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.

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.

Power-oriented resistance training combined with high-intensity interval training in pre-frail and frail older people: comparison between traditional and cluster training set configurations on the force-velocity relationship, physical function and frailty.

OBJECTIVES: To analyse the force-velocity relationship changes in response to two different training programmes differing in the set configuration (cluster vs. traditional), and their impact on physical function and frailty in pre-frail and frail older adults. METHODS: 43 pre-frail and frail (Frailty Phenotype ≥ 1 criteria) older adults (81.4 ± 5.1 years) participated in this study. Participants were assigned to cluster (CT; n = 10; 10-s intra-set rest), traditional (TT; n = 13; no intra-set rest) or control (CON; n = 20) groups. Force-velocity relationship (F0, V0 and Pmax), physical function (Short Physical Performance Battery, SPPB) and frailty (Frailty Phenotype, FP) were assessed at baseline and after the training programme. RESULTS: Both CT and TT groups showed similar improvements in Pmax after training (CT = + 36.7 ± 34.2 W; TT = + 33.8 ± 44.6 W; both p < 0.01). V0 was improved by both CT (+ 0.08 ± 0.06 m s-1; p < 0.01), and TT (+ 0.07 ± 0.15 m s-1, p > 0.05). F0 remained unchanged in CT (+ 68.6 ± 224.2 N, p > 0.05) but increased in TT (+ 125.4 ± 226.8 N, p < 0.05). Finally, SPPB improved in both training conditions (CT = + 2.3 ± 1.3 points; TT = + 3.0 ± 1.2 points; both p < 0.05) and in the CON group (+ 0.9 ± 1.4 points, p < 0.05). CT and TT reduced their FP (CT = - 1.1 criteria; TT = - 1.6 criteria; both p < 0.01), while no changes were observed in the CON group (- 0.2 criteria, p = 0.38). CONCLUSIONS: Both training methods were equally effective for improving Pmax, physical function and reducing frailty in pre-frail and frail older people. TT may be effective for improving both force and velocity parameters, while CT may be effective for improving velocity parameters alone, although further research is required to confirm these findings.

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.

Optimization of VO2 and VCO2 outputs for the calculation of resting metabolic rate using a portable indirect calorimeter.

This study aimed to compare the Cosmed K5 portable indirect calorimeter, using the mixing chamber mode and face mask, with a stationary metabolic cart when measuring the resting metabolic rate (RMR) and to derive fitting equations if discrepancies are observed. Forty-three adults (18-84 years) were assessed for their RMR for two 30-min consecutive and counterbalanced periods using a Cosmed K5 and an Oxycon Pro. Differences among devices were tested using paired sample Student's t-tests, and correlation and agreement were assessed using Pearson's correlation coefficients, intraclass correlation coefficient and Bland-Altman plots. Forward stepwise multiple linear regression models were performed to develop fitting equations for estimating differences among devices when assessing oxygen uptake (VO2 diff , mL·min-1 ) and carbon dioxide production (VCO2 diff , mL·min-1 ). Furthermore, the Oxycon Pro was tested before being confirmed as a reference device. Significant differences between devices were found in most metabolic and ventilatory parameters, including the primary outcomes of VO2 and VCO2 . These differences showed an overestimation of the Cosmed K5 in all metabolic outcomes, except for Fat, when compared to the Oxycon Pro. When derived fitting equations were applied (VO2 diff - 139.210 + 0.786 [weight, kg] + 1.761 [height, cm] - 0.941 [Cosmed K5 VO2 , mL·min-1 ]; VCO2 diff - 86.569 + 0.548 [weight, kg] + 0.915 [height, cm] - 0.728 [Cosmed K5 VCO2 , mL·min-1 ]), differences were minimized, and agreement was maximized. This study provides fitting equations which allow the use of the Cosmed K5 for reasonably optimal RMR determinations.

Predictors of Maintained Transitions Between Robustness and Prefrailty in Community-Dwelling Older Spaniards.

