Exploring the interplay of frailty, physical function, physical activity, nutritional status, and their association with quality of life and depressive symptoms in older adults with the frailty phenotype

This study aimed to explore the interplay between frailty, physical function, physical activity, nutritional status, and their impact on the quality of life and depressive status in older adults with frailty.


| INTRODUCTION
Population ageing is a prevalent global phenomenon in the 21st century, 1 resulting in a progressive decline in physiological and functional capacities known as frailty. 2 Frailty is increasingly common among older adults, with approximately half of the European population experiencing some degree of this condition. 3is condition renders individuals vulnerable to adverse health outcomes, such as falls, dependency, fractures, and hospitalizations, 4 significantly impacting the everyday lives of our older adults.
Extensive research has demonstrated that frailty is associated with a decline in the quality of life of older adults, which is a multidimensional construct reflecting an individual's perception of their life situation, encompassing cultural goals, expectations, standards, and concerns. 5Additionally, frailty's association with adverse outcomes such as pain, mobility limitations, and weakness may contribute to depression. 6ven the intricate relationships between frailty, quality of life, and depression in older adults, it is crucial to explore potentially modifiable factors closely related to their daily lives.Notably, physical function has shown significant impacts on both quality of life 7 and depression 8 in community older adults.Similarly, higher levels of physical activity have been associated with improved quality of life and reduced depressive symptoms. 9Furthermore, nutritional status has been linked to better quality of life 10 and reduced depression 11 in older adults.Despite extensive research on these factors in the older population, limited investigation has specifically addressed their contribution to the quality of life and depression status of older adults with current frailty symptoms.
Identifying and addressing these modifiable factors can lead to tailored interventions that improve the well-being and mental health of older adults, ultimately enhancing their overall quality of life.
Therefore, this study aims to assess the associations of physical function, physical activity, and inactivity with the quality of life and depressive status of older adults with frailty.By understanding these relationships, we can develop targeted interventions that positively impact the lives of older adults with frailty and promote healthier ageing.

| MATERIALS AND METHODS
The present multicentre cross-sectional study was conducted in the Spanish provinces of Cádiz and Málaga (Spain) between March and September 2022.The study was approved by the Ethics Committee of Provincial Research of Málaga (reference FRAGSALUD, date 31/ 01/2019), and all procedures followed the principles outlined in the Declaration of Helsinki for human studies.Participants who expressed interest in the study received a written informed consent form detailing all procedures and potential risks.They were required to sign the written informed consent before the study began.

| Participants
This study included a total of 235 Spanish older adults (74.41 � 7.77 years), of whom 157 were females.Participant's characteristics are shown in Table 1.To be included in the study, participants had to meet the following criteria: (i) be 65 years old or older, and (ii) present at least one condition of Fried's frailty phenotype.Participants who were institutionalized or exhibited symptoms of dementia were excluded from this study.

| Frailty
The frailty status of the participants was evaluated based on Fried's frailty criteria, 2 which assessed unintentional weight loss, selfreported exhaustion and fatigue, low weekly physical activity (measured through the short version of the Minnesota Leisure Time Activity Questionnaire), 12 low gait speed (measured using the 4.57-m gait test), and low handgrip strength (Takei tkk5401, Takei Scientific Instruments, Ltd, Tokyo, Japan).

| Physical function
The participants' physical function was evaluated using the Short Physical Performance Battery (SPPB), which is a valid and reliable tool for older people. 13The SPPB assesses three physical domains: (i) balance, which includes three tests (side-by-side, semitandem, and tandem stands), (ii) gait speed over 4 m, and (iii) lower body performance using the five-repetition sit-to-stand test.
Participants' performance in each domain was compared to normative data and scored between 0 and 4 points.Participants who were unable to perform the test were given a score of 0. The final score ranged from 0 (highly dependent) to 12 (totally independent).

