The Design and Rationale of a Phase 2b, Randomized, Double-Blinded, and Placebo-Controlled Trial to Evaluate the Safety and Efficacy of Lomecel-B in Older Adults with Frailty.

BACKGROUND: Frailty in older adults is a rapidly growing unmet medical need. It is an aging-related syndrome characterized by physical decline leading to higher risk of adverse health outcomes. OBJECTIVES: To evaluate the efficacy of Lomecel-B, an allogeneic medicinal signaling cell (MSC) formulation, in older adults with frailty. DESIGN: This multicenter, randomized, parallel-arm, double-blinded, and placebo-controlled phase 2b trial is designed to evaluate dose-range effects of Lomecel-B for frailty on physical functioning, patient-reported outcomes (PROs), frailty status, and biomarkers. SETTING: Eight enrolling clinical research centers, including the Miami Veterans Affairs Medical Center. PARTICIPANTS: Target enrollment is 150 subjects aged 70-85 years of any race, ethnicity, or gender. Enrollment criteria include a Clinical Frailty Score of 5 ("mild") or 6 ("moderate"), a 6MWT of 200-400 m, and serum tumor necrosis factor-alpha (TNF-α) ≥2.5 pg/mL. INTERVENTION: A single intravenous infusion of Lomecel-B (25, 50, 100, or 200 million cells) or placebo (N=30/arm). Patients are followed for 365 days for safety, and the efficacy assessments performed at 90, 180, and 270 days. MEASUREMENTS: The primary endpoint is change in 6MWT in the Lomecel-B-treated arms versus placebo at 180 days post-infusion. Secondary and exploratory endpoints include change in: 6MWT and other physical function measures at all time points; PROs; frailty status; cognitive status; and an inflammatory biomarkers panel. A pre-specified sub-study examines vascular/endothelial biomarkers. Safety is evaluated throughout the trial. RESULTS: The trial is conducted under a Food and Drug Administration Investigational New Drug (IND), with Institutional Review Board approval, and monitoring by an NIH-appointed independent Data Safety Monitoring Board. CONCLUSION: This clinical trial investigates the use of a regenerative medicine strategy for frailty in older adults. The results will further the understanding of the potential for Lomecel-B in the geriatric condition of frailty.

Lactoferrin for the treatment of age-associated inflammation - A pilot study.

BACKGROUND: Chronic inflammation (CI) is a common trait of aging associated with adverse outcomes including mortality. We hypothesized that recombinant human Lactoferrin (rhLf) would reduce chronic inflammation of aging. METHODS: Thirty-six community dwelling older adults were randomly assigned to rhLf or placebo treatment in 1:1 ratio for 3 months. IL-6, sTNFR1, Comprehensive Metabolic Panel (CMP), and Complete Blood Count (CBC) were measured at baseline, 1 month, 3 months, and 6 months. Physical and cognitive measures were completed at same timepoints, including 4-m walking speed (m/s), grip strength (kg), 6-min walking distance (m), home activity measured by accelerometer, trail making test - Part A (s) and - Part B (s), and Digit symbol substitution test (number correctly coded). Primary outcomes were differences in IL-6 and sTNFR1 concentrations evaluated by generalized linear model with log-link and gamma family distribution, controlling for baseline cytokine concentrations. RESULTS: rhLF was well-tolerated. There were a significant number of abdominal complaints and increased drop-out rate in placebo group. Participants in rhLf arm had non-significant lower mean percent increase in IL6 at 3 months (rhLf mean IL-6 6% lower than control, P = 0.843), and sTNFaR1 (rhLf mean 2% lower than control, P = 0.36). No significant changes were observed for the cognitive or physical measures. CONCLUSION: Treatment with rhLf did not significantly alter serum IL6 or sTNFR1 concentrations of older adults. This study may have been underpowered to detect difference, but provided evidence that a larger sample-size could more definitively determine the effect of rhLF on age-associated CI.

Anthropogenic modification of forests means only 40% of remaining forests have high ecosystem integrity.

