Condición física, clínica y fragilidad de adultos mayores en Cali, Colombia / Physical and clinical condition and fragility of older adults in Cali, Colombia

Introducción: A nivel mundial el envejecimiento de la población ha sido un tema de interés a investigar, debido a la carga de morbimortalidad y los costos en salud que ocasiona. Así, resulta relevante indagar sobre aquellos aspectos que hacen más vulnerables a los adultos mayores. Objetivo: Comparar la condición física y clínica según la fragilidad en adultos mayores de Cali, Colombia. Materiales y métodos: Estudio descriptivo transversal en adultos mayores de la ciudad de Cali, Colombia. El estudio tuvo aval ético institucional y todos los adultos mayores aceptaron participar firmando el consentimiento informado. Se usó la batería corta de desempeño físico (SPPB), y se compararon variables sociodemográficas, físicas y clínicas. y por nivel de fragilidad en vigoroso, prefrágil y frágil. Resultados: Se vincularon 470 adultos mayores con una edad promedio de 71,15±7,50 años, y en su mayoría del género femenino. Se presentaron diferencias estadísticamente significativas con un valor de p≤0,05 en la edad, estado socioeconómico, comuna, enfermedad, índice de masa corporal, actividad física, desempeño físico y riesgo de caídas; presentando mayor compromiso el grupo de fragilidad. Conclusión: El grupo de adultos mayores clasificados como frágiles presentaban menor condición física y clínica comparado con los grupos pre-frágiles y vigorosos. (AU)

Introduction: Worldwide, the aging of the population has been a topic of interest to investigate, due to the burden of morbidity and mortality and the health costs it causes. Thus, it is relevant to investigate those aspects that make older adults more vulnerable. Objective: To compare the physical and clinical condition according to frailty in older adults from Cali, Colombia. Materials and methods: Cross-sectional descriptive study in older adults from the city of Cali, Colombia. The study had institutional ethical endorsement and all the older adults agreed to participate by signing the informed consent. The short physical performance battery (SPPB) was used, and sociodemographic, physical and clinical variables and by level of frailty were compared in vigorous, pre-frail and frail. Results: Four hundred and seventy older adults with an average age of 71.15±7.50 years and mostly female were enrolled. There were statistically significant differences, P≤0.05 in age, socioeconomic status, commune, disease, body mass index, physical activity, physical performance, and risk of falls. The fragility group presented greater compromise. Conclusion: The group of older adults classified as frail had a lower physical and clinical condition compared to the pre-frail and vigorous groups. (AU)

The causal association between circulating cytokines with the risk of frailty and sarcopenia under the perspective of geroscience.

Introduction: Circulating cytokines were considered to play a critical role in the initiation and propagation of sarcopenia and frailty from observational studies. This study aimed to find the casual association between circulating cytokines and sarcopenia and frailty from a genetic perspective by two-sample Mendelian randomization (MR) analysis. Methods: Data for 41 circulating cytokines were extracted from the genome-wide association study dataset of 8,293 European participants. Inverse-variance weighted (IVW) method, MR-Egger, and weighted median method were applied to assess the relationship of circulating cytokines with the risk of aging-related syndromes and frailty. Furthermore, MR-Egger regression was used to indicate the directional pleiotropy, and Cochran's Q test was used to verify the potential heterogeneity. The "leave-one-out" method was applied to visualize whether there was a causal relationship affected by only one anomalous single-nucleotide polymorphisms. Results: Genetic predisposition to increasing levels of interleukin-10 (IL-10), IL-12, and vascular endothelial growth factor (VEGF) was associated with the higher risk of low hand grip strength according to the IVW method [R = 1.05, 95% CI = 1.01-1.10, P = 0.028, false discovery rate (FDR)-adjusted P = 1.000; OR = 1.03, 95% CI = 1.00-1.07, P = 0.042, FDR-adjusted P = 0.784; OR = 1.02, 95% CI = 1.00-1.05, P = 0.038, FDR-adjusted P = 0.567]. Furthermore, genetically determined higher macrophage colony-stimulating factors (M-CSFs) were associated with a lower presence of appendicular lean mass (OR = 1.01, 95% CI = 1.00-1.02, P = 0.003, FDR-adjusted P = 0.103). Monokine induced by interferon-γ (MIG) and tumor necrosis factor-beta (TNF-ß) were associated with a higher risk of frailty (OR = 1.03, 95% CI = 1.01-1.05, P < 0.0001, FDR-adjusted P = 0.012; OR = 1.01, 95% CI = 1.00-1.03, P = 0.013, FDR-adjusted P = 0.259). In this study, we did not find heterogeneity and horizontal pleiotropy between the circulating cytokines and the risk of frailty and sarcopenia. Conclusion: Genetic predisposition to assess IL-10, IL-12, and VEGF levels was associated with a higher risk of low hand grip strength and M-CSF with the presence of appendicular lean mass. The high levels of TNF-ß and MIG were associated with a higher risk of frailty. More studies will be required to explore the molecular biological mechanisms underlying the action of inflammatory factors.

