanilla D, Taetzsch A, et al. The effects of Tai Chi, resistance training, and diet on physical function in obese older women. J Aging Res. 2014;2014:140–8.
12. Patton DE, Duff K, Schoenberg MR, et al. RBANS index discrepancies: Base rates for older adults. Arch Clin Neuropsychol. 2006;21:151–60.
13. Beatty WW. RBANS analysis of verbal memory in multiple sclerosis. Arch Clin Neuropsychol. 2004;19:825–34.
14. Mervis CB, Robinson BF, Pani JR. Visuospatial Construction. American Journal of Human Genetics. 1999;65:1222-9.
15. Rabin LA, Paré N, Saykin AJ, et al. Differential Memory Test Sensitivity for Diagnosing Amnestic Mild Cognitive Impairment and Predicting Conversion to Alzheimer’s Disease. Neuropsychology, development, and cognition Section B, Aging, neuropsychology and cognition. 2009;16:357-76.

THE EFFECT OF PHYSICAL EXERCISE ON FRAIL OLDER PERSONS: A SYSTEMATIC REVIEW

 

R.B. SILVA1, H. ALDORADIN-CABEZA1, G.D. ESLICK2, S. PHU3,4, G. DUQUE3,4

 

1. Sydney Medical School Nepean, The University of Sydney, PO Box 63, Penrith, NSW, Australia 2750; 2. The Whiteley-Martin Research Centre, The University of Sydney, PO Box 63, Penrith, NSW, Australia 2750; 3. Department of Medicine, Melbourne Medical School – Western Precinct, The University of Melbourne, St. Albans, VIC, Australia 3021; 4. Australian Institute for Musculoskeletal Science (AIMSS), The University of Melbourne and Western Health, St. Albans, VIC, Australia 3021.
Corresponding author: Prof. Gustavo Duque, MD, PhD, FRACP, Australian Institute for Musculoskeletal Sciences (AIMSS), The University of Melbourne and Western Health, Level 3 WCHRE Building, 176 Furlong Road, St Albans VIC 3021, Tel: +61 3 8395 8121; Facsimile: +61 3 8395 8258, Email: gustavo.duque@unimelb.edu.au

 

J Frailty Aging 2017;6(2):91-96
Published online March 8, 2017, http://dx.doi.org/10.14283/jfa.2017.7


Abstract

Physical exercise is one of the most effective non-pharmacological interventions aimed to improve mobility and independence in older persons. The effect of physical exercise and the most effective type of exercise in frail older persons remain undefined. This systematic review examines the effectiveness of physical exercise on frail older persons. Seven databases were search for randomized control trials which assessed the effect of exercise on participants who were identified as being frail using specific and validated criteria. Nine articles were reviewed from eight studies, from which seven used a validated definition of frailty. Based on the articles analyzed in our systematic review, the evidence suggests that exercise has a positive effect on various measures used to determine frailty including cognition, physical functioning, and psychological wellbeing. Some studies revealed that exercise may prevent or delay the onset of frailty which can enhance quality of life in older adults. Despite the evidence for exercise interventions in frail older adults, it appears that there is no clear guidance regarding the most effective program variables. The reviewed studies were generally long in duration (≥6 months) with sessions lasting around 60 minutes performed three or more times per week, including multicomponent exercises. In conclusion, although exercise interventions appear to be effective in managing the various components of frailty and preventing/delaying the onset of frailty, the most effective exercise program in this population remains unidentified.

Key words: Older adults, frailty, exercise, aging.


 

Introduction

Frailty is a common term used to describe poor health and functional status in older persons, which is associated with an increased risk for morbidity and mortality (1). It affects one in ten older adults, with women at increased risk with almost double the rates of males (2). The concept of frailty is complex and therefore several efforts have been made attempting to develop a specific definition utilizing valid clinical criteria. In fact, a recent effort to determine an operational definition of frailty concluded that there was no single operational definition which was widely accepted, particularly with regards to diagnostic criteria (3). Depending on the method used, several diagnostic criteria for frailty exist including physical parameters, serum markers for chronic inflammation, cognitive status, and even social and psychological dimensions (4,5). The range of definitions and diagnostic criteria for frailty are one of the greatest limiting factors in developing a valid and reliable intervention for frail older adults.
Amongst the interventions to treat frailty, exercise appears to be one of the most natural choices and has in many ways been referred to as a ‘drug’ from which health benefits can be obtained through optimal prescription (6). In healthy older adults, exercise has been found to improve function, muscle and bone mass, metabolism and cognition (7). In frail older adults, studies have shown that physical exercise can improve some components of this syndrome such as cognitive impairment (8), chronic inflammation (9), and physical parameters (10,11) thus contributing to the maintenance of independent living in this particular population.
However, and due to the variety of clinical criteria used to identify frailty in these and other studies (12-15), the evaluation of the global effect of exercise on frailty as well as the most effective type and dose of exercise in frail older individuals remains unknown. The objective of this study was to analyze the effectiveness of physical exercise on the most common components of frailty, and to compare this effect between subjects that were classified as frail using validated and specific but non-validated diagnostic criteria.

 

Methods

Data Sources and Selection: The study was developed based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) (16) following previously established objectives and methods. Our search looked for all studies published in English language between April 2001 and October 2016 in electronic databases including Medline, Embase, Pubmed, Cochrane Central Register of Controlled Trials (CENTRAL), PEDro (Physiotherapy Evidence Database), AMED (Allied and Complementary Medicine), OT Seeker (Occupational Therapy) using a combination (and/or) of the following MESH terms: frailty, frail older adults and frail elderly; exercise, exercise therapy, muscle stretching exercises, resistance training, physical fitness, physical exertion.
Inclusion criteria were studies published in English language, randomized controlled trials (RCTs) in which at least one group performed physical exercise as an intervention, which was compared to a control group, outcomes including frailty criteria, both male and female, and 60 years or older. Exclusion criteria were lack of placebo or control group, lack of specific or validated defining criteria for frailty, or instances where exercise was combined with other interventions in the exercise group.
Data Extraction: Data from studies selected for full analysis were collected by three independent investigators using a standardized form with the following items: Author and year of publication, country where research was held, setting of subjects, sex and age of participants, sample size of study, number of groups assessed, validated or non-validated criteria for frailty, variables used to assess frailty, classification of frailty, number of groups assessed, number of participants in each group at the beginning of study, number of participants in each group at the end of study, type of exercise performed, length of exercise program (duration, frequency per week and length of each session) activities performed in the control group and any additional group, time of follow-up, and outcomes about some components of frailty. Disagreements regarding inclusion and exclusion of studies and extracted data were resolved by consensus between investigators. Due to the heterogeneity of exercise program variables, outcome measures and frailty components evaluated in the studies it was not possible to analyze the data quantitatively by meta-analysis.

 

Results

Of the 820 potentially relevant references screened on database (Figure 1), 129 were selected for assessment which included reading abstracts. After reviewing the abstracts, 105 were excluded due to duplicity of the data or lack of specific criteria to assess frailty. Full text from 24 articles were analyzed and 15 were excluded because of unclear or inexact definition for frailty or lack or clear exercise protocols. This resulted in 9 articles from 8 studies included in the final analysis with subsequent data collection and analysis completed by all the investigators.
The analyzed studies were held in the USA (13-15, 17, 18), Australia (19), Spain (20), Finland (21), and Canada (12) with participants residing in settings of community (12, 14, 17-21) and nursing homes (13,15). All studies had two groups, one intervention and one control with most of participants being women in both groups (~70%). All the studies chosen for the systematic review were published after 2002, with four studies published between 2002 and 2010 and five published from 2010-2016.

 

Figure 1 Flowchart of literature search results

Figure 1
Flowchart of literature search results

In total, 1796 individuals participated in the studies, of which 936 performed physical exercise and 860 did not. Various methods were used for the assessment of frailty in each study. Two studies (14, 17) used non-validated criteria and classified participants as moderately or severely frail based on two tests of physical capability (rapid gait and sit to stand) which had been linked to functional decline and disability. Participants were considered severely frail if they scored greater than 10 seconds on the rapid gait test and could not stand from a hard-back chair with their arms folded. If the participants met only one of these criteria, they were classified as moderately frail.
The Frailty phenotype (4) was the most commonly used tool for diagnosing frailty in the studies reviewed, appearing in five of the nine studies (12, 18-21). In this assessment, subjects are classed as being frail if they presented with three or more of the following five symptoms being 1) unintentional weight loss (>10lb in past year) 2) muscular weakness (lowest 20% by gender and body mass index) 3) fatigue (self-report) 4) slow gait speed (slowest 20% by gender and height) and 5) low physical activity/sedentariness.
The study by Langrois et al. (12), comprehensively assessed frailty, classing participants as frail only if they met at least two of the following three different diagnostic criteria: a) Frailty phenotype b) a score of ≤28/36 in the modified Physical Performance Test (PPT) by Binder et al., (22) and (c) identified as frail according to the geriatrician’s judgment (mildly frail or worse on the clinical frailty scale) after assessing the 70 possible deficits of the frailty index of Rockwood et al., (5). To be classified as non-frail, participants could not meet any of the three defined frailty criteria.
In Greenspan et al. (10) and Wolf et al. (12), participants were classified as transitioning to frail on the basis of criteria developed by Speechley and Tinetti et al., (23) that defined adults as vigorous, frail, or transitionally frail on the basis of ten attributes: age, gait and balance, walking activity for exercise, other physical activity for exercise, presence or absence of depression, use of sedatives, near-vision status, upper- and lower-extremity strength (force-generating capacity), and lower-extremity disability. Adults who were defined as ‘vigorous’ were those who had at least three ‘vigorous’ and no more than two frail attributes. Frail adults were defined as those who had at least four frail attributes and no more than one vigorous attribute. Adults who were transitionally frail were those who do not meet the criteria for the frail or vigorous group. A summary of the study and participant characteristics can be found in Table 1.