| Physical activity
Physical activity and inactivity levels were measured using a wristworn accelerometer (GENEActiv, ActivInsights Ltd.).To ensure accurate results, participants wore the accelerometer on their nondominant wrist for at least six consecutive days.Only data from participants who wore the accelerometer for a minimum of 16 h per day on at least 4 days (including at least three weekdays and one weekend day) were considered valid.
Accelerometers were set at 60 Hz, and raw data were downloaded using GENEActiv software version 3.  15,16 In addition, Moderate-to-Vigorous Physical Activity (MVPA) was also calculated as any activity ≥104 mG.

| Nutritional status
Participants' body mass was measured using a digital scale (Omron Medizintechnik, Mannheim, Germany), with shoes, heavy clothing, and accessories removed.Body height was measured while standing on the Frankfort plane, after exhaling normally, using a staturemeasuring instrument (SECA 225).Body Mass Index (BMI) was calculated using the formula: body mass (kg)/height (m). 2 Waist, arm, and leg circumferences were measured using a metallic nonextensible tape (Lufkin W606PM) at their thinnest for waist perimeter, and longest for arm and leg circumference points.
The Mini Nutritional Assessment (MNA) was employed to assess the participant's nutritional risk. 17This assessment comprises questions related to various aspects, such as lifestyle, medication, mobility, number of meals, food and fluid intake, autonomy of feeding, and self-perception of health and nutrition.By summing up the MNA scores, individuals can be categorized into different nutritional statuses: adequate nutritional status (MNA ≥24), proteincalorie undernutrition (MNA ≤17), or at risk for malnutrition (MNA between 17 and 23.5).The MNA is a validated questionnaire suitable for populations aged 65 and above, 18 demonstrating high sensitivity, specificity, and diagnostic accuracy. 17,19Additionally, we calculated the score of the MNA Short Form (MNA-SF), 19 which comprises the first six items of the MNA.The total score ranges from 0 to 14, with a score of >11 indicating adequate nutrition and a score of ≤11 indicating a risk of malnutrition or malnourishment.

| Health-related quality of life
The EuroQoL 5-Dimension 5-Level (EQ-5D-5L) 20 was used to assess the health-related quality of life of our older participants.This questionnaire has shown excellent psychometric properties 21 and has been validated in the Spanish population. 22This questionnaire comprises five dimensions (mobility, self-care, usual activities, pain/ discomfort, and anxiety/depression) and is validated for the Spanish population.Participants rated each dimension on a five-point scale from 1 (no problems) to 5 (extreme problems), which were then combined into a five-digit number indicating their health status.After generating 3125 possible health states, a formula was used to convert them into a single health index that ranges from 0 to 1, with 1 representing the maximum score achievable. 23rthermore, the questionnaire incorporated a Visual Analogue Scale (VAS) to assess participants' general health.The VAS consisted of a scale ranging from 0 (representing the worst imaginable health status) to 100 (representing the best imaginable health status).Participants were asked to indicate the score that best represented their health status on the day of the evaluation.

| Depressive status
The depressive status was assessed using the Yesavage 15-item Geriatric Depression Scale (GDS-15), which is a validated screening tool for depression in older individuals. 24The GDS-15 has a binary response pattern (yes or no) and assesses only cognitive symptoms of a major depressive episode experienced during the last 15 days, excluding somatic depressive symptoms such as difficulty sleeping, appetite changes, poor concentration, and fatigue.Scores on this scale range from 0 to 15, with scores below 5 indicating a normal range, scores between 5 and 9 indicating mild depression and scores above 10 indicating moderate to severe depression.

| Statistical analyses
Categorical variables are presented as counts and percentages, while continuous variables are presented as mean � standard deviation (SD).The normality of the continuous variables was assessed using the Kolmogorov-Smirnov test.
Descriptive analyses were performed to characterize the study sample, while Student's t-test and chi-square tests were used to investigate any differences between female and male participants.
Single linear regression analyses were conducted to assess the connections between Fried's frailty components and both healthrelated quality of life and depressive symptoms.
Linear regression analyses using the stepwise method were conducted to investigate the relationships between physical frailty, physical activity, and nutritional status with health-related quality of life and depressive symptoms.Five models were fitted, with the EQ-5D-5L Index, EQ-5D-5L VAS, and GDS-15 score as outcome vari- Considering the potential impact of depressive status on physical activity, as indicated by previous research, 25 a comparison between individuals within the normal range and those with moderate depression was conducted using a Student's t-test.Additionally, a sensitivity analysis involved linear regression, excluding individuals with moderate depression from the analysis.As the sensitivity analysis did not alter the results (refer to Supplementary Tables S1 and   S2), no further analyses were undertaken.
All analyses were performed by using the IBM SPSS Statistics version 26 software (SPSS Inc.) and STATA 13.0 (StataCorp LLC), with a significance set at p < 0.05.

