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

## TL;DR

Cancer survivors, especially young ones, often face age-related health issues due to treatments, and this review explores how biological aging processes might explain these effects.

## Contribution

This review synthesizes current evidence on molecular hallmarks of accelerated aging in young cancer survivors and highlights potential biomarkers for risk assessment.

## Key findings

- Epigenetic age acceleration is consistently observed in cancer survivors and correlates with treatment and health conditions.
- Clonal hematopoiesis is enriched in survivors and may indicate long-term cardiovascular and hematologic risks.
- Immune dysregulation and inflammaging underscore the systemic impact of cancer therapies on aging pathways.

## Abstract

More children, teenagers, and young adults survive cancer today than ever before, but many develop health problems years after their treatment has ended. These problems often look similar to conditions usually seen in much older adults, such as heart disease, hormone changes, memory difficulties, or second cancers. This has raised the important question of whether cancer treatment speeds up the body’s natural aging processes. In this review, we bring together current knowledge about biological changes that may explain why some survivors experience earlier or more severe long-term health issues. We look at different signs of aging inside the body, such as changes in DNA regulation, stress on blood-forming cells, inflammation, immune system weakness, and energy production in cells. By summarizing the latest research, we aim to show how these changes develop, how they may interact, and how they could help identify survivors at higher risk for future health problems. Understanding these biological aging processes may guide new ways to monitor health, prevent complications, and design treatments that protect long-term wellbeing in young cancer survivors.

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.