OBJECTIVES: We aimed to explore predictors of sustained transitions (those that are maintained for an extra follow-up) between robustness and prefrailty in both directions. DESIGN: Longitudinal population-based cohort. SETTING AND PARTICIPANTS: Community-dwelling Spaniards 65 years or older from the Toledo Study of Healthy Ageing. METHODS: The Fried's frailty phenotype was measured over 3 waves (2006-2009, 2011-2013, and 2014-2017). Multiple logistic regressions compared individuals following the pattern robust-prefrail-prefrail with those who remained robust across waves, and those following the pattern prefrail-robust-robust with those who remained prefrail, for sociodemographic, clinical, life-habits, dependency for activities of daily living, upper and lower extremities' strength variables. The Fried's items of those who remained prefrail and those who became robust were compared. RESULTS: Mean age was 72.3 years (95% CI: 71.8-72.8) and 57.9% (52.7%-63.0%) were women. After multivariate adjustment, predictors (apart from age) of the sustained transition robustness-prefrailty were as follows: number of drugs taken (odds ratio: 1.37; 95% CI: 1.14-1.65), not declaring the amount of alcohol consumed (8.32; 1.78-38.88), and grip strength (0.92 per kg; 0.86-0.99). Predictors of the sustained transition prefrailty-robustness were as follows: drinking alcohol (0.2; 0.05-0.83), uricemia (0.67; 0.49-0.93), number of chair stands in 30 seconds (1.14; 1.01-1.28), and grip strength (1.12; 1.05-1.2). Low grip strength was associated with a lower probability of regaining robustness. CONCLUSIONS AND IMPLICATIONS: Prediction of sustained transitions between the first stages of frailty development can be achieved with a reduced number of variables and noting whether the Fried's item leading to a diagnosis of prefrailty is low grip strength. Our results suggest the need to intensify interventions on deprescription, quitting alcohol, and strengthening of upper and lower limbs.

Physical performance measures in frailty screening: diagnostic and prognostic accuracy in the Toledo Study of Healthy Ageing.

INTRODUCTION: The present study aimed to explore the diagnostic and prognostic accuracy of standard and population-specific Physical Performance Measures (PPMs) cut-off points for frailty screening. DESIGN: Prospective cohort study. SETTING AND PARTICIPANTS: Population-based study including 2328 subjects from the Toledo Study of Healthy Aging (age = 76.37 ± 6.78). Data related to frailty status and PPMs was collected at baseline visit (2011-2013). Mortality and hospitalization were ascertained up to March 2019 and December 2017, respectively, whereas disability onset and worsening were evaluated in the 2015-2017 visit. METHODS: Gait speed and Short Physical Performance Battery population-specific cut-off points for frailty were computed using receiver operating characteristics (ROC) curve analysis. Head-to-head comparison of associations with adverse events against existing reference values (SPPB≤6, GS < 0.8 m/s) and classical (Frailty Phenotype, Frailty Index) and newly incorporated frailty tools (12- and 5-item Frailty Trait Scale) were explored through logistic and Cox regressions. Predictive ability was compared through areas under the curves (AUCs) for disability onset/worsening and integrated AUCs for mortality and hospitalization (time-censoring adverse events). RESULTS: PPMs population-specific cut-off points (SPPB ≤7 and GS ≤ 0.75 m/s for males; SPPB ≤4 and GS ≤ 0.5 for females) outperformed published reference thresholds in terms of diagnostic accuracy. Frailty identified through PPMs was associated with adverse events (death, hospitalization and incident disability) similarly to that assessed using the newly incorporated tools and showed similar prognostic accuracy (mortality [IAUCs≈0.7], hospitalization [IAUCs≈0.8] and disability onset/worsening [AUCs≈0.62]), except for the tool used to assess frailty. CONCLUSIONS: Our results suggest that PPMs might serve as the first screen to identify candidates for further frailty assessment and exploration of underlying mechanisms, allowing opportunistic on-time screening in different settings (community and primary care) in which frailty instruments are rarely implementable.

Differential Association of Frailty and Sarcopenia With Mortality and Disability: Insight Supporting Clinical Subtypes of Frailty.

