CoAGE Research Projects
PhD position on ‘Multi-organ ageing clocks’ in Bonn, Germany
Ageing is a major risk factor for most chronic non-communicable diseases, including neurodegenerative and cerebrovascular diseases. However, the effects of ageing vary among individuals and can even differ between organ systems. Consequently, biological age serves as a more informative marker of ageing compared to chronological age. Initial ageing clocks were derived from blood-based molecular markers, including epigenetic, proteomic, metabolic, and inflammation clocks. More recently, estimating biological age at the organ system level has become possible thanks to advances in machine learning and the accessibility of phenotypical data from large population cohorts. However, the reproducibility of these clocks across studies is limited.
This PhD thesis aims to enhance the estimation of biological age across the CoAGE cohorts and explore the relation of the biological age gap across different organ systems. We will establish a German multi-organ clock and validate it against proxies of health status (e.g., the frailty index) and molecular ageing clocks to assess its potential as an ageing biomarker. Finally, we will investigate its potential in predicting cardio- and cerebrovascular and neurodegenerative diseases across German cohorts.
Supervision: Monique Breteler (DZNE Bonn)
PhD position on ‘Association of the pituitary-thyroid axis with COVID-19 infection and vaccine-based immune response in the general German population’ in Greifswald, Germany
Different organs like thymus, spleen or lymph nodes are important for proper functioning of the body’s immune system. The involvement of thyroid hormones (T3 and T4), that are secreted in response to thyroid stimulating hormone (TSH) from pituitary glands, target the immune system to modulate specific immune responses like natural killer cell activity, antiviral action of interferon and proliferation of T and B-lymphocytes. Some studies associated thyroid dysfunction (lower fT3, fT4, TT3) with a variety of poor outcomes during COVID-19 infections including critically increased in-hospital mortality, prolonged hospital stay and increased serum biomarkers of inflammation and cardiac injury in COVID‑19 patients. Despite the association, a study using Mendelian randomization models did not find any susceptibility to COVID-19 in patients with thyroid dysfunction. It remains an open question whether and to which extend COVID‑19 infections influence thyroid functions and vice versa.
The aim of the proposed CoAGE PhD project is to assess whether antibody titres correlate with proper thyroid functioning after COVID-19 infection or vaccination within the Study of Health in Pomerania (SHIP). In all SHIP cohorts, measurements of TSH, fT3, fT4 and anti-TPO-antibodies as well as sonographic measurements of thyroid volume, nodules and thyroid patterns are available. In SHIP-COVID, a large number of COVID-related parameters like anti-spike and anti-nucleocapsid proteins antibodies have been measured at different time points in around 800 individuals of the SHIP-START cohort. We will use different regression models to analyse the association of thyroid size and functional parameters with the immune response induced by SARS-CoV-2 infection and vaccination. In addition, we will also investigate the association of inflammatory parameters (hsCRP, fibrinogen and white blood cells count) with the COVID-19 infection as well as with the thyroid functional parameters. This will enable us to understand the role of a healthy thyroid in combatting viral infections.
We will extend the study with the similar set of analyses to other German Cohorts like the Gutenberg Health Study and the German National Cohort.
Supervision: Henry Völzke (Greifswald University Medicine)
PhD position on ‘Biomarkers for heart failure: Improving personalised risk prediction in the ageing population’ in Hamburg, Germany
Cardiovascular diseases (CVD) represent the leading non-communicable diseases (NCD) associated with the highest NCD death rates globally. Heart failure (HF), a major CVD, is the most common cause of hospitalization and in‐hospital death throughout Germany. The high incidence shows a rising trend as the population ages, and the disease is not only related to high mortality and morbidity, but also to lower quality of life and extensive health expenditures, making it a major public health issue. Due to the growing HF burden, there is a need for improved risk assessment, early detection, and prognostication of HF to facilitate disease management. Existing risk prediction models are usually limited to traditional CVD risk factors. However, those often fail to accurately estimate an individual’s full risk to develop HF, and at granting prognostic utility.
Improving these models by adding impactful risk markers is crucial to inform personalised approaches for precision prevention in those at highest risk for developing HF. By exposing the activity of multiple HF-associated pathways and structural changes, circulating and imaging-based biomarkers have the potential to better estimate risk and prognosis in the ageing population, and to out-perform existing risk prediction models by adding valuable information and taking into account a comprehensive and differentiated personal profile. The improved personalised risk prediction may lead to a better identification of high-risk individuals, subsequently inform patients in short- and long-term prognosis, therapy and care. Ultimately, this will result in a reduction of HF disease burden and support healthy ageing.
Hamburg offers a large-scale dataset from a population-based cohort study including a wide range of deep phenotype variables, also covering lab-based biomarkers, imaging and genetic data, which can be used to address this research topic.
Supervision: Stefan Blankenberg (Medical Center Hamburg-Eppendorf, UKE)
PhD position on ‘Epidemiology of sex-dimorphisms of lipid metabolism and vascular phenotypes’ in Leipzig, Germany
Metabolic and cardiovascular phenotypes often express pronounced sex-dimorphisms. The molecular background of these observations is incompletely understood. Hormones acting as transcription factors and genetic sex-interactions are supposed to contribute to this phenomenon. To develop targeted and individualized therapies, there is a need to unravel the underlying molecular-genetic networks.
