Uncertainty redefines biological age
- 1Tsinghua University
Abstract
Biological aging clocks typically summarize complex biological profiles as a single age estimate, yet how uncertain these estimates are and whether this uncertainty represents a distinct, biologically meaningful dimension of human aging remain unclear. Here we develop a probabilistic framework to derive biological age gap (BAG) and biological age uncertainty (BAU) from the mean and width of predicted-age distributions in more than 450,000 UK Biobank participants, evaluate their prospective associations with aging-related outcomes, and characterize the molecular and genetic foundations of BAU through cross-omic profiling, genome-wide association studies and tissue and functional mapping. BAU was weakly correlated with BAG and increased with age-signal disagreement across individual molecules and discrete organs, linking uncertainty to reduced coherence of aging biological systems. Higher BAU was associated with mortality, loss of healthspan and multimorbidity independently of BAG, with mortality hazard ratios of 1.24 (95% CI, 1.23-1.26) and 1.40 (95% CI, 1.37-1.43) per standard deviation for NMR-derived and proteomic-derived BAU, respectively. Longitudinal increases in NMR-derived BAU were associated with subsequent health decline, and mortality associations were replicated using routine-blood-derived BAU in three independent external cohorts. Cross-omic analyses linked BAU to inflammation, metabolic regulation and tissue remodelling. Genetic analyses revealed overlapping but distinct architectures of BAU and BAG, with tissue and functional mapping further implicating immune and lipid-metabolic processes. This study establishes a framework for characterizing biological age through both its mean deviation and uncertainty, defining BAU as a new dimension of human aging that links the coherence of aging signals to future health vulnerability.
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BibTeX
@misc{li2026uncertainty,
title = {{Uncertainty redefines biological age}},
author = {Y. Li and G. Feng and S. Yan and Q. Huang and J. Jiang and Z. Pei and L. X. Tay and K. Li and Z. Pan and Z. Yuan and L. Gao and J. S. Ji and L. Ke and K. Gu and Q. Di},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.26.26364091},
url = {https://www.medrxiv.org/content/10.64898/2026.09.26.26364091v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Uncertainty redefines biological age
AU - Y. Li
AU - G. Feng
AU - S. Yan
AU - Q. Huang
AU - J. Jiang
AU - Z. Pei
AU - L. X. Tay
AU - K. Li
AU - Z. Pan
AU - Z. Yuan
AU - L. Gao
AU - J. S. Ji
AU - L. Ke
AU - K. Gu
AU - Q. Di
PY - 2026
DA - 2026/09/26
PB - medRxiv
DO - 10.64898/2026.09.26.26364091
UR - https://www.medrxiv.org/content/10.64898/2026.09.26.26364091v1
AB - Biological aging clocks typically summarize complex biological profiles as a single age estimate, yet how uncertain these estimates are and whether this uncertainty represents a distinct, biologically meaningful dimension of human aging remain unclear. Here we develop a probabilistic framework to derive biological age gap (BAG) and biological age uncertainty (BAU) from the mean and width of predicted-age distributions in more than 450,000 UK Biobank participants, evaluate their prospective associations with aging-related outcomes, and characterize the molecular and genetic foundations of BAU through cross-omic profiling, genome-wide association studies and tissue and functional mapping. BAU was weakly correlated with BAG and increased with age-signal disagreement across individual molecules and discrete organs, linking uncertainty to reduced coherence of aging biological systems. Higher BAU was associated with mortality, loss of healthspan and multimorbidity independently of BAG, with mortality hazard ratios of 1.24 (95% CI, 1.23-1.26) and 1.40 (95% CI, 1.37-1.43) per standard deviation for NMR-derived and proteomic-derived BAU, respectively. Longitudinal increases in NMR-derived BAU were associated with subsequent health decline, and mortality associations were replicated using routine-blood-derived BAU in three independent external cohorts. Cross-omic analyses linked BAU to inflammation, metabolic regulation and tissue remodelling. Genetic analyses revealed overlapping but distinct architectures of BAU and BAG, with tissue and functional mapping further implicating immune and lipid-metabolic processes. This study establishes a framework for characterizing biological age through both its mean deviation and uncertainty, defining BAU as a new dimension of human aging that links the coherence of aging signals to future health vulnerability.
ER -