The search for biomarkers that quantify biological aging (particularly 'omic'-based biomarkers) has intensified in recent years. Such biomarkers could predict aging-related outcomes and could serve... Show moreThe search for biomarkers that quantify biological aging (particularly 'omic'-based biomarkers) has intensified in recent years. Such biomarkers could predict aging-related outcomes and could serve as surrogate endpoints for the evaluation of interventions promoting healthy aging and longevity. However, no consensus exists on how biomarkers of aging should be validated before their translation to the clinic. Here, we review current efforts to evaluate the predictive validity of omic biomarkers of aging in population studies, discuss challenges in comparability and generalizability and provide recommendations to facilitate future validation of biomarkers of aging. Finally, we discuss how systematic validation can accelerate clinical translation of biomarkers of aging and their use in gerotherapeutic clinical trials.Robust validation of biomarkers of aging will be critical to their clinical translation; here, authors review the key challenges and propose recommendations to overcome them. Show less
Background Odanacatib, a cathepsin K inhibitor, reduces bone resorption while maintaining bone formation. Previous work has shown that odanacatib increases bone mineral density in postmenopausal... Show moreBackground Odanacatib, a cathepsin K inhibitor, reduces bone resorption while maintaining bone formation. Previous work has shown that odanacatib increases bone mineral density in postmenopausal women with low bone mass. We aimed to investigate the efficacy and safety of odanacatib to reduce fracture risk in postmenopausal women with osteoporosis.Methods The Long-term Odanacatib Fracture Trial (LOFT) was a multicentre, randomised, double-blind, placebo-controlled, event-driven study at 388 outpatient clinics in 40 countries. Eligible participants were women aged at least 65 years who were postmenopausal for 5 years or more, with a femoral neck or total hip bone mineral density T-score between -2.5 and -4.0 if no previous radiographic vertebral fracture, or between -1.5 and -4.0 with a previous vertebral fracture. Women with a previous hip fracture, more than one vertebral fracture, or a T-score of less than -4.0 at the total hip or femoral neck were not eligible unless they were unable or unwilling to use approved osteoporosis treatment. Participants were randomly assigned (1:1) to either oral odanacatib (50 mg once per week) or matching placebo. Randomisation was done using an interactive voice recognition system after stratification for previous radiographic vertebral fracture, and treatment was masked to study participants, investigators and their staff, and sponsor personnel. If the study completed before 5 years of double-blind treatment, consenting participants could enrol in a double-blind extension study (LOFT Extension), continuing their original treatment assignment for up to 5 years from randomisation. Primary endpoints were incidence of vertebral fractures as assessed using radiographs collected at baseline, 6 and 12 months, yearly, and at final study visit in participants for whom evaluable radiograph images were available at baseline and at least one other timepoint, and hip and non-vertebral fractures adjudicated as being a result of osteoporosis as assessed by clinical history and radiograph. Safety was assessed in participants who received at least one dose of study drug. The adjudicated cardiovascular safety endpoints were a composite of cardiovascular death, myocardial infarction, or stroke, and new-onset atrial fibrillation or flutter. Individual cardiovascular endpoints and death were also assessed. LOFT and LOFT Extension are registered with ClinicalTrials.gov (number NCT00529373) and the European Clinical Trials Database (EudraCT number 2007-002693-66).Findings Between Sept 14, 2007, and Nov 17, 2009, we randomly assigned 16 071 evaluable patients to treatment: 8043 to odanacatib and 8028 to placebo. After