Prenatal metal exposures and childhood telomere length attrition

SUMMARY ABSTRACT Accelerated biological aging poses significant risks to health and mortality, yet the underlying factors remain poorly understood. Telomere length (TL), a biomarker of biological aging, is inversely associated with chronological age and indicative of aging-related disease susceptibility. Telomeres shorten more rapidly during the first two decades of life due to accelerated physical growth, particularly in infancy and adolescence. Childhood exposures have been linked to TL in later life, emphasizing the importance of these developmental periods in influencing later-life health trajectories. While prenatal toxic metal exposures are associated with TL in infancy, there is limited understanding of the association between essential metals and TL. The gut microbiome (GM) is another important component of healthy aging, with recent studies indicating an association between GM composition in childhood and TL. GM composition is influenced by metal exposures, and the GM also influences xenobiotic toxicity. Specific metal- and metal-microbial cliques, subgroups of metals and microbes, may be associated with TL attrition, as not all metals and all gut microbes likely influence TL jointly. The concept of cliques provides a unique measure to assess associations lying between individual components and mixtures. However, few, if any, studies have investigated the complex associations between metals, microbes, and longitudinal TL attrition from birth to late childhood. Given the potential links between metals, microbes, and TL, we hypothesize that mixtures of metals and specific metal-microbial cliques are associated with TL attrition. The long-term goal of this work is to better understand the interactions between environmental exposures and GM on health and aging across the lifespan. Our overall objective is to investigate and model the complex interactions among prenatal metal exposures, GM, and their influence on TL attrition from early to late childhood. The proposed study will employ a robust methodology, utilizing mixture methods, interpretable machine learning, and causal inference, and will draw on data from the well-characterized pediatric cohort in Mexico City. Specific objectives include identifying associations between prenatal metal exposure mixtures and biological age acceleration, pinpointing subgroups of children susceptible to accelerated TL aging based on metal cliques, exploring interactions between prenatal metals and childhood gut microbiome cliques in late childhood, and their association with TL in childhood. Our study team is highly motivated and well-positioned to complete the proposed study. Despite the complexity of the project, its significance lies in paving the way for targeted interventions aimed at preventing adverse health outcomes from an early developmental stage by identifying early targets for metal and microbial interventions. This research is part of a broader continuum, aiming to address the complexities of accelerated biological aging for long-term health benefits.