Unraveling the relationship between high-sensitivity C-reactive protein and frailty: evidence from longitudinal cohort study and genetic analysis.

BACKGROUND: This study aimed to investigate the association of high-sensitivity C-reactive protein (hs-CRP) with incident frailty as well as its effects on pre-frailty progression and regression among middle-aged and older adults. METHODS: Based on the frailty index (FI) calculated with 41 items, 6890 eligible participants without frailty at baseline from China Health and Retirement Longitudinal Study (CHARLS) were categorized into health, pre-frailty, and frailty groups. Logistic regression models were used to estimate the longitudinal association between baseline hs-CRP and incident frailty. Furthermore, a series of genetic approaches were conducted to confirm the causal relationship between CRP and frailty, including Linkage disequilibrium score regression (LDSC), pleiotropic analysis, and Mendelian randomization (MR). Finally, we evaluated the association of hs-CRP with pre-frailty progression and regression. RESULTS: The risk of developing frailty was 1.18 times (95% CI: 1.03-1.34) higher in participants with high levels of hs-CRP at baseline than low levels of hs-CRP participants during the 3-year follow-up. MR analysis suggested that genetically determined hs-CRP was potentially positively associated with the risk of frailty (OR: 1.06, 95% CI: 1.03-1.08). Among 5241 participants with pre-frailty at baseline, we found pre-frailty participants with high levels of hs-CRP exhibit increased odds of progression to frailty (OR: 1.39, 95% CI: 1.09-1.79) and decreased odds of regression to health (OR: 0.84, 95% CI: 0.72-0.98) when compared with participants with low levels of hs-CRP. CONCLUSIONS: Our results suggest that reducing systemic inflammation is significant for developing strategies for frailty prevention and pre-frailty reversion in the middle-aged and elderly population.

Causal effects of blood pressure and the risk of frailty: a bi-directional two-sample Mendelian randomization study.

Observational studies have indicated that high blood pressure (BP) may be a risk factor to frailty. However, the causal association between BP and frailty remains not well determined. The purpose of this bi-directional two-sample Mendelian randomization (MR) study was to investigate the causal relationship between BP and frailty. Independent single nucleotide polymorphisms (SNPs) strongly (P < 5E-08) associated with systolic BP (SBP), diastolic BP (DBP), and pulse pressure (PP) were selected as instrumental variables. Two different published genome-wide association studies (GWAS) on BP from the CHARGE (n = 810,865) and ICBP (n = 757,601) consortia were included. Summary-level data on frailty index (FI) were obtained from the latest GWAS based on UK Biobank and Swedish TwinGene cohorts (n = 175,226). Inverse variance weighted (IVW) approach with other sensitivity analyses were used to calculate the causal estimate. Using the CHARGE dataset, genetic predisposition to increased SBP (ß = 0.135, 95% CI = 0.093 to 0.176, P = 1.73E-10), DBP (ß = 0.145, 95% CI = 0.104 to 0.186, P = 3.14E-12), and PP (ß = 0.114, 95% CI = 0.070 to 0.157, p = 2.87E-07) contributed to a higher FI, which was validated in the ICBP dataset. There was no significant causal effect of FI on SBP, DBP, and PP. Similar results were obtained from different MR methods, indicating good stability. There was potential heterogeneity detected by Cochran's Q test, but no horizontal pleiotropy was observed in MR-Egger intercept test (P > 0.05). These findings evinced that higher BP and PP were causally associated with an increased risk of frailty, suggesting that controlling hypertension could reduce the risk of frailty.

Association between inflammatory bowel disease and frailty: a two-sample Mendelian randomization study.