OBJECTIVES: Sarcopenia and frailty have been shown separately to predict disability and death in old age. Our aim was to determine if sarcopenia may modify the prognosis of frailty regarding both mortality and disability, raising the existence of clinical subtypes of frailty depending on the presence of sarcopenia. DESIGN: A Spanish longitudinal population-based study. SETTING AND PARTICIPANTS: The population consists of 1531 participants (>65 years of age) from the Toledo Study of Health Aging. METHODS: Sarcopenia and frailty were assessed following Foundation for the National Institutes of Health criteria and the Fried Frailty Phenotype, respectively. Mortality was assessed using the National Death Index. Functional status was determined using Katz index. We ran multivariate logistics and proportional hazards models adjusting for age, sex, baseline function, and comorbidities. RESULTS: Mean age was 75.4 years (SD 5.9). Overall, 70 participants were frail (4.6%), 565 prefrail (36.9%), and 435 sarcopenic (28.4%). Mean follow-up was 5.5 and 3.0 years for death and worsening function, respectively. Furthermore, 184 participants died (12%) and 324 worsened their functioning (24.8%). Frailty and prefrailty were associated with mortality and remained significant after adjustment by sarcopenia [hazard risk (HR) 3.09, 95% confidence interval (CI) 1.84-5.18; P < .001; HR 1.58, 95% CI 1.12-2.24, P = .01]. However, the association of sarcopenia with mortality was reduced and became nonsignificant (HR 1.43, 95% CI 0.99-2.07, P = .057) when both frailty and sarcopenia were included in the same model. In the disability model, frailty and sarcopenia showed a statistically significant interaction (P = .016): both had to be present to predict worsening of disability. CONCLUSIONS AND IMPLICATIONS: Sarcopenia plays a relevant role in the increased risk of functional impairment associated to frailty, but that seems not to be the case with mortality. This finding raises the need of assessing sarcopenia as a cornerstone of the clinical work after diagnosing frailty.

Impact of Relative Muscle Power on Hospitalization and All-Cause Mortality in Older Adults.

BACKGROUND: The purpose of this study was to evaluate the relationship of lower-limb muscle power with mortality and hospitalization. METHODS: A total of 1 928 participants from the Toledo Study for Healthy Aging were included. Muscle power was assessed with the 5-repetition sit-to-stand test and participants were classified into different groups of relative power (ie, normalized to body mass) according to sex-specific tertiles and their inability to perform the test. Mean follow-up periods for hospitalization and all-cause mortality were 3.3 and 6.3 years, respectively. RESULTS: Compared to the high relative muscle power group, men with low (HR [95% CI] = 2.1 [1.2-3.6]) and women with very low and low (HR [95% CI] = 4.7 [3.0-7.4] and 1.8 [1.2-2.7]) relative power had an increased age-adjusted risk of hospitalization. After adjusting for several covariates (age, physical activity, body mass index education, depression, comorbidities, disability, and handgrip strength), these effects were attenuated (men and women with very low relative power: HR [95% CI] = 1.6 [0.9-2.9] and 2.8 [1.6-4.9]). The very low relative muscle power group had also an increased all-cause mortality risk (age-adjusted) in both men and women (HR [95% CI] = 2.3 [1.4-3.9] and 2.9 [1.6-5.3]). After adjusting for all the covariates, a significantly increased mortality risk was observed only in men (HR [95% CI] = 2.1 [1.1-3.8]; women HR [95% CI] = 1.6 [0.8-3.2]), with very low levels of relative power. CONCLUSIONS: Relative muscle power was independently and negatively associated with mortality and hospitalization in older adults. An augmented all-cause mortality risk was noted in the lowest group of relative muscle power.

Transitions Between Frailty States and Its Predictors in a Cohort of Community-Dwelling Spaniards.

OBJECTIVES: Study the frequency and determinants of frailty transitions in a community-dwelling older population. DESIGN: Population-based prospective longitudinal study [The Toledo Study of Healthy Ageing (TSHA)]. SETTING AND PARTICIPANTS: 1748 community-dwelling individuals aged >65 years living in Toledo, a Spanish province. METHODS: Frailty was measured with the Fried phenotype. Logistic models were used to assess the associations of sociodemographic, clinical, life-habits, functional, physical performance, and analytical variables with frailty transitions (losing robustness, transitioning from prefrailty to robustness, and from prefrailty to frailty) over a median of 5.2 years. RESULTS: Mean age on enrolment was 75 years, and 55.8% were females. At baseline, 10.3% were frail and 43.1% prefrail. At follow-up, 35.8% of the frail individuals recovered to a prefrail and 15.1% to a robust state. In addition, 43.7% of the prefrail participants became robust, but 14.5% developed frailty. Of those robust at baseline, 32.9% became prefrail and 4.2% frail. In multivariate logistic models, chair-stands had a predictive role in all transitions studied: linearly in keeping robustness and with a floor effect (5 stands) in transitions from prefrailty to robustness and (inversely) from prefrailty to frailty. More depressive symptoms were associated with unfavorable transitions. Not declaring the amount of alcohol drunk and low grip strength were associated with loss of robustness. Hearing and cognitive impairment, low physical activity and smoking with transitioning from prefrailty to frailty. Autonomy for instrumental activities of daily living and uricemia were associated with transitions between robustness and prefrailty in both directions. Increasing body mass index in the range of moderate to severe obesity hampered regaining robustness. CONCLUSIONS AND IMPLICATIONS: Spontaneous improvement of frailty measured with the Fried phenotype is frequent, mainly to prefrailty. Most of the variables associated with transitions are modifiable and suggest research topics and interventions to reduce frailty in clinical and social care settings.

