Heterogeneous metabolomic aging across the same age and prediction of health outcome

Existing metabolomic clocks exhibit deficiencies in capturing the heterogeneous aging rates among individuals with the same chronological age. Yet, the modifiable and non-modifiable factors in metabolomic aging have not been systematically studied. Here, we leveraged metabolomic profiles of 239,291 UK Biobank participants for 10-year all-cause mortality prediction to generate and validate a new aging measure--MetaboAgeMort. The MetaboAgeMort showed significant associations with all-cause mortality, cause-specific mortality, and diverse incident diseases. Adding MetaboAgeMort to conventional risk factors model improved the predictive ability of 10-year mortality. We identified 99 modifiable factors for MetaboAgeMort, where 16 factors representing pulmonary function, body composition, socioeconomic status, dietary quality, smoking status, alcohol intake, and disease status showed quantitatively stronger associations. The genetic analyses revealed 99 genomic risk loci and 271 genes associated with MetaboAgeMort. Our study illuminates heterogeneous metabolomic aging across the same age, which provides avenues for developing anti-aging therapies and personalized interventions. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by Grants from Research Center of Prevention and Treatment of Senescence Syndrome, School of Medicine Zhejiang University (2022010002), "Pioneer" and "Leading Goose" R&D Programs of Zhejiang Province (2023C03163), the National Natural Science Foundation of China (72374180), the Fundamental Research Funds for the Central Universities, Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province (2020E10004), and Zhejiang University Global Partnership Fund (188170-11103). The funders had no role in the study design; data collection, analysis, or interpretation; in the writing of the report; or in the decision to submit the article for publication. ### 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: This research was conducted using the UK Biobank resource under application number 61856. The North West Multi-Centre Research Ethics Committee gave ethical approval for the UK Biobank and is renewed every 5 years, which allowed researchers to use data from UK Biobank without an additional ethical clearance. All participants have provided signed informed consent. 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 All data produced are available online at [www.ukbiobank.ac.uk/register-apply][1]. [1]: http://www.ukbiobank.ac.uk/register-apply