Why Do Childhood Cancer Survivors Age Faster?

Childhood cancer survivors often face cognitive difficulties many years after treatment. This study shows that these difficulties are linked to the accelerated biological aging of the body, especially epigenetic changes that cause cells to "age" faster than normal. Contrary to what was previously thought, telomere shortening does not seem to explain these cognitive problems. Identifying this type of premature aging can help predict risks, monitor brain health, and develop strategies to improve the quality of life of these survivors over time.

Currently, more than five hundred thousand people who had childhood cancer live in the United States. A worrying fact is that more than forty percent of these people experience lasting cognitive difficulties many years after the end of treatment.

These difficulties involve important brain functions such as attention, memory, planning and decision-making ability, speed of reasoning, and information processing. Problems in these areas can directly affect quality of life, school performance, autonomy in adulthood, social relationships, and job opportunities.

For a long time, it was believed that only treatments that directly affect the central nervous system, that is, the brain and spinal cord, caused these cognitive impairments. However, more recent research shows that other types of treatment can also affect the brain, even without being directed at it.

Radiotherapy applied to other parts of the body and chemotherapies that damage the genetic material of cells can have indirect effects on the nervous system. An example of this is survivors of Hodgkin's lymphoma, who generally do not receive direct treatment to the brain, but still experience greater difficulties with attention and memory and a higher risk of stroke, factors that increase the likelihood of dementia in the future.

These effects occur because cancer treatments can cause microscopic damage to the body's cells. They can alter DNA structure, interfere with cellular function, impair communication between cells, and compromise tissue integrity. When these aggressions occur during childhood, a critical period of growth and development, they can modify how the body and brain mature.

As a consequence, many survivors follow a different aging trajectory than expected, showing signs of biological, physical, and cognitive aging earlier than the general population.

Over time, the accumulation of this cellular damage can lead to processes associated with premature aging, such as chronic inflammation, increased oxidative stress (a type of damage caused by free radicals), weakening of the immune system, telomere shortening, and epigenetic alterations.

Telomeres are structures located at the ends of chromosomes that protect DNA, and their shortening is a known marker of cellular aging. Epigenetic alterations involve chemical changes that affect how genes are activated or deactivated, without altering the DNA sequence. One example of this is the so-called epigenetic age acceleration, which indicates that cells appear to be biologically older than a person's actual age.

Studies show that childhood cancer survivors have shorter telomeres and a greater acceleration of epigenetic aging compared to people who have never had cancer. These markers have already been associated, in elderly individuals without a history of cancer, with cognitive decline and diseases such as dementia, especially in functions like memory, attention, and executive control. However, until recently, it was unknown whether these same associations also occurred in young childhood cancer survivors.

Research conducted with breast cancer patients helped clarify this point. These studies demonstrated that chemotherapy and radiotherapy can cause lasting changes in DNA methylation, a specific type of epigenetic alteration. These changes were associated with cognitive and functional difficulties and remained present for up to two years after the end of treatment, indicating that the effects of cancer and its therapy can extend for many years.

To deal with the enormous amount of epigenetic alterations observed, scientists have developed tools called "epigenetic clocks," which estimate the biological age of cells. Some of these watches measure chronological age, others assess the risk of disease and death, and the most recent analyze the speed of aging in the body.

Previous results already indicated that childhood cancer survivors show clear signs of premature aging even ten years or more after treatment. However, it remained to be understood whether this accelerated biological aging was directly linked to the cognitive difficulties observed in this population. This study was developed precisely to answer this question.

Researchers have found that accelerated epigenetic aging, meaning the body aging biologically faster than expected, is associated with poorer cognitive performance. In contrast, telomere length showed no direct relationship with the cognitive functions assessed.

The analyses took into account whether or not the survivors had received treatments targeting the central nervous system, since this type of therapy can reduce the so-called cognitive reserve, making the brain more vulnerable to premature aging.

Among the survivors who received direct treatment to the central nervous system, those with greater accelerated epigenetic aging showed worse results in tests of attention, processing speed, and executive functions.

Among those who did not receive this type of treatment, the association was also observed, especially in aspects related to attentional stability. In both groups, telomere length did not have a significant impact on cognitive performance.

These findings are important because they suggest that accelerated epigenetic aging may serve as a biological marker to identify survivors at higher risk of premature cognitive aging.

Furthermore, since epigenetic changes can be modified, these results pave the way for the development of interventions aimed at preserving brain health and reducing long-term cognitive impacts in people who have survived childhood cancer.

READ MORE:

Epigenetic age acceleration, telomere length, and neurocognitive function in long-term survivors of childhood cancer

AnnaLynn M. Williams, Nicholas S. Phillips, Qian Dong, Matthew J. Ehrhardt, Nikesha Gilmore, Kah Poh Loh, Xiaoxi Meng, Kirsten K. Ness, Melissa M. Hudson, Leslie L. Robison, Zhaoming Wang, and Kevin R. Krull

Nature Communications. 16, Article number: 10655 (2025). 27 November 2025DOI: 10.1038/s41467-025-65664-5

Abstract:

Survivors of childhood cancer are prone to neurocognitive impairment and premature aging, raising concerns about early onset dementia. In this cross-sectional study, 1413 survivors of childhood cancer complete a neuropsychological battery. Mean leukocyte telomere length residual (mLTL) and epigenetic age acceleration (EAA) from five different epigenetic clocks, are derived from linear regression of mLTL or epigenetic age on chronological age. Among survivors treated with CNS-directed therapy, higher EAA, measured by PCGrimAge, or DunedinPACE is associated with worse performance on multiple measures of attention, processing speed, and executive functions (p’s < 0.05). Among non-CNS-treated survivors, results are similar for PCGrimAge, however, DunedinPACE is specifically associated with attention variability (p < 0.05). mLTL is not associated with neurocognition. EAA is associated with worse neurocognitive function and may identify survivors at risk for accelerated cognitive aging or serve as an efficacy biomarker for neurocognitive interventions.