Title Promoter Affiliations Abstract "Exposure to airborne particles and ageing pathways in the ENVIRONAGE birth cohort: integrating inflamming pathways with telomeres" "Michelle PLUSQUIN" "Environmental Biology" "The impact of air pollution on human health is a worldwide threat, moreover, current evidence suggests that health effects occur even at concentrations below the WHO guideline levels. In utero exposure has been associated with increased risk of adverse birth outcomes and damage to biomolecules, but also has an impact on disease development later in life. Of particular concern are recent studies describing effects of exposure to small particles on molecular ageing. Aging is influenced by both genetic and environmental factors interacting from early life on. Apart from singular pathways involved in aging, the complexity lies in extensive crosstalk between aging biomarkers. In this project I will integrate 2 molecular systems in early life: (i) telomeres, one of the most studied mechanisms of aging because their shortening reflect the limit of a cell to reproduce itself, a key feature of cellular ageing; (ii) ""inflamming"", a theory that describes that inflammation, that in early life and adulthood neutralize harmful agents, can become detrimental during ageing. I will study how these 2 systems are affected by air pollution at birth and in early life in the ENVIRONAGE (ENVIRmental influence on AGEing in early life) birth cohort. The study currently consists of 1200 newborns and enrolment is ongoing including a follow-up study with measures of health outcomes. My project will lead to a better understanding of the mechanisms trough which aging pathways diverge by air pollutants." "ATHLETE Fellowship program: Telomere length in childhood and its multiomics signatures" "Tim NAWROT" "Environmental Biology" "Telomere length is a marker of biological ageing, and a short telomere length in early life predicts lifespan and disease susceptibility in later life. A number of studies have been carried out to identify genetics1-4, epigenomics5, transcriptomics6 and metabolomics7 profiles associated with telomere length. However, most of the population-based findings so far were in adults despite that telomere length in early life is an important determinant of telomere length in adulthood8,9. In addition, little has been reported combining different omics layers in the study of telomere biology, while multi-omics analyses could suggest relevant pathways with a stronger consistency, and would be capable of identifying key molecular processes in a broader range. Studies suggested that oxidative stress is one of the main drivers of telomere shortening10. Telomere shortening thus reflects the harshness of the environment an individual has experienced. Studying the stress-related difference in multi-omics signature of telomere length would improve our understanding of stress-induced telomere dynamics. In the multi-center Human Early Life Exposome (HELIX) project11, data has been preprocessed and harmonized for leukocyte telomere length, genome-wide genotyping, DNA methylation, gene and miRNA expression, serum and urine metabolomics, and plasma proteomics. In this study, we aim to explore the multi-omics signature of childhood telomere length which will point to relevant biological pathways, and how this multi-omics signature behaves differentially under potential stressors of biological ageing" "The prenatal exposome and cardiovascular fetal programming: the role of telomere ageing dynamics." "Tim NAWROT" "Environmental Biology" "Human ageing is a complex physiological process responsive to environmental exposures during the life course. Attrition of telomeres (the ends of our chromosomes) is considered a primary hallmark of ageing. Ageing starts as early as from life in the womb. Maternal pregnancy exposures may have important persistent effects on the telomere biology system of newborns. Newborns with short telomeres are assumed to be predisposed to a more advanced ageing phenotype early and later in life. In this project the role of short telomeres in newborns in relation to biological and cardiovascular ageing phenotypes will be studied after a follow-up at the age of 4-6. The persistent effects of prenatal exposures – using an ""exposome"" approach – will be evaluated in these relationships. Furthermore telomere length regulatory targets at birth will be investigated to further understand early life ageing. This project is embedded in the framework of the ongoing birth cohort ENVIRONAGE." "Long-term effects of metal pollution: linking telomere dynamics, biological aging, infection and fitness." "Andrea Grunst" "Behavioural Ecology & Ecophysiology" "Past studies have largely ignored the effects of toxic pollutants on long-term processes, including the rate of biological aging. Metal pollution may have particularly strong effects on aging rates by increasing disease and oxidative