a median follow-up of 36.5 months (IQR 34.43-40.15) 4297 women assigned to odanacatib and 3960 assigned to placebo enrolled in LOFT Extension (total median follow-up 47.6 months, IQR 35.45-60.06). In LOFT, cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 3.7% (251/6770) versus 7.8% (542/6910), hazard ratio (HR) 0.46, 95% CI 0.40-0.53; hip fractures 0.8% (65/8043) versus 1.6% (125/8028), 0.53, 0.39-0.71; non-vertebral fractures 5.1% (412/8043) versus 6.7% (541/8028), 0.77, 0.68-0.87; all p<0.0001. Combined results from LOFT plus LOFT Extension for cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 4.9% (341/6909) versus 9.6% (675/7011), HR 0.48, 95% CI 0.42-0.55; hip fractures 1.1% (86/8043) versus 2.0% (162/8028), 0.52, 0.40-0.67; non-vertebral fractures 6.4% (512/8043) versus 8.4% (675/8028), 0.74, 0.66-0.83; all p<0.0001. In LOFT, the composite cardiovascular endpoint of cardiovascular death, myocardial infarction, or stroke occurred in 273 (3.4%) of 8043 patients in the odanacatib group versus 245 (3.1%) of 8028 in the placebo group (HR 1.12, 95% CI 0.95-1.34; p=0.18). New-onset atrial fibrillation or flutter occurred in 112 (1.4%) of 8043 patients in the odanacatib group versus 96 (1.2%) of 8028 in the placebo group (HR 1.18, 0.90-1.55; p=0.24). Odanacatib was associated with an increased risk of stroke (1.7% [136/8043] vs 1.3% [104/8028], HR 1.32, 1.02-1.70; p=0.034), but not myocardial infarction (0.7% [60/8043] vs 0.9% [74/8028], HR 0.82, 0.58-1.15; p=0.26). The HR for all-cause mortality was 1.13 (5.0% [401/8043] vs 4.4% [356/8028], 0.98-1.30; p=0.10). When data from LOFT Extension were included, the composite of cardiovascular death, myocardial infarction, or stroke occurred in significantly more patients in the odanacatib group than in the placebo group (401 [5.0%] of 8043 vs 343 [4.3%] of 8028, HR 1.17, 1.02-1.36; p=0.029, as did stroke (2.3% [187/8043] vs 1.7% [137/8028], HR 1.37, 1.10-1.71; p=0.0051).Interpretation Odanacatib reduced the risk of fracture, but was associated with an increased risk of cardiovascular events, specifically stroke, in postmenopausal women with osteoporosis. Based on the overall balance between benefit and risk, the study's sponsor decided that they would no longer pursue development of odanacatib for treatment of osteoporosis. Copyright (C) 2019 Elsevier Ltd. All rights reserved. Show less
Background. Genome-wide association studies (GWAS) may yield insights into longevity. Methods. We performed a meta-analysis of GWAS in Caucasians from four prospective cohort studies: the Age, Gene... Show moreBackground. Genome-wide association studies (GWAS) may yield insights into longevity. Methods. We performed a meta-analysis of GWAS in Caucasians from four prospective cohort studies: the Age, Gene/Environment Susceptibility-Reykjavik Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Longevity was defined as survival to age 90 years or older (n = 1,836); the comparison group comprised cohort members who died between the ages of 55 and 80 years (a = 1,955). In a second discovery stage, additional genotyping was conducted in the Leiden Longevity Study cohort and the Danish 1905 cohort. Results. There were 273 single-nucleotide polymorphism (SNP) associations with p < .0001, but none reached the prespecified significance level of 5 x 10(-8). Of the most significant SNPs, 24 were independent signals, and 16 of these SNPs were successfully genotyped in the second discovery stage, with one association for rs9664222, reaching 6.77 x 10(-7) for the combined meta-analysis of CHARGE and the stage 2 cohorts. The SNP lies in a region near MINPPI (chromosome 10), a well-conserved gene involved in regulation of cellular proliferation. The minor allele was associated with lower odds of survival past age 90 (odds ratio = 0.82). Associations of interest in a homologue of the longevity assurance gene (LASS3) and PAPPA2 were not strengthened in the second stage. Conclusion. Survival studies of larger size or more extreme or specific phenotypes may support or reline these initial findings. Show less