| RESULTS
Table 2 presents the total outcomes and differences between men and women.Men had a better physical frailty status, as evidenced by their higher SPPB score, better performance in the 4.57-m gait and handgrip strength tests, and a higher score in the EQ-5D-5L Index.
Women had a higher prevalence of self-reported exhaustion and fatigue and obtained a higher score on the GDS-15 compared to men.
The associations between Fried's frailty criteria and EQ-5D-5 L Index and EQ-5D-5L VAS and depression symptoms are presented in Table 3. Reporting an unintended weight loss higher than 5% and having a low handgrip strength was associated with a higher depressive score.Reporting exhaustion and fatigue for more than 5 days was associated with a lower EQ-5D-5L score index and a higher depressive score.
Table 4 presents the associations between physical frailty, physical activity, and nutritional status with EQ-5D-5L Index, EQ-5D-5L VAS, and GDS-15 score.For the EQ-5D-5L Index, the time spent walking 4 m, the score in the MNA-SF questionnaire, sex, and leg perimeter emerged as the most important predictors, collectively explaining 23.5% of the variance.Regarding EQ-5D-5L VAS, the main predictors were the score in the MNA-SF questionnaire, leg perimeter, and the time spent in light physical activity, accounting for 9.6% of the variance.Moreover, for the depression score in pre-frail/frail older adults, the significant predictors were the score in the MNA-SF questionnaire, sex, the time spent in moderate physical activity, and leg perimeter, which together accounted for 21.1% of the variance.
Table 5 displays the crude and adjusted odds ratios for the associations between the components of Fried's frailty phenotype assessment, physical frailty, physical activity, and nutritional status with depressive status in older adults.The results show that selfreported exhaustion and fatigue, particularly for more than 3 days per week, as well as the time taken to walk 4 m, were statistically significant risk factors for depressive symptoms.The combination of these variables in the risk factor score was also considered as a significant risk factor.Conversely, daily MPA and MVPA time, arm and leg perimeter, and the score on the MNA questionnaire were found to be significant protective factors against depressive symptoms.The combination of these variables in the protective factor score was also considered as a significant protective factor.

