Biomarkers of frailty.

Several biomarkers have been proposed to identify frailty, a multisystemic age-related syndrome. However, the complex pathophysiology and the absence of a consensus on a comprehensive and universal definition make it challenging to pinpoint a singular biomarker or set of biomarkers that conclusively characterize frailty. This review delves into the main laboratory biomarkers, placing special emphasis on those associated with various pathways closely tied to the frailty condition, such as inflammation, oxidative stress, mitochondrial dysfunction, metabolic and endocrine alterations and microRNA. Additionally, we provide a summary of different clinical biomarkers encompassing different tools that have been proposed to assess frailty. We further address various imaging biomarkers such as Dual Energy X-ray Absorptiometry, Bioelectrical Impedance analysis, Computed Tomography and Magnetic Resonance Imaging, Ultrasound and D3 Creatine dilution. Intervention to treat frailty, including non-pharmacological ones, especially those involving physical exercise and nutrition, and pharmacological interventions, that include those targeting specific mechanisms such as myostatin inhibitors, insulin sensitizer metformin and with special relevance for hormonal treatments are mentioned. We further address the levels of different biomarkers in monitoring the potential positive effects of some of these interventions. Despite the availability of numerous biomarkers, their performance and usefulness in the clinical arena are far from being satisfactory. Considering the multicausality of frailty, there is an increasing need to assess the role of sets of biomarkers and the combination between laboratory, clinical and image biomarkers, in terms of sensitivity, specificity and predictive values for the diagnosis and prognosis of the different outcomes of frailty to improve detection and monitoring of older people with frailty or at risk of developing it, being this a need in the everyday clinical practice.

Frailty Influences the Relationship between the Soluble Receptor for Advanced Glycation-End Products and Mortality in Older Adults with Diabetes Mellitus.

INTRODUCTION: Frailty is prevalent among older adults with diabetes mellitus. Elevated serum levels of the soluble receptor for advanced glycation-end products (sRAGE) predict mortality in frail older adults. The evidence that sRAGE is also related to higher mortality in older adults with diabetes mellitus is inconsistent. Therefore, this study explored if frailty status influences the relationship between sRAGE and mortality in older adults with this condition. METHODS: We analysed data of 391 participants with diabetes mellitus (median age, 76 years) from four European cohorts enrolled in the FRAILOMIC project. Frailty was evaluated at baseline using Fried's criteria. Serum sRAGE was determined by ELISA. Participants were stratified by frailty status (n = 280 non-frail and 111 frail). Multivariate Cox proportional hazards regression and Kaplan-Meier survival analysis were used to assess the relationship between sRAGE and mortality. RESULTS: During 6 years of follow-up, 98 participants died (46 non-frail and 52 frail). Non-survivors had significantly higher baseline levels of sRAGE than survivors (median [IQR]: 1,392 [962-2,043] pg/mL vs. 1,212 [963-1,514], p = 0.008). High serum sRAGE (>1,617 pg/mL) was associated with increased mortality in the whole diabetes sample after adjustment for relevant confounders (HR 2.06, 95% CI: 1.36-3.11, p < 0.001), and there was an interaction between sRAGE and frailty (p = 0.006). Accordingly, the association between sRAGE and mortality was stronger in the frail group compared to the non-frail group (HR 2.52, 95% CI: 1.30-4.90, p = 0.006 vs. HR 1.71, 95% CI: 0.91-3.23, p = 0.099, respectively). Likewise, Kaplan-Meier curves showed a significant difference in survival rates between frail participants with high sRAGE and those with low sRAGE (p = 0.001), whereas no survival difference was seen in the non-frail group (p = 0.09). CONCLUSIONS: Frailty status influences the relationship between sRAGE and mortality in older adults with diabetes mellitus. Determination of sRAGE in this population could be a useful tool for risk stratification.

Relationship of endogenous plasma concentrations of ß-hydroxy ß-methyl butyrate (HMB) with frailty in community dwelling older adults with type-2 diabetes mellitus.