Many global environmental agendas, including halting biodiversity loss, reversing land degradation, and limiting climate change, depend upon retaining forests with high ecological integrity, yet the scale and degree of forest modification remain poorly quantified and mapped. By integrating data on observed and inferred human pressures and an index of lost connectivity, we generate a globally consistent, continuous index of forest condition as determined by the degree of anthropogenic modification. Globally, only 17.4 million km2 of forest (40.5%) has high landscape-level integrity (mostly found in Canada, Russia, the Amazon, Central Africa, and New Guinea) and only 27% of this area is found in nationally designated protected areas. Of the forest inside protected areas, only 56% has high landscape-level integrity. Ambitious policies that prioritize the retention of forest integrity, especially in the most intact areas, are now urgently needed alongside current efforts aimed at halting deforestation and restoring the integrity of forests globally.

ICFSR Task Force Perspective on Biomarkers for Sarcopenia and Frailty.

Biomarkers of frailty and sarcopenia are essential to advance the understanding of these conditions of aging and develop new diagnostic tools and effective treatments. The International Conference on Frailty and Sarcopenia Research (ICFSR) Task Force - a group of academic and industry scientists from around the world -- met in February 2019 to discuss the current state of biomarker development for frailty and sarcopenia. The D3Cr dilution method, which assesses creatinine excretion as a biochemical measure of muscle mass, was suggested as a more accurate measure of functional muscle mass than assessment by dual energy x-ray absorptiometry (DXA). Proposed biomarkers of frailty include markers of inflammation, the hypothalamic-pituitary-adrenal (HPA) axis response to stress, altered glucose insulin dynamics, endocrine dysregulation, aging, and others, acknowledging the complex multisystem etiology that contributes to frailty. Lack of clarity regarding a regulatory pathway for biomarker development has hindered progress; however, there are currently several international efforts to develop such biomarkers as tools to improve the treatment of individuals presenting these conditions.

Novel Frailty Screening Questionnaire (FSQ) Predicts 8-year Mortality in Older Adults in China.

BACKGROUND: Although frailty status greatly impacts health care in countries with rapidly aging populations, little is known about the frailty status in Chinese older adults. OBJECTIVES: Given the increased health care needs associated with frailty, we sought to develop an easily applied self-report screening tool based on four of the syndromic frailty components and sought to validate it in a population of older adults in China. DESIGN: Prospective epidemiological cohort study. SETTING: Community-dwelling residents living in Beijing, China. PARTICIPANTS: 1724 community-dwelling adults aged ≥60 years in 2004 with an 8-year follow up. MEASUREMENTS: We developed a simple self-report frailty screening tool-the Frailty Screening Questionnaire (FSQ)-based on the modified Fried frailty components. The predictive ability for outcome was assessed by age and sex adjusted Cox proportional hazards model. RESULTS: According to FSQ criteria, 7.1% of the participants were frail. Frailty was associated with poor physical function, fractures, falls, and mortality. Both frailty and pre-frailty were associated with a higher mortality rate: frailty-hazards ratio (HR), 3.94, 95% confidence interval (CI), 3.16-4.92, P<0.001; pre-frailty-HR, 1.89; 95% CI, 1.57-2.27, P <0.001; adjusted models for this variable did not affect the estimates of the association. Among the four frailty components, slowness was the strongest predictor of mortality. The combination of the four components provided the best risk prediction. CONCLUSIONS: FSQ is a self-report frailty measurement tool that can be rapidly performed to identify older adults with higher risk of adverse health outcomes.

Production and characterization of a novel HPV anti-L2 monoclonal antibody panel.