stress. Telomeres protect the ends of chromosomes, shorten with age and stress exposure, and modulate cellular senescence. Telomeres have recently emerged as markers of long-term stress exposure and aging, but have rarely been studied in free-living populations exposed to pollutants. Using great tits (Parus major) as a model species, I will comprehensively explore how metal pollution affects biological aging by quantifying telomere dynamics in juveniles and adults, and determining whether aging-related changes also occur in sexual signals, behavior and fitness. I will test state-dependent models that predict behavioral shifts in individuals with reduced life expectancies, as predicted to occur due to metal exposure and telomere loss. Further, I will assess whether infectious disease (malaria) in metal-exposed birds contributes to elevating oxidative stress and telomere attrition. I will study nest box populations of great tits across a pollution gradient, and experimentally expose nestlings to metals and antioxidants. This study will make a pioneering contribution to evolutionary biology by testing theories of aging and state-dependent behavior in the context of metal pollution, and have critical importance to conservation biology." "Transcriptomic profiles related to telomere length within a life course epidemiology context" "Tim NAWROT" "Environmental Biology" "Telomeres, the distal ends of chromosomes protect them from structural degradation. Telomere length is highly heritable and erosion leads to an increasingly vulnerable structural integrity of the chromosomes. It is considered a marker of overall biological age compared with chronological age. During my Ph. D. years, I will study gene expression patterns (full gene expression analysis), in association with variation in telomere length in two different age groups: newborns and middle-aged to elderly people. To unravel ageing related pathways at the level of the expression of genes influencing telomere length over the life span is groundbreaking. This must lead to 1/ new biomarker discovery of ageing; 2/ understanding the similarity or differences of gene expression patterns on ageing over the lifespan. Finally, I will study the influence of environmental factors (including diet [folic acid and vitamin D] and air pollution) on the identified ageing pathways. Both my training in biostatistics as well as in biomedical sciences is integrated in my fellowship proposal." "Early life determinants of healthy ageing during the first two decades of life: from the telomere interactome to clinical phenotypes." "Stefaan De Henauw" "Department of Public Health and Primary Care, Department of Public health" "The WHO defines health as “a state of complete physical, mental, and social well-being, but not merely as the absence of disease or infirmity”. Ageing starts before birth and depends on factors that operate throughout life, and hence, the concept of healthy ageing also encompasses healthy growing and healthy living. Indeed, disorders in adults often find their origin in risk factors operative in early life. Senescence or biological ageing is the endogenous process of cumulative changes to molecular and cellular structures leading to disrupting metabolism with time. We study over the first two decades of life how genetic, environmental, nutritional and lifestyle factors, and their interactions, via telomere “interactome” differentiate healthy from unhealthy ageing. In line with the WHO definition of health, differentiation between healthy and unhealthy ageing / growing should start before progression to overt disease, when prevention or intervention still remain possible. The proposal builds on existing cohorts in newborns and children and adolescents, who underwent extensive high-fidelity phenotyping with available biobanks and longitudinal follow-up. " "Linking mitochondrial and telomere dysfunction in newborn tissues: TP53, SIRT1 and PPARGC1 alpha as a central hub?" "Tim NAWROT" "Environmental Biology" "Ageing processes are universal, inevitable, and start at the very beginning of life with an acceleration at middle-age. In later life, ageing is associated with cancer, metabolic outcomes, cardiovascular disorders, and neurodegenerative diseases. Exposures to external factors can influence the process of ageing in a positive (i.e. physical activity, healthy diet) or negative manner (i.e. smoking, lack of exercise, stress, etc.). Therefore, it is of great public health importance to investigate external factors that accelerate underlying ageing processes. In the last decade, air pollution has been pinpointed as one of the major global health problems affecting adults, children and newborns worldwide. Growing evidence shows that exposure to ambient air pollution during the most vulnerable stage in life, the in utero period, affects the development of age-related diseases as well. This grant will allow me to conduct fundamental research to