BACKGROUND: Supplementation with ß-hydroxy ß-methyl butyrate (HMB) appears to be effective in preserving muscle in older adults. However, the association between endogenously produced HMB with frailty has not been studied in people with chronic disease. OBJECTIVES: The purpose of this study is to explore whether an association exists between endogenous HMB levels and frailty status in older adults with type-2 diabetes mellitus (T2DM). METHODS: Data were taken from the Toledo Study of Healthy Ageing, a community-dwelling aged (65 years+) cohort. Frailty was assessed at baseline and at 2.99 median years according to the Frailty Phenotype (FP) standardized to our population and the Frailty Trait Scale 12 (FTS12). The associations between HMB levels and frailty were assessed using three nested multivariate logistic regressions and segmented by sex. Glucose, HMB and glucose interaction, age and body composition were used as covariables. RESULTS: 255 participants (mean age 75.3 years, 52.94% men) were included. HMB levels showed an inverse cross-sectional association with frailty, which was modified when the interaction term HMB*glucose was included, remaining significant only for FTS12 [OR (95% CI): 0.436 (0.253, 0.751), p-value 0.003]. The association between HMB endogenous levels and FTS12 appears to be independent of sex, in which the association was maintained after adjusting for the covariates. However, there appears to be threshold points for glucose levels, above which the protective effect of HMB is lost: 145.4 mg/dl adjusted by gender for the whole sample and 149.6 mg/dl and 138.9 mg/dl for men and women, respectively. Endogenous HMB levels were not found to be associated with incident frailty. CONCLUSIONS: Cross-sectional analysis revealed that endogenous HMB levels were inversely associated with frailty as assessed by the FTS12 in older people with T2DM. This association was found to be dependent on circulating fasted glucose levels.

PKC Inhibition Improves Human Penile Vascular Function and the NO/cGMP Pathway in Diabetic Erectile Dysfunction: The Role of NADPH Oxidase.

Erectile dysfunction (ED) is a frequent and difficult-to-treat condition in diabetic men. Protein kinase C (PKC) is involved in diabetes-related vascular and cavernosal alterations. We aimed to evaluate the role of PKC in endothelial dysfunction and NO/cGMP impairment associated with diabetic ED in the human corpus cavernosum (CC) and penile resistance arteries (PRAs) and the potential mechanisms involved. Functional responses were determined in the CC and PRAs in patients with non-diabetic ED and diabetic ED undergoing penile prosthesis insertion. PKC activator 12,13-phorbol-dibutyrate (PDBu) impaired endothelial relaxations and cGMP generation in response to acetylcholine in the CC from non-diabetic ED. PDBu also impaired responses to a PDE5 inhibitor, sildenafil, in non-diabetic ED patients. Conversely, a PKC inhibitor, GF109203X, improved endothelial, neurogenic, and PDE5-inhibitor-induced relaxations and cGMP generation only in the CC in diabetic ED patients. Endothelial and PDE5-inhibitor-induced vasodilations of PRAs were potentiated only in diabetes. Improvements in endothelial function in diabetes were also achieved with a specific inhibitor of the PKCß2 isoform or an NADPH-oxidase inhibitor, apocynin, which prevented PDBu-induced impairment in non-diabetic patients. PKC inhibition counteracted NO/cGMP impairment and endothelial dysfunction in diabetes-related ED, potentially improving response to PDE5 inhibition.

Development of Continuous Assessment of Muscle Quality and Frailty in Older Patients Using Multiparametric Combinations of Ultrasound and Blood Biomarkers: Protocol for the ECOFRAIL Study.