Changes in Health Behaviors, Mental and Physical Health among Older Adults under Severe Lockdown Restrictions during the COVID-19 Pandemic in Spain.

We used data from 3041 participants in four cohorts of community-dwelling individuals aged ≥65 years in Spain collected through a pre-pandemic face-to-face interview and a telephone interview conducted between weeks 7 to 15 after the beginning of the COVID-19 lockdown. On average, the confinement was not associated with a deterioration in lifestyle risk factors (smoking, alcohol intake, diet, or weight), except for a decreased physical activity and increased sedentary time, which reversed with the end of confinement. However, chronic pain worsened, and moderate declines in mental health, that did not seem to reverse after restrictions were lifted, were observed. Males, older adults with greater social isolation or greater feelings of loneliness, those with poorer housing conditions, as well as those with a higher prevalence of chronic morbidities were at increased risk of developing unhealthier lifestyles or mental health declines with confinement. On the other hand, previously having a greater adherence to the Mediterranean diet and doing more physical activity protected older adults from developing unhealthier lifestyles with confinement. If another lockdown were imposed during this or future pandemics, public health programs should specially address the needs of older individuals with male sex, greater social isolation, sub-optimal housing conditions, and chronic morbidities because of their greater vulnerability to the enacted movement restrictions.

New Insights on the Conversion Reaction Mechanism in Metal Oxide Electrodes for Sodium-Ion Batteries.

Due to the abundance and low cost of exchanged metal, sodium-ion batteries have attracted increasing research attention for the massive energy storage associated with renewable energy sources. Nickel oxide (NiO) thin films have been prepared by magnetron sputtering (MS) deposition under an oblique angle configuration (OAD) and used as electrodes for Na-ion batteries. A systematic chemical, structural and electrochemical analysis of this electrode has been carried out. The electrochemical characterization by galvanostatic charge-discharge cycling and cyclic voltammetry has revealed a certain loss of performance after the initial cycling of the battery. The conversion reaction of NiO with sodium ions during the discharge process to generate sodium oxide and Ni metal has been confirmed by X-ray photoelectron spectra (XPS) and micro-Raman analysis. Likewise, it has been determined that the charging process is not totally reversible, causing a reduction in battery capacity.

A robust machine learning framework to identify signatures for frailty: a nested case-control study in four aging European cohorts.

Phenotype-specific omic expression patterns in people with frailty could provide invaluable insight into the underlying multi-systemic pathological processes and targets for intervention. Classical approaches to frailty have not considered the potential for different frailty phenotypes. We characterized associations between frailty (with/without disability) and sets of omic factors (genomic, proteomic, and metabolomic) plus markers measured in routine geriatric care. This study was a prevalent case control using stored biospecimens (urine, whole blood, cells, plasma, and serum) from 1522 individuals (identified as robust (R), pre-frail (P), or frail (F)] from the Toledo Study of Healthy Aging (R=178/P=184/F=109), 3 City Bordeaux (111/269/100), Aging Multidisciplinary Investigation (157/79/54) and InCHIANTI (106/98/77) cohorts. The analysis included over 35,000 omic and routine laboratory variables from robust and frail or pre-frail (with/without disability) individuals using a machine learning framework. We identified three protective biomarkers, vitamin D3 (OR: 0.81 [95% CI: 0.68-0.98]), lutein zeaxanthin (OR: 0.82 [95% CI: 0.70-0.97]), and miRNA125b-5p (OR: 0.73, [95% CI: 0.56-0.97]) and one risk biomarker, cardiac troponin T (OR: 1.25 [95% CI: 1.23-1.27]). Excluding individuals with a disability, one protective biomarker was identified, miR125b-5p (OR: 0.85, [95% CI: 0.81-0.88]). Three risks of frailty biomarkers were detected: pro-BNP (OR: 1.47 [95% CI: 1.27-1.7]), cardiac troponin T (OR: 1.29 [95% CI: 1.21-1.38]), and sRAGE (OR: 1.26 [95% CI: 1.01-1.57]). Three key frailty biomarkers demonstrated a statistical association with frailty (oxidative stress, vitamin D, and cardiovascular system) with relationship patterns differing depending on the presence or absence of a disability.

