To characterize the proteomic signature of chronological age, 1,301 proteins were measured in plasma using the SOMAscan assay (SomaLogic, Boulder, CO, USA) in a population of 240 healthy men and ...women, 22–93 years old, who were disease‐ and treatment‐free and had no physical and cognitive impairment. Using a p ≤ 3.83 × 10−5 significance threshold, 197 proteins were positively associated, and 20 proteins were negatively associated with age. Growth differentiation factor 15 (GDF15) had the strongest, positive association with age (GDF15; 0.018 ± 0.001, p = 7.49 × 10−56). In our sample, GDF15 was not associated with other cardiovascular risk factors such as cholesterol or inflammatory markers. The functional pathways enriched in the 217 age‐associated proteins included blood coagulation, chemokine and inflammatory pathways, axon guidance, peptidase activity, and apoptosis. Using elastic net regression models, we created a proteomic signature of age based on relative concentrations of 76 proteins that highly correlated with chronological age (r = 0.94). The generalizability of our findings needs replication in an independent cohort.
SOMAscan is an aptamer-based proteomics assay capable of measuring 1,305 human protein analytes in serum, plasma, and other biological matrices with high sensitivity and specificity. In this work, we ...present a comprehensive meta-analysis of performance based on multiple serum and plasma runs using the current 1.3 k assay, as well as the previous 1.1 k version. We discuss normalization procedures and examine different strategies to minimize intra- and interplate nuisance effects. We implement a meta-analysis based on calibrator samples to characterize the coefficient of variation and signal-over-background intensity of each protein analyte. By incorporating coefficient of variation estimates into a theoretical model of statistical variability, we also provide a framework to enable rigorous statistical tests of significance in intervention studies and clinical trials, as well as quality control within and across laboratories. Furthermore, we investigate the stability of healthy subject baselines and determine the set of analytes that exhibit biologically stable baselines after technical variability is factored in. This work is accompanied by an interactive web-based tool, an initiative with the potential to become the cornerstone of a regularly updated, high quality repository with data sharing, reproducibility, and reusability as ultimate goals.
Older age is a strong shared risk factor for many chronic diseases, and there is increasing interest in identifying aging biomarkers. Here, a proteomic analysis of 1301 plasma proteins was conducted ...in 997 individuals between 21 and 102 years of age. We identified 651 proteins associated with age (506 over-represented, 145 underrepresented with age). Mediation analysis suggested a role for partial
-epigenetic control of protein expression with age. Of the age-associated proteins, 33.5% and 45.3%, were associated with mortality and multimorbidity, respectively. There was enrichment of proteins associated with inflammation and extracellular matrix as well as senescence-associated secretory proteins. A 76-protein proteomic age signature predicted accumulation of chronic diseases and all-cause mortality. These data support the use of proteomic biomarkers to monitor aging trajectories and to identify individuals at higher risk of disease to be targeted for in depth diagnostic procedures and early interventions.
Recent clinical trials have demonstrated that colchicine may have metabolic and cardiovascular and benefits in at-risk patients; however, the mechanisms through which colchicine may improve outcomes ...are still unclear. We sought to examine colchicine's effects on circulating inflammatory and metabolic molecules in adults with obesity and metabolic syndrome (MetS).
Blood samples were collected pre- and post-intervention during a double-blind randomized controlled trial in which 40 adults with obesity and MetS were randomized to colchicine 0.6 mg or placebo twice-daily for 3 months. Serum samples were analyzed for 1305 circulating factors using the SomaScan Platform. The Benjamini-Hochberg procedure was used to adjust the false discovery rate (FDR) for multiple testing.
At baseline, age (48.0 ± 13.8 vs. 44.7 ± 10.3 years) and BMI (39.8 ± 6.4 vs. 41.8 ± 8.2 kg/m
) were not different between groups. After controlling for the FDR, 34 molecules were significantly changed by colchicine. Colchicine decreased concentrations of multiple inflammatory molecules, including C-reactive protein, interleukin 6, and resistin, in addition to vascular-related proteins (e.g., oxidized low-density lipoprotein receptor, phosphodiesterase 5A). Conversely, relative to placebo, colchicine significantly increased concentrations of eight molecules including secreted factors associated with metabolism and anti-thrombosis.
