Risk assessment in clinical practice depends largely on clinical phenotypes, including age, sex, body mass index, blood pressure and comorbidities. Routine laboratory data remain underutilised despite their accessibility and low cost. Using data from the Singapore Longitudinal Ageing Studies (n = 5,409; follow-up median 11.4 years), we developed a mortality prediction model based on routine laboratory biomarkers. We derived a biological age (age quotient, or AQ) score, and investigated its role as a mediator between lifestyle risk factors and mortality. Both models and association analyses were validated in the US National Health and Nutrition Examination Survey (n = 6,593) and UK Biobank (n = 290,949) cohorts. AQ was significantly elevated in deceased individuals (P<0.0001). AQ acceleration was also observed (P<0.0001). In overall survival discrimination, AQ outperformed chronological age (C-index 0.629 [SE 0.011] vs 0.606 [SE 0.011]), indicating superior prognostic prediction. Additionally, incorporation of AQ into a baseline model containing chronological age resulted in an improvement in model fit (likelihood ratio test, P<0.0001), consistent with incremental predictive value for mortality beyond chronological age alone. Mediation analysis supports a partial mediating role for AQ in the relationship between lifestyle factors and mortality. In a 57-patient subset, higher AQ was associated with increased TET2 clonal hematopoiesis burden (β≈0.016 per +1 AQ year), suggesting a potential link between AQ acceleration, CH risk and diseases of aging, requiring validation in larger cohorts. We identified differential associations between lifestyle factors and groups of biological age components, indicating selective effects across biological systems. These findings provide an evidence-based framework for earlier and more accurate identification of high-risk individuals, offering a practical and easy-to-implement tool to inform preventive strategies.

Y.J, L.X, R.H.C.M, T.M.H. and J.Y. are inventors on a provisional patent #10202600079P related to the findings of this study. T.M.H and C.H. are employees and shareholders of Lucence Diagnostics Pte Ltd.

This study was funded by the Agency for Science, Technology and Research (A*STAR) Industry Alignment Fund - Industry Collaboration Fund (I2001E0065) and Singapore Strategic Cohorts Consortium - Singapore Chinese Health Study (P2022-02).

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:

Institutional Review Board of the National University of Singapore gave ethical approval for this work (04-140).

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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).

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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

Conflict of Interest: Y.J, L.X, R.H.C.M, T.M.H. and J.Y. are inventors on a provisional patent #10202600079P related to the findings of this study. T.M.H and C.H. are employees and shareholders of Lucence Diagnostics Pte Ltd.

Ethical statement: This study is approved by the National University of Singapore Institutional Review Board (04-140) and conducted in accordance with the ethical principles outlined in the Belmont Report and the Declaration of Helsinki. Informed written consent was obtained from all study participants.

NHANES data are publicly available from the National Center for Health Statistics at https://www.cdc.gov/nchs/nhanes/index.htm. UK Biobank data are protected and not publicly available due to data privacy regulations; they are accessible to approved researchers for health-related research in the public interest through the UK Biobank Access Management System.