Higher sRAGE Levels Predict Mortality in Frail Older Adults with Cardiovascular Disease.

INTRODUCTION: The evidence that blood levels of the soluble receptor for advanced glycation end products (sRAGE) predict mortality in people with cardiovascular diseases (CVD) is inconsistent. To clarify this matter, we investigated if frailty status influences this association. METHODS: We analysed data of 1,016 individuals (median age, 75 years) from 3 population-based European cohorts, enrolled in the FRAILOMIC project. Participants were stratified by history of CVD and frailty status. Mortality was recorded during 8 years of follow-up. RESULTS: In adjusted Cox regression models, baseline serum sRAGE was positively associated with an increased risk of mortality in participants with CVD (HR 1.64, 95% CI 1.09-2.49, p = 0.019) but not in non-CVD. Within the CVD group, the risk of death was markedly enhanced in the frail subgroup (CVD-F, HR 1.97, 95% CI 1.18-3.29, p = 0.009), compared to the non-frail subgroup (CVD-NF, HR 1.50, 95% CI 0.71-3.15, p = 0.287). Kaplan-Meier analysis showed that the median survival time of CVD-F with high sRAGE (>1,554 pg/mL) was 2.9 years shorter than that of CVD-F with low sRAGE, whereas no survival difference was seen for CVD-NF. Area under the ROC curve analysis demonstrated that for CVD-F, addition of sRAGE to the prediction model increased its prognostic value. CONCLUSIONS: Frailty status influences the relationship between sRAGE and mortality in older adults with CVD. sRAGE could be used as a prognostic marker of mortality for these individuals, particularly if they are also frail.

Frailty Trait Scale-Short Form: A Frailty Instrument for Clinical Practice.

OBJECTIVES: To develop short versions of the Frailty Trait Scale (FTS) for use in clinical settings. DESIGN: Prospective population-based cohort study. SETTING AND PARTICIPANTS: Data from 1634 participants from the Toledo Study for Healthy Aging. METHODS: The 12-item Frailty Trait Scale (FTS) reduction was performed based on an area under the curve (AUC) analysis adjusted by age, sex, and comorbidity. Items that maximized prognostic information for adverse events were selected. Each item score was done at the same time as the reduction, identifying the score that maximized the predictive ability for adverse events. For each short version of the FTS, cutoffs that optimized the prognostic information (sensitivity and specificity) were chosen, and their predictive value was later compared with a surrogate gold standard for frailty (the Fried Phenotype). RESULTS: Two short forms, the 5-item (FTS5) (range 0-50) and 3-item (FTS3) (range 0-30), were identified, both with AUCs for health adverse events similar to the 12-item FTS. The identified cutoffs were >25 for the FTS5 scale and >15 for the FTS3. The frailty prevalence with these cutoffs was 24% and 20% for the FTS5 and FTS3, respectively, whereas frailty according to Fried Phenotype (FP) reached 8% and prefrailty reached 41%. In general, the FTS5 showed better prognostic performance than the FP, especially with prefrail individuals, in whom the FTS5 form identified 65% of participants with an almost basal risk and 35% with a very high risk for mortality (OR: 4) and frailty (OR: 6.6-8.7), a high risk for hospitalization (OR: 1.9-2.1), and a moderate risk for disability (OR: 1.7) who could be considered frail. The FTS3 form had worse performance than the FTS5, showing 31% of false negatives between frail participants identified by FP with a high risk of adverse events. CONCLUSIONS AND IMPLICATIONS: The FTS5 is a short scale that is easy to administer and has a similar performance to the FTS, and it can be used in clinical settings for frailty diagnosis and evolution.