In adults with obesity, colchicine significantly affected concentrations of proteins involved in the innate immune system, endothelial function and atherosclerosis, uncovering new mechanisms behind its cardiometabolic effects. Further research is warranted to investigate whether colchicine's IL-6 suppressive effects may be beneficial in COVID-19.
Introduction
Mobility disability is a powerful indicator of poor health in older adults. The biological and pathophysiological mechanism underlying the development of mobility disability remains ...unknown. This study conducted a data‐driven discovery phase investigation to identify plasma proteins that predict the incidence of mobility disability in community‐dwelling older adults without mobility disability at baseline.
Methods
We investigated 660 women and men, aged 71.9 ± 6.0 (60–94) years, who participated in the Invecchiare in Chianti, “Aging in the Chianti Area” study and completed the 400‐m walk at fast pace (400‐m walk) at enrollment. Median follow‐up time was 8.57 interquartile, 3.20–9.08 years. SOMAscan technology was used to measure 1,301 plasma proteins at enrollment. The incident of mobility disability was defined as inability to complete the 400‐m walk. Protein‐specific Cox proportional hazard model was adjusted for sex, age, and other important covariates.
Results
Plasma levels of 75 proteins predicted mobility disability (p < .05). Significant proteins were enriched for the KEGG “PI3K‐Akt signaling,” “phagosomes,” and “cytokine–cytokine receptor interaction” pathways. After multiple comparison adjustment, plasma cathepsin S (CTSS; hazard ratio HR 1.33, 95% CI: 1.17, 1.51, q = 0.007), growth/differentiation factor 15 (GDF15; HR: 1.45, 95% CI: 1.23, 1.72, q = 0.007), and thrombospondin‐2 (THBS2; HR: 1.44, 95% CI: 1.22, 1.69, q = 0.007) remained significantly associated with high risk of losing mobility.
Conclusion
CTSS, GDF15, and THBS2 are novel blood biomarkers associated with new mobility disability in community‐dwelling individuals. Overall, our analysis suggests that cellular senescence and inflammation should be targeted for prevention of mobility disability.
Among 1,301 plasma proteins assessed, cathepsin S, thrombospondin‐2, and growth/differentiation factor 15 significantly and independently predicted mobility loss in 660 community‐dwelling adults. Proteins associated with mobility loss were enriched for senescence‐associated secretory phenotype and for proteins in the PI3K‐Akt, phagosome, or cytokine–cytokine receptor interaction pathways. High plasma levels of SASP‐induced proteins related to inflammation and phagocytes activation mark a condition of high risk of mobility loss.
Pneumocystis jirovecii is a major cause of life-threatening pneumonia in immunosuppressed patients including transplant recipients and those with HIV/AIDS, yet surprisingly little is known about the ...biology of this fungal pathogen. Here we report near complete genome assemblies for three Pneumocystis species that infect humans, rats and mice. Pneumocystis genomes are highly compact relative to other fungi, with substantial reductions of ribosomal RNA genes, transporters, transcription factors and many metabolic pathways, but contain expansions of surface proteins, especially a unique and complex surface glycoprotein superfamily, as well as proteases and RNA processing proteins. Unexpectedly, the key fungal cell wall components chitin and outer chain N-mannans are absent, based on genome content and experimental validation. Our findings suggest that Pneumocystis has developed unique mechanisms of adaptation to life exclusively in mammalian hosts, including dependence on the lungs for gas and nutrients and highly efficient strategies to escape both host innate and acquired immune defenses.
Although mitochondrial dysfunction has been implicated in aging, physical function decline, and several age-related diseases, an accessible and affordable measure of mitochondrial health is still ...lacking. In this study we identified the proteomic signature of muscular mitochondrial oxidative capacity in plasma. In 165 adults, we analyzed the association between concentrations of plasma proteins, measured using the SOMAscan assay, and skeletal muscle maximal oxidative phosphorylation capacity assessed as post-exercise phosphocreatine recovery time constant (τ
) by phosphorous magnetic resonance spectroscopy. Out of 1301 proteins analyzed, we identified 87 proteins significantly associated with τ
, adjusting for age, sex, and phosphocreatine depletion. Sixty proteins were positively correlated with better oxidative capacity, while 27 proteins were correlated with poorer capacity. Specific clusters of plasma proteins were enriched in the following pathways: homeostasis of energy metabolism, proteostasis, response to oxidative stress, and inflammation. The generalizability of these findings would benefit from replication in an independent cohort and in longitudinal analyses.