BACKGROUND: An association has been identified between inflammatory bowel disease (IBD) and frailty; however, the causal nature of this connection remains uncertain. We consequently conducted a two-sample Mendelian randomization (MR) analysis to explore this particular association. METHODS: We acquired distinct datasets for inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative colitis (UC), and frailty from the published genome-wide association studies (GWAS) database, meticulously selecting instrumental variables (IVs). Subsequently, we employed a bidirection MR to examine the causal relationship between IBD (including CD and UC) and frailty. We utilized statistical methods, with a primary emphasis on inverse-variance weighted (IVW), accompanied by a series of sensitivity analyses to confirm heterogeneity and pleiotropy influenced the outcomes of the MR. RESULTS: We found positive causal effects of genetically increased frailty risk on IBD (OR: 1.015, 95% CI 1.005-1.025, P = 0.004). Furthermore, when scrutinizing specific IBD subtypes, both Crohn's disease (CD) and ulcerative colitis (UC) demonstrated an increased predisposition to frailty (OR: 1.018, 95% CI 1.01-1.027, P < 0.05) and (OR = 1.016, 95% CI 1.005-1.027, P < 0.05). Nevertheless, despite the consistent trends observed in the weighted median and MR-Egger regression analyses for both conditions, statistical significance remained elusive. Notably, the results of the inverse MR analysis did not establish an association between frailty and an elevated risk of IBD development. CONCLUSIONS: Our research indicates that IBD, encompassing both CD and UC, may augment the propensity for frailty. Clinical practitioners must prioritize early frailty assessment in individuals afflicted with inflammatory bowel disease, inclusive of Crohn's disease and ulcerative colitis, facilitating proactive measures and timely interventions. However, our findings do not provide evidence supporting a causal effect of frailty on IBD (including CD and UC). Consequently, further studies are essential to explore the intricate mechanisms that clarify the effect of frailty on IBD.

Physical activity, sedentary behavior, and the risk of frailty and falling: A Mendelian randomization study.

BACKGROUND: Due to inconclusive evidence from observational studies regarding the impact of physical activity (PA) and sedentary behavior on frailty and falling risk, we conducted a two-sample Mendelian randomization analysis to investigate the causal associations between PA, sedentary behavior, and frailty and falls. METHODS: We extracted summary data from genome-wide association studies conducted among individuals of European ancestry, encompassing PA (n = 90 667-608 595), sedentary behavior (n = 372 609-526 725), frailty index (n = 175 226), and falling risk (n = 451 179). Single nucleotide polymorphisms associated with accelerometer assessed fraction >425 milligravities, self-reported vigorous activity, moderate to vigorous physical acticity (MVPA), leisure screen time (LST), and sedentary behavior at work were taken as instrumental variables. The causal effects were primarily estimated using inverse variance weighted methods, complemented by several sensitivity and validation analyses. RESULTS: Genetically predicted higher levels of PA were significantly associated with a reduction in the frailty index (accelerometer assessed fraction >425 milligravities: ß = -0.25, 95% CI = -0.36 to -0.14, p = 1.27 × 10-5 ; self-reported vigorous activity: ß = -0.13, 95% CI = -0.20 to -0.05, p = 7.9 × 10-4 ; MVPA: ß = -0.28, 95% CI = -0.40 to -0.16, p = 9.9 × 10-6 ). Besides, LST was significantly associated with higher frailty index (ß = 0.18, 95% CI = 0.14-0.22, p = 5.2 × 10-20 ) and higher odds of falling (OR = 1.13, CI = 1.07-1.19, p = 6.9 × 10-6 ). These findings remained consistent throughout sensitivity and validation analyses. CONCLUSIONS: Our study offers evidence supporting a causal relationship between PA and a reduced risk of frailty. Furthermore, it underscores the association between prolonged LST and an elevated risk of frailty and falls. Therefore, promoting PA and reducing sedentary behavior may be an effective strategy in primary frailty and falls prevention.

The bidirectional association between frailty index and cardiovascular disease: A Mendelian randomization study.

BACKGROUND AND AIM: Observational studies have suggested a relationship between frailty and cardiovascular disease (CVD), but the causality is still uncertain. We used bidirectional Mendelian randomization (MR) design to investigate the potential causal associations between frailty and four main CVDs, including hypertension, myocardial infarction (MI), heart failure (HF), and atrial fibrillation (AF). METHODS AND RESULTS: Independent single-nucleotide polymorphisms for frailty index (FI) and CVDs (hypertension, MI, HF, and AF) were selected as genetic instruments based on European-descent genome-wide association studies (GWASs). Summary-level data for outcomes on FI (n = 175,226), hypertension (n = 463,010), MI (n = 171,875), HF (n = 977323), and AF (n = 1,030,836) was derived from five large-scale GWASs of European ancestry. We used the inverse-variance weighted (IVW) method to examine the bidirectional associations between FI and CVDs in the main analyses. In the IVW MR analyses, genetically determined high FI was significantly associated with increased risks of hypertension (odds ratio [OR] per 1-SD increase: 1.07 [95 % confidence interval, 1.05-1.08]), MI (OR per 1-SD increase: 1.74 [1.21-2.51]), HF (OR per 1-SD increase: 1.28 [1.10-1.48]), and AF (OR per 1-SD increase: 1.20 [1.08-1.33]). In addition, genetically determined hypertension (beta: 1.406 [1.225-1.587]), MI (beta: 0.045 [0.023-0.067]), HF (beta: 0.105 [0.066-0.143]) and AF (beta: 0.021 [0.012-0.031]) were significantly associated with high FI. These findings were robustly supported by a series of sensitivity analyses with different MR models. CONCLUSIONS: We found potential bidirectional causal associations between elevated FI and increased risks of CVD, suggesting mutual risk factors between frailty and CVD.

