Multi-organ MRI digitizes biological aging clocks across proteomics, metabolomics, and genetics

Abstract Leveraging clinical phenotypes1,2, neuroimaging3, proteomics4, metabolomics5, and epigenetics6, biological aging clocks across organ systems and tissues have advanced our understanding of human aging and disease. In this study, we expand this biological aging clock framework to multi-organ magnetic resonance imaging (MRI) by developing 7 organ-specific MRI-based biological age gaps (MRIBAGs), including the brain, heart, liver, adipose tissue, spleen, kidney, and pancreas. Leveraging imaging, genetic, proteomic, and metabolomic data from 313,645 individuals curated by the MULTI consortium, we link the 7 MRIBAGs to 2,923 plasma proteins, 327 metabolites, and 6,477,810 common genetic variants. These associations reveal organ-specific and cross-organ interconnection landscapes, identifying distinct molecular signatures related to organ aging. Genome-wide associations identify 53 MRIBAG-locus pairs (P<5×10D8). Genetic correlation and Mendelian randomization analyses further support organ-specific and cross-organ interconnections with 9 phenotype-based1,2, 11 proteome-based7, and 5 metabolome-based aging clocks5, as well as 525 disease endpoints. Through functional gene mapping and Bayesian colocalization analysis linking evidence from genetics, proteomics, and metabolomics, we prioritize 9 druggable genes as targets for future anti-aging treatments. Finally, we demonstrate the clinical relevance of the 7 MRIBAGs in predicting disease endpoints (e.g., diabetes mellitus), all-cause mortality, and capturing differential and heterogeneous cognitive decline trajectories over 240 weeks of treatment with the Alzheimer’s disease drug (Solanezumab). Sex differences are evident across multiple organ systems, manifesting at structural, molecular, and genetic levels. In summary, we developed 7 MRI-based aging clocks that enhance the existing multi-organ biological aging framework, offer multi-scale insights into aging biology, and demonstrate clinical potential to advance future aging research. Competing Interest Statement B.W.D. is an inventor of the DunedinPACE epigenetic clock, which is licensed by Duke University and the University of Otago to TruDiagnostic, from which he receives royalties (DunedinPACE is freely available to researchers). All other authors declare no competing interests. Funding Statement Dr. Junhao Wen and the Laboratory of AI and Biomedical Science (LABS) are supported by the start-up funding from Columbia University. The MULTI consortium (J.W; UK Biobank Application Number: 647044) aims to integrate multi-organ imaging and multi-omics data to advance our understanding of human aging and disease mechanisms. This study used the UK Biobank resource under Application Number 35148 (D.C.; NIA grant number: RF1 AG054409). We want to express our sincere gratitude to the UK Biobank team for their invaluable contribution to advancing clinical research in our field (https://www.ukbiobank.ac.uk/). We want to acknowledge the participants and investigators of the FinnGen study and the PGC consortium, and we thank FinnGen (https://www.finngen.fi/en) and PGC (https://pgc.unc.edu/) for their generosity in sharing the GWAS summary statistics with the scientific community. We thank the BLSA participants and staff for their participation and continued dedication. The BLSA protocol was approved by the Institutional Review Board of the National Institute of Environmental Health Science, National Institutes of Health (03AG0325). The A4 Study was a secondary prevention trial in preclinical Alzheimer's disease, aiming to slow cognitive decline associated with brain amyloid accumulation in clinically normal older individuals. The A4 Study was funded by a public-private-philanthropic partnership, including funding from the National Institutes of Health-National Institute on Aging, Eli Lilly and Company, Alzheimer's Association, Accelerating Medicines Partnership, GHR Foundation, an anonymous foundation, and additional private donors, with in-kind support from Avid Radiopharmaceuticals, Cogstate, Albert Einstein College of Medicine and the Foundation for Neurologic Diseases. The companion observational Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) Study was funded by the Alzheimer's Association and GHR Foundation. The A4 and LEARN Studies were led by Dr. Reisa Sperling at Brigham and Women's Hospital, Harvard Medical School, and Dr. Paul Aisen at the Alzheimer's Therapeutic Research Institute (ATRI) at the University of Southern California. The A4 and LEARN Studies were coordinated by ATRI at the University of Southern California, and the data are made available under the auspices of the Alzheimer’s Clinical Trial Consortium through the Global Research & Imaging Platform (GRIP). The complete A4 Study Team list is available at: https://www.actcinfo.org/a4-study-team-lists/. We want to acknowledge the dedication of the study participants and their partners who made the A4 and LEARN Studies possible. D.R.M, W.A.K, and F.A were supported by the Intramural Research Program (IRP) of the NIH, National Institute on Aging (NIA). We acknowledge the leadership of the Brain Imaging Genetics (BIG) workgroup, led by Dr. Tavia Evans, Dr. Natalia Vilor-Tejedor, and Dr. Junhao Wen, within the International Society to Advance Alzheimer's Research and Treatment (ISTAART) community, for advocating brain imaging genetics in Alzheimer's and aging research. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The MULTI consortium is approved by the Institutional Review Board at Columbia University (AAAV6751). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes ↵# Consortium/study representatives: Dr. Junhao Wen