BACKGROUND: Frailty resulting from the loss of muscle quality can potentially be delayed through early detection and physical exercise interventions. There is a demand for cost-effective tools for the objective evaluation of muscle quality, in both cross-sectional and longitudinal assessments. Literature suggests that quantitative analysis of ultrasound data captures morphometric, compositional, and microstructural muscle properties, while biological assays derived from blood samples are associated with functional information. OBJECTIVE: This study aims to assess multiparametric combinations of ultrasound and blood-based biomarkers to offer a cross-sectional evaluation of the patient frailty phenotype and to track changes in muscle quality associated with supervised exercise programs. METHODS: This prospective observational multicenter study will include patients aged 70 years and older who are capable of providing informed consent. We aim to recruit 100 patients from hospital environments and 100 from primary care facilities. Each patient will undergo at least two examinations (baseline and follow-up), totaling a minimum of 400 examinations. In hospital environments, 50 patients will be measured before/after a 16-week individualized and supervised exercise program, while another 50 patients will be followed up after the same period without intervention. Primary care patients will undergo a 1-year follow-up evaluation. The primary objective is to compare cross-sectional evaluations of physical performance, functional capacity, body composition, and derived scales of sarcopenia and frailty with biomarker combinations obtained from muscle ultrasound and blood-based assays. We will analyze ultrasound raw data obtained with a point-of-care device, along with a set of biomarkers previously associated with frailty, using quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Additionally, we will examine the sensitivity of these biomarkers to detect short-term muscle quality changes and functional improvement after a supervised exercise intervention compared with usual care. RESULTS: At the time of manuscript submission, the enrollment of volunteers is ongoing. Recruitment started on March 1, 2022, and ends on June 30, 2024. CONCLUSIONS: The outlined study protocol will integrate portable technologies, using quantitative muscle ultrasound and blood biomarkers, to facilitate an objective cross-sectional assessment of muscle quality in both hospital and primary care settings. The primary objective is to generate data that can be used to explore associations between biomarker combinations and the cross-sectional clinical assessment of frailty and sarcopenia. Additionally, the study aims to investigate musculoskeletal changes following multicomponent physical exercise programs. TRIAL REGISTRATION: ClinicalTrials.gov NCT05294757; https://clinicaltrials.gov/ct2/show/NCT05294757. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/50325.

Response rates and associated factors after a multicomponent intervention in frail older adults with diabetes.

BACKGROUND: Type 2 diabetes mellitus (T2DM) and frailty are associated with functional decline in older population. OBJECTIVE: To explore the individual response to a multimodal intervention on functional performance. DESIGN: A cluster-randomised multicentre clinical trial. SETTING: Outpatients in hospital or primary care. SUBJECTS: 843 (77.83 years, 50.65% men) prefrail and frail individuals ≥70 years with T2DM. METHODS: Participants were allocated to usual care group (UCG) or a multicomponent intervention group (IG): 16-week progressive resistance training, seven nutritional and diabetological educational sessions and achievement of glycated haemoglobin (7-8%) and blood pressure (<150 mmHg) targets. Functional performance was assessed with the Short Physical Performance Battery (SPPB) at 1 year. We used multivariate binomial and multinomial logistic regression models to explore the effect of the IG, and adherence on the outcomes studied, in several adjusted models. RESULTS: 53.7% in the IG versus 38.0% in the UCG improved by at least 1 point in their SPPB score [OR (95% CI): 2.07 (1.43, 2.98), P value <0.001]. Age, SPPB score and number of frailty criteria met decreased the probability of improving the SPPB score. Factors associated with worsening were pertaining to IG (decreased), age, SPPB score and the number of frailty criteria (increased). An adherence ≥84% was needed to achieve benefits, reaching the peak in the probability of improving SPPB when this was ≥85% [OR(95%CI): 2.38 (1.29, 4.79), P value 0.014]. CONCLUSIONS: Factors predicting the likelihood of improvement in a multimodal programme in pre-frail and frail older adults with diabetes are age, basal SPPB score, the number of frailty criteria and adherence.

Fat Mass Accounts for Insulin Resistance Impact on Functional Decline and Mortality in Nondiabetic Older Adults.