The major capsid protein of HPV, L1, assembles into pentamers that form a T = 7 icosahedral particle, but the location of the co-assembled minor capsid protein, L2, remains controversial. Several researchers have developed useful monoclonal antibodies targeting L2, but most react with linear epitopes toward the N-terminus. As a means to better define the virus capsid and better assess the localization and exposure of L2 epitopes in the context of assembled HPV, we have developed a panel of 30 monoclonal antibodies (mAbs) which target the N-terminus of L2 amino acids 11-200, previously defined as a broadly protective immunogen. Select mAbs were processed with enzymes and anti-L2 Fabs were generated. These new mAb/Fab probes will be beneficial in future studies to unravel the placement of L2 and to help better define the role of L2 in the HPV lifecycle and the nature of the broadly protective epitopes.

Association of intraoperative changes in brain-derived neurotrophic factor and postoperative delirium in older adults.

BACKGROUND: Delirium is common after surgery, although the aetiology is poorly defined. Brain-derived neurotrophic factor (BDNF) is a neurotrophin important in neurotransmission and neuroplasticity. Decreased levels of BDNF have been associated with poor cognitive outcomes, but few studies have characterized the role of BDNF perioperatively. We hypothesized that intraoperative decreases in BDNF levels are associated with postoperative delirium. METHODS: Patients undergoing spine surgery were enrolled in a prospective cohort study. Plasma BDNF was collected at baseline and at least hourly intraoperatively. Delirium was assessed using rigorous methods, including the Confusion Assessment Method (CAM) and CAM for the intensive care unit. Associations of changes in BDNF and delirium were examined using regression models. RESULTS: Postoperative delirium developed in 32 of 77 (42%) patients. The median baseline BDNF level was 7.6 ng ml -1 [interquartile range (IQR) 3.0-11.2] and generally declined intraoperatively [median decline 61% (IQR 31-80)]. There was no difference in baseline BDNF levels by delirium status. However, the percent decline in BDNF was greater in patients who developed delirium [median 74% (IQR 51-82)] vs in those who did not develop delirium [median 50% (IQR 14-79); P =0.03]. Each 1% decline in BDNF was associated with increased odds of delirium in unadjusted {odds ratio [OR] 1.02 [95% confidence interval (CI) 1.00-1.04]; P =0.01}, multivariable-adjusted [OR 1.02 (95% CI 1.00-1.03); P =0.03], and propensity score-adjusted models [OR 1.02 (95% CI 1.00-1.04); P =0.03]. CONCLUSIONS: We observed an association between intraoperative decline in plasma BDNF and delirium. These preliminary results need to be confirmed but suggest that plasma BDNF levels may be a biomarker for postoperative delirium.

Co-Localization of Macrophage Inhibitory Factor and Nix in Skeletal Muscle of the Aged Male Interleukin 10 Null Mouse.

Chronic inflammation is associated with muscle weakness and frailty in older adults. The antagonistic cross-talk between macrophage migration inhibitory factor (Mif), an anti-apoptotic cytokine and NIP3-like protein X (Nix), a pro-apoptotic mitochondrial protein, may play a role in mitochondrial free radical homeostasis and inflammatory myopathies. We examined Nix-Mif interaction in inflammation and aging using young and old, IL-10tm/tm (a rodent model of chronic inflammation) and C57BL/6 mice. In this study, we observed that Nix and Mif were co-localized in skeletal muscles of aged and inflamed mice. We show an inflammation- and age-related association between Nix and Mif gene expression, with the strongest positive correlation observed in old IL-10tm/tm skeletal muscles. The IL-10tm/tm skeletal muscles also had the highest levels of oxidative stress damage. These observations suggest that Nix-Mif cross-talk may play a role in the interface between chronic inflammation and oxidative stress in aging skeletal muscles.

Frailty and Health-Related Quality of Life in End Stage Renal Disease Patients of All Ages.