Complement hyperactivation, angiopathic thrombosis and protein-losing enteropathy (CHAPLE disease) is a lethal disease caused by genetic loss of the complement regulatory protein CD55, leading to ...overactivation of complement and innate immunity together with immunodeficiency due to immunoglobulin wasting in the intestine. We report in vivo human data accumulated using the complement C5 inhibitor eculizumab for the medical treatment of patients with CHAPLE disease. We observed cessation of gastrointestinal pathology together with restoration of normal immunity and metabolism. We found that patients rapidly renormalized immunoglobulin concentrations and other serum proteins as revealed by aptamer profiling, re-established a healthy gut microbiome, discontinued immunoglobulin replacement and other treatments and exhibited catch-up growth. Thus, we show that blockade of C5 by eculizumab effectively re-establishes regulation of the innate immune complement system to substantially reduce the pathophysiological manifestations of CD55 deficiency in humans.
Background Cancer is a life-threatening disease that triggers not only vulnerability to distressing symptoms but also a meaning-making process that may lead to post-traumatic growth. As people often ...struggle to integrate cancer illness into their meaning system to reach an adaptive meaning, psychological interventions focused on a reappraisal of the illness experience can facilitate this process. This multicenter randomized controlled trial (RCT) was primarily aimed at assessing the efficacy of a writing intervention known as a guided disclosure protocol (GDP), compared to a generic writing intervention, in promoting post-traumatic growth in stage I-III breast and colon cancer patients at the end of their adjuvant chemotherapy. Methods Between January 2016 and August 2020 recruitment of eligible subjects took place during follow-up clinical consultations. Assessment occurred at baseline (T0), after the intervention (T1, 3 months from baseline), and at 6 months from baseline (T2). Both interventions consisted of three 20-min writing sessions to be performed once every two weeks. Change in post-traumatic growth was assessed using the Posttraumatic Growth Inventory, meaning with the Constructed Meaning Scale, and psychological distress with the Impact of Event Scale and the Hospital Anxiety and Depression Scale. Results In the five participating centers, 102 eligible patients were randomized and 72 participants completed follow-up evaluation. Most patients were women (79.4%), had breast cancer (68.6%), and stage I (27.5%), or stage II (44.1%) disease. Mean differences did not reach statistical significance for any of the dependent variables. However, an effect of the GDP, although not statistically relevant, was observed after the intervention in terms of enhanced post-traumatic growth and increased distress measured with the Impact of Event Scale. Conclusion This is the first RCT investigating the efficacy of a GDP in cancer patients having post-traumatic growth as the primary aim. Though GDP is a promising intervention in promoting post-traumatic growth, the lack of statistical significance of our findings may be due to the study being underpowered, hence this trial should be replicated with an adequate sample size, paying attention to supporting recruitment. Clinical trial registration: ClinicalTrials.gov , identifier: 2015/0024360.
Frailty is a risk factor for poor health outcomes in older adults. The aim of this study was to identify plasma proteomic biomarkers of frailty in 752 men and women older than 65 years of age from ...the InCHIANTI study. One thousand three hundred one plasma proteins were measured using an aptamer-based assay. Associations of each protein with frailty status were assessed using logistic regression and four proteins creatine kinase M-type (CKM), B-type (CKB), C-X-C motif chemokine ligand 13 (CXCL13), and thrombospondin 2 (THBS2) were associated with frailty status. Two proteins, cyclin-dependent kinase 5 (CDK5/CDK5R1) and interleukin 1 alpha (IL1A), were associated with worsening of frailty status over time in volunteers free of frailty at baseline. Using partial least squares discriminant analysis (PLS-DA), data of 1301 proteins was able to discriminate between frail and non-frail with a 2% error rate. The proteins with greater discriminatory ability represented the inflammation, blood coagulation, and cell growth pathways. The utility of these proteins as biomarkers of frailty should be further explored.
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