Assessing causality between inflammatory bowel diseases with frailty index and sarcopenia: a bidirectional Mendelian randomization study.

BACKGROUND: Previous studies have found that frailty and sarcopenia are commonly diagnosed in inflammatory bowel disease (IBD) patients, indicating an association between these conditions. Nonetheless, the cause‒effect connection between IBD, frailty, and sarcopenia remains unclear. METHODS: We sourced the genetic variants for the exposures and outcomes from publicly accessible, extensive genome-wide association studies (GWAS). Specifically, we obtained IBD data from the International IBD Genetics Consortium, frailty index (FI) data from the United Kingdom Biobank and Swedish TwinGene, and sarcopenia data from a recent GWAS meta-analysis. Five methods, including inverse variance weighted (IVW), simple mode, MR-Egger, weighted mode, and the weighted median, were used to proceed with MR estimates. We also performed heterogeneity and horizontal pleiotropy tests. RESULTS: Our results indicated a positive causal relationship between ulcerative colitis (UC) (IVW: ß = 0.014, 95% CI, 0.006 to 0.021, p = 0.001) and Crohn's disease (CD) (IVW: ß = 0.012; 95% CI, 0.006 to 0.018, p = 2e-04) with the FI. However, we uncovered no proof of a cause-and-effect relationship between UC (IVW: ß = 0.001, 95% CI, -0.015 to 0.017, p = 0.344) or CD (IVW: ß = 0.003, 95% CI, -0.009 to 0.015, p = 0.214) and sarcopenia. Additionally, in the inverse order, we also discovered no cause-and-effect connection between FI or sarcopenia on UC or CD in this study. CONCLUSION: The MR analysis showed a positive causal association between IBD and FI, indicating that IBD patients may exhibit aging-related characteristics. Therefore, frailty assessments should be conducted as early as possible in IBD patients.

Lung function and the risk of frailty in the European population: a mendelian randomization study.

BACKGROUND: Epidemiological evidence has suggested a relationship between lung function and frailty, but the precise nature of the causality remains unclear. In this study, we applied a two-sample Mendelian randomization (MR) analysis to determine the causal effects of lung function on frailty. METHODS: Single nucleotide polymorphisms (SNPs) independently related (P ≤ 5E-08) to lung function, as identified by genome-wide association study (GWAS), were applied as instrumental variables (IV). The association with frailty index (FI) was investigated using summary-level data from the latest GWAS on FI (n = 175,226). Different statistical methods were employed to evaluate the causal estimates between lung function and FI. The pleiotropy, heterogeneity, and leave-one-out analysis were applied to confirm the stability of the MR estimates. RESULTS: Using the random-effect inverse-variance weighted approach, genetically proxied forced expiratory volume in the first second (FEV1), ratio of FEV1 on forced vital capacity (FVC) [FEV1/FVC], and peak expiratory flow (PEF) were significantly and inversely associated with FI (FEV1, ß = -0.08, P = 2.03E-05; FEV1/FVC, ß = -0.06, P = 9.51E-06; PEF, ß = -0.07, P = 4.09E-04) with good statistical power (99.7-100%). However, no significant association was observed between FVC and FI (ß = -0.01, P = 0.681). Leave-one-out analysis showed that there was no single SNP driving the bias of the estimates. There was potential heterogeneity, but no obvious pleiotropy was founded in this MR study. CONCLUSIONS: Our findings indicate that impaired pulmonary function is closely related to the risk of frailty. Enhancing lung function in the elderly population may contribute to the prevention of frailty to a certain extent.

[Association of lifestyle and apolipoprotein E gene with risk for cognitive frailty in elderly population in China].

