Decoding Early-Onset Aging After Cancer: Hallmarks, Biomarkers, and Future Directions for Childhood and Young Adult Survivorship.

Abstract

Survival rates for children, adolescents, and young adults (CAYA) with cancer have markedly improved over recent decades, resulting in a rapidly growing population of long-term survivors. However, many of these individuals experience late and long-term treatment-related effects that resemble conditions typically associated with advanced age, including cardiovascular disease, endocrine dysfunction, neurocognitive impairment, and secondary malignancies. This clinical constellation has led to the concept of therapy-induced accelerated aging, suggesting that cancer treatments provoke biological changes that mirror, and may accelerate, physiological aging processes. In this review, we examine current evidence for aging-associated molecular hallmarks in CAYA cancer survivors, focusing on epigenetic alterations, genomic instability, chronic inflammation, cellular senescence, telomere attrition, and mitochondrial dysfunction. Epigenetic age acceleration is consistently observed across multiple survivor cohorts and correlates with treatment exposures, lifestyle factors, and chronic health conditions, positioning DNA methylation-based clocks as promising integrative biomarkers. Likewise, clonal hematopoiesis-reflecting persistent genomic stress-appears enriched in survivors, particularly decades after therapy, and may serve as an indicator of long-term cardiovascular and hematologic risk. Immune dysregulation, inflammaging, and senescence markers further underscore the systemic impact of cancer therapies on biological aging pathways. While telomere shortening and mitochondrial alterations also contribute to this phenotype, their standalone biomarker utility remains limited. Together, these hallmarks highlight the multifaceted nature of accelerated aging in CAYA survivors. Future work integrating multi-omics biomarkers with clinical phenotyping will be essential to identify high-risk individuals, guide targeted interventions, and advance personalized survivorship care.