OBJECTIVE: To assess the potential role of body composition in the association of insulin resistance (IR) with functional decline and mortality in nondiabetic older persons. DESIGN: Longitudinal population-based cohort of community-dwelling people from Toledo, Spain, aged 65 years or older. SETTING AND PARTICIPANTS: A total of 1114 nondiabetic persons from the Toledo Study of Healthy Aging cohort (mean age: 74.5, 56.10% female) with complete data at baseline were included. Only 914 participants had fully assessment of functional evaluation during the follow-up period. METHODS: IR was determined by the homeostasis model assessment index (HOMA-IR) at baseline while frailty was assessed by the Frailty Trait Scale-5 (FTS-5) at baseline and after 2.99 years' median follow-up period. A total of 319 participants experienced functional decline (2.5-point reduction in the FTS-5 score). A total of 143 deaths were recorded (6.31 years median follow-up) from the Spanish National Death Index. Body compositions were determined using dual-energy x-ray absorptiometry. Multivariate regression models analyzed the effect of HOMA-IR on outcomes, with age, sex, Charlson index, and number of medications included in the basic adjustment model. RESULTS: A 1-logaritmic unit increment in HOMA-IR increased the risk of functional decline after basic adjustment [odds ratio (95% confidence interval): 1.41 (1.09-1.83), P = .009]. This significant association was lost when further adjusted for total fat mass [1.14 (0.86-1.50)] and trunk fat mass [1.03 (0.77-1.37)], which accounted for 62.92% and 91.49% of the association. HOMA-IR was inversely associated with mortality risk [hazard ratio 0.66 (0.49-0.87), P = .0037], an association lost after adjustment for total fat mass [0.74 (0.55-1.01)] and trunk fat mass [0.80 (0.58-1.09)], accounting for 29.05% and 45.78% of the association. Adjustment by lean mass did not modify any of the associations. CONCLUSIONS AND IMPLICATIONS: Body fat mass, especially in the trunk region, mediates the association of IR with functional decline and to a lesser extent with reduced risk of mortality in nondiabetic older subjects.

Effectiveness of a randomized intervention by a geriatric team in frail hospital inpatients in non-geriatric settings: FRAILCLINIC project.

BACKGROUND: Little research has been undertaken on the benefits of frailty management within different hospital settings. The objective of this study is to provide evidence on the viability and effectiveness of frailty management in non-geriatric hospital settings on mortality and functional decline after discharge. METHODS: Data from the FRAILCLINIC (NCT02643069) study were used. FRAILCLINIC is a randomized controlled trial developed in non-geriatric hospital inpatient settings (emergency room, cardiology and surgery) from Spain (2), Italy (2) and the United Kingdom (1). Inpatients must met frailty criteria (according to the Frailty Phenotype and/or FRAIL scale), ≥75 years old. The control group (CG) received usual care. The intervention group (IG) received comprehensive geriatric assessment (CGA) and a coordinated intervention consisting in recommendations to the treating physician about polypharmacy, delirium, falls, nutrition and physical exercise plus a discharge plan. The main outcomes included functional decline (worsening ≥5 points in Barthel Index) and mortality at 3 months. We used multivariate logistic regression models adjusted by age, gender and the Charlson index. Intention-to-treat (ITT) and per-protocol (PP) analyses were used. RESULTS: Eight hundred twenty one participants (IG: 416; mean age 83.00 ± 4.91; 51.44% women; CG: 405; mean age 82.46 ± 6.03; 52.35% women) were included. In the IG, 77.16% of the participants followed the geriatric team's recommendations as implemented by the treating physicians. The intervention showed a benefit on functional decline and mortality [OR: 0.67(0.47-0.96), P-value 0.027 and 0.29(0.14-0.57), P-value < 0.001, respectively) when fully followed by the treating physician. A trend to benefit (close to statistical significance) in functional decline and mortality were also observed when any of the recommendations were not followed [OR (95% CI): 0.72 (0.51-1.01), P-value: 0.055; and 0.64 (0.37-1.10), P-value: 0.105, respectively]. CONCLUSIONS: An individualized intervention in frail in-patients reduces the risk of functional deterioration and mortality at 3 months of follow-up when a care management plan is designed and followed.

Association between endogenous plasma beta-hydroxy-beta-methylbutyrate levels and frailty in community-dwelling older people.