| DISCUSSION
Various factors can significantly be associated with the well-being of the older population.Our study findings revealed maintaining a good nutritional status was found to be a protective factor for both quality of life and depression in pre-frail and frail older adults living in the community.Self-reported fatigue and exhaustion, along with slow gait speed, were significantly associated with a worse quality of life and higher depressive scores.Finally, different significant associations were observed concerning physical activity.LPA was associated with a better self-reported quality of life, whereas higher levels of MPA were linked to lower levels of depression in this population.
Additionally, Unintentional weight loss has demonstrated an association with elevated scores on the depression scale.These factors may be potentially associated with each other.Inadvertent weight loss in older adults could exacerbate depressive symptoms, potentially diminishing the motivation or feasibility to procure or prepare food. 26is, in turn, could result in caloric-protein malnutrition, precipitating further weight loss and exacerbating other important factors for ageing such as frailty. 27 optimal nutritional status and mitigating complications linked to unintentional weight loss. 26tritional status emerges as a pivotal and modifiable risk factor exerting a significant influence on disease prevention, a fact wellestablished through numerous studies, particularly concerning older adults. 28Within our study, we discerned a noteworthy correlation between elevated scores in the MNA-SF and an enhanced quality of life, as assessed by both the EQ-5D-5L Index and EQ-5D-5L VAS evaluations.These findings among older adults characterized by prefrailty or frailty align harmoniously with prior investigations, underscoring that improved dietary quality in healthy older adults is linked to elevated levels of life quality. 29Furthermore, our study unveiled a protective dimension wherein reduced malnutritional risk served as a mitigating factor against depression susceptibility within our study cohort.The intricate interplay between nutritional risk, quality of life, and depression susceptibility likely involves multifaceted mechanisms, with an array of nutrients fulfiling pivotal roles in mental wellbeing.Just as nutrients stand as vital keystones in overall human physiological processes, the brain specifically necessitates select nutrients to underpin its architecture, facilitate efficient neurotransmission, and shield against neuronal injury and demise. 30erefore, ensuring an optimal nutritional status among older adults grappling with pre-frailty or frailty may not solely yield beneficial impacts on their mental well-being, engendering an elevated quality of life and reduced depression risk, but may also be associated with the enhancement of their physical functionality.
Regarding physical function, our study explored various domains including handgrip strength, balance, gait speed, and lower body strength and their associations with the quality of life and depression in pre-frail and frail older adults.Interestingly, within this spectrum, it was handgrip strength and gait speed emerged as noteworthy contributors to both quality of life and depression in older adults with frailty phenotype.Handgrip strength is one of the key factors used to detect frailty in older people more than using chronological age alone. 31Moreover, a significant correlation between diminished handgrip strength and higher rates of depression has been observed in older adults, regardless of gender or nationality. 32,33A plausible link between handgrip strength and depression may lie in the sense of psychological well-being that physical strength can evoke.Notably, various studies have drawn connections between greater physical strength and other factors influencing depression, such as enhanced self-rated health, 34 reduced stress and negative emotions, as well as increased optimism and self-esteem. 35milarly, previous research has consistently identified gait speed as a reliable predictor of adverse outcomes in older adults. 36The present study delved into the associations of gait speed with the quality of life of pre-frail and frail older adults.In this regard, a slower performance in the 4-m gait test was significantly associated with a lower score in the EQ-5D-5L Index, showing an association between gait speed and the quality of life of older adults with frailty.The potential impact of improving gait speed on the quality of life of older adults with frailty is reinforced by findings from other studies which have observed an improvement in health-related quality of life in older adults after increasing their gait speed following interventions targeting exercise programs. 37However, it is worth mentioning that the association between gait speed and quality of life was only found in the EQ-5D-5L Index, suggesting that a slow gait speed may be related to the quality of life of older adults with frailty without their conscious awareness.Slower gait speed has been linked to a higher risk of developing depression in older adults. 38One possible explanation for this relationship is that a slower gait speed may indicate reduced mobility and physical activity, leading to a more sedentary lifestyle and potentially social isolation, which are known risk factors for depression in the elderly. 38ven that grip strength and gait speed are pivotal indicators of frailty, 31,36 39 In our study, we found significant associations between physical activity, at different intensities, and both the quality of life and depressive symptoms in older adults with frailty.Regarding the quality of life, our results demonstrated that frail older adults who engaged in more daily LPA reported a higher self-reported quality of life measured using the EQ-5D-5L VAS.This finding is consistent with previous research 40 and suggests that an increase in LPA levels may be positively associated with the perceived quality of life in this population.One possible explanation for this association is that LPA is closely related to activities of daily living, which may enhance self-efficacy 41 and subsequently improve the perception of quality of life.Regarding depression, higher levels of MVPA, particularly MPA, were associated with lower depression scores and served as a protective factor against depression in older adults with frailty.These findings align with intervention programs that have shown reductions in depression levels among older adults engaging in moderate physical activity. 42The physiological implications of moderate physical activity, encompassing fluctuations in endorphin levels and the mitigation of cortisol, likely contribute to the amelioration of depressive symptoms experienced by the participants. 42ronic fatigue has a profound impact on the quality of life in older adults, leading to decreased levels of well-being 43 and significantly contributing to the development of depression in this population. 44Our study findings align with this evidence also in pre-frail and frail older individuals, given that experiencing fatigue and exhaustion for more than 5 days per week was associated with lower levels of quality of life (both in EQ-5D-5 L score index and VAS) and higher scores on the depression scale.Fatigue has been proposed not only as an indicator of frailty 2 but also as a factor associated with accelerated ageing. 45Fatigue is influenced by various potential CASALS ET AL.
factors, encompassing social, mental, and physical aspects.Consequently, interventions targeting exhaustion and fatigue in this population should adopt a multi-faceted approach, addressing not only improvements in physical function but also incorporating mental and social activities.
Our multicenter cross-sectional study conducted among community-dwelling frail and pre-frail older adults has some important limitations that need to be acknowledged.Firstly, the crosssectional design of the study restricts our ability to establish causal relationships or track changes in variables over time.Therefore, the findings should be interpreted as associations rather than indicating causation.Secondly, there is a possibility of selection bias, as our study only included individuals residing in the community, which may limit the generalizability of the results.Additionally, the exclusion of individuals with certain health conditions may introduce some degree of bias in the findings.

