The multiomics blueprint of the individual with the most extreme lifespan

Abstract

Extreme human lifespan, exemplified by supercentenarians, presents a paradox in understanding aging: despite advanced age, they maintain relatively good health. To investigate this duality, we have performed a high-throughput multiomics study of the world's oldest living person, interrogating her genome, transcriptome, metabolome, proteome, microbiome, and epigenome, comparing the results with larger matched cohorts. The emerging picture highlights different pathways attributed to each process: the record-breaking advanced age is manifested by telomere attrition, abnormal B cell population, and clonal hematopoiesis, whereas absence of typical age-associated diseases is associated with rare European-population genetic variants, low inflammation levels, a rejuvenated bacteriome, and a younger epigenome. These findings provide a fresh look at human aging biology, suggesting biomarkers for healthy aging, and potential strategies to increase life expectancy. The extrapolation of our results to the general population will require larger cohorts and longitudinal prospective studies to design potential anti-aging interventions.

We thank Yoana Veselinova for the drawing of the graphical abstract. Research in the M.E. group is funded by the CERCA Programme/Generalitat de Catalunya (MCIN/AEI/10.13039/501100011033/); the European Regional Development Fund, "A way to make Europe" ERDF (Project PID2021-125282OB-I00 and PID2024-159192OB-I00); Departament de Recerca i Universitats/Generalitat de Catalunya (2021 SGR 01494); European Union under THRIVE grant agreement no. 101136622; "La Caixa" Research Foundation; and the Cellex Foundation (CEL007). E.S.-P. is a fellow of the Spanish Ministry of Science, Innovation and Universities, under FPI contract no. PRE2022-105015. G.F. is a recipient of Ayuda Investigador AECC 2023 (INVES234765FERR), Fundación Científica AECC. C.Q.-D. is a fellow of the Spanish Ministry of Science, Innovation and Universities, under FPU contract no. FPU22/01655. E.M.'s work in this publication was supported by the Ramón y Cajal fellowship RYC2021-032359-I, funded by the Spanish Ministry of Science and the Catalan Government. Agency for Management of University and Research Grants (AGAUR, 2021 SGR 01586). Research in the A.N. group is supported by the I+D+i project PID2021-127792NB-I00, funded by MCIN/AEI/10.13039/501100011033 (FEDER Una manera de hacer Europa), and "Unidad de Excelencia María de Maeztu", funded by the AEI (CEX2018-000792-M) and Departament de Recerca i Universitats de la Generalitat de Catalunya (GRC 2021 SGR 0467). Research in the R.C.-T. group is funded by the Departament de Recerca i Universitats/Generalitat de Catalunya (2021 SGR 01366). Research in the S.M. group was supported by the Instituto de Salud Carlos III (PI20/00328) and the M. C. Andreu Memorial Fund. J. R.-B. was supported by a doctoral grant from the Universitat Oberta de Catalunya. Research in the M.A.B. laboratory is funded by the European Union, project ERC-AvG Shelterins (GA 882385), Horizon 2020 Programme. The mass spectrometry work was supported by the John and Lucille Van Geest Foundation and the National Institute for Health and Care Research Leicester Biomedical Research Centre. M.E. is an ICREA Research Professor. Special thanks are given to personnel taking care of M116 and to all of the biobank technicians involved in and contributing to keeping samples and procedures for the current research, with special mention to Gerard Pardo Albiñana.