BACKGROUND: Frailty is associated with worse health-related quality of life (HRQOL) in older adults and worse clinical outcomes in adults of all ages with end stage renal disease (ESRD). It is unclear whether frail adults of all ages with ESRD are more likely to experience worse HRQOL. OBJECTIVE: The goal of this study was to identify factors associated with worsening HRQOL in this population. DESIGN, SETTING AND MEASUREMENTS: We studied 233 adults of all ages with ESRD enrolled (11/2009-11/2013) in a longitudinal cohort study. Frailty status was measured at enrollment and HRQOL was reported (Excellent, Very Good, Good, Fair or Poor) at the initial assessment and follow-up (median follow-up 9.4 months). We studied factors associated with Fair/Poor HRQOL at follow-up using logistic regression and factors associated with HRQOL change using multinomial regression. All models were adjusted for age, sex, race, education, BMI, diabetes status, history of a previous transplant, type of dialysis and time between assessments. RESULTS: Fair/Poor HRQOL was reported by 28% at initial assessment and 33% at follow-up. 47.2% of participants had stable HRQOL, 22.8% better HRQOL, and 30.0% worse HRQOL at follow-up (P<0.001). In adjusted models, only frailty was associated with Fair/Poor HRQOL at follow-up (OR: 2.79, 95% CI: 1.32-5.90) and worsening HRQOL at follow-up (RR: 2.91, 95%CI: 1.08-7.80). CONCLUSIONS: Frail adults of all ages with ESRD are more likely to experience fair/poor HRQOL and worsening HRQOL over time. Frailty represents a state of decreased physiologic reserve that impacts not only clinical outcomes but also the patient-centered outcome of HRQOL.

Coagulation factor XII genetic variation, ex vivo thrombin generation, and stroke risk in the elderly: results from the Cardiovascular Health Study.

BACKGROUND: The relationships of thrombin generation (TG) with cardiovascular disease risk are underevaluated in population-based cohorts. OBJECTIVES: To evaluate the relationships of TG influenced by the contact and tissue factor coagulation pathways ex vivo with common single-nucleotide polymorphisms (SNPs) and incident cardiovascular disease and stroke. PATIENTS/METHODS: We measured peak TG (pTG) in baseline plasma samples of Cardiovascular Health Study participants (n = 5411), both with and without inhibitory anti-factor XIa antibody (pTG/FXIa(-) ). We evaluated their associations with ~ 50 000 SNPs by using the IBCv2 genotyping array, and with incident cardiovascular disease and stroke events over a median follow-up of 13.2 years. RESULTS: The minor allele for an SNP in the FXII gene (F12), rs1801020, was associated with lower pTG in European-Americans (ß = - 34.2 ± 3.5 nm; P = 3.3 × 10(-22) ; minor allele frequency [MAF] = 0.23) and African-Americans (ß = - 31.1 ± 7.9 nm; P = 9.0 × 10(-5) ; MAF = 0.42). Lower FXIa-independent pTG (pTG/FXIa(-) ) was associated with the F12 rs1801020 minor allele, and higher pTG/FXIa(-) was associated with the ABO SNP rs657152 minor allele (ß = 16.3 nm; P = 4.3 × 10(-9) ; MAF = 0.37). The risk factor-adjusted ischemic stroke hazard ratios were 1.09 (95% confidence interval CI 1.01-1.17; P = 0.03) for pTG, 1.06 (95% CI 0.98-1.15; P = 0.17) for pTG/FXIa(-) , and 1.11 (95% CI 1.02-1.21; P = 0.02) for FXIa-dependent pTG (pTG/FXIa(+) ), per one standard deviation increment (n = 834 ischemic strokes). In a multicohort candidate gene analysis, rs1801020 was not associated with incident ischemic stroke (ß = - 0.02; standard error = 0.08; P = 0.81). CONCLUSIONS: These results support the importance of contact activation pathway-dependent TG as a risk factor for ischemic stroke, and indicate the importance of F12 SNPs for TG ex vivo and in vivo.

Frailty and mortality in kidney transplant recipients.