Table 1 Study and participants summary characteristics

Table 1
Study and participants summary characteristics

NF = No Frailty. PF = Pre Frail.  F = Frailty

Exercise program design in the studies varied, with differences in exercises performed, session duration, frequency and length of intervention (Table 2). The type of exercises performed in each study included balance and strength training only (14, 17), tai chi (13, 15), mobility exercises (19) and multicomponent exercise programs including stretching, balance, strength and aerobic training (12, 18, 20, 21). Session duration typically lasted between 30-60 minutes (12, 14, 17-19, 21), with one study lasting for 65 minutes (20) and two studies progressing from an initial duration of 60 minutes to 90 minutes by the end of the study (13, 15). Frequency of sessions performed each week ranged between twice a week (13, 15, 21) to a minimum of three up to five times a week (12, 14, 17-19, 20). Finally, intervention duration included 12 weeks (12), 24 weeks (20), 6 months (14, 17), 48 weeks (13, 15) and 12 months (18, 19, 21).
In terms of the control groups, participants were either provided with usual care (12, 19-21) or educational sessions (13-15, 17, 18). In the cases of usual care, participants were instructed to maintain current levels of activity (if any) and provided with usual community care and medical management. Educational session frequency varied for each study, with participants being exposed to education every 6 months (14, 17) or weekly (13, 15, 18) lasting for up to an hour each session. Topics covered in educational sessions included proper nutrition, management of medications, physical activity, sleep hygiene, immunizations, falls prevention and mental health.
In terms of outcomes, the reviewed studies included assessments for activities of daily living (17), disability (13, 14, 19), physical performance (12, 20, 21), mobility (17, 19), depression (15, 20), falls (15, 20, 21), cognition (12, 20) and quality of life (12, 19). Post intervention frailty criteria were also outcome measures in three studies (17, 18, 20).

Table 2 Exercise program summary characteristics

Table 2
Exercise program summary characteristics

 

Discussion

This systematic review has analyzed the effectiveness of physical activity on components of frailty in frail older people, which were classified based on validated and non-validated diagnostic criteria for frailty. The quality analysis of the studies provides evidence that exercise can improve cognition and psychological wellbeing, prevents decline in physical function and may even have an effect a reversing frailty in older adults. Adverse events included falls (14, 17) and musculoskeletal complaints (14, 17, 19) which were reported in three articles with no significant differences between intervention and control groups. This may be attributed to the nature of populations studied, with musculoskeletal complaints pre-existing in one study (19).
Cognitive function plays an increasingly important role in ageing, as evident in the prevalence of dementia at 5-7% in adults over 60 years (24), which is expected to increase dramatically with ageing populations around the world. Langlois et al. (12) performed a comprehensive cognitive assessment including assessments for cognitive functioning, verbal reasoning, processing speed, working memory, episodic memory and executive function and found significant improvements in working memory, processing speed and executive functions. Improved cognitive function was also evident in Tarazona-Santabalbina et al. (20) with improved Mini Mental State Examination (MMSE) scores found in the intervention group. Psychological wellbeing including measures for social functioning, depression and mood also showed significant improvements (12, 20). Given the lack of follow up in the two studies, it is difficult to determine whether exercise produces enduring cognitive gains in frail older adults. However, a previous study in older adults at risk for Alzheimer Disease has suggested that cognitive gains persisted for another 12 months post exercise (25).
Given that the implementation of exercise programs in sedentary older adults classed as being frail provides a large reserve for improvement, it was expected that physical performance and mobility would be significantly improved or maintained with exercise intervention. Improvements in gait speed and performance of the short physical performance battery (SPPB) and performance of activities of daily living using the Physical Performance Test (PPT) were found in one study (20). Other studies revealed improved strength and gait (17), slower rate of decline in function (14) and improved scores for the Functional Independence Measure (FIM) (21). The physical improvements reported included gains in mobility, strength and aerobic endurance suggests that exercise can benefit frail older adults by reducing disability and maintaining independence and ability to self-care.
Falls occur in up to 40% of community dwelling older adults, with increased rates in those residing in long term care (26). Data from the reviewed studies showed inconclusive results on falls rates in frail adults (15, 20, 21). In two studies, despite a trend towards a reduction in falls rates (15,20) and risk factors for falls (20), no statistically significant changes were evident. This was opposed to Perttila et al. (21) who showed significantly reduced rate of falls in those who scored greater than 2 in the Frailty Phenotype, classed as ‘advanced frail’. The pre-frail group also reduced falls rates to a lesser but still significant effect. Given the prevalence of balance exercise in the three studies, the variation in results may have been due to the design of exercise program implemented, with the exercise program in Perttila et al. (21) closely representing that of effective falls prevention programs as reviewed by Sherrington et al. (27).
Finally, three studies measured the direct impact of exercise on specific frailty criteria with one using measures linked to functional decline and disability (17), one using the validated Frailty Phenotype (18) and one using the both the Frailty Phenotype and validated Edmonton Frailty Scale (20). In all the reviewed studies, performance in criteria for the diagnosis of frailty was significantly reduced in the exercise group with either no change or increased risk found in the control groups. This was somewhat expected given the physical nature of frailty criteria employed in all studies. One study (20) also incorporated the Edmonton Frailty Scale which accounts for other measures such as nutrition, mood and cognition, however, no data were provided regarding the specific area for improved scores. Overall, exercise was suggested to play an important role in preventing and delaying the onset of frailty based on physical aspects measured in the Frailty Phenotype. Considering the previously mentioned results for cognition and psychological wellbeing, the use of other validated scales such as the Clinical Frail Scale or Frailty Index may have also shown improvements.
With regards to the most effective dose of exercise, our review showed that the most common exercise program used was multi-component and provided exercises targeting balance and muscular strength. Frequency of exercise was typically 3 sessions per week, with session duration lasting for approximately one hour. All except one intervention lasted for a minimum of six months (12). However, despite the relatively short intervention, benefits were still obtained in cognitive performance and psychological well-being. Only one study included a follow up period which suggested the maintenance of physical improvements. Given the various outcome measures taken, it appears that interventions taking place a minimum of three times per week, lasting for 60 minutes a session, over the course of a minimum of six months may be most effective in delaying frailty by improving components of frailty such as physical performance, cognitive function and psychological well-being.
Several limitations were present when we analyzed the effects of exercise on frailty parameters in the literature. The first of which refers to the lack of a universally accepted criteria for diagnosing frailty. For example, Fried et al. (4) conceptualized frailty as a geriatric syndrome resulting from cumulative decline in multiple physiologic systems and define that frailty is present when three of five criteria among: unintentional weight loss, self-reported exhaustion, poor grip strength, slow walking speed, and low physical activity are present. In contrast, Rockwood et al. (5) describe the concept of frailty as a “multidimensional syndrome of loss of reserves (energy, physical ability, cognition, health) that gives rise to vulnerability” and included impairment of cognition, mood, mobility, balance, Activities of Daily Living (ADLs), instrumental ADLs, nutrition and others comorbidities. The lack of inclusion for cognitive and psychological components is another limitation in our paper given that the studies reviewed all focused on physical presentations when using the Frailty Phenotype.
Another limitation in our study related to the exercise program design. That is, the type of exercise performed, frequency of sessions each week, duration and length of programs. Given the improvements reported in each study, it is difficult to identify which components of exercise are most effective for frail older adults. A previous systematic review (27) evaluated exercise interventions on the several components of frailty by using studies that mentioned the word “frail’ and found that exercise training had a positive impact on the frail older adults and should be used for the management of frailty. However, only three (6%) of studies used a validated measure to define frailty. In our article, seven of the nine studies reviewed (78%) contained well validated criteria for the diagnosis of frailty, with the other two articles using specific measures which have been linked to functional decline and disability.
In conclusion, our systematic review differs from previous reviews as it focused solely on the effect of exercise on specific and clinically defined frail subjects. Based on evidence to date, physical exercise is effective at improving components of frailty in older people who are sedentary. Exercise can also play a role in preventing or delaying the onset of frailty. However, the effect of exercise on falls rates in frail older adults is less clear and should be a consideration for future research. There remains some confusion regarding the most effective exercise program variables, however, it appears that multicomponent programs incorporating strength, balance and aerobic exercise lasting for 60 minutes, three or more times per week for a minimum of six months is most effective. Further research on the effect of exercise in clinically defined frail older adults and control of exercise program variables is needed to determine the optimum doses of exercise to achieve gains.

