Aging is a major risk factor for most diseases, and accelerated biological aging is increasingly recognized in many chronic diseases.¹ Chronological age refers to the time that has elapsed since birth, whereas biological age reflects functional, cellular, and tissue age. Accelerated biological aging is when one's biological age outpaces chronological age.

Emerging Evidence of Accelerated Aging in CHD

In heart disease, accelerated biological aging has been linked to heart failure with a fourfold increased risk of death and hospitalization.² Specifically in congenital heart disease (CHD), epidemiological studies have shown that CHD is associated with an increased risk of age-related diseases; cardiovascular diseases such as heart failure, myocardial infarction, and stroke; and noncardiac conditions such as metabolic syndrome, cancer, and neurocognitive deficits in adult life.³ These diseases occur more often and at an earlier age than in non-CHD individuals.

Aging is often associated with frailty, a state of age-associated decline in functional reserve. Children with CHD performed worse than control patients in all five domains of frailty.⁴ In a multicenter study of >800 adults with CHD, more than one-half were prefrail or frail and more than one-third had evidence of cognitive dysfunction.⁵ Frailty in CHD was associated with older age, female sex, higher hemodynamic burden, and more comorbidities.

Telomere length and DNA methylation clocks serve as biomarkers of biological aging. Current evidence on telomere dynamics in CHD is limited, with only one study directly examining telomere length in this population.⁶ In that study, adults with CHD (mean age 25 years) demonstrated telomeres that were 23% shorter than those of healthy control patients, and leukocyte telomere length showed a clear inverse correlation with cumulative exposure to radiological procedures.

Epigenetic clocks based on DNA methylation represent another marker of aging. Specific methylation patterns reflect the cumulative influence of environmental, behavioral, and psychological factors on aging and can be used to estimate biological age and predict health span. Since their introduction in the early 2010s, several epigenetic clocks have been developed. In a pilot study, Drury et al. found that the Fontan circulation is indeed associated with accelerated biological aging, with DNA methylation age advanced by 4.9 years compared with control patients.⁷

Potential Mechanisms of Aging

Accelerated biological aging in CHD is likely driven by a combination of early-life physiological, behavioral, psychological, environmental, and genetic factors.³ Early exposure to surgical stress, chronic hypoxemia, and cumulative low-dose ionizing radiation may initiate cellular injury and telomere shortening, setting the stage for lifelong vulnerability.^6,8,9 Persistent systemic inflammation, particularly in cyanotic lesions or after repeated interventions, could further accelerate aging through oxidative stress, cytokine activation, and impaired repair mechanisms.

Lifestyle and behavioral contributors, including sedentary activity, elevated body mass index, and suboptimal nutrition, may amplify these processes, whereas psychological stressors such as depression, perceived stress, and loneliness are associated with telomere attrition and heightened inflammatory responses.^1,9 Together, these predictors may converge to produce an accelerated aging phenotype that could manifest across multiple organ systems and influence long-term outcomes in this growing patient population. Lifelong abnormal hemodynamics and early surgical trauma have given rise to the concept of "young patients with old hearts."

The fundamental mechanisms underlying aging are not well understood. Aging is driven by multiple, complex, and intertwined pathophysiological processes. These mechanisms (shown in Figure 1) include cellular senescence and inflammation, mitochondrial dysfunction, clonal hematopoiesis of indeterminate potential, metaflammation and dysbiosis, and epigenetic modifications.¹ Inflammation and oxidative stress are heightened in the CHD population.¹⁰ Proteins from circulating microvesicles in the Fontan circulation have a majority of dysregulated proteins related to complement activation, oxidative stress, and cell death, suggesting impaired cell survival and endothelial integrity.¹⁰

These findings align with the broader aging framework, implying that chronic hemodynamic stress, endothelial injury, and oxidative stress may amplify core aging mechanisms in CHD. The search for a better understanding of biomarkers behind the accelerated biological aging process could improve risk stratification, tailor surveillance, and identify interventions that may prevent or mitigate end-organ dysfunction and improve quality of life across the lifespan.

Figure 1: Fundamental Mechanisms Underlying Aging

Created in BioRender. Woo, J. (2025) https://BioRender.com/vekdb5l.
CHD = congenital heart disease; Me1 = monomethylation.

References

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