Biological age acceleration and mortality risk among U.S. adults with cardio-kidney-metabolic syndrome, stages 0–3

Q: What are the key findings of this study?

Phenotypic age acceleration positivity independently increased the risk of all-cause mortality by 103% (HR 2.03) compared to non-accelerated biological age in adults with CKM stages 0-3.

Q: What is the clinical evidence from this study?

Study design: Cohort. Population: Cardio-Kidney-Metabolic (CKM) syndrome stages 0-3 (n=16837). Intervention: Phenotypic Age Acceleration (PAA) vs. Non-accelerated biological age. Primary outcome: All-cause mortality (HR 2.03, 95% CI 1.82-2.26, p=<0.001).

Q: What does this research mean for the field?

Biological age acceleration, specifically measured by KDM-BAA and PAA positivity, independently increases the risk of all-cause mortality by 41% and 103%, respectively, among adults with cardio-kidney-metabolic syndrome stages 0-3. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

To evaluate the associations of Klemera-Doubal Method Biological Age Acceleration (KDM-BAA) and Phenotypic Age Acceleration (PAA) with all-cause and cause-specific mortality in U.S. adults with cardio-kidney-metabolic syndrome stages 0–3, and to establish risk prediction models.

Xiaoqiang Chen; Yisen Huang; Yingxuan Huang; Yingyi Li; Xinqi Chen; Yubin Wang; Xiaoqiang Liu

doi:10.1097/md.0000000000050450

August 28, 2026MedicineOpen Access

Biological age acceleration and mortality risk among U.S. adults with cardio-kidney-metabolic syndrome, stages 0–3

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Key result

Phenotypic age acceleration is linked to ~103% higher all-cause mortality in early-stage CKM.

HR 2.03
95% CI 1.82-2.26
P<0.001
n=16,837

Figures

Why the study?

To evaluate the associations of KDM-BAA and PAA with all-cause and cause-specific mortality in U.S. adults with CKM syndrome stages 0–3 and establish risk prediction models.

Does biological age acceleration predict mortality in U.S. adults with Cardio-Kidney-Metabolic syndrome stages 0-3?

Key Points

To evaluate the associations of Klemera-Doubal Method Biological Age Acceleration (KDM-BAA) and Phenotypic Age Acceleration (PAA) with all-cause and cause-specific mortality in U.S. adults with cardio-kidney-metabolic syndrome stages 0–3, and to establish risk prediction models.
Analyzed data from 16,837 participants (representing 90,153,719 weighted individuals) with CKM stages 0–3 from NHANES 1999–2010 and 2015–2018 linked to National Death Index mortality data through December 31, 2019.
Calculated biological age acceleration residuals using the Klemera-Doubal Method (KDM-BA) and Phenotypic Age algorithms.
Assessed mortality risks across a median follow-up of 11.33 years using multivariable Cox proportional hazards models and constructed LASSO-Cox nomograms for 10- and 20-year mortality prediction.
Over a median follow-up of 11.33 years, 10.8% of the weighted population died (9,754,249 deaths), including 2.9% from CVD (2,635,057 deaths) and 7.9% from non-CVD causes (7,119,191 deaths).
After multivariable adjustment, KDM-BAA positivity significantly increased the risk of all-cause mortality (HR = 1.41, 95% CI 1.29–1.54), CVD mortality (HR = 1.74, 95% CI 1.46–2.09), and non-CVD mortality (HR = 1.31, 95% CI 1.19–1.44).
PAA positivity showed higher risk elevations for all-cause (HR = 2.03, 95% CI 1.82–2.26), CVD (HR = 1.79, 95% CI 1.46–2.18), and non-CVD mortality (HR = 2.12, 95% CI 1.87–2.41), with LASSO-Cox nomograms achieving validation AUCs of 0.765 at 10 years and 0.757 at 20 years.