 

Conflict of interest: No conflict of interest to disclose.

 

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20.    Tarazona-Santabalbina FJ, Gomez-Cabrera MC, Perez-Ros P et al. A multicomponent exercise intervention that reverses frailty and improves cognition, emotion and social networking in the community-dwelling frail elderly: A randomized clinical trial. J Am Med Dir Assoc 2016;17:426-433.
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EXERCISE INTERVENTIONS FOR PRESERVING PHYSICAL FUNCTION AMONG CANCER SURVIVORS IN MIDDLE TO LATE LIFE

 

C.W. DAUM, S.K. COCHRANE, J.D. FITZGERALD, L. JOHNSON, T.W. BUFORD

 

Department of Agin and Geriatric Research, University of Florida College of Medicine, Gainesville, FL, USA

Corresponding author: Thomas W. Buford, Department of Aging and Geriatric Research, University of Florida, Gainesville, FL 32611, Telephone: 352-273-5918, Fax: 352-273-5920, Email: tbuford@ufl.edu

 


Abstract

The purpose of this review was to evaluate randomized controlled trials aiming to preserve the functional status, i.e. physical capabilities, of middle-aged and older cancer survivors through a structured, physical exercise intervention. The study team performed a thorough search of the literature using six online databases. This literature search limited included studies to randomized controlled trials which implemented a structured physical activity intervention for middle- and older-aged adults diagnosed with cancer. Studies were also required include at least one objective measure of physical function as a dependent outcome. This literature search yielded thirty-eight studies. The majority of the literature reviewed was successful in improving several functional outcomes including time needed to rise from a chair or distance covered during the six-minute walk test. A large number of published trials also suggest that exercise is effective in decreasing fatigue. However, a lack of trials investigating outcomes in older populations (≥ 65 years) was noted in this review. The results of this review suggest that a structured exercise program may be physically beneficial for middle-aged to older cancer survivors. Particularly, such interventions could preserve the functional status of cancer patients and, consequently, improve their long-term health outcomes. Future implications include further investigation into strictly older cancer patient populations, as outcomes related to exercise might differ between older and middle-aged adults.

 

Key words: Exercise, exercise therapy, cancer treatment, physical function, cancer survivor.


 

Introduction

Functional status, determined by measures of physical performance, is an important predictor of health outcomes in older adults. The capacity to perform basic physical functions is a central aspect of health-related quality of life (1) and a key predictor of hospitalization, surgical outcomes, and mortality (2, 3). Accordingly, maintenance of independent functioning is a critical factor in preserving the health and well-being of older adults. In the U.S., nearly half of the 37.3 million persons aged ≥ 65 years report having one or more physical limitations in performing essential daily tasks (4). The adverse outcomes associated with these limitations have created a significant burden on healthcare systems, which is likely to become more substantial given that older adults represent the fastest growing segment of the population (5). As a result, the development of methods to maintain the health and independence of older persons is an important public health goal. 

Numerous co-morbid conditions contribute to the progression of functional decline among older adults; cancer being among the most prevalent and most debilitating. Over 60% of the 14.5 million cancer survivors in the U.S. are over 65 years of age, and the number of older cancer survivors is expected to increase by nearly 30% in the next decade. The monumental healthcare costs ($37-48 billion) associated with treatment of older cancer survivors are expected to increase similarly. Notably, the financial and human costs of cancer survivorship continue long past diagnoses and initial treatment (6, 7). Yet evidence-based treatments which address the complex long-term medical needs of older cancer survivors are lacking (6, 7). Consequently, the development of efficacious interventions to enhance the long-term health and wellness of older cancer survivors is an important research goal with public health implications.

To date, physical exercise is currently the only intervention consistently demonstrated to attenuate functional decline among older adults. However, many cancer survivors face unique challenges (e.g. depression, fatigue, cognitive decline) which may limit the extent of functional improvement in response to physical exercise. These challenges may be particularly acute among patients who have undergone treatment with radiation and/or chemotherapy. The objective of this manuscript was to therefore review the available literature related to studies of exercise for preservation of functional status in late life. Notably, prior reviews have evaluated the efficacy of exercise for improving quality of life outcomes and the physical function of all-age cancer patients (8, 9). However, to our knowledge, this would be the first review of the literature related to the use of physical exercise in the preservation of functional status among older cancer survivors.

 

Methods

Literature Search

A thorough literature search was conducted using literature available through the University of Florida Online Library, PubMed, MEDLINE, NIH Reporter, the Cochrane Library, and Web of Science. We conducted these searches using the following search keywords: exercise therapy/exercise treatment/physical activity/exercise/cancer treatment/intervention/physical function AND cancer/androgen suppression therapy/chemotherapy/cancer survivor. The goal of this literature search was to collect publications that will improve the understanding of older cancer patients’ responses to physical exercise interventions. Specifically, the efficacy of such interventions in preserving the physical function of these individuals was the main focus of our search. The included literature was limited to randomized controlled trials which involved a structured physical activity intervention – e.g. aerobic training, strength training, etc. – and incorporated at least one objective measure of physical function (e.g. 6-Minute-Walk-Test, timed up and go, etc.).  Initial searches focused on older adults (i.e. > 65 years of age), however our search was later broadened to include middle-aged adults (> 45 years) given the relative scarcity of trials for older cancer survivors. The scope of the search was then further narrowed to focus on prostate, breast, and mixed tumor types, as little relevant literature exists outside of these designations. Mixed tumor types were defined as controlled trials in which the study cohorts were composed of patients with varying cancer types. Furthermore, trials addressing exercise treatment in conjunction with palliative care were excluded as palliative care was outside the scope of this review. 

 

Results

Study Characteristics

A review of the literature provided 38 studies that met our requirements for inclusion (10-47). All studies were controlled trials that lasted between 21 days and 18 months in duration and were published between 1989 and 2015.  These studies overwhelmingly included dependent outcomes related to functional fitness, physiologic predictors of function, and exercise behavior. Of those reviewed, 20 studies examined the effectiveness of exercise interventions during treatment for cancer (10, 12, 14, 17-21, 23-27, 30, 31, 43-47) and 18 studies include post-treatment participants or cancer survivors (11, 13, 15, 16, 22, 28, 29, 32-42). The studies were categorized based on type of cancer as well as completion of treatment, and the resultant categories include prostate cancer, breast cancer during treatment, breast cancer after treatment, and mixed tumors. These categories represent the four areas in which the majority of the literature is available.  

In total, 3,398 individuals participated in the studies reviewed. A significant portion of these participants came from the RENEW trial (N=641), which makes up nearly 20% of the individuals in this review. The exercise modalities reviewed and deemed safe for aging cancer patients and survivors include aerobic exercise (10-14, 16-24, 26, 28-30, 33-45, 47), resistance exercise (11-14, 17, 19, 21, 22, 24-27, 29, 32-35, 37-42, 45), qigong classes (which include elements of Tai Chi) (15), Nia exercise (a combination of martial arts, yoga, and dance) (31), Greek traditional dance classes (32), and soccer training (46). Aerobic and resistance interventions were either home-based or center-based and were performed at varying levels of intensities across studies. Two studies included separate aerobic and resistance interventions (17, 26). Reference group activities included standard care (10-14, 16-18, 20, 23, 26, 28-33, 35-37, 40, 43-47) stretching classes (15, 21), wait-list controls (19, 25), relaxation (27), physiotherapy (24), psychotherapy (34), delayed exercise (22), or home-based exercise (39). We assessed outcome variables for each study, but we did not evaluate subjective measures such as quality of life and pain given prior reviews on these topics (8, 9). 

Prostate Cancer

A total of 738 prostate cancer patients, 598 actively undergoing treatment, participated in nine trials ranging from N= 21 to N = 155 (14, 15, 19, 23, 25, 26, 39, 45, 46).The mean age of participants in these studies was 69.2 years old, with all studies having a mean age > 65 years old. Individuals undergoing treatment had been prescribed androgen suppression/deprivation therapy (14, 19, 25, 45, 46), or radiation therapy (23, 26). Two studies were composed of prostate cancer survivors not actively undergoing treatment, and these individuals were classified as older, fatigued, and sedentary (15, 39). Trial durations ranged from eight weeks to twelve months. All prostate studies are represented in Table 1. 