Objective: To investigate the impact of lifestyle, apolipoprotein E (ApoE) gene, and their interaction on the risk for cognitive frailty in the elderly population in China. Methods: The study participants were from the Chinese Longitudinal Healthy Longevity Survey. The information about their lifestyles were collected by questionnaire survey, and a weighted lifestyle score was constructed based on ß coefficients associated with specific lifestyles to assess the combined lifestyle. ApoE genotypes were assessed by rs429358 and rs7412 single nucleotide polymorphisms. Cognitive frailty was assessed based on cognitive function and physical frailty. Cox proportional hazards regression model was used to analyze the association of lifestyle and ApoE gene with the risk for cognitive frailty and evaluate the multiplicative and additive interactions between lifestyle and ApoE gene. Results: A total of 5 676 elderly persons, with median age [M (Q1, Q3)] of 76 (68, 85) years, were included, in whom 615 had cognitive frailty. The analysis by Cox proportional hazards regression model indicated that moderate and high levels of dietary diversity could reduce the risk for cognitive frailty by 18% [hazard ratio (HR)=0.82, 95%CI: 0.68-1.00] and 28% (HR=0.72, 95%CI: 0.57-0.91), respectively; moderate and high levels of physical activity could reduce the risk by 31% (HR=0.69, 95%CI: 0.56-0.85) and 23% (HR=0.77, 95%CI: 0.64-0.93), respectively. Healthy lifestyle was associated with a 40% reduced risk for cognitive frailty (HR=0.60, 95%CI: 0.46-0.78). ApoE ε4 allele was associated with a 26% increased risk for cognitive frailty (HR=1.26, 95%CI: 1.02-1.56). No multiplicative or additive interactions were found between lifestyle and ApoE gene. Conclusions: Dietary diversity and regular physical activity have protective effects against cognitive frailty in elderly population. Healthy lifestyle can reduce the risk for cognitive frailty in elderly population regardless of ApoE ε4 allele carriage status.

Exploring causality between bone mineral density and frailty: A bidirectional Mendelian randomization study.

OBJECTIVE: The bidirectional correlation between low bone mineral density (BMD) and frailty, despite its extensive documentation, still lacks a conclusive understanding. The objective of this Mendelian randomization (MR) study is to investigate the bidirectional causal relationship between BMD and frailty. METHODS: We utilized summary statistics data for BMD at different skeletal sites-including heel BMD (e-BMD, N = 40,613), forearm BMD (FA-BMD, N = 8,143), femoral neck BMD (FN-BMD, N = 32,735), and lumbar spine BMD (LS-BMD, N = 28,489), alongside frailty index (FI, N = 175,226) data in participants of European ancestry. MR analysis in our study was conducted using well-established analytical methods, including inverse variance weighted (IVW), weighted median (WM), and MR-Egger approaches. RESULTS: We observed negative causal estimates between genetically predicted e-BMD (IVW ß = - 0.020, 95% confidence interval (CI) = - 0.038, - 0.002, P = 0.029) and FA-BMD (IVW ß = -0.035, 95% CI = -0.066, -0.004, P = 0.028) with FI. However, the results did not reach statistical significance after applying the Bonferroni correction, with a significance threshold set at P < 0.0125 (0.05/4). There was no causal effect of FN-BMD (IVW ß = - 0.024, 95% CI = -0.052, 0.004, P = 0.088) and LS-BMD (IVW ß = - 0.005, 95% CI = -0.034, 0.024, P = 0.749) on FI. In the reverse Mendelian randomization (MR) analysis, we observed no causal effect of FI on BMD at various skeletal sites. CONCLUSION: Our study provides support for the hypothesis that low BMD may be a potential causal risk factor for frailty, but further research is needed to confirm this relationship. However, our findings did not confirm reverse causality.

Epigenetic age biomarkers and risk assessment in adult spinal deformity: a novel association of biological age with frailty and disability.