Study Design

Type

Cohort (n=16,837)

Multicenter

Yes

Structured PICO

Does biological age acceleration predict mortality in U.S. adults with Cardio-Kidney-Metabolic syndrome stages 0-3?

P

Population

16,837 U.S. adults aged 20 and older with Cardio-Kidney-Metabolic syndrome stages 0-3, followed for a median of 11.33 years.

E

Exposure

Biological age acceleration (BAA) defined by Klemera-Doubal Method (KDM-BAA) or Phenotypic Age Acceleration (PAA) positivity

C

Comparator

No biological age acceleration (KDM-BAA or PAA negativity)

O

Outcome

All-cause mortality, cardiovascular mortality, and non-cardiovascular mortalityhard clinical

Main Result

Hazard Ratio: 2.03 (95% CI 1.82–2.26)

p-value: p=<0.001

Biological age acceleration, particularly Phenotypic Age Acceleration, independently predicts long-term all-cause and cardiovascular mortality in adults with early-stage (0-3) Cardio-Kidney-Metabolic syndrome.

Limitations

Observational study design with potential for residual confounding.
Biological age was only calculated at baseline without tracking trajectories over time.
Inconsistent measurement of some inflammatory markers like IL-6 and TNF-α.
Applicability of CKM staging in other ethnicities requires further prospective validation.
Self-reported data is prone to recall bias.

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Implication

Phenotypic age acceleration may aid mortality prediction in early CKM stages; hypothesis-generating and warrants prospective validation before clinical adoption.

Abstract

This study aims to evaluate the associations of Klemera-Doubal Method Biological Age Acceleration (KDM-BAA) and Phenotypic Age Acceleration (PAA) with all-cause and cause-specific mortality in U.S. adults with Cardio-Kidney-Metabolic (CKM) syndrome stages 0–3 and to establish risk prediction models. Data were obtained from 16,837 participants in NHANES 1999–2010 and 2015–2018, linked to mortality through 2019. Biological age was estimated using KDM-BA and Phenotypic Age algorithms, with residuals defining Biological Age Acceleration (BAA). Cox proportional hazards models were applied, and LASSO-Cox nomograms were developed for mortality prediction. Over a median follow-up of 11.33 years, 10.8% of the weighted population (9.75 million adults) died. After full adjustment for confounders, KDM-BAA positivity increased the risk of all-cause, CVD, and non-CVD mortality by 41%, 74%, and 31%, respectively; PAA positivity showed even larger increases – 103%, 79%, and 112%. Both metrics consistently exhibited a positive association in multiple subgroups and sensitivity analyses. The LASSO-Cox-based nomogram showed favorable discrimination (training AUCs 0.776 and 0.775 at 10 and 20 years; validation AUCs 0.765 and 0.757, respectively) and good calibration, suggesting potential clinical applicability. BAA independently predicts long-term mortality among individuals with CKM stages 0–3. PAA provides superior prognostic value, supporting the importance of monitoring biological aging to guide early intervention and improve long-term outcomes.

Discussion

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Cite This Study

Chen et al. (2026) conducted a cohort in Cardio-Kidney-Metabolic (CKM) syndrome stages 0-3 (n=16,837). Phenotypic Age Acceleration (PAA) vs. Non-accelerated biological age was evaluated on All-cause mortality (HR 2.03, 95% CI 1.82-2.26, p=<0.001). Phenotypic age acceleration positivity independently increased the risk of all-cause mortality by 103% (HR 2.03) compared to non-accelerated biological age in adults with CKM stages 0-3.

synapsesocial.com/papers/6a93f0696c1a8fb52e79c913 https://doi.org/10.1097/md.0000000000050450

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Biological age acceleration and mortality risk among U.S. adults with cardio-kidney-metabolic syndrome, stages 0–3

Figures

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Biological age acceleration and mortality risk among U.S. adults with cardio-kidney-metabolic syndrome, stages 0–3

Figures

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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