We have previously described strong associations between frailty, a measure of physiologic reserve initially described and validated in geriatrics, and early hospital readmission as well as delayed graft function. The goal of this study was to estimate its association with postkidney transplantation (post-KT) mortality. Frailty was prospectively measured in 537 KT recipients at the time of transplantation between November 2008 and August 2013. Cox proportional hazards models were adjusted for confounders using a novel approach to substantially improve model efficiency and generalizability in single-center studies. We precisely estimated the confounder coefficients using the large sample size of the Scientific Registry of Transplantation Recipients (n = 37 858) and introduced these into the single-center model, which then estimated the adjusted frailty coefficient. At 5 years, the survivals were 91.5%, 86.0% and 77.5% for nonfrail, intermediately frail and frail KT recipients, respectively. Frailty was independently associated with a 2.17-fold (95% CI: 1.01-4.65, p = 0.047) higher risk of death. In conclusion, regardless of age, frailty is a strong, independent risk factor for post-KT mortality, even after carefully adjusting for many confounders using a novel, efficient statistical approach.

Novel gene variants predict serum levels of the cytokines IL-18 and IL-1ra in older adults.

Activation of inflammatory pathways measured by serum inflammatory markers such as interleukin-18 (IL-18) and interleukin-1 receptor antagonist (IL-1ra) is strongly associated with the progression of chronic disease states in older adults. Given that these serum cytokine levels are in part a heritable trait, genetic variation may predict increased serum levels. Using the Cardiovascular Health Study and InCHIANTI cohorts, a genome-wide association study was performed to identify genetic variants that influence IL-18 and IL-1ra serum levels among older adults. Multiple linear regression models characterized the association between each SNP and log-transformed cytokine values. Tests for multiple independent signals within statistically significant loci were performed using haplotype analysis and regression models conditional on lead SNP in each region. Multiple SNPs were associated with these cytokines with genome-wide significance, including SNPs in the IL-18-BCO gene region of chromosome 2 for IL-18 (top SNP rs2250417, P=1.9×10(-32)) and in the IL-1 gene family region of chromosome 2 for IL-1ra (rs6743376, P=2.3×10(-26)). Haplotype tests and conditional linear regression models showed evidence of multiple independent signals in these regions. Serum IL-18 levels were also associated with a region on chromosome 2 containing the NLRC4 gene (rs12989936, P=2.7×10(-19)). These data characterize multiple robust genetic signals that influence IL-18 and IL-1ra cytokine production. In particular, the signal for serum IL-18 located on chromosome two is novel and potentially important in inflammasome triggered chronic activation of inflammation in older adults. Replication in independent cohorts is an important next step, as well as molecular studies to better understand the role of NLRC4.

Frailty and early hospital readmission after kidney transplantation.

Early hospital readmission (EHR) after kidney transplantation (KT) is associated with increased morbidity and higher costs. Registry-based recipient, transplant and center-level predictors of EHR are limited, and novel predictors are needed. We hypothesized that frailty, a measure of physiologic reserve initially described and validated in geriatrics and recently associated with early KT outcomes, might serve as a novel, independent predictor of EHR in KT recipients of all ages. We measured frailty in 383 KT recipients at Johns Hopkins Hospital. EHR was ascertained from medical records as ≥1 hospitalization within 30 days of initial post-KT discharge. Frail KT recipients were much more likely to experience EHR (45.8% vs. 28.0%, p = 0.005), regardless of age. After adjusting for previously described registry-based risk factors, frailty independently predicted 61% higher risk of EHR (adjusted RR = 1.61, 95% CI: 1.18-2.19, p = 0.002). In addition, frailty improved EHR risk prediction by improving the area under the receiver operating characteristic curve (p = 0.01) as well as the net reclassification index (p = 0.04). Identifying frail KT recipients for targeted outpatient monitoring and intervention may reduce EHR rates.

[Rivermead assessment of somatosensory performance: validation of a German version (RASP-DT)]. / Rivermead Assessment of Somatosensory Performance : Validierung einer deutschen Version (RASP DT).

