Revolutionary Environmental Metalloproteomics for Aging Science and Prevention

Summary The proposed R35 program will advance metalloproteomics research and applications to better understand the role of metals in aging and brain health, aiming to address the limited tools available for assessing metal- protein interactions in age-related diseases, in particular dementia and cognitive impairment. Around 40% of human proteins rely on metal ions, directly as metalloproteins or indirectly as cofactors. Metals like copper, iron, and zinc, essential for protein functions, play critical roles in brain health, and disruptions in these metals are linked to cognitive decline and dementia risk, particularly in individuals with APOE4 alleles. Neurotoxic metals, such as lead, disrupt essential metal functions through molecular mimicry and oxidative stress, which can promote amyloid β (Aβ) plaque formation and hyperphosphorylated tau (ptau), among pathogenic mechanisms with a role in the development of dementia and cognitive impairment. Building on the scientific leadership and research productivity of the PI, a highly accomplished inter-disciplinary team, and our cutting- edge metallomics research facility, this research program will integrate multiple mass spectrometry (MS) technologies to develop novel biomarkers that quantify metal-protein molecules, stable isotope ratios, and metals and metal-protein levels in brain-derived extracellular vesicles (EVs) as a surrogate of the target tissue (Area 1). These biomarkers will then be incorporated into observational (Area 2) and experimental (Area 3) studies, to analyze complex interactions between metals and proteins associated with brain health outcomes. The program leverages data and samples from observational studies with extensive brain imaging, biomarkers and clinical data, and clinical trials like TACT2, which investigates the effects of chelation therapy on metal burden reduction, providing a unique perspective on metal-protein modifications in brain health. Additionally, we will integrate our novel metal-protein biomarkers multi-omics and machine learning (Area 4) to serve as surrogate biomarkers that can be widely available and enhance the understanding of the metalloproteome’s impact on disease pathogenesis and aging. The key research areas––developing biomarkers, mapping their associations with aging-related diseases, testing experimental modifications, and connecting biomarkers with multi-omics data to identify mechanistic pathways––could reveal novel targets and strategies for healthy aging interventions, fostering collaborations and transforming approaches to precision medicine and public health. This work promises to significantly expand the understanding of metal-protein interactions in aging, informing future preventive and therapeutic interventions for neurodegenerative diseases. Project Number: 1R35ES037866-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Environmental Health Sciences (NIEHS) | Principal Investigator: Ana Navas-Acien | Institution: COLUMBIA UNIVERSITY HEALTH SCIENCES, NEW YORK, NY | Award Amount: $942,408 | Activity Code: R35 | Study Section: Special Emphasis Panel[ZRG1 KUDS-N (57)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11224328