 

Table 1 Prostate Cancer

*Functional fitness assessed as the maximum number of repetitions of a standardized chair sit-to-stand test; †Muscle strength was measured by an eight repetition maximum of horizontal bench press and leg extension; ‡Denotes resistance intervention outcome §Denotes aerobic intervention outcome;  Population values are Mean ± Standard Deviation (SD) or Mean ± SD Exercise Group; SD Control Group in cases which cohort SD was not reported; Median and/or range were included in population values if mean and/or SD were not reported; + indicates a statistically significant increase in the variable in response to the exercise intervention;  – indicates a statistically significant decrease in the variable in response to the exercise intervention; 0 indicates no statistically significant relationship found; VO2 max: Peak Oxygen Consumption; BMI: Body Mass Index

 

Three trials employed combined aerobic and resistance exercise interventions (14, 19, 39). Two of these trials measured aerobic capacity through a 400 meter walk test[39] or a six-minute walk test (19). Intervention groups significantly improved in 400 meter walk test times and in walking distance compared to a home-based exercise control. These trials also reported that the combined intervention did not change fatigue for the exercise group compared to a control. One trial measured lower body performance via a timed chair rise time test, and a twice-weekly supervised aerobic and resistance home-based exercise program significantly decreased chair rise with a mediation effect of 1.7 (0.6 to 4.5) compared to a standard care control (39). A separate study assessed functional fitness as the maximum number of chair sit-to-stand repetitions, and the 12-week aerobic and resistance exercise lifestyle program increased in the exercise group by 3.66 repetitions compared to the standard care control. This intervention also significantly decreased participant fatigue – as measured by Functional Assessment of Cancer Therapy-Fatigue scores – by 3.1 points compared to the control (14).   

Two trials implemented strictly aerobic interventions (23, 26). These assessed aerobic capacity by submaximal aerobic capacity measures (23) or peak oxygen consumption (VO2 max) (26). The 24-week aerobic intervention increased exercise group VO2 max by 1.4 ml/kg/min, and the 8-week aerobic intervention increased exercise group submaximal aerobic capacity by 2.8 metabolic equivalents. Both were compared to standard care controls. The 8-week aerobic intervention also measured lower body strength with a timed, five-repetition chair sit-and-stand test. Participants in the tri-weekly aerobic exercise intervention had between-group comparison pre- to post-radiotherapy score decreases of 1.7 ± 0.9 in the time taken to complete the five repetitions compared to the standard care control (23). An additional two trials employed resistance exercise interventions (25, 26). Both trials measured upper- and lower-body strength using eight-repetition maximum tests for bench press and leg press. For lower body muscular fitness, leg press repetitions increased by 11.8 in the intervention group and decreased by 1.6 in the control group (25). Lower- and upper-body strength were superior with resistance training (P<.001 for both) when compared to a control and aerobic training (26). Additionally, both trials decreased fatigue levels compared to controls. 

A soccer training intervention for patients undergoing androgen deprivation therapy measured VO2 max, lean body mass, knee-extensor strength, and percent body fat (46). The trial improved lean body mass and improved muscle strength for knee extensors (1RM) in the intervention group (P < 0.001). Sit-to-stand repetitions increased significantly compared to a control with a mean change score of 1.4. However, the intervention was unable to significantly change VO2 max compared to the control. An intervention employing qigong classes (exercise that incorporates meditation and Chinese martial arts) for fatigued and sedentary survivors was able to increase fatigue assessment scores (higher score=less fatigued) – as measured by the Functional Assessment Chronic Illness Therapy-Fatigue Scale (scale 0-52) – for exercise participants by 5 points compared to a stretching class (15). A home-based diet and exercise intervention for prostate cancer patients measured fatigue and aerobic capacity by a six-minute walk test. The intervention increased exercise group six-minute walk test scores by 36.5 meters compared to a standard care control. No significant change was seen with fatigue (45). 

Breast Cancer during Treatment 

A total of ten exercise intervention studies exist which included individuals with breast cancer actively undergoing chemotherapy or radiation therapy (10, 17, 20, 21, 27, 30, 31, 43, 44, 47). The studies ranged in sample sizes from N=14 to N=242 individuals, and in total the ten studies were comprised of 740 participants. The mean age of individuals in these trials was 50.3 years old, with no studies focusing on older breast cancer survivors (> 65 years). These studies included a combined aerobic-resistance intervention (21), aerobic interventions (10, 17, 20, 30, 43, 44, 47), resistance training (17, 27), and a Nia exercise program (31). All breast cancer during treatment studies are represented in Table 2. 

 

Table 2 Breast Cancer During Treatment

*Denotes resistance intervention outcome; † Denotes aerobic intervention outcome; ‡Muscle strength was measured by an eight repetition maximum of horizontal bench press and leg extension; §Short-Form 36 Health Status Survey Measuring Physical Function; | |Muscle strength was measured for isometric and isokinetic muscle capacity of upper and lower extremity muscle groups; Population values are Mean ± Standard Deviation (SD) or Mean ± SD Exercise Group; SD Control Group in cases which cohort SD was not reported; Median and/or range were included in population values if mean and/or SD were not reported; + indicates a statistically significant increase in the variable in response to the exercise intervention;  – indicates a statistically significant decrease in the variable in response to the exercise intervention ; 0 indicates no statistically significant relationship found VO2 max: Peak Oxygen Consumption   

 

One study assigned participants to either an aerobic or resistance intervention and assessed aerobic capacity, fatigue, and muscle strength. Aerobic capacity was measured by peak oxygen consumption, and the intervention increased VO2 max by approximately 8% for the aerobic exercise group compared to a usual care control. For the resistance exercise group, the resistance intervention was able to increase eight repetition maximums for leg and chest press by approximately 30% compared to the usual care control. Fatigue, as measured by the Functional Assessment of Cancer Therapy-Anemia scale, did not change significantly for either exercise group compared to the control (17). A separate trial employed a five-week, combined aerobic and resistance exercise for stage I-III breast cancer patients. Fatigue was assessed via the brief fatigue inventory questionnaire (scale 0-10), and the intervention was able to significantly decrease (p<0.05) scores for the exercise group compared to a stretching control (21). 

A total of six studies employed a home-based or center-based aerobic exercise intervention (10, 20, 30, 43, 44, 47).Four of these measured aerobic capacity or physical function through peak oxygen consumption (VO2 max) (10, 20) or submaximal aerobic capacity measures (43, 44). Trials that assessed VO2 max had conflicting results. A 16-week, aerobic intervention was unable to significantly change peak oxygen consumption measurements for the exercise group compared to a control (10). However, a 12-week, aerobic intervention was able to increase VO2 max by 21.9% for the exercise group compared to a standard care control (20). A 26-week, home-based aerobic intervention was able to increase participants measures of submaximal aerobic capacity by 2.4% compared to a standard care control (44). An aerobic interventions also showed success in decreasing the exercise groups’ fatigue levels (30). One trail measured physical function through the Short-Form 36 Health Status Survey, and the 26-week, home-based aerobic intervention was able to increase scores for the exercise group by 9.8 points compared to a standard care control (44). 

One study examined the effects of a twelve-week, progressive resistance training intervention (27). Muscle strength was measured through muscle capacity of upper and lower extremities, and the intervention was able to increase isokinetic and isometric muscle strength (p<0.0001) compared to a relaxation control. Aerobic capacity was assessed by peak oxygen consumption, but no significant change was found for the exercise group compared to the control. Numerical group differences and changes were not reported for muscle strength and aerobic capacity. This trial also measured fatigue through the Fatigue Assessment Questionnaire (scale 0-10), and the intervention was able to decrease the exercise group’s scores by 0.5 points compared to the relaxation control. 

A Nia exercise program was employed in a group of breast cancer patients undergoing radiation therapy (31). Nia exercise combines forms of yoga, dancing, and martial arts as a comprehensive exercise approach. This trial measured cardiovascular fitness through a six-minute walk test, but the intervention did not significantly change distance walked between the exercise and control group. The trial also assessed fatigue through the Functional Assessment Chronic Illness Therapy-Fatigue Scale (scale 0-160). The Nia exercise intervention increased fatigue scores (higher score=less fatigue) for the intervention group by 7.1% compared to the standard care control.  

Breast Cancer after Treatment 

Studies in the breast cancer after treatment group included individuals who were assigned to an exercise intervention after completion of treatment for breast cancer. Nine studies (11, 16, 22, 28, 29, 32, 33, 35, 36) totaling 384 participants ranged in length from 6 weeks to 18 months and sample sizes N=14 to N=104. The mean age of these breast cancer patients was 55.6 years old, with no studies focusing on older survivors. Exercise interventions included aerobic exercise, (16, 28) combined aerobic and resistance exercise, (11, 22, 29, 33, 35) a home-based moderate physical activity program, (36) and a combined Greek traditional dance and resistance program (32). Control groups included standard care (11, 16, 28, 29, 32, 33, 35, 36) and a delayed exercise group that completed the exercise intervention after a 12-week waiting period (22). All breast cancer after treatment studies are represented in Table 3. 