Homocysteine and C-Reactive Protein Levels Are Associated With Frailty in Older Spaniards: The Toledo Study for Healthy Aging.

High-sensitivity C-reactive protein (hsCRP) and homocysteine (Hcy) are inflammation markers but are also related to cardiovascular diseases, disability, or higher risk of death. Although inflammation is considered to be associated with frailty, data regarding the association between hsCRP or Hcy and frailty are controversial or scarce, especially with respect to their association with prefrailty. Thus, our objective was to study the association of hsCRP and Hcy with prefrailty and frailty in 1,211 Spanish men and women aged 65-98 years from the Toledo Study for Healthy Aging (TSHA) cohort, classified according to Fried's criteria. Hcy was independently associated with frailty (odds ratio [OR] = 1.06; 95% confidence interval [CI]: 1.01-1.12), whereas hsCRP was independently associated with both prefrailty (OR = 1.03; 95% CI: 1.01-1.06) and frailty (OR = 1.07; 95% CI: 1.02-1.12). Furthermore, both markers were positively correlated with the number of Fried's criteria that were met and were independently associated with the criteria of exhaustion (Hcy: OR = 1.03, 95% CI: 1.00-1.06), weakness (hsCRP: OR = 1.03, 95% CI: 1.01-1.05), and low physical activity (hsCRP: OR = 1.04, 95% CI: 1.02-1.06). Thus, our results highlight the importance of inflammation in age-related physical decline and, in particular, its association with fatigue, low strength, and decreased physical activity.

Associations of fat-soluble micronutrients and redox biomarkers with frailty status in the FRAILOMIC initiative.

BACKGROUND: A poor fat-soluble micronutrient (FMN) and a high oxidative stress status are associated with frailty. Our aim was to determine the cross-sectional association of FMNs and oxidative stress biomarkers [protein carbonyls (PrCarb) and 3-nitrotyrosine] with the frailty status in participants older than 65 years. METHODS: Plasma levels of vitamins A (retinol), D3 , E (α-tocopherol and γ-tocopherol) and carotenoids (α-carotene and ß-carotene, lycopene, lutein/zeaxanthin, and ß-cryptoxanthin), PrCarb, and 3-nitrotyrosine were measured in 1450 individuals of the FRAILOMIC initiative. Participants were classified into robust, pre-frail, and frail using Fried's frailty criteria. Associations between biomarkers and frailty status were assessed by general linear and logistic regression models, both adjusted for cohort, season of blood sampling, gender, age, height, weight, and smoking. RESULTS: Robust participants had significantly higher vitamin D3 and lutein/zeaxanthin concentrations than pre-frail and frail subjects; had significantly higher γ-tocopherol, α-carotene, ß-carotene, lycopene, and ß-cryptoxanthin concentrations than frail subjects, and had significantly lower PrCarb concentrations than frail participants in multivariate linear models. Frail subjects were more likely to be in the lowest than in the highest tertile for vitamin D3 (adjusted odds ratio: 2.15; 95% confidence interval: 1.42-3.26), α-tocopherol (2.12; 1.39-3.24), α-carotene (1.69; 1.00-2.88), ß-carotene (1.84; 1.13-2.99), lycopene (1.94; 1.24-3.05), lutein/zeaxanthin (3.60; 2.34-5.53), and ß-cryptoxanthin (3.02; 1.95-4.69) and were more likely to be in the highest than in the lowest tertile for PrCarb (2.86; 1.82-4.49) than robust subjects in multivariate regression models. CONCLUSIONS: Our study indicates that both low FMN and high PrCarb concentrations are associated with pre-frailty and frailty.

Increased levels of soluble Receptor for Advanced Glycation End-products (RAGE) are associated with a higher risk of mortality in frail older adults.

