Proteomic aging clock predicts mortality and risk of common age-related diseases in diverse populations

Circulating plasma proteins play key roles in human health and can potentially be used to measure biological age, allowing risk prediction for age-related diseases, multimorbidity and mortality. Here we developed a proteomic age clock in the UK Biobank (n = 45,441) using a proteomic platform comprising 2,897 plasma proteins and explored its utility to predict major disease morbidity and mortality in diverse populations. We identified 204 proteins that accurately predict chronological age (Pearson r = 0.94) and found that proteomic aging was associated with the incidence of 18 major chronic diseases (including diseases of the heart, liver, kidney and lung, diabetes, neurodegeneration and cancer), as well as with multimorbidity and all-cause mortality risk. Proteomic aging was also associated with age-related measures of biological, physical and cognitive function, including telomere length, frailty index and reaction time. Proteins contributing most substantially to the proteomic age clock are involved in numerous biological functions, including extracellular matrix interactions, immune response and inflammation, hormone regulation and reproduction, neuronal structure and function and development and differentiation. In a validation study involving biobanks in China (n = 3,977) and Finland (n = 1,990), the proteomic age clock showed similar age prediction accuracy (Pearson r = 0.92 and r = 0.94, respectively) compared to its performance in the UK Biobank. Our results demonstrate that proteomic aging involves proteins spanning multiple functional categories and can be used to predict age-related functional status, multimorbidity and mortality risk across geographically and genetically diverse populations

Recontacting biobank participants to collect lifestyle, behavioural and cognitive information via online questionnaires : lessons from a pilot study within FinnGen

OBJECTIVES: To recontact biobank participants and collect cognitive, behavioural and lifestyle information via a secure online platform. DESIGN: Biobank-based recontacting pilot study. SETTING: Three Finnish biobanks (Helsinki, Auria, Tampere) recruiting participants from February 2021 to July 2021. PARTICIPANTS: All eligible invitees were enrolled in FinnGen by their biobanks (Helsinki, Auria, Tampere), had available genetic data and were >18 years old. Individuals with severe neuropsychiatric disease or cognitive or physical disabilities were excluded. Lastly, 5995 participants were selected based on their polygenic score for cognitive abilities and invited to the study. Among invitees, 1115 had successfully participated and completed the study questionnaire(s). OUTCOME MEASURES: The primary outcome was the participation rate among study invitees. Secondary outcomes included questionnaire completion rate, quality of data collected and comparison of participation rate boosting strategies. RESULTS: The overall participation rate was 18.6% among all invitees and 23.1% among individuals aged 18-69. A second reminder letter yielded an additional 9.7% participation rate in those who did not respond to the first invitation. Recontacting participants via an online healthcare portal yielded lower participation than recontacting via physical letter. The completion rate of the questionnaire and cognitive tests was high (92% and 85%, respectively), and measurements were overall reliable among participants. For example, the correlation (r) between self-reported body mass index and that collected by the biobanks was 0.92. CONCLUSION: In summary, this pilot suggests that recontacting FinnGen participants with the goal to collect a wide range of cognitive, behavioural and lifestyle information without additional engagement results in a low participation rate, but with reliable data. We suggest that such information be collected at enrolment, if possible, rather than via post hoc recontacting.publishedVersionPeer reviewe

Micrornas in Extracellular Vesicles as Novel Biomarkers in Environmental Epidemiology

Despite important achievements of Environmental Epidemiology in identifying major environmental health problems in recent years, little is known about the underlying biological mechanisms that link environmental exposures to certain outcomes. Recent discovery of extracellular vesicles (EVs) as a novel mechanism of cellular communication has opened new avenues for non-invasive access to subclinical molecular signals, which might help exposing such mechanisms. In this work, we evaluate the potential of microRNAs, molecular signals that are contained in EVs circulating in the blood, as biomarkers in two very important environmental health problems: (a) the causal association between air pollution and cardiovascular disease and (b) the association between prenatal lead exposure and impaired fetal growth. For this work, we used cutting-edge and high-throughput methods to isolate EVs from the blood of study participants, and profile their content in microRNAs (evmiRNAs). We further incorporated a broad array of sophisticated statistical methods to (a) determine the association of ambient particulate matter of <2.5μm diameter (PM2.5) and evmiRNAs (Chapter 1), (b) determine the association between prenatal lead exposure and fetal growth (Chapter 2), and (c) evaluate the potential of evmiRNAs as early biomarkers of fetal growth impairment (Chapter 3). The findings from Chapter 1 showed positive associations between long-term exposure to PM2.5 and levels of evmiRNAs in the blood circulation of older individuals, several of which were found to be enriched in biological pathways related to cardiovascular disease. Results from Chapter 2 showed a negative association between prenatal exposure to lead and birthweight-for-gestational age (BWGA), and revealed that the magnitude of the association is much bigger in the lower percentiles of the BWGA distribution. Finally, the findings from Chapter 3 suggested that levels of evmiRNAs provide a very promising opportunity for the development of minimally-invasive biomarkers to detect and monitor impaired fetal growth early in pregnancy. This work demonstrates the tremendous potential of evmiRNAs in the field of Environmental Epidemiology. EVs and their content provide an unprecedented, yet easily accessible source of molecular signals that can help us better understand the biological mechanisms involved in linking environmental exposures to certain outcomes.Air Pollution; Cardiovascular Disease; Extracellular Vesicles; Exosomes; Microvesicles; microRNAs; Lead Exposure; Birthweight; Pregnancy; Quantile Regression; C14MC; C19M

Additional file 1: Figure S1. of Ambient particulate matter and microRNAs in extracellular vesicles: a pilot study of older individuals