BACKGROUND: Frailty is a key element in healthy ageing in which muscle performance plays a main role. Beta-hydroxy-beta-methylbutyrate (HMB) supplementation has shown favourable effects in modulating protein synthesis, improving muscle mass and function in interventional studies. Decreased age-related endogenous HMB levels have been shown in previous studies. The aim of the present study is to assess whether there is an association between endogenous plasma HMB levels and frailty. METHODS: Data from 1290 subjects (56.98% women; mean ± standard deviation age 74.6 ± 5.95 years) from the Toledo Study for Healthy Aging were obtained. Participants had their frailty status qualified according to Fried's Frailty Phenotype (FFP) score and the Frailty Trait Scale in its 12-domain version (FTS-12). Plasma HMB levels were analysed by an ultrahigh-performance liquid chromatography tandem mass spectrometry. Differences between groups (frail vs. non-frail) were tested using Mann-Whitney U test, Kruskal-Wallis test and chi-squared test. The association between HMB and frailty was assessed by multivariate linear and logistic regressions when frailty was analysed as continuous and binary, respectively. Models were adjusted by age, gender, comorbidity, body composition and protein intake. RESULTS: HMB levels were lower in those aged ≥75 years than in those aged 65-74 years, with an inverse linear relationship between age and HMB levels (ß = -0.031; P = 0.018), mainly accounted by males (ß = -0.062; P = 0.002). HMB levels were higher in men (0.238 ± 0.065 vs. 0.193 ± 0.051 ng/mL; P ≤ 0.001). HMB levels were significantly lower in frail than in non-frail individuals: 0.204 ± 0.058 versus 0.217 ± 0.063 ng/dL (P = 0.001) according to the FFP and 0.203 ± 0.059 versus 0.219 ± 0.063 ng/mL (P < 0.001) according to FTS-12. These differences showed a dose-dependent profile when we compared them by quintiles of HMB (P for trend: 0.022; 0.012 and 0.0004, respectively, for FFP, FTS-12 binary and FTS-12 continuous). Variables associated with low HMB levels were body mass index, strength, exhaustion and weight loss. Frailty was associated with HMB levels in all the adjusted models, including the fully adjusted ones, no matter the tool used (odds ratio: 0.45 [0.26, 0.77] for FFP and 0.36 [0.20, 0.63] for FTS-12 binary; ß = -4.76 [-7.29, -2.23] for FTS-12 score). This association was also observed when the analyses were done by quintiles, showing such association since Q4 (FFP), Q2 (FTS-12 binary) and Q3 (FTS-12 score). The associations were observed in the whole sample and in each gender. CONCLUSIONS: There is an inverse association between HMB levels and frailty status. These findings support the design of targeted clinical trials to evaluate the effect of HMB supplementation in older frail people with low HMB levels.

Hard-to-Heal Wound Healing: Superiority of Hydrogel EHO-85 (Containing Olea europaea Leaf Extract) vs. a Standard Hydrogel. A Randomized Controlled Trial.

Chronic wounds, especially those that are hard-to-heal, constitute a serious public-health problem. Although progress has been made in the development of wound dressings for healing, there is little high-quality evidence of their efficacy, with no evidence of superiority in the use of one hydrogel over another. To evaluate the superiority of a hydrogel (EHO-85), containing Olea europaea leaf extract (OELE), over a standard hydrogel (SH), the promotion and/or improvement of healing of difficult-to-heal wounds was compared in a prospective, parallel-group multicenter, randomized, observer-blinded, controlled trial ("MACAON"). Non-hospitalized patients with pressure, venous or diabetic foot-ulcers difficult-to-heal were recruited and treated with standard care, and EHO-85 (n = 35) or VariHesive (n = 34) as SH. Wound-area reduction (WAR; percentage) and healing rate (HR; mm2/day) were measured. EHO-85 showed a statistically significant superior effect over VariHesive. At the end of the follow-up period, the relative WAR decreased by 51.6% vs. 18.9% (p < 0.001), with a HR mean of 10.5 ± 5.7 vs. 1.0 ± 7.5 mm2/day (p = 0.036). EHO-85 superiority is probably based on its optimal ability to balance the ulcer bed, by modulating pH and oxidative stress. That complements the wetting and barrier functions, characteristics of conventional hydrogels. These results support the use of EHO-85 dressing, for treatment of hard-to-heal ulcers. Trial Registration AEMPS:PS/CR623/17/CE.

Essential steps in primary care management of older people with Type 2 diabetes: an executive summary on behalf of the European geriatric medicine society (EuGMS) and the European diabetes working party for older people (EDWPOP) collaboration.