OBJECTIVE: Surgery for spinal deformity has the potential to improve pain, disability, function, self-image, and mental health. These surgical procedures carry significant risk and require careful selection, optimization, and risk assessment. Epigenetic clocks are age estimation tools derived by measuring the methylation patterns of specific DNA regions. The study of biological age in the adult deformity population has the potential to shed insight onto the molecular basis of frailty and to improve current risk assessment tools. METHODS: Adult patients who underwent deformity surgery were prospectively enrolled. Preoperative whole blood samples were used to assess epigenetic age and telomere length. DNA methylation patterns were quantified and processed to extract 4 principal component (PC)-based epigenetic age clocks (PC Horvath, PC Hannum, PC PhenoAge, and PC GrimAge) and the instantaneous pace of aging (DunedinPACE). Telomere length was assessed using both quantitative polymerase chain reaction (telomere to single gene [T/S] ratio) and a methylation-based telomere estimator (PC DNAmTL). Patient demographic and surgical data included age, BMI, American Society of Anesthesiologists Physical Status Classification System class, and scores on the Charlson Comorbidity Index, adult spinal deformity frailty index (ASD-FI), Edmonton Frail Scale (EFS), Oswestry Disability Index, and Scoliosis Research Society-22r questionnaire (SRS-22r). Medical or surgical complications within 90 days of surgery were collected. Spearman correlations and beta coefficients (ß) from linear regression, adjusted for BMI and sex, were calculated. RESULTS: Eighty-three patients were enrolled with a mean age of 65 years, and 45 were women (54%). All patients underwent posterior fusion with a mean of 11 levels fused and 33 (40%) 3-column osteotomies were performed. Among the epigenetic clocks adjusted for BMI and sex, DunedinPACE showed a significant association with ASD-FI (ß = 0.041, p = 0.002), EFS (ß = 0.696, p = 0.026), and SRS-22r (ß = 0.174, p = 0.013) scores. PC PhenoAge showed associations with ASD-FI (ß = 0.029, p = 0.028) and SRS-22r (ß = 0.159, p = 0.018) scores. PC GrimAge showed associations with ASD-FI (ß = 0.029, p = 0.037) and SRS-22r (ß = 0.161, p = 0.025) scores. Patients with postoperative complications were noted to have shorter telomere length (T/S 0.790 vs 0.858, p = 0.049), even when the analysis controlled for BMI and sex (OR = 1.71, 95% CI 1.07-2.87, p = 0.031). CONCLUSIONS: Epigenetic clocks showed significant associations with markers of frailty and disability, while patients with postoperative complications had shorter telomere length. These data suggest a potential role for aging biomarkers as components of surgical risk assessment. Integrating biological age into current risk calculators may improve their accuracy and provide valuable information for patients, surgeons, and payers.

Skeletal muscle DNA methylation: Effects of exercise and HIV.

Aging, human immunodeficiency virus (HIV) infection, and antiretroviral therapy modify the epigenetic profile and function of cells and tissues, including skeletal muscle (SkM). In some cells, accelerated epigenetic aging begins very soon after the initial HIV infection, potentially setting the stage for the early onset of frailty. Exercise imparts epigenetic modifications in SkM that may underpin some health benefits, including delayed frailty, in people living with HIV (PWH). In this first report of exercise-related changes in SkM DNA methylation among PWH, we investigated the impact of 24 weeks of aerobic and resistance exercise training on SkM (vastus lateralis) DNA methylation profiles and epigenetic age acceleration (EAA) in older, virally suppressed PWH (n = 12) and uninfected controls (n = 18), and associations of EAA with physical function at baseline. We identified 983 differentially methylated positions (DMPs) in PWH and controls at baseline and 237 DMPs after training. The influence of HIV serostatus on SkM methylation was more pronounced than that of exercise training. There was little overlap in the genes associated with the probes most significantly differentiated by exercise training within each group. Baseline EAA (mean ± SD) was similar between PWH (-0.4 ± 2.5 years) and controls (0.2 ± 2.6 years), and the exercise effect was not significant (p = 0.79). EAA and physical function at baseline were not significantly correlated (all p ≥ 0.10). This preliminary investigation suggests HIV-specific epigenetic adaptations in SkM with exercise training but confirmation in a larger study that includes transcriptomic analysis is warranted.

Utilizing multimodal approach to identify candidate pathways and biomarkers and predicting frailty syndrome in individuals from UK Biobank.

Frailty, a prevalent clinical syndrome in aging adults, is characterized by poor health outcomes, represented via a standardized frailty-phenotype (FP), and Frailty Index (FI). While the relevance of the syndrome is gaining awareness, much remains unclear about its underlying biology. Further elucidation of the genetic determinants and possible underlying mechanisms may help improve patients' outcomes allowing healthy aging.Genotype, clinical and demographic data of subjects (aged 60-73 years) from UK Biobank were utilized. FP was defined on Fried's criteria. FI was calculated using electronic-health-records. Genome-wide-association-studies (GWAS) were conducted and polygenic-risk-scores (PRS) were calculated for both FP and FI. Functional analysis provided interpretations of underlying biology. Finally, machine-learning (ML) models were trained using clinical, demographic and PRS towards identifying frail from non-frail individuals.Thirty-one loci were significantly associated with FI accounting for 12% heritability. Seventeen of those were known associations for body-mass-index, coronary diseases, cholesterol-levels, and longevity, while the rest were novel. Significant genes CDKN2B and APOE, previously implicated in aging, were reported to be enriched in lipoprotein-particle-remodeling. Linkage-disequilibrium-regression identified specific regulation in limbic-system, associated with long-term memory and cognitive-function. XGboost was established as the best performing ML model with area-under-curve as 85%, sensitivity and specificity as 0.75 and 0.8, respectively.This study provides novel insights into increased vulnerability and risk stratification of frailty syndrome via a multi-modal approach. The findings suggest frailty as a highly polygenic-trait, enriched in cholesterol-remodeling and metabolism and to be genetically associated with cognitive abilities. ML models utilizing FP and FI + PRS were established that identified frailty-syndrome patients with high accuracy.