BACKGROUND: Sensory deficits after stroke are common and impact motor regeneration and the total length of hospital stay as well as quality of life factors including the independence to conduct daily life activities. There is currently no existing reliable and standardized assessment tool to measure somatosensory performance in the German language. The aim of our study was to translate the original version of the Rivermead assessment for somatosensory performance (RASP) into German and to study its reliability in a German-speaking population sample. METHODS: The translation of the English original version followed the protocol of the Medical Outcomes Trust. The German version was assessed with 60 patients with first time presentation of subacute stroke and AC1 coefficients were calculated to measure interrater reliability for the different subtests. RESULTS: The mean AC1 value was 0.75 (range 0.58-0.81). The interrater reliability was good to excellent for all subtests. CONCLUSION: The German version of the RASP (RASP-DT) developed in this study is a reliable assessment instrument for sensory deficits after stroke.

The association of genetic variants in interleukin-1 genes with cognition: findings from the cardiovascular health study.

The inflammatory cytokine interleukin-1 (IL1) potentially plays a role in cognitive deterioration through pathology due to a dementing disorder or due to an aging process. Study of genetic variants in the IL1 genes has been mostly limited to diseases such as Alzheimer's, however, there may be benefit to studying a continuous measure of cognition. Using data from the Cardiovascular Health Study, we evaluate genetic variation in the genes encoding inflammatory agonists IL1A and IL1B, and the antagonist IL1RN, with repeated measures of global cognition (3MS) and processing speed (DSST), using mixed effects models. We found statistically significant minor allele SNP associations with baseline performance on the 3MS in the IL1RN gene for Caucasians (rs17042917: beta=0.47, 95%CI=0.09, 0.85, p=0.016; rs4251961: beta=-0.36, 95%CI=-0.13,-0.60, p=0.0027; rs931471: beta=0.39, 95%CI=0.13, 0.65, p=0.0032), and the IL1B gene for African Americans (rs1143627: beta=1.6, 95%CI=0.48, 2.8; p=0.006 and rs1143634: beta=2.09, 95%CI=0.39, 3.8; p=0.016). Associations appear to be weaker in a subgroup with higher education level. Upon removing those diagnosed with dementia, effect sizes and statistical significance attenuated. These results provide supporting evidence that genetic variants in IL1 genes may be involved in inflammatory-related lowered cognition, that higher education may modify genetic predisposition, and that these associations may be driven by a dementia process.

Transcobalamin-II variants, decreased vitamin B12 availability and increased risk of frailty.

OBJECTIVE: This project was designed to follow-up prior evidence that demonstrated a significant association between vitamin B12 transport and metabolism and the frailty syndrome in community-dwelling older women. The cross-sectional relationship between genetic variants within six candidate genes along this pathway with serum methylmalonic acid (MMA) levels and frailty was evaluated in this same population of older women. METHODS: Baseline measures were collected prior to folate fortification from 326 women in the Women's Health and Aging Studies I and II. Odds ratios and statistical tests were estimated for single SNP and haplotype via linear regression models for serum MMA, a marker for available vitamin B12, and in logistic regression models for frailty. RESULTS: Fifty-six SNPs from CBS, MTHFR, MTR, MTRR, TCN1 and TCN2 genes were genotyped. Several SNPs in MTHFR, MTR and MTRR demonstrated a modest association to elevated MMA, while SNPs in TCN2 showed significant association to the frailty syndrome. TCN2 polymorphisms, particularly one SNP reported to be in perfect LD with functional variant Pro259Arg, were significantly associated with increased odds of frailty, after adjustment for age, presence of cardiovascular disease and elevated MMA (OR = 2.25, p-value = 0.009). CONCLUSIONS: Using MMA as a marker for vitamin B12, these results suggest that TCN2 gene variants may lead to decreased vitamin B12 availability, leading to reduced energy metabolism, ultimately contributing to frailty pathology. Further studies to determine the biological role of functional TCN2 polymorphisms in frailty are needed.

Markers of B-vitamin deficiency and frailty in older women.