During this PhD project, we plan to perform comprehensive sex-specific multi-omics data analyses of lipidomics profiles available in our cohorts based on deep molecular profiling. We will also analyse sex-differences between subclinical cardiovascular disease traits, respective longitudinal trajectories and cardiovascular endpoints and their relationships to lipidomics profiles. Summarizing these insights, we perform sex-specific causal networks of several cardiovascular traits and disease endpoints. These networks are compared to identify branching points of related pathomechanisms. We will extend the study with a similar set of analyses to other German Cohorts like the Gutenberg Health study.
Supervision: Markus Scholz (University of Leipzig Medical Center)
PhD position on ‘Deciphering the Interplay between Ageing and Thrombotic Disease: Mechanisms and Implications’ in Mainz, Germany
Due to demographic developments in Germany, research into ageing is becoming increasingly important. Ageing is a highly complex process that is often associated with multimorbidity and reduced quality of life and has therefore become one of the greatest challenges for healthcare systems. Thrombotic diseases, i.e. cardiovascular diseases in which blood clots form and block blood vessels, are one of the most common causes of morbidity and mortality worldwide. The incidence rises sharply with increasing age, although the underlying mechanisms are still poorly understood.
This doctoral thesis will give you the opportunity to investigate the diverse and complex research questions on the influence of ageing processes on thrombotic diseases from an epidemiological, medical and molecular biological perspective. To this end, multidimensional data from a large long-term cohort study, the Gutenberg Health Study (GHS, www.gutenberg-gesundheitsstudie.de), will be analysed using innovative methods. Due to the size of the study and the unique depth of data for each study participant at several points in time, it is regarded as a multidisciplinary lighthouse project for Mainz as a centre of ageing research. The design of the GHS as a life-span study covers the entire age spectrum, so that early ageing processes and their role in the risk of thrombotic diseases can already be investigated. By networking with other population-based cohort studies as part of the CoAGE graduate programme and integrating the data, the research questions can be examined meta-analytically and the results validated. As part of the project, you will be able to network and collaborate with leading international scientists as part of a multidisciplinary team.
Supervision: Philipp Wild (University Medical Center Mainz)
PhD position on ‘The role of the urban exposome on cardiometabolic multimorbidity and mortality’ in Munich, Germany
A growing number of studies have shown an association between air pollution and all-cause mortality and cardiovascular mortality, but there is a gap in research on other environmental exposures and their outcomes. It is also un-clear whether people with cardiometabolic disease are more vulnerable to the adverse effects of environmental factors. Therefore, we aim to investigate the association between several long-term environmental exposures and mortality and cardiometabolic multimorbidity.
The NAKO has recruited more than 200,000 individuals between 2014 and 2019 in both sexes aged between 19 to 74 years. NAKO has assembled morbidity and mortality follow-up data until 2023. We will use geocoded data of multiple long-term environmental exposures of the urban exposome, e.g. air pollution, traffic noise, ambient air temperature, greenness and built environment indicators, which were assessed in the EU-funded EXPANSE project (Exposome Powered tools for healthy living in urbAN Settings). These novel urban risk and protection factors will be linked to NAKO participants’ residencies by the Environmental data unit. The outcomes of interest are all-cause and cause-specific mortality and prevalent and incident cardiometabolic disease.
As part of the PhD work, we will apply single-exposure models to quantify effects of each exposure on the outcomes of interest. The secondary aim of this project is to assess the effect modification of pre-existing cardiometabolic disease on the environmental exposure – mortality association and whether environmental exposures promote multi-morbidity. This NAKO-based study will contribute substantial evidence on the association of environmental exposures with mortality and cardiometabolic multimorbidity due to its high exposure contrasts and longitudinal health data. Moreover, it allows the assessment of the potential modifying role of prevalent cardiometabolic disease on these associations. We will extend the study with a similar set of analyses to other German Cohorts like the Gutenberg Health study.
Supervision: Annette Peters (Helmholtz Munich)
PhD position on ‘Sarcopenia, Sarcopenic Obesity and Healthy Ageing’ in Munich, Germany
Sarcopenia, a progressive muscle disorder, often occurs in ageing or obese individuals due to shared risk factors, e.g. sedentary lifestyle, unhealthy diet, ageing and acute and chronic diseases. Sarcopenic obesity, a combination of sarcopenia and excess adipose tissue, appears to be more severe than obesity alone, with the underlying mechanisms remaining unknown.
The mechanisms likely to be involved include low-grade inflammation, lipotoxicity, mitochondrial dysfunction, oxidative stress, myosteatosis and insulin resistance. Recent advances in high-throughput proteomics have allowed us to further elucidate these molecular mechanisms. Novel proteomics measurements have recently been completed in the Cooperative Health Research in the Region of Augsburg (KORA) Age study at baseline.
The aim of the proposed CoAGE PhD project is to assess the association of these novel protein biomarkers with sarcopenia and sarcopenic obesity in order to further elucidate the underlying metabolic pathways of these disease outcomes. Validation of the obtained results in other population-based cohorts with available proteomics data is anticipated. Furthermore, Mendelian randomization analyses are planned to further elucidate the potential causal role of the identified protein candidates in disease development. We will extend the study with a similar set of analyses to other German Cohorts like the Gutenberg Health study.
Supervision: Barbara Thorand (Helmholtz Munich)