We present an executive summary of a guideline for management of type 2 diabetes mellitus in primary care written by the European Geriatric Medicine Society, the European Diabetes Working Party for Older People with contributions from primary care practitioners and participation of a patient's advocate. This consensus document relies where possible on evidence-based recommendations and expert opinions in the fields where evidences are lacking. The full text includes 4 parts: a general strategy based on comprehensive assessment to enhance quality and individualised care plan, treatments decision guidance, management of complications, and care in case of special conditions. Screening for frailty and cognitive impairment is recommended as well as a comprehensive assessment all health conditions are concerned, including end of life situations. The full text is available online at the following address: essential_steps_inprimary_care_in_older_people_with_diabetes_-_EuGMS-EDWPOP___3_.pdf.

Upregulation of Orai Channels Contributes to Aging-Related Vascular Alterations in Rat Coronary Arteries.

Vascular territories display heterogeneous sensitivity to the impacts of aging. The relevance of the STIM/Orai system to vascular function depends on the vascular bed. We aimed to evaluate the contribution of the STIM/Orai system to aging-related vascular dysfunction in rat coronary circulation. Vascular function was evaluated according to myography in coronary arteries from young (three-month-old) and older (twenty-month-old) rats. The effects of aging and STIM/Orai inhibition on the contraction and relaxation of the coronary arteries and on the protein expression of STIM-1, Orai1, and Orai3 in these vessels were determined. Aging-related hypercontractility to serotonin and endothelin-1 in arteries from male rats was reversed by STIM/Orai inhibition with YM-58483 or by specifically blocking the Orai1 channel with Synta66. The inhibitory effects of Synta66 on coronary vasoconstriction were also observed in older female rats. YM-58483 relaxed serotonin- but not KCl-contracted arteries from males. STIM/Orai inhibition improved defective endothelial vasodilations in aged arteries, even in the presence of NO synthase and cyclooxygenase inhibitors, but not in KCl-contracted segments. YM-58483 significantly enhanced relaxations to calcium-activated potassium channel stimulation in aged vessels. Increased protein expression of Orai1 and Orai3 was detected in arterial homogenates and sections from older rats. Upregulation of the Orai channel contributes to aging-related coronary dysfunction, revealing a potential target in reducing CVD risk.

EHO-85, Novel Amorphous Antioxidant Hydrogel, Containing Olea europaea Leaf Extract-Rheological Properties, and Superiority over a Standard Hydrogel in Accelerating Early Wound Healing: A Randomized Controlled Trial.

Many advanced wound healing dressings exist, but there is little high-quality evidence to support them. To determine the performance of a novel amorphous hydrogel (EHO-85) in relation to its application, we compared its rheological properties with those of other standard hydrogels (SH), and we assessed the induction of acceleration of the early stages of wound healing as a secondary objective of a prospective, multicenter, randomized, observer-blinded, controlled trial. The patients were recruited if they had pressure, venous, or diabetic foot ulcers and were treated with EHO-85 (n = 103) or VariHesive® (SH) (n = 92), and their response was assessed by intention-to-treat as wound area reduction (WAR (%)) and healing rate (HR mm2/day) in the second and fourth weeks of treatment. Results: EHO-85 had the highest shear thinning and G'/G″ ratio, the lowest viscous modulus, G″, and relatively low cohesive energy; EHO-85 had a significantly superior effect over SH in WAR and HR, accelerating wound healing in the second and fourth weeks of application (p: 0.002). This superiority is likely based on its optimal moisturizing capacity and excellent pH-lowering and antioxidant properties. In addition, the distinct shear thinning of EHO-85 facilitates spreading by gentle hand pressure, making it easier to apply to wounds. These rheological properties contribute to its improved performance.

Frailty detection in older adults via fractal analysis of acceleration signals from wrist-worn sensors.