| CONCLUSIONS
Our study provides valuable insights into the associations of modifiable factors on the well-being of older adults.A good nutritional status emerges as a key contributor to improved quality of life and reduced depressive symptoms in older adults with frailty.In addition to this, physical activity emerges as a significant protective factor, with light physical activity positively influencing perceived quality of life, and moderate physical activity proving beneficial in reducing depressive symptoms.Lastly, the presence of exhaustion and fatigue, along with slow gait speed, is negatively associated with both the quality of life and depressive status in this population.These findings underscore the importance of addressing frailty indicators and promoting physical activity and proper nutrition to enhance the wellbeing of older adults with frailty phenotype, which could lead to a better quality of life and mental health outcomes.

ables. Model 1
included age and sex.Model 2 included physical frailty variables obtained through the SPPB, such as Side-by-side, Semitandem, Tandem test, 4-m gait test, Sit-to-Stand Test, and SPPB score.Model 3 included physical activity variables, such as Total LPA, MPA, VPA, and MVPA, as well as inactivity.Model 4 included nutritional status variables, including anthropometric and body composition measures like BMI, waist, arm and leg circumferences, and the scores of MNA and MNA-SF.Finally, model 5 included all significant predictors from the four previous models.Moreover, logistic regression models were fitted to investigate the relationship between depressive states -and various factors, such as frailty, physical frailty, physical activity, and nutritional status.The initial associations were analysed without adjustments; however, due to observed variations in depressive symptoms between men and women, and considering that this was the only set of descriptive data displaying a significant association in the model, sex was incorporated as a covariate in the adjusted model for a more nuanced understanding of the relationships.Odds ratios, 95% confidence intervals, and p-values were reported for each model.Risk factor and protective factor scores were calculated by including variables with odds ratios higher than 1 in the risk factors category and variables with odds ratios lower than 1 in the protective factors category.The standardization process involved transforming the values using the formula: standardized value = (value -mean)/SD.
Participant characteristics by sex.
T A B L E 1Note: Values are expressed as counts (percentages) or mean � standard deviation, and statistically significant values (p < 0.05) are bolded.CASALS ET AL.

058 0.019 −0.276 0.002 −11.849 4.679 −0.271 0.018 1.931 0.597 0.300 0.003
Outcome characteristics according to sex.Regression analyses of Fried's frailty criteria and quality of life and depression in older adults.Regression analyses of physical frailty, physical activity, nutritional status, and quality of life and depression in older adults.Dimensions 5 Level; GDS, Geriatric Depression Scale; LPA, Light Physical Activity; MNA, Mininutritional Assessment; MNA-SF, Mininutritional Assessment Short Form; MPA, Moderate Physical Activity; MVPA, Moderate to Vigorous Physical Activity; SPPB, Short Physical Performance Battery; VAS, Visual Analogue Scale.Associations of frailty, physical frailty, physical activity and nutritional status with depression in older adults.
Consequently, the implementation of nutritional support interventions may prove instrumental in preserving CASALS ET AL.T A B L E 2 Note: Significant associations are highlighted in bold.Abbreviations: EQ-5D-5, L; EuroQol, 5 Dimensions 5 Level; GDS, Geriatric Depression Scale.; Ref, Reference value; VAS, Visual Analogue Scale.CASALS ET AL.T A B L E 4 T A B L E 5