Genetic liability to frailty in relation to functional outcome after ischemic stroke.

BACKGROUND: Frailty appears to be associated with unfavorable prognosis after stroke in observational studies, but the causality remains largely unknown. AIMS: The aim of this study is to investigate the potential causal effect of frailty on functional outcome at 3 months after ischemic stroke using the Mendelian randomization (MR) framework. METHODS: Genetic instruments for frailty index were identified in a genome-wide association study meta-analysis including 175,226 individuals of European descent. Corresponding genetic association estimates for functional outcome after ischemic stroke at 90 days were taken from the Genetic of Ischemic Stroke Functional Outcome (GISCOME) network of 6021 patients. We performed inverse-variance weighted MR as the main analyses, followed by several alternate methods and sensitivity analyses. RESULTS: In univariable MR, we found evidence that genetically predicted higher frailty index (odds ratio (OR) = 5.12; 95% confidence interval (CI) = 1.31-20.09; p = 0.019) was associated with worse functional outcome (modified Rankin Scale score ⩾3) after ischemic stroke. In further multivariable MR adjusting for potential confounding traits including body mass index, C-reactive protein, inflammatory bowel disease, and smoking initiation, the overall patterns between genetic liability to frailty and poor functional outcome status remained. Sensitivity analyses with complementary methods and with model unadjusted for baseline stroke severity (OR = 4.19; 95% CI = 1.26-13.90; p = 0.019) yielded broadly concordant results. CONCLUSIONS: The present MR study suggested a possible causal effect of frailty on poor functional outcome after ischemic stroke. Frailty might represent a potential target for intervention to improve recovery after ischemic stroke.

Assessment of Bidirectional Relationships between Frailty and Mental Disorders: A Bidirectional Mendelian Randomization Study.

OBJECTIVES: Although observational studies have reported the association between frailty and mental disorders, the causality remains unclear. We aimed to evaluate the bidirectional causal association between frailty levels and mental disorders using a 2-sample Mendelian randomization (MR) analysis. DESIGN: A bidirectional, 2-sample Mendelian randomization (MR) analysis. SETTING AND PARTICIPANTS: Instrumental variables were obtained from large-scale genome-wide association study (GWAS) of a European-descent population for frailty index (FI, n = 175,226), Fried Frailty Score (FFS, n = 386,565), major depressive disorder (MDD, n = 674,452), bipolar disorder (n = 353,899), anxiety and stress-related disorder (ASRD, n = 31,880), and schizophrenia (n = 127,906). METHODS: Two-sample MR analyses were conducted using inverse variance-weighted method, with sensitivity analyses using MR-Egger, weighted median, and simple median methods. RESULTS: Per SD increase in genetically predicted FI and FFS increased the risk of MDD [odds ratio (OR) 1.56, 95% CI 1.27-1.94, P = 3.65 × 10-5, and OR 1.67, 95% CI 1.26-2.20, P = 3.02 × 10-4, respectively]. Per-SD increase in genetically predicted FI also increased the risk of ASRD (OR 2.76, 95% CI 1.36-5.60, P = .005). No significant effect was observed for frailty levels on the risk of bipolar disorder and schizophrenia. In the reverse direction, genetically predicted MDD was associated with higher FI (ß 0.182, 95% CI 0.087-0.277, P = 1.79 × 10-4) and FFS (ß 0.121, 95% CI 0.087-0.155, P = 4.43 × 10-12). No reliable evidence supported the effects of genetically predicted bipolar disorder, ASRD, or schizophrenia on frailty levels. CONCLUSIONS AND IMPLICATIONS: A bidirectionally causal association exists between frailty levels and MDD, and higher FI is associated with a higher risk of ASRD. No reliable evidence suggested the causal associations of other mental disorders with frailty. Our findings provided evidence for introduction of psychological-related strategies in management of frailty.

OVCH1 Antisense RNA 1 is differentially expressed between non-frail and frail old adults.