Purpose: Frailty is a reversible multidimensional syndrome that puts older people at a high risk of adverse health outcomes. It has been proposed to emerge from the dysregulation of the complex system dynamics of physiologic control systems. We propose the analysis of the fractal complexity of hand movements as a new method to detect frailty in older adults. Methods: FRAIL scale and Fried's phenotype scores were calculated for 1209 subjects-72.4 (5.2) y.o. 569 women-and 1279 subjects-72.6 (5.3) y.o. 604 women-in the pubicly available NHANES 2011-2014 data set, respectively. The fractal complexity of their hand movements was assessed with a detrended fluctuation analysis (DFA) of their accelerometry records and a logistic regression model for frailty detection was fit. Results: Goodness-of-fit to a power law was excellent (R2>0.98). The association between complexity loss and frailty level was significant, Kruskal-Wallis test (df = 2, Chisq = 27.545, p-value <0.001). The AUC of the logistic classifier was moderate (AUC with complexity = 0.69 vs. AUC without complexity = 0.67). Conclusion: Frailty can be characterized in this data set with the Fried phenotype. Non-dominant hand movements in free-living conditions are fractal processes regardless of age or frailty level and its complexity can be quantified with the exponent of a power law. Higher levels of complexity loss are associated with higher levels of frailty. This association is not strong enough to justify the use of complexity loss after adjusting for sex, age, and multimorbidity.

Integrated health system to assess and manage frailty in community dwelling: Co-design and usability evaluation.

Objective: We aimed to co-create and evaluate an integrated system to follow-up frailty in a community dwelling environment and provide a multi-modal tailored intervention. Frailty and dependency among the older population are a major challenge to the sustainability of healthcare systems. Special attention must be paid to the needs and particularities of frail older persons as a vulnerable group. Methods: To ensure the solution fits all the stakeholders' needs, we performed several participatory design activities with them, such as pluralistic usability walkthroughs, design workshops, usability tests and a pre-pilot. The participants in the activities were older people; their informal carers; and specialized and community care professionals. In total, 48 stakeholders participated. Results: We created and evaluated an integrated system consisting of four mobile applications and a cloud server, which has been evaluated through a 6-months clinical trial, where secondary endpoints were both usability and user experience evaluation. In total, 10 older adults and 12 healthcare professionals participated in the intervention group using the technological system. Both patients and professionals have positively evaluated their applications. Conclusion: Both older adults and healthcare professionals have considered the resulted system easy to use and learn, consistent and secure. In general terms, they also would like to keep using it in the future.

Amino Acid Profiles in Older Adults with Frailty: Secondary Analysis from MetaboFrail and BIOSPHERE Studies.

An altered amino acid metabolism has been described in frail older adults which may contribute to muscle loss and functional decline associated with frailty. In the present investigation, we compared circulating amino acid profiles of older adults with physical frailty and sarcopenia (PF&S, n = 94), frail/pre-frail older adults with type 2 diabetes mellitus (F-T2DM, n = 66), and robust non-diabetic controls (n = 40). Partial least squares discriminant analysis (PLS-DA) models were built to define the amino acid signatures associated with the different frailty phenotypes. PLS-DA allowed correct classification of participants with 78.2 ± 1.9% accuracy. Older adults with F-T2DM showed an amino acid profile characterized by higher levels of 3-methylhistidine, alanine, arginine, ethanolamine, and glutamic acid. PF&S and control participants were discriminated based on serum concentrations of aminoadipic acid, aspartate, citrulline, cystine, taurine, and tryptophan. These findings suggest that different types of frailty may be characterized by distinct metabolic perturbations. Amino acid profiling may therefore serve as a valuable tool for frailty biomarker discovery.

Patterns of Dietary Blood Markers Are Related to Frailty Status in the FRAILOMIC Validation Phase.

The influence of nutritional factors on frailty syndrome is still poorly understood. Thus, we aimed to confirm cross-sectional associations of diet-related blood biomarker patterns with frailty and pre-frailty statuses in 1271 older adults from four European cohorts. Principal component analysis (PCA) was performed based on plasma levels of α-carotene, ß-carotene, lycopene, lutein + zeaxanthin, ß-cryptoxanthin, α-tocopherol, γ-tocopherol and retinol. Cross-sectional associations between biomarker patterns and frailty status, according to Fried's frailty criteria, were assessed by using general linear models and multinomial logistic regression models as appropriate with adjustments for the main potential confounders. Robust subjects had higher concentrations of total carotenoids, ß-carotene and ß-cryptoxanthin than frail and pre-frail subjects and had higher lutein + zeaxanthin concentrations than frail subjects. No associations between 25-Hydroxyvitamin D3 and frailty status were observed. Two distinct biomarker patterns were identified in the PCA results. The principal component 1 (PC1) pattern was characterized by overall higher plasma levels of carotenoids, tocopherols and retinol, and the PC2 pattern was characterized by higher loadings for tocopherols, retinol and lycopene together and lower loadings for other carotenoids. Analyses revealed inverse associations between PC1 and prevalent frailty. Compared to participants in the lowest quartile of PC1, those in the highest quartile were less likely to be frail (odds ratio: 0.45, 95% CI: 0.25-0.80, p = 0.006). In addition, those in the highest quartile of PC2 showed higher odds for prevalent frailty (2.48, 1.28-4.80, p = 0.007) than those in the lowest quartile. Our findings strengthen the results from the first phase of the FRAILOMIC project, indicating carotenoids are suitable components for future biomarker-based frailty indices.