identify key players that link prenatal air pollution exposure with mitochondria and telomeres - two hallmarks that define the ""core axis of ageing""." "Developmental and later life effects of light and noise pollution: physiological stress, telomere dynamics and fitness." "Melissa Grunst" "Behavioural Ecology & Ecophysiology" "Organisms have evolved adaptations to environmental challenges, but anthropogenic environments introduce novel stressors. Light and noise pollution are increasingly pervasive, and lacking historical predecessors, may overwhelm coping mechanisms and induce physiological stress. Exposure to light and noise pollution may be particularly influential early in life, when developmental trajectories are sensitive to stressful conditions. Yet, little is known regarding effects of light or noise exposure during development, especially in natural populations. Studies to date examining how light and noise pollution affect adult animals have also been limited in scope, and have largely employed short-term metrics of physiological state. Using great tits (Parus major) as a model organism, I will: (1) experimentally examine how light at night affects physiological stress in developing birds, (2) use an observational study to assess effects of noise pollution on developmental stress, and (3) explore how light and noise pollution interact to effect health status and fitness in personality-typed adults. I will use two powerful approaches that have not been previously applied in this context: measuring corticosterone in feathers (long-term metric of stress status), and assessing telomere degradation rates (marker of aging rate). Living in light and noisy environments has consequences that are relevant across many taxa. This study will motivate action to mitigate these effects." "Early life determinants of healthy ageing during the first two decades of life: from the telomere interactome to clinical phenotypes" "Tim NAWROT" "Environmental Biology" "The WHO defines health as ""a state of complete physical, mental, and social well-being, but not merely as the absence of disease or infirmity"". Ageing starts before birth and depends on factors that operate throughout life, and hence, the concept of healthy ageing also encompasses healthy growing and healthy living. Indeed, disorders in adults often find their origin in risk factors operative in early life. Senescence or biological ageing is the endogenous process of cumulative changes to molecular and cellular structures leading to disrupting metabolism with time. We study over the first two decades of life how genetic, environmental, nutritional and lifestyle factors, and their interactions, via telomere ""interactome"" differentiate healthy from unhealthy ageing. In line with the WHO definition of health, differentiation between healthy and unhealthy ageing / growing should start before progression to overt disease, when prevention or intervention still remain possible. The proposal builds on existing cohorts in newborns and children and adolescents, who underwent extensive high-fidelity phenotyping with available biobanks and longitudinal follow-up." "Conformationally locked G4-decoy oligonucleotides for selective telomerase inhibition and development of a nucleic acid-based anti-telomerase PROTAC strategy" "Annemieke Madder" "Department of Pharmaceutics, Department of Organic and Macromolecular Chemistry, University of Sydney, Imperial College London" "G-Quadruplex (G4) nucleic acids have received increasing attention not only as targets for small molecule or oligonucleotide-based therapeutic strategies but also due their use as therapeutic aptamers (e.g. AS1411, in clinical trials as anti-nucleolin aptamer), given their known binding to transcription factors and other DNA-binding proteins. An exceptionally relevant target in this field is telomerase, an enzyme that is overexpressed in cancer cells. Many small-molecule G4-binding ligands for telomerase inhibition have been synthesized, but none of them succeeded clinical trials, mainly due to selectivity issues. Here, we aim at developing an entirely new approach for human telomerase inhibition. By introducing modifications to covalently “staple"" a human-telomeric structure-switching G4-DNA, we will strive at selective stabilization of the parallel G4 conformation in order to maximize its interaction with the enzyme. Different chemistries for intrastrand covalent bond formation will be considered, as well as additional structural variations (use of synthetic nucleosides, such as LNAs), to ensure stable binding of our decoy G4 to the target enzyme, ultimately resulting in inhibition of telomerase activity. In the last and most challenging part of the project, we aim at delivering the first example of a G4-based PROTAC approach by linking the best-performing stabilized G4 analogue to an E3-ligase ligand, for further ubiquitination and proteasome degradation of telomerase."