 

Table 3 Breast Cancer after Treatment

* Short-Form 36 Health Status Survey Measuring Physical Function; †Muscle Strength measured by recording weight used for bicep curls, leg presses, and chest extensions; Population values are Mean ± Standard Deviation (SD) or Mean ± SD Exercise Group; SD Control Group in cases which cohort SD was not reported; Median and/or range were included in population values if mean and/or SD were not reported; + Indicates a statistically significant increase in the variable in response to the exercise intervention;  – Indicates a statistically significant decrease in the variable in response to the exercise intervention; 0 Indicates no statistically significant relationship found; VO2 max: Peak Oxygen Consumption; BMI: Body Mass Index

 

Studies that employed a combined aerobic and resistance intervention assessed aerobic capacity through a six-minute walk test, (11, 35) VO2 max, (29) and submaximal aerobic capacity measures (22). All four of these combined interventions reported increases in participant’s measurement of aerobic capacity at the commencement of the trials compared to standard care controls. Muscle strength was assessed by either leg extension strength (35) or by recording weight used for bicep curls, leg presses, and chest extensions(22). Measurements of leg extension strength increased by an average of 25.4 newtons in the combined exercise group compared to a standard care control. The recorded weight used for bicep curls, leg presses, and chest extensions increased by an average of 71% for the combined intervention group compared to a standard care control. One study assessed physical function through the Short-Form 36 Health Status Survey, but did not show a significant change in participant’s scores by the end of the intervention compared to a standard care control (33).  

Two total studies used strictly aerobic exercise interventions (16, 28). Both assessed aerobic capacity through VO2 max. A fifteen-week aerobic intervention reported a 14.4% increase in peak oxygen consumption for the exercise group compared to a standard care control (28). However, a 12-week, moderate-intensity aerobic intervention reported no significant change in peak oxygen for the exercise group compared to a standard care control (16). A six-week home-based, moderate physical activity intervention reported an increase in six-minute walk test measurements with the exercise group walking an average of 97 feet farther in six minutes compared to a standard care control (36). 

An intervention that combined resistance exercise with a Greek traditional dance course measured physical function through a six-minute walk test score, while also assessing handgrip strength (32). Six-minute walk test scores increased by an average of 55.21 meters in the exercise group compared to a standard care control. Handgrip strength was assessed using a baseline handheld dynamometer, and the exercise group averaged a 21% increase in strength compared to the control at the end of the trial.  

Mixed Tumors

Ten studies enrolled a total of 1,536 participants with mixed tumor types and ranged from 21 days to 12 weeks in duration.(12, 13, 18, 24, 34, 37, 38, 40-42) The mean age of these participants was 59.8 years old, with four studies having a mean age > 65 years. Sample sizes ranged from N=18 to N=641. The exercise interventions implemented in these studies included aerobic exercise, (18, 40) combined resistance and aerobic exercise, (12, 13, 24, 37) and home-based exercise.(34, 38, 41, 42) Controls were standard care, (12, 13, 18, 37, 40) standard physiotherapy, (24) or psychotherapy (34). All mixed tumor studies are represented in Table 4.

 

Table 4 Mixed Tumors

*Measured by one repetition maximum of leg press, chest press, and pull down; †Short-Form 36 Health Status Survey Measuring Physical Function/Functional Decline; ‡Type of testing not reported; §Measured via the basic and advanced lower extremity function subscales of the Late Life Function and Disability Index.; | |Functional Assessment of Cancer Therapy-Anemia measuring patient-reported physical function ; Population values are Mean ± Standard Deviation (SD) or Mean ± SD Exercise Group; SD Control Group in cases which cohort SD was not reported; Median and/or range were included in population values if mean and/or SD were not reported; + Indicates a statistically significant increase in the variable in response to the exercise intervention ; – Indicates a statistically significant decrease in the variable in response to the exercise intervention ; 0 Indicates no statistically significant relationship found  ; VO2 max: Peak Oxygen Consumption; BMI: Body Mass Index

 

Two trials implemented aerobic exercise interventions (18, 40). A ten-week, light to moderate aerobic intervention assessed aerobic capacity though submaximal oxygen consumption measures. The intervention increased submaximal aerobic capacity in the intervention by 15.9% compared to a standard care control (40). Additionally, a twelve-week, aerobic exercise intervention increased VO2 max by 43% in the exercise group compared to a usual care control. This trial also assessed physical function and fatigue through FACT-Anemia scores subscales of function and fatigue. The aerobic intervention increased mean intervention group physical function scores by 7.2 points (scale of 0-188) and increased mean fatigue scores by 4 points (scale 0-52; higher score=less fatigue) compared to the standard care control (18). 

A total of four studies employed a combined aerobic and resistance exercise program (12, 13, 24, 37). All of these trials measured muscle strength through upper/lower body strength, (12) quad muscle strength, (13) and abdominal muscle strength (24). Exact measurements of muscle strength for the Starting Again trial-a breast, ovarian, testicular, and prostate cancer group rehabilitation program-were not reported (37). A six-week, high intensity resistance and aerobic intervention reported an average 29.6% weight improvement for one-repetition maximums for the exercise group compared to a standard care control (12). A four-week, combined intervention assessed quad muscle strength, but reported no significant change in strength for the intervention compared to a standard care control (13). 

Two combined aerobic and resistance interventions assessed aerobic capacity through measures of VO2 max. A three-week, combined intervention reported a 24.4% increase for the intervention group compared to a standard physiotherapy control (24). A six-week, high intensity resistance and aerobic intervention reported an average 10.7% increase in VO2 max for the intervention group compared to a standard care control. This trial also assessed physical function through Short-Form 36 Health Status Surveys (SF-36), and fatigue through the European Organization for Treatment and Research of Cancer Quality of Life Questionnaire. The study reported an average 2.2 SF-36 score increase and an average 6.6 QLQ-C30 score decrease for the intervention compared to the control (12). 

Three studies examining the RENEW trial, a large home-based exercise intervention for older, overweight cancer survivors, attempted to assess physical function, functional decline, and lower extremity function (38, 41, 42). All trials measured physical function or rates of functional decline through SF-36 score measures. One intervention assessing the rate of functional decline decreased SF-36 scores by 2.3% for the exercise group. However, SF-36 scores decreased by 7.8% for the control group that did not receive the exercise intervention (41). A separate trial also found similar results, as the intervention decreased SF-36 scores by 2.15 points for the exercise group, but individuals of the control group experienced a decline of 4.84 points at the end of the trial. Lower extremity function scores were assessed via the basic and advanced lower extremity function subscales of the Late Life Function and Disability Index. The intervention increased scores slightly (0.34 points), while control group participants showed a decreased of 1.89 points (42). Lastly, a trial distinguished physical function and lower extremity function between high-to-light physical activity (HLPA), moderate-to-vigorous physical activity (MVPA), and low-to-light physical activity (LLPA) groups. Survivors who increased HLPA and decreased or stabilized MVPA, scored 3.04 points higher on SF-36 scales and 2.28 points higher on basic lower extremity function scales compared to survivors who decreased MVPA or maintained stable MVPA and HLPA (38).

 

Discussion

The objective of the present review was to evaluate the extant literature related to the use of physical exercise for improving functional status among middle-aged and older cancer survivors. To our knowledge, this is the first review specifically focused on the use of exercise to maintain physical function among middle-aged and older cancer survivors. The results of this review suggest that these patients may physically benefit from exercise during and after cancer treatment as the majority of published trials demonstrated reasonable efficacy of exercise in improving functional status among these populations. Notably, there are several ongoing trials that should be monitored closely so their results can be compared to the findings of this review (48-50).

Among the various cancer groups highlighted in this review, prostate and mixed tumor groups had by far the highest number of studies focusing on older cancer patients. The majority of these various interventions showed success in lowering rates of functional decline and improving objective measures of physical function for these aging populations. These results are consistent with other trials that have implemented exercise as a form treatment for geriatric patients suffering from other diseases known to accelerate functional decline. For instance, studies examining the effects of physical activity on older individuals suffering from cardiovascular disease have shown that exercise is capable of attenuating age-related decline caused by hypertension or heart failure (51). Similar results have been shown in elderly populations diagnosed with osteoporosis, as exercise has proved successful in increasing bone density and improving other physical outcomes for these patients (52). Overall, it is encouraging that the results of interventions for those suffering from cancer, a separate disease widely known to negatively impact physical function, are comparable with other trials showing improvement for aging populations. 