OBJECTIVE: To evaluate the association between markers of vitamins B12, B6 and folate deficiency and the geriatric syndrome of frailty. DESIGN: Cross-sectional study of baseline measures from the combined Women's Health and Aging Studies. SETTING: Baltimore, Maryland. PARTICIPANTS: Seven hundred three community-dwelling women, aged 70-79. MEASUREMENTS: Frailty was defined by five-component screening criteria that include weight, grip strength, endurance, physical activity and walking speed measurements and modeled as binary and 3-level polytomous outcomes. Independent variables serum vitamin B6, vitamin B12, methylmalonic acid, total homocysteine, cystathionine and folate were modeled continuously and as abnormal versus normal. RESULTS: Serum biomarker levels varied significantly by race. All analyses were race-stratified and results are reported only for Caucasian women due to small African American sample size. In polytomous logistic regression models of 3-level frailty, Caucasian women with increasing MMA, defined either continuously or using a predefined threshold, had 40-60% greater odds of being prefrail (p-values < 0.07) and 1.66-2.33 times greater odds of being frail (p-values < 0.02) compared to nonfrails after adjustment for age, education, low serum carotenoids, alcohol intake, cardiovascular disease and renal impairment. Both binary and polytomous frailty models evaluating vitamin B12 as the main exposure estimated odds ratios that were similar in trend yet slightly less significant than the MMA results. CONCLUSIONS: These results suggest that vitamin B12 deficiency may contribute to the frailty syndrome in community-dwelling older women. Future studies are needed to explore these relationships longitudinally.

Serum antioxidants, inflammation, and total mortality in older women.

The inflammatory cytokine interleukin-6 (IL-6) has been linked to poor health outcomes in older adults. Oxidative stress triggers the production of IL-6, and antioxidant micronutrients play a critical role in decreasing this inflammatory response. The authors sought to identify the relations between serum levels of antioxidant nutrients and IL-6 and mortality in older women. Levels of alpha- and beta-carotene, lycopene, lutein/zeaxanthin, alpha-cryptoxanthin, total carotenoids, retinol, alpha-tocopherol, zinc, and selenium were measured at baseline in 619 participants in Women's Health and Aging Study I (Baltimore, Maryland, 1992-1998). IL-6 was measured at baseline and at follow-up 1 and 2 years later, and all-cause mortality was determined over a 5-year period. Participants with the highest serum levels of alpha-carotene, total carotenoids, and selenium were significantly less likely to be in the highest tertile of serum IL-6 at baseline (p < 0.0001). Those with the lowest levels of alpha- and beta-carotene, lutein/zeaxanthin, and total carotenoids were significantly more likely to have increasing IL-6 levels over a period of 2 years. Those with the lowest selenium levels had a significantly higher risk of total mortality over a period of 5 years (hazard ratio = 1.54, 95% confidence interval: 1.03, 2.32). These findings suggest that specific antioxidant nutrients may play an important role in suppressing IL-6 levels in disabled older women.

IL-6 gene variation is not associated with increased serum levels of IL-6, muscle, weakness, or frailty in older women.

Elevated levels of the inflammatory cytokine IL-6 are associated with the development of disability, frailty, and mortality in older adults. These outcomes are likely mediated through inflammatory activity that alters hormones, skeletal muscle, and the immune system. Polymorphic variants in the IL-6 gene influence IL-6 expression. We hypothesized that IL-6 alleles associate with increased serum of IL-6, decreased muscle strength, and frailty, and tested this in the Women's Health and Aging cohorts. We genotyped 463 participants age 70-79, and identified three common IL-6 haplotype blocks for the Caucasian (n=363) and African American (n=100) subsets. Using linear and logistic regression, and adjusting for age, BMI, race, and osteoarthritis, we identified no significant or clinically meaningful relationship between any single IL-6 single nucleotide polymorphism (SNP) or any IL-6 haplotype and serum IL-6 level, grip, knee, or hip strength, or frailty. Given that the promoter SNP (rs1800795) has been reported to influence IL-6 levels and health outcomes, we performed a similar association study in the In Chianti population (n=266) and confirmed lack of association. These results suggest that IL-6 gene variation may not be an important factor in the determination of elevated IL-6 levels and related phenotypes found in older women.