Differential utility of various frailty diagnostic tools in non-geriatric hospital departments of several countries: A longitudinal study.

BACKGROUND: There is limited knowledge on the performance of different frailty scales in clinical settings. We sought to evaluate in non-geriatric hospital departments the feasibility, agreement and predictive ability for adverse events after 1 year follow-up of several frailty assessment tools. METHODS: Longitudinal study with 667 older adults recruited from five hospitals in three different countries (Spain, Italy and United Kingdom). Participants were older than 75 years attending the emergency room, cardiology and surgery departments. Frailty scales used were Frailty Phenotype (FP), FRAIL scale, Tilburg and Groningen Frailty Indicators, and Clinical Frailty Scale (CFS). Analyses included the prevalence of frailty, degree of agreement between tools, feasibility and prognostic value for hospital readmission, worsening of disability and mortality, by tool and setting. RESULTS: Emergency Room and cardiology were the settings with the highest frailty prevalence, varying by tool between 40.4% and 67.2%; elective surgery was the one with the lowest prevalence (between 13.2% and 38.2%). The tools showed a fair to moderate agreement. FP showed the lowest feasibility, especially in urgent surgery (35.6%). FRAIL, CFS and FP predicted mortality and readmissions in several settings, but disability worsening only in cardiology. CONCLUSIONS: Frailty is a highly frequent condition in older people attending non-geriatric hospital departments. We recommend that based upon their current feasibility and predictive ability, the FRAIL scale, CFS and FP should be preferentially used in these settings. The low concordance among the tools and differences in prevalence reported and predictive ability suggest the existence of different subtypes of frailty.

Pulmonary function is associated with frailty, hospitalization and mortality in older people: 5-year follow-up.

BACKGROUND: The relationship between pulmonary impairment and frailty has rarely been studied in community-dwelling older adults. OBJECTIVE: This study aimed to analyze the association between pulmonary function and frailty (prevalent and incident), identifying the best cut-off points to detect frailty and its association with hospitalization and mortality. METHODS: A longitudinal observational cohort study with 1188 community-dwelling older adults was taken from the Toledo Study for Healthy Aging. The forced expiratory volume in the first second (FEV1) and the forced vital capacity (FVC) were measured with spirometry. Frailty was evaluated using the Frailty Phenotype and Frailty Trait Scale 5. Associations between pulmonary function and frailty, hospitalization and mortality in a 5-year follow-up and the best cut-off points for FEV1 and FVC were analyzed. RESULTS: FEV1 and FVC were associated with frailty prevalence (OR from 0.25 to 0.60), incidence (OR from 0.26 to 0.53), and hospitalization and mortality (HR from 0.35 to 0.85). The cut-off points of pulmonary function identified in this study: FEV1 (≤1.805 L for male and ≤1.165 L for female) and FVC (≤2.385 L for male and ≤1.585 L for female) were associated with incident frailty (OR: 1.71-4.06), hospitalization (HR: 1.03-1.57) and mortality (HR: 2.64-5.17) in individuals with and without respiratory diseases (P < 0.05 for all). CONCLUSION: Pulmonary function was inversely associated with the risk of frailty, hospitalization and mortality in community-dwelling older adults. The cut-off points for FEV1 and FVC to detect frailty were highly associated with hospitalization and mortality in the 5-year follow-up, regardless of the existence of pulmonary diseases.