With the benefits of exercise interventions as a form of cancer treatment for middle-aged to older adults becoming more tangible, it is imperative that future trials study populations strictly made up of older adults. As stated previously, this review saw a significant gap in the literature for exercise in only older patient populations (≥ 65 years old). It is paramount that more of these studies examine this population because of the dramatic clinical costs of functional decline and the rapidly growing population of older adults. It may also be important to evaluate the efficacy of creative interventions designed to facilitate adherence among these populations. Examples of such interventions may include the use of dancing, yoga, or interactive video games. For instance, one ongoing study is examining the efficacy of video game exercise interventions on a group of older breast cancer survivors (53). It is possible that cancer patients might perceive these nontraditional exercise interventions as less strenuous, potentially leading to higher motivation and commitment to the regimens. These types of interventions, specifically dancing, may also attenuate cognitive decline- an independent predictor of functional decline among older adults and common side effect of chemotherapy (54-56). Prior studies of the general geriatric population have demonstrated cognitive-motor benefits from both dancing and traditional exercise performed with music (57, 58). 

Like any study, there were some limitations to this review. First, not every study in this review used blinding methods (blinding of outcome assessor, blinding of care provider, etc.), and several studies (10, 19, 20, 23, 28, 32, 33, 35, 40, 43, 47) had very small samples sizes. Additionally, the exercise modalities, durations, and disease stages were not all standardized across the reviewed trials, which may have led to variance among outcome measurements. However, all studies did utilize supervised intervention programs and employed parallel comparison control groups. Also, the availability of substantial literature regarding prostate and breast cancer was a positive given that these two forms of cancer are by far the most prevalent among older adults (59). 

To conclude, the role of exercise interventions in attenuating functional decline in cancer patients offers some very positive implications. This review found that cancer-related fatigue could be lowered through resistance or aerobic exercise in multiple cancer types. This is likely a very important effect for the patient given that reduced fatigue can greatly influence the functional status of cancer patients (60). Additionally, the ability of interventions to increase the aerobic capacity and muscle strength of individuals can point towards improvements in their diagnoses. Amelioration of all these physical outcomes could lead to lower patient morbidity and mortality rates. However, those implementing exercise in a clinical setting should be wary of patient’s responses to varying intensities and modalities of the interventions. In summary, the results of this review suggest that the use of exercise as a form of cancer treatment may be vital for maintaining and improving the physical health of middle-aged and older cancer survivors. 

 

Funding: No direct funding was used for this manuscript.

Acknowledgements: This work was partially supported by the University of Florida Claude D. Pepper Older Americans Independence Center, funded through the National Institutes of Health (P30AG028740).

Conflicting Interest: None.

 

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FISH OILS AND THEIR POTENTIAL IN THE TREATMENT OF SARCOPENIA

 

S.R. GRAY, M. DA BOIT

 

Musculoskeletal Research Programme, Institute of Medical Sciences, University of Aberdeen

Corresponding Author: Dr Stuart Gray, Room 106 Health Sciences Building, Musculoskeletal Research Programme, Institute of Medical Sciences, Foresterhill, University of Aberdeen, AB25 2ZD, United Kingdom, e-mail: s.r.gray@abdn.ac.uk

J Frailty Aging 2013;2(4):211-216
Published online February 11, 2016, http://dx.doi.org/10.14283/jfa.2013.31


Abstract

We are living in an “ageing society” meaning that there will be an increase in the incidence of age related health problems. One issue consistently observed in ageing is for muscle mass and strength to be reduced, a condition termed sarcopenia. The consequences of these changes are numerous and include a reduction in quality of life and an increased risk of falls. The mechanisms underlying sarcopenia remain to be elucidated but include an anabolic resistance to both nutrients and exercise and so the search for strategies to overcome this resistance is of great importance. There are several nutritional strategies purported to be useful in the treatment of sarcopenia and in recent years the n-3 PUFAs found in fish oil have been of increasing interest. This review will discuss the main nutritional interventions used in the treatment of sarcopenia with a focus on fish oils.

Key words: Aging, fish oil, exercise, nutrition, sarcopenia.


 

Background

With increasing age comes an increase in the incidence of several clinical problems, such as arthritis, cardiovascular disease, hypertension and Alzheimer’s disease. One other major change that occurs in older people is the dramatic alteration in body composition, with a loss of lean mass (i.e. skeletal muscle) and an increase in fat mass. The loss in skeletal muscle (approximately 0.5-2.0% per year) was termed sarcopenia by Michael Rosenberg in 1989, (1) and occurs even in healthy active older individuals. In order to carry out numerous activities of daily living, such as stepping on to a bus or rising from a chair, one requires a degree of muscle strength and function which is often not present in sarcopenia. We therefore see substantial impairments in muscle strength and functional abilities which can reduce older adults’ quality of life and increase the risk of falls and subsequent hospitalisation (2). Reporting incidences of sarcopenia can be problematic due to issues in diagnosis (3) but an incidence of 13-24% in those aged 50-70 years and up to 50% in those over 80yrs of age are regularly quoted (4). Similar complexities are present when trying to quantify the economic cost of sarcopenia but this was estimated to be $18.5 billion in the United States in the year 2000 (5). Taken together it is clear why we need to further our understanding of the mechanisms underlying sarcopenia and any potential treatments available.

At present the precise mechanisms which underlie sarcopenia remain to be elucidated and we will briefly introduce some of these potential mechanisms, which are also summarised in Figure 1. It has been shown that approximately 5% of the variance in leg lean mass can be attributed to genetic causes (6) making this an unlikely cause of sarcopenia. Although this does not mean there are no important genes in sarcopenia it does show why the majority of research has focussed on investigating other more environmental causes.

Early research found that older muscle was characterised by denervation and loss of alpha-motoneurons occurs, which is associated with a small increase in the size of motor units, suggesting that there may be a degree of reinnervation occurring (7). Several recent studies have confirmed these findings making it likely motoneuron loss and incomplete fibre reinnervation by the remaining motoneurons has a role in the aetiology of sarcopenia. On top of these alterations in motoneurons we also see differences in the satellite cell numbers and function with age. A twofold reduction in satellite cell numbers has been found in old muscle and these cells also have a reduced proliferative capacity in response to muscle injury, leading to dysfunctional regeneration (8).

It has been known for some time that there are dramatic changes in endocrine function that occur with age and that these effects are gender dependent (9). The most marked of these changes relate to the pancreas, with a decrease in insulin production and peripheral insulin sensitivity, and the thyroid, with a reduction in plasma thyroxine and increase in thyrotropin stimulating hormone. In males a gradual change in hypothalamic-pituitary-gonadal axis function has been observed, characterised by a decrease in circulating free and total testosterone termed the “andropause” (10). As testosterone has well documented anabolic effects it is possible that this andropause may play a role in sarcopenia in males. While some studies have found beneficial effects of testosterone treatment (11), these effects are generally small and probably do not outweigh the potential side effects of treatment. When females reach the menopause there is a decrease in ovarian oestrogen production which has been associated with the decline in muscle strength, although in general the research doesn’t fully support this assertion (12).

It has been previously demonstrated that sarcopenia is characterised by a state of chronic low grade inflammation, i.e. a two-four fold elevation in circulating inflammatory cytokines. Such elevations in cytokines (i.e. IL-6 and TNF-α) have been found to correlate with functional disability and may be involved in sarcopenia through effects on pathways controlling protein metabolism (13, 14). Circulating levels of myostatin have also recently been suggested to play a role in sarcopenia as it is known to inhibit muscle growth resulting in atrophy (15). Until recently it was not possible to test circulating myostatins role in human ageing as it could not be reliably measured. Now, using a well validated assay, it has been shown that neither myostatin nor its related factors differed in sarcopenic men (compared to young and old non-sarcopenic men) (16).

As mentioned elevation in inflammatory cytokines are purported to be involved in sarcopenia through interference with protein metabolism. Whether these cytokines are the causative factor in age related changes in protein metabolism remains to be established but, regardless of cause, there are clear differences in protein metabolism (i.e. muscle protein synthesis (MPS) and muscle protein breakdown (MPB)) when young and old are compared. Several researchers have shown that under resting/fasting conditions MPS is not different between young and old, but in response to an anabolic stimuli (in this case amino acids) the increase in MPS is attenuated in older people (17). Furthermore when MPB is measured there is no difference in basal MPB with age but there is a blunted inhibition of MPB in response to insulin (18). These alterations in protein metabolism demonstrate what has been termed an “anabolic resistance”, to stimuli such as amino acids and insulin, in older muscle, with these changes having a deleterious effect on the ability of older muscle to increase or maintain its size appropriately.

Another anabolic stimuli, for muscle, is resistance exercise and it is known that such exercise can have beneficial effects on muscle mass and function even in those over the age of 90 years (19). However older people do not adapt as well as younger to resistance exercise and this anabolic resistance to exercise has been demonstrated after a single exercise session, with a reduction in MPS (20), and after more prolonged resistance exercise training, with an attenuated increase in muscle volume (as measured by MRI) and strength (21).