While some old adults stay healthy and non-frail up to late in life, others experience multimorbidity and frailty often accompanied by a pro-inflammatory state. The underlying molecular mechanisms for those differences are still obscure. Here, we used gene expression analysis to understand the molecular underpinning between non-frail and frail individuals in old age. Twenty-four adults (50% non-frail and 50% frail) from InCHIANTI study were included. Total RNA extracted from whole blood was analyzed by Cap Analysis of Gene Expression (CAGE). CAGE identified transcription start site (TSS) and active enhancer regions. We identified a set of differentially expressed (DE) TSS and enhancer between non-frail and frail and male and female participants. Several DE TSSs were annotated as lncRNA (XIST and TTTY14) and antisense RNAs (ZFX-AS1 and OVCH1 Antisense RNA 1). The promoter region chr6:366,786,54-366,787,97;+ was DE and overlapping the longevity CDKN1A gene. GWAS-LD enrichment analysis identifies overlapping LD-blocks with the DE regions with reported traits in GWAS catalog (isovolumetric relaxation time and urinary tract infection frequency). Furthermore, we used weighted gene co-expression network analysis (WGCNA) to identify changes of gene expression associated with clinical traits and identify key gene modules. We performed functional enrichment analysis of the gene modules with significant trait/module correlation. One gene module is showing a very distinct pattern in hub genes. Glycogen Phosphorylase L (PYGL) was the top ranked hub gene between non-frail and frail. We predicted transcription factor binding sites (TFBS) and motif activity. TF involved in age-related pathways (e.g., FOXO3 and MYC) shows different expression patterns between non-frail and frail participants. Expanding the study of OVCH1 Antisense RNA 1 and PYGL may help understand the mechanisms leading to loss of homeostasis that ultimately causes frailty.

Causal relationship between frailty and chronic obstructive pulmonary disease or asthma: A two sample bidirectional Mendelian randomization study.

BACKGROUND: Observational studies have established a strong association between frailty and obstructive lung diseases. However, the causal nature of this association remains unclear. To address this gap, we conducted a bidirectional Mendelian randomization (MR) study to investigate the causal relationship between frailty, as measured by the frailty index (FI), and chronic obstructive pulmonary disease (COPD) or asthma. METHODS: The latest meta-analysis of genome-wide association studies for FI, which included individuals of European ancestry from UK Biobank and TwinGene (N = 175,226), yielded the genetic instruments for frailty and outcome summary statistics. The genetic instrument for COPD and asthma, as well as the outcome summary data, were derived from the GWAS conducted on individuals of European ancestry from the FinnGen, with a sample size of 16,410 cases and 283,589 controls for COPD, and 37,253 cases and 187,112 controls for asthma. The analysis of MR was conducted employing the inverse-variance weighted (IVW) method, complemented by the weighted median method, MR-Egger regression, and MR pleiotropy residual sum and outlier (MR-PRESSO) test. RESULTS: Our results showed that genetically predicted higher FI was significantly associated with increased risk of COPD (odds ratio [OR] 1.75, 95 % confidence interval [CI] 1.29-2.36) and asthma (OR 2.10, 95 % CI 1.44-3.16). In the reverse direction analysis, genetic liability to both COPD (beta 0.06, 95 % CI 0.01-0.10) and asthma (beta 0.08, 95 % CI 0.06-0.11) showed significant associations with a higher FI. CONCLUSIONS: Our research has reinforced the existing evidence supporting a reciprocal causal relationship between frailty and obstructive lung diseases. A deeper comprehension of this interconnection is imperative for the prevention and treatment of obstructive lung diseases.

The epigenetics of frailty.

The conceptual change of frailty, from a physical to a biopsychosocial phenotype, expanded the field of frailty, including social and behavioral domains with critical interaction between different frailty models. Environmental exposures - including physical exercise, psychosocial factors and diet - may play a role in the frailty pathophysiology. Complex underlying mechanisms involve the progressive interactions of genetics with epigenetics and of multimorbidity with environmental factors. Here we review the literature on possible mechanisms explaining the association between epigenetic hallmarks (i.e., global DNA methylation, DNA methylation age acceleration and microRNAs) and frailty, considered as biomarkers of aging. Frailty could be considered the result of environmental epigenetic factors on biological aging, caused by conflicting DNA methylation age and chronological age.

The present narrative review describes the available evidence about epigenetic biological markers of frailty considered aging biomarkers, among others. Aging biomarkers can help in identifying frail and older individuals affected by multiple diseases to further increase the power of composite biomarker panels in the diagnostic and prognostic process. Among combined biomarkers, epigenetic regulators with different methylation patterns and small molecules such as microRNAs are included. Given that frailty involves multiple biological systems, it is possible to define it according to a novel model, including emotional and social domains and the influence of environmental factors, named the biopsychosocial phenotype. Different epigenetic biomarkers of frailty, from the first generation to the more specific and recent second-generation epigenetic aging biomarkers, may account for factors linked to different cellular types, such as heterogeneity, and a reverse causation process that requires integration with gene expression. A better understanding of the relationships among frailty, multimorbidity and overall mortality will help us to identify the best therapeutic targets.