OBJECTIVE: to evaluate the relationship between serum levels of the soluble Receptor for Advanced Glycation End-products (sRAGE) and mortality in frail and non-frail older adults. METHODS: we studied 691 subjects (141 frail and 550 non-frail) with a median age of 75 years from two population-based cohorts, the Toledo Study of Healthy Aging and the AMI study, who were enrolled to the FRAILOMIC initiative. Multivariate Cox proportional hazards regression and Kaplan-Meier survival analysis were used to assess the relationship between baseline sRAGE and mortality. RESULTS: during 6 years of follow-up 101 participants died (50 frail and 51 non-frail). Frail individuals who died had significantly higher sRAGE levels than those who survived (median [IQR]: 1563 [1015-2248] vs 1184 [870-1657] pg/ml, P = 0.006), whilst no differences were observed in the non-frail group (1262 [1056-1554] vs 1186 [919-1551] pg/ml, P = 0.19). Among frail individuals higher sRAGE levels were associated with an increased risk of death after adjustment for relevant covariates (HR = 2.72 per unit increment in ln-sRAGE, 95%CI 1.48-4.99, P = 0.001). In contrast, in non-frail individuals sRAGE showed no association with mortality. Survival curves demonstrated that among frail individuals the incidence of death was significantly higher in the top sRAGE quartile compared to the three lower quartiles (P = 0.002). Area under the ROC curve analysis demonstrated that for frail individuals, inclusion of sRAGE in the hazard model increased its predictive accuracy by ~3%. CONCLUSIONS: sRAGE is an independent predictor of mortality among frail individuals. Determination of sRAGE in frail subjects could be useful for prognostic assessment and treatment stratification.

Sedentary behaviour, physical activity, and sarcopenia among older adults in the TSHA: isotemporal substitution model.

BACKGROUND: The associations between free-living physical activity (PA) and sedentary behaviour (SB) and sarcopenia in older people and its determinants are controversial. Self-reporting, the use of one-size-fits-all cut-points for intensity categorization when using accelerometers and the absence of a clear sarcopenia definition hampered explorations. The aim of this study is to describe the associations between objectively measured PA patterns and sarcopenia and its determinants. METHODS: Subjects aged >65 with valid accelerometry and sarcopenia-related measures from Toledo Study of Healthy Aging (TSHA) were included. Muscle mass (MM) was estimated by dual-energy X-ray absorptiometry. Handgrip strength (HS) was measured by dynamometry. Physical performance assessment relied on gait speed (GS). Sarcopenia presence was ascertained using Foundation for the National Institutes of Health (FNIH) criteria. PA and SB were estimated by ActiTrainer worn for 1 week and classified into time spent in SB and different PA intensity bands [light PA (LPA) and moderate-to-vigorous PA (MVPA)] using age-specific cut-points. Different multivariate linear and logistic regression models [(i) single-parameter, (ii) partition, and (iii) isotemporal substitution models] were used for estimating associations between PA, SB, and sarcopenia determinants and sarcopenia rates, respectively. All models adjusted for age, sex, co-morbidities (Charlson index), and functional ability (Katz and Lawton indexes). RESULTS: Five hundred twelve subjects from the TSHA had available data (78.08 ± 5.71 years of age; 54.3% women). FNIH sarcopenia assessment was performed in 497 subjects (23.3% were sarcopenic). In the linear regression, the single-parameter model showed an association between MVPA and all sarcopenia determinants. In the partition model, MVPA was associated with greater MM and GS. The isotemporal substitution showed that reallocating 1 h/day of MVPA displacing SB was associated with greater values in MM [ß = 0.014; 95% confidence interval (CI) = 0.004, 0.024; P < 0.01], GS (ß = 0.082; 95% CI = 0.054, 0.110; P < 0.001), and HS (ß = 0.888; 95% CI = 0.145, 1.631; P < 0.05). In the logistic regression, the single-parameter model yielded a significant association between 1 h/day increase in MVPA and sarcopenia reduction [odds ratio (OR) = 0.522; 95% CI = 0.367, 0.726; P < 0.001], as did the partition model (OR = 0.555; 95% CI = 0.376, 0.799; P < 0.01). The reallocation of 1 h/day SB only yielded a significant lower sarcopenia risk by almost 50% when it was substituted with MVPA, whereas the substitution of 15 min/day yielded a significant lower sarcopenia risk by 15% (P < 0.001) but did not show any association when it was substituted with LPA. CONCLUSIONS: An increase in MVPA replacing SB and LPA was associated with a reduction in sarcopenia prevalence and better performance across its determinants (MM, GS, and HS). LPA did not show any significant effect.