Nutritional Interventions in Sarcopenia

Several nutritional strategies have been proposed to have potential benefits in the treatment of sarcopenia and we will discuss two main interventions now and briefly summarise the available evidence before discussing the potential for fish oil to be efficacious in sarcopenia. There are several nutritional interventions, such as antioxidants, that we will not cover here and readers are directed to one of the many excellent reviews in this area (e.g. 22).

Figure 1 Potential mechanisms underlying, and the consequences of, sarcopenia

 

MPS: Muscle protein synthesis, MPB: Muscle protein breakdown.

 

Protein

The importance of protein in ageing is highlighted by the findings that elderly individuals, in general, consume less than the recommendations for daily protein intake (0.8 g/kg/day) (23). Evidence of this importance is seen in epidemiological studies where older individuals with the highest daily protein intake lost around 40% less lean mass compared to those with the lowest daily protein intake (24). As several researchers have shown that protein, particularly leucine, has an anabolic effect in muscle this lack of protein may contribute to sarcopenia (25; 26). However, as mentioned earlier older muscle does not respond with the same magnitude of increase in MPS as younger muscle (17, 27) but an anabolic effect, although diminished, is still observed and this has lead some researchers to suggest that older adults should consume between 1.0 and 1.5 g of protein/kg/day (22), although the long term benefits of this remain to be fully elucidated.

As resistance exercise is also known to have anabolic effects it is hypothesised that combined exercise and protein regimens may maximise protein metabolism in older adults. In young adults protein supplementation has been found to increase MPS, inhibit MPB, and result in an overall positive protein balance after exercise (e.g. 28), supporting the assertion that increases in dietary protein are able to maximise adaptations to resistance exercise. In older individuals the results are more ambiguous. In healthy older adults it has recently been demonstrated that an extra 15 g/day protein has no beneficial effects on the adaptations in muscle size and strength after 24 weeks of resistance exercise (29). However, in a separate study it was found that a total of 30 g/day protein resulted in an increase in lean mass after 24 weeks of resistance exercise training, with no such change in the placebo group, in frail individuals (30). On a more cautionary note there were no improvements in muscle function in the protein group, over those observed in the placebo group. The ultimate goal of any such intervention is to improve muscle function and so whether protein supplementation will be useful in sarcopenia remains to be established.

Vitamin D

Vitamin D is found in dietary sources such as oily fish (e.g. salmon and sardines), eggs, fortified fat spreads and breakfast cereals but the majority is produced in the skin, from cholesterol, when exposed to sufficient sunlight. Amongst the many clinical consequences of vitamin D deficiency muscle weakness is consistently observed (e.g. 31). More recent research has also shown that low serum 25(OH)D is associated with a more rapid loss of muscle mass and function (32). In recent years research investigating the role of vitamin D in muscle has increased after it was shown that Vitamin D receptors are found in skeletal muscle tissue and that their expression decreases with age (33). Several randomised control trials have now been carried out investigating whether Vitamin D supplementation can improve muscle function in older adults, which in general demonstrate a benefit of supplementation on muscle function and the risk of falls (34). When combined with exercise there are only a handful of studies investigating Vitamin D supplementation, generally finding no beneficial effects on adaptations (34).

Introduction to n-3 polyunsaturated fatty acids

Polyunsaturated fatty acids (PUFAs) are vital components in the cell membranes of all cells in the bodies. The two main fatty acids found in fish oil, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which can also be produced in the body from alpha-linolenic acid although the magnitude of conversion is extremely low (35), are known to have beneficial effects in many diseases and conditions, such as cardiovascular disease (36), atherosclerosis (37), diabetes (38) and neurological conditions such as Alzheimer’s disease and dementia (39). Many of these benefits are purported to be due to the ability of these fatty acids to modulate immune function and inflammation. The normal Western diet contains relatively high quantities of the n-6 PUFA arachidonic acid (AA) and low levels of EPA/DHA. This means that the phospholipids of inflammatory cells (i.e. monocytes, neutrophils and lymphocytes) from human blood contain 10-20% AA, 0.5-1.0% EPA and 2-4% DHA (for review see 40). Any increase in EPA/DHA consumption can alter this phospholipid composition, via an incorporation into the cell membranes, increasing EPA/DHA content with a concomitant reduction in AA content (41).
This change in cell phospholipid composition has many effects on cell function and inflammatory processes. These changes include alterations to the membranes physical properties (i.e. fluidity), cell signalling (i.e. alterations in the function of membrane bound receptors or intracellular signal transduction) and the patterns of lipid mediators released, on which we will now focus. As AA is normally the predominant fatty acid found in cell membranes it is also most frequent source for the production of eicosanoids and it is generally the case that AA derived eicosanoids, such as prostaglandin E2 will act in a pro-inflammatory manner, although this may be an oversimplification (42). With an increase in EPA content in cell membranes it is used more frequently as a substrate for eicosanoid production, resulting in the production of a different series of lipid mediators (e.g. prostaglandin E3). In general, although not always (43), these EPA derived mediators are less potent in their pro-inflammatory actions (44) and may therefore have beneficial anti-inflammatory effects. A further beneficial effect may also be derived from the metabolism of EPA and DHA to produce products called resolvins and protectins which have anti-inflammatory effects and important roles in the resolution of inflammation (45).

It can be seen, therefore, that EPA/DHA may be useful in the treatment of conditions with an inflammatory component and may therefore be useful in the treatment of benefits of intrathecal baclofen cost sarcopenia, which we know also has an inflammatory component.

Fish oils and sarcopenia

Research in 2008 in the Hertfordshire study found that in ~3000 people grip strength increased for every extra portion of oily fish that an individual consumed per week, indicating that the n-3 PUFAs found in oily fish may be an important determinant of muscle strength in older adults (46). Furthermore in early animal studies it was shown that EPA/DHA can stimulate protein anabolism, insulin-induced glucose metabolism and potentially attenuate the age related loss of lean mass (47-49). While these studies were indicative of a beneficial effect of EPA/DHA, in muscle wasting human intervention studies were needed to demonstrate this.

In early human studies of cancer cachexia (i.e., the involuntary weight loss due to depletion of both muscle mass and adipose tissue seen in cancer patients), there are some studies indicating an anabolic/protective effect in skeletal muscle (50, 51). However, in a recent systematic review on fish oil consumption and muscle loss in advanced cancer the final conclusion was that positive effects were detected only in smaller trials with poor methodology while in larger randomized controlled trials significant benefits were not observed (52). As the underlying mechanisms responsible for the loss of muscle mass in cancer and sarcopenia are quite different, studies in older adults were required to uncover whether EPA/DHA can have any beneficial effects in sarcopenia.

This was therefore recently addressed in a study by Smith et al. (53) who measured MPS and anabolic signalling pathways before and after 8 weeks of n-3 PUFA supplementation (1.86 g/d EPA and 1.50 g/d DHA) in healthy older adults. Supplementation with EPA/DHA increased MPS, in part, through activation of the p70s6k signalling pathway, findings this groups also replicated in young and middle-aged groups (54). Specifically EPA/DHA supplementation increased MPS during a hyperaminoacidaemic hyperinsulinaemic clamp but did not change the basal protein synthesis or circulating markers of inflammation. On a cautionary note this study shows an effect of EPA/DHA stimulation on an acute measure such as clamp stimulated MPS but it remains to be determined whether there will be any long term effects on muscle mass and/or function.

There has also been some research to determine whether the combination of EPA/DHA and resistance exercise can maximise protein anabolism and reduce the burden of sarcopenia. Rodacki et al. (55) investigated the effect of 90 days of resistance exercise on the neuromuscular system (muscular activation and force) in older women, with or without EPA/DHA supplementation (2 g/d) and they reported that resistance exercise undertaken with EPA/DHA supplementation enhanced the adaptations in neuromuscular function and functional capacity (chair-rising test) in older women. In this study no placebo supplements were given and so caution may be wise when interpreting these results. In support of their findings, however, within our lab we have found similar results, with the increase in strength and functional abilities after resistance exercise approximately two-fold higher in those taking EPA/DHA as opposed to placebo, with no change in circulating markers of inflammation (unpublished results). These are the first studies showing the importance of EPA/DHA supplementation in enhancing the adaptive responses to resistance exercise and may indicate the potential for fish oils to be useful in the treatment of sarcopenia.

