Premature Aging as an Accumulation of Deficits in Young Adult Survivors of Pediatric Cancer

AnnaLynn M. Williams, PhD; Jeanne Mandelblatt, MD, MPH; Mingjuan Wang, MS; Gregory T. Armstrong, MD, MSCE; Nickhill Bhakta, MD, MPH; Tara M. Brinkman, PhD; Wassim Chemaitilly, MD; Matthew J. Ehrhardt, MD, MS; Daniel A. Mulrooney, MD, MS; Brent J. Small, PhD; Zhaoming Wang, PhD; Deokumar Srivastava, PhD; Leslie L. Robison, PhD; Melissa M. Hudson, MD; Kirsten K. Ness, PhD; Kevin R. Krull, PhD


J Natl Cancer Inst. 2023;115(2):200-207. 

In This Article

Abstract and Introduction


Background: We aimed to characterize premature aging as an accumulation of deficits in survivors of pediatric cancer compared with community controls and examine associations with host and treatment factors, neurocognition, and mortality.

Methods: Pediatric cancer survivors (n = 4000, median age = 28.6, interquartile range [IQR] = 23–35 years; 20 years postdiagnosis: IQR = 15–27), and community participants without a history of cancer serving as controls (n = 638, median age = 32, IQR = 25–40 years) completed clinical assessments and questionnaires and were followed for mortality through April 30, 2020 (mean [SD] follow-up = 7.0 [3.4] years). A deficit accumulation index (DAI) score was calculated from 44 aging-related items including self-reported daily function, psychosocial symptoms, and health conditions. Items were weighted from 0 (absent) to 1 (present and/or most severe), summed and divided by the total yielding a ratio (higher = more deficits). Scores less than 0.20 are robust, and 0.06 is a clinically meaningful difference. Linear regression compared the DAI in survivors and controls with an age*survivor or control interaction. Logistic regression and Cox-proportional hazards estimated the risk of neurocognitive impairment and death. Models were minimally adjusted for age, sex, and race and ethnicity.

Results: The adjusted mean DAI among survivors at age 30 years was 0.16 corresponding to age 63 years in controls (33 years premature aging; β = 0.07, 95% confidence interval [CI] = 0.06 to 0.08; P < .001). Cranial and abdominal radiation, alkylators, platinum, and neurosurgery were associated with worse DAI (P ≤ .001). Higher scores were associated with increased risk of neurocognitive impairment in all domains (P < .001) and increased risk of death (DAI = 0.20–0.35, hazard ratio = 2.80, 95% CI = 1.97 to 3.98; DAI ≥ 0.35, hazard ratio = 5.08, 95% CI = 3.52 to 7.34).

Conclusion: Pediatric cancer survivors experience clinically significant premature aging. The DAI may be used to identify survivors at greatest risk of poor health outcomes.


Aging has been described as an accumulation of molecular damage ultimately leading to tissue and organ dysfunction and physiologic dysregulation.[1] In the general population, age is the most significant risk factor for outcomes such as cancer, functional decline, neurocognitive impairment, and mortality. The substantial variability in development of disease and functional decline among individuals of the same chronological age suggests heterogeneity in age-related accumulation of damage.

This variability may be exacerbated in cancer survivors whose treatment causes molecular damage, including changes to DNA structure, cellular function, signaling, and tissue integrity.[2] In pediatric patients, these exposures happen during development and may set survivors on a unique aging trajectory. Further, early molecular damage may make survivors more vulnerable to the negative health implications of social and environmental influences encountered during aging (eg, socioeconomic factors, smoking).[3] Survivors of pediatric cancer have higher than expected rates of chronic health conditions, physiologic frailty, and neurocognitive impairment as well as elevated telomere attrition and epigenetic age, all of which suggest premature aging.[4–11]

We propose a deficit accumulation index (DAI) framework to assess aging, which will expand previous work in survivors of pediatric cancer by considering the accumulation of multiple deficits across various health and functional domains.[12] A comprehensive and integrated approach to measuring individual aging is important because components that contribute to aging are multifactorial and interdependent. Accumulation of multiple and interdependent deficits increases the risk of mortality and, theoretically, biologic aging and physiologic dysregulation.[12,13] Using this approach, integration of large and small effects can be considered using information that on its own may only weakly correlate with an outcome. For example, the accumulation of deficits has predicted dementia in the general population when individual risk factors could not.[14]

We aimed to characterize aging as an accumulation of deficits in survivors of pediatric cancer relative to community controls, identify associated host and treatment factors, and examine associations with aging-related outcomes including neurocognition and mortality. The DAI framework has not been applied in survivors of pediatric cancer and provides multiple advantages over previous work done in this population (eg, chronic health cumulative burden, frailty). Including a focus on assessment of diverse aging-related items across multiple systems and the DAI may be used on a continuous scale to detect more subtle, but clinically meaningful, changes over time that may help assess response in intervention trials. Importantly, administering the DAI requires no specific training. Aging-related items included in the DAI may be extracted from medical records or assessed by questionnaires making them a feasible way to identify survivors at risk for aging-related outcomes.