Corresponding Author
Key Words: biological age, genetic predisposition, KDM-BA acceleration, PhenoAge acceleration, valvular heart disease
Biological aging is a complex, nonlinear process that shows substantial heterogeneity in its relationship with chronological age.1 Individuals of the same chronological age may experience markedly different rates of biological aging because of comorbid conditions, environmental exposures, genetic predisposition, and lifestyle behavior.1 Multiple biomarker-, genotyping-, and imaging-based measures of biological age have been proposed; yet, the modest correlations between these metrics suggest they assess distinct aspects of aging.1,2 Similarly, biological heart age has been estimated with composite models incorporating biochemical and cardiac imaging biomarkers, but their prognostic value remains uncertain.
Biological aging biomarkers were reported to be associated with mortality, healthy aging, and age-related conditions. However, their performance in predicting aging-related diseases such as cardiovascular disease, coronary artery disease, and heart failure varied.3 Although these biomarkers are all intended to capture accelerated aging, they differ substantially in the biological domains assessed and their clinical utility.2,3 Notably, data linking biomarker-based measures of biological age to the incidence of valvular heart disease (VHD) remain limited, despite growing evidence from noninvasive cardiac imaging–based risk scores.
In a recent issue of JACC: Asia, Zhu et al4 evaluated the association of 2 biochemical aging metrics, the Klemera–Doubal Method Biological Age, and the PhenoAge, with incident VHD in middle-aged participants from the United Kingdom Biobank. The investigators also examined the joint effects and potential interactions between biological aging and genetic susceptibility, as measured by a polygenic risk score, on the development of VHD.
The authors included 341,460 individuals free of VHD at baseline. Their analysis was restricted to common aging-associated VHD and excluded conditions such as rheumatic disease. Over a median follow-up of 13.6 years, the cumulative incidence was 2.4% for VHD, 1.2% for mitral regurgitation, 1.0% for aortic stenosis, and 0.4% for aortic regurgitation. They found that individuals who had a lower biological than chronological age had significantly lower VHD incidence, while those with a higher biological than chronological age showed significantly higher VHD risk. Moreover, biological aging markers demonstrated significant additive and synergistic effects with polygenic risk scores in predicting VHD, with aging-associated risk independent of genetic susceptibility.
The recognition of biological aging as an independent risk factor for incident VHD has important clinical implications. Given the absence of effective medical therapies to halt the progression of VHD, understanding the contribution of biological aging may offer new avenues for refining prediction and potentially informing preventive strategies. Biological age metrics may help characterize healthy aging trajectories, identify deviations from expected aging patterns, and improve risk stratification beyond traditional factors. Future studies need to determine whether integrated models combining biomarker, imaging, and genotyping-based measures provide improved cardiovascular risk calibration, particularly in vulnerable populations where traditional risk factors do not explain why they develop VHD earlier than other populations. Ultimately, incorporating biological aging into a broader framework for the management of incident cardiovascular disease, coronary artery disease, heart failure, and VHD that addresses interconnected cardiometabolic, immunologic, and genetic pathways may support the development of strategies to promote healthy cardiovascular aging at both the individual and population levels.
Funding Support and Author Disclosures
The author has reported that he has no relationships relevant to the contents of this paper to disclose.
Footnotes
The author attests they are in compliance with human studies committees and animal welfare regulations of the author’s institution and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
References
- 1.Wu J.W., Yaqub A., Ma Y., et al. Biological age in healthy elderly predicts aging-related diseases including dementia. Sci Rep. 2021;11(1) doi: 10.1038/s41598-021-95425-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Raisi-Estabragh Z., Szabo L., Schuermans A., et al. Noninvasive techniques for tracking biological aging of the cardiovascular system: JACC family series. JACC Cardiovasc Imaging. 2024;17(5):533–551. doi: 10.1016/j.jcmg.2024.03.001. [DOI] [PubMed] [Google Scholar]
- 3.Forrester S.N., Baek J., Hou L., Roger V., Kiefe C.I. A comparison of 5 measures of accelerated biological aging and their association with incident cardiovascular disease: the CARDIA study. J Am Heart Assoc. 2024;13(8) doi: 10.1161/JAHA.123.032847. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Zhu Y.J., Suo X.Y., Guo J., et al. Accelerated biological aging, genetic predisposition, and incident valvular heart disease. JACC Asia. 2026;6(1):41–51. doi: 10.1016/j.jacasi.2025.06.011. [DOI] [PMC free article] [PubMed] [Google Scholar]