What also remains to be established are the mechanisms through which EPA/DHA may help in the maintenance of muscle mass with age, a few of which are indicated in Figure 2. The original hypothesis in this field was that EPA/DHA would improve the maintenance of muscle mass due to their anti-inflammatory properties (42). This may not, however, be the case as, in our recent work and that of Smith et al (53), improvements in MPS and muscle function were observed without changes in circulating cytokines. Other potential mechanisms underlying the effects of EPA/DHA on muscle include improvements in insulin sensitivity. Enhanced insulin sensitivity may increase the insulin-derived inhibition of MPB and also increase the delivery of amino acids to muscle via increases in blood flow (56). A further mechanism may relate to the increase in EPA/DHA incorporated into the skeletal muscle membranes altering signal transduction pathways involved in protein metabolism. Indeed in our recent work (49), in aging rats, we found that EPA/DHA supplementation increased the activation of the signal transduction enzyme family phosphoinositide 3-kinases (PI 3-kinases) which catalyses the conversion of phosphatidylinositol (4,5)-biphosphate (PIP2) to phosphatidylinositol (3,4,5)-triphosphate (PIP3) in the inner leaflet of the plasma membrane (57). Due to the increase in EPA/DHA in the muscle cell membrane we hypothesize that there was an increase in PIP3 potency (58), which resulted in the observed increase in the downstream p70s6k, a crucial protein in the maintenance and increase of muscle mass (59). There is very little experimental evidence, at present, to support or refute these mechanisms and so further well mechanistic experiments are needed in this area.

Figure 2 Potential mechanisms underlying the beneficial effects of fish oil in sarcopenia

EPA/DHA: eicosapentaenoic acid/docosahexaenoic acid, PIP3: phosphatidylinositol (3,4,5)-triphosphate, PGE2: prostaglandin E2, AA: amino acids, MPB: Muscle protein breakdown, MPS: Muscle protein synthesis.

Conclusion

The potential benefits of the n-3 PUFAs found in fish oil in the treatment of sarcopenia could be of great benefit to older adults and the burden on health care systems, particularly within this “ageing society”. The review has highlighted the current data available investigating n-3 PUFAs and the loss of muscle associated with age and it appears that there may be beneficial physiological effects of n-3 PUFAs in sarcopenia, but whether these translate into clinically significant benefits and the underlying mechanisms behind any effect remain to be discovered.

Conflict of Interests: The authors have no conflict of interests to declare.   

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EXERCISE: AN IMPORTANT KEY TO PREVENT PHYSICAL AND COGNITIVE FRAILTY

 

M.C. DULAC1, M. AUBERTIN-LEHEUDRE1,2

 

1. Faculty of Science, Department of Exercise Science, Université du Québec à Montréal, Montréal, Canada; 2. Centre de recherche de l’Institut universitaire de gériatrie de Montréal, Montréal, Canada

Corresponding author: Mylene Aubertin-Leheudre, Faculty of Science, Department of Exercise Science, Sciences Biologiques Building, SB-4615, 141 av president Kennedy, Montréal, Quebec, Canada, H3C 3P8, Phone: 514-987-3000 #5018, Fax: 514-987-6166, Email: aubertin-leheudre.mylene@uqam.ca

 


 

The life expectancy of older individuals continues to increase with persons aged 70 years and more representing the fastest growing proportion of the western population (1). At the same time, this extended life should involve the preservation of autonomy through the maintenance of physical and cognitive function. However, with normal aging, people will develop frailty. Thus, identifying cost-effective interventions, which prevent frailty, is one of the most important challenges of health care systems. The difficulty in developing specific interventions to prevent or delay frailty is due to the complexity of the phenomenon, which involves many different physiological, cognitive, and psychological systems. Because no single manifestation of frailty can encompass the whole of the symptoms or signs present, consensual exercise training guidelines remain paradoxically difficult. Therefore, the aim of this review is to address an overview of the literature regarding the effect of exercise/physical activity in the prevention of physical and cognitive frailty.

 

Exercise and physical frailty  

Although there is not a universally accepted operational definition of frailty, the most commonly used definition of a physical phenotype of frailty comes from the Fried Frailty Index (FFI). Fried proposed identifying frailty in the individual by observing the presence of at least three of the five following symptoms: shrinking (nutritional/metabolic component assessed by unintentional weight loss), weakness (indicated by muscle strength), poor endurance and energy (per self-reported exhaustion), slowness (demonstrated by slow walking speed) and low amounts of physical activity (2).

There is evidence to suggest that history of leisure time physical activity (LTPA) is related to frailty. In fact; Savela et al. showed that people with high LTPA had up to 80% lower risk of frailty compared to sedentary subjects (3). This conclusion has been confirmed by others who observed that regularly engaged exercise activities in elderly individuals were less likely to develop frailty through a 5 year period than those who were sedentary (4, 5).

The benefits of exercise in improving functional capacities which include daily living activities, falls and quality of life of frail older adults has been considerably reported through reviews or meta-analyses (6-9). Regarding the literature, low intensity resistance training (10, 11) , power resistance training (12), multimodal (13, 14); could be recommended to older frail individuals but not flexibility home programs or chair based exercises alone (10, 15, 16). In addition, aerobic exercise could also counteract physical frailty through the improvement of the maximal oxygen uptake (Vo2max)(17) and increased muscle mass(18, 19).

 

Exercise and Cognitive frailty 

It is not satisfactory to define frailty in the physical domain alone since there are other factors that have not yet been examined, but are recognized as part of the frailty syndrome such as cognition. While physical frailty is a widely recognized problem in the elderly, cognitive frailty has only recently become the focus of inquiry. Recently, the International Academy of Nutrition and Aging (IANA) and the International Association of Gerontology and Geriatrics (IAGG) summarized cognitive frailty as a heterogeneous clinical manifestation characterized by the simultaneous presence of physical frailty and cognitive impairment, in the absence of dementia (20).

It is well establish that aerobic exercises such as walking may prevent the decline in cognitive function in non-frail older adults (21-23). However, few studies have examined the effect of other types of exercises (tai-chi, body and mind, resistance training) on cognitive function. For example, it has been observed that resistance training contributes positively and significantly in the improvement of brain functional plasticity, executive function and response inhibition (24, 25). There is also evidence to suggest that home based exercises may improve executive function, specifically response inhibition, after 6 months (26). Moreover, studies have shown that Tai Chi could positively affect cognitive performance in older adults (27). It should also be noted that combining aerobic training to resistance training is more efficient in improving cognitive function in older adults than aerobic or resistance training alone (28, 29). However, current evidence is limited, and research is needed on the role of exercise parameters (e.g. volume, types, and intensity) on specific cognitive functions. Indeed, it has been reported that the volume, intensity and variation of physical activities as well as the history of practice was positively associated with processing speed, memory, mental flexibility, executive function and overall cognitive function (30, 31). Finally it has been proposed that exercise could prevent cognitive frailty through an improvement on brain plasticity, structural brain reserves and cerebral blood flow (32-34).

Thus, even if exercise is promising to improve cognitive decline with age in non-frail individuals, to our knowledge only one study has been conducted to improve cognitive function using exercise alone in frail older adults (35). This study concluded that aerobic training combined to resistance training is efficient to improve executive functions, processing speed and working memory. Thus, RCT using exercise training to counteract cognitive frailty are needed in frail elderly because this population is poorly studied.

 

Practical guidelines 

Overall, it is important to propose an exercise program reproducible at home including gradual increases in the volume, intensity, complexity and type of all of the exercises through resistance, aerobic, as well as body and mind training. Since 64 % of older people are considered as sedentary, increasing the long-term adherence is important in order to create a specific training program that includes regular changes in the intensity and type of exercises and is feasible at home (counteract the transportation). 

More specifically, resistance-training programs should be performed two to three times per week, with two sets of 8–12 repetitions at an intensity that starts at 20%–30% and progresses to 80% of 1RM. In addition, progressively, we could increase the tempo to turn on power training, which is more efficient to improve or maintain muscle quality. All these exercises should be realized in exercise rooms under supervision or at home using for example Swissball; free-weight, elastic band, chair and others with occasional supervision. To optimize the functional capacity of individuals, resistance/power training programs should be combined with exercises in which daily activities are simulated, such as the sit-to- stand, tandem foot standing, heel–toe walking, line walking, stepping practice, standing on one leg, weight transfers (from one leg to the other). These exercises are often offered through body and mind activities such as tai chi and pilates. Aerobic training should include walking with changes in pace and direction, treadmill walking, step-ups, stair climbing, and stationary cycling. Aerobic exercise may start at 5–10min during the first weeks of training and progress to 15–30 min for the remainder of the program. The Rate of Perceived Exertion scale should be used for prescribing the exercise intensity, and an intensity of 12–14 on the Borg scale appears to be well tolerated.  

In General, to prevent physical and cognitive frailty adverse effects, frail older adults could practice multimodal physical activity programs (resistance/power, aerobic and body and mind exercise) at least twice a week during 30-45 min per session at moderate to high intensity. In addition, to optimize the physical training prescription and meet these goals in subjects with physical and/or cognitive frailty, the most effective type of exercise program should be identified by considering the optimal combination of intensity, volume, and frequency training that would promote neuromuscular, muscular and cardiovascular adaptations and thus result in improved functional and cognitive capacity in the frail elderly.

 

Conflict of Interest: None

 

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