Morphological characterization of serum extracellular vesicles (EVs). Preparations of EVs were imaged by transmission electron microscopy (TEM). (a) non-labeled EVs, (b) EVs labeled with gold-conjugated anti-CD63 antibody, (c) EVs labeled with gold-conjugated anti-CD81 antibody. Images were taken by a JEOL 1200EX microscope coupled with an AMT 2 k CCD camera, at the Harvard Medical School Electron Microscopy Core. (DOCX 4627 kb

Conic optimization: theory and applications

1 This work discusses the roles of second-order cone programming, these tasks are a special class semidefinitního programming. The work summarized basic de- finitions, properties and claims known about these tasks. Special attention is paid to methods of solving SOCP problems. In the last part of the paper are formu- lated in some special tasks of mathematical programming (linear programming, quadratic programming, ...) as special cases of SOCP problems

Ambient particulate matter and microRNAs in extracellular vesicles: a pilot study of older individuals

Background: Air pollution from particulate matter (PM) has been linked to cardiovascular morbidity and mortality; however the underlying biological mechanisms remain to be uncovered. Gene regulation by microRNAs (miRNAs) that are transferred between cells by extracellular vesicles (EVs) may play an important role in PM-induced cardiovascular risk. This study sought to determine if ambient PM2.5 levels are associated with expression of EV-encapsulated miRNAs (evmiRNAs), and to investigate the participation of such evmiRNAs in pathways related to cardiovascular disease (CVD). Methods: We estimated the short- (1-day), intermediate- (1-week and 1-month) and long-term (3-month, 6-month, and 1-year) moving averages of ambient PM2.5 levels at participants’ addresses using a validated hybrid spatio-temporal land-use regression model. We collected 42 serum samples from 22 randomly selected participants in the Normative Aging Study cohort and screened for 800 miRNAs using the NanoString nCounter® platform. Mixed effects regression models, adjusted for potential confounders were used to assess the association between ambient PM2.5 levels and evmiRNAs. All p-values were adjusted for multiple comparisons. In-silico Ingenuity Pathway Analysis (IPA) was performed to identify biological pathways that are regulated by PM-associated evmiRNAs. Results: We found a significant association between long-term ambient PM2.5 exposures and levels of multiple evmiRNAs circulating in serum. In the 6-month window, ambient PM2.5 exposures were associated with increased levels of miR-126-3p (0.74 ± 0.21; p = 0.02), miR-19b-3p (0.52 ± 0.15; p = 0.02), miR-93-5p (0.78 ± 0.22; p = 0.02), miR-223-3p (0.74 ± 0.22; p = 0.02), and miR-142-3p (0.81 ± 0.21; p = 0.03). Similarly, in the 1-year window, ambient PM2.5 levels were associated with increased levels of miR-23a-3p (0.83 ± 0.23; p = 0.02), miR-150-5p (0.90 ± 0.24; p = 0.02), miR-15a-5p (0.70 ± 0.21; p = 0.02), miR-191-5p (1.20 ± 0.35; p = 0.02), and let-7a-5p (1.42 ± 0.39; p = 0.02). In silico pathway analysis on PM2.5-associated evmiRNAs identified several key CVD-related pathways including oxidative stress, inflammation, and atherosclerosis. Conclusions: We found an association between long-term ambient PM2.5 levels and increased levels of evmiRNAs circulating in serum. Further observational studies are warranted to confirm and extend these important findings in larger and more diverse populations, and experimental studies are needed to elucidate the exact roles of evmiRNAs in PM-induced CVD. Electronic supplementary material The online version of this article (doi:10.1186/s12989-016-0121-0) contains supplementary material, which is available to authorized users

miRNA Profiles in Extracellular Vesicles From Serum Early in Pregnancies Complicated by Gestational Diabetes Mellitus

Abstract Context Underlying mechanisms leading to gestational diabetes mellitus (GDM) are still under investigation, and it is unclear whether the placenta plays a role in triggering glucose intolerance or if its functions are modified in response to the hyperglycemia. Circulating miRNAs are involved in placental development and function and are encapsulated in extracellular vesicles (EVs). Objective To compare differential expression of miRNAs in circulating EVs in pregnancies complicated by GDM vs controls. Methods This was a case-control study nested in a prospective pregnancy cohort including 23 women with GDM and 46 matched controls. The presence of serum EVs in early pregnancy was validated by transmission electron microscopy. Placental dimensions were assessed at 11 to 13 weeks of gestation. Differential expression of 17 miRNAs encapsulated in EVs (miR‒122-5p, miR‒132-3p, miR-1323, miR‒182-3p, miR‒210-3p, miR‒29a-3p, miR‒29b-3p, miR‒342-3p, miR‒517-5p, miR‒517a-3p, miR‒518b, miR-520h, miR‒525-5p, miR‒136-5p, miR‒342-3p, miR‒376c-5p, and miR‒494-3p) was assessed using quantitative reverse transcription PCR. Results EVs were present in the early phase of placentation (6 to 15 weeks of gestation) in both cases and controls. No differences were observed for placental dimensions and estimated placental volume between GDM and control groups. Ten miRNAs (miR‒122-5p; miR‒132-3p; miR‒1323; miR‒136-5p; miR‒182-3p; miR‒210-3p; miR‒29a-3p; miR‒29b-3p; miR‒342-3p, and miR-520h) showed significantly higher levels in GDM cases than in controls (P ≤ 0.05). Bioinformatics analysis showed that these miRNAs are involved in trophoblast proliferation/differentiation as well as in insulin secretion/regulation and glucose transport in pregnant women. Conclusion The miRNA content of blood EVs may be a promising avenue for studying the early effect of impaired glucose metabolism on placental development. </jats:sec