BACKGROUND: Cellular senescence, measured by expression of the cell cycle kinase inhibitor p16 INK4a , may contribute to accelerated aging in survivors of childhood, adolescent, and young adult cancer. The authors measured peripheral blood T-lymphocyte p16 INK4a expression among pediatric and young adult cancer survivors, hypothesizing that p16 INK4a expression is higher after chemotherapy and among frail survivors. METHODS: A cross-sectional cohort of young adult survivors and age-matched, cancer-free controls were assessed for p16 INK4a expression and frailty. Newly diagnosed pediatric patients underwent prospective measurements of p16 INK4a expression before and after cancer therapy. Frailty was measured with a modified Fried frailty phenotype evaluating sarcopenia, weakness, slowness, energy expenditure, and exhaustion. RESULTS: The cross-sectional cohort enrolled 60 survivors and 29 age-matched controls with a median age of 21 years (range, 17-29 years). The prospective cohort enrolled 9 newly diagnosed patients (age range, 1-18 years). Expression of p16 INK4a was higher among survivors compared with controls (9.6 vs 8.9 log 2 p16 units; 2-sided P = .005, representing a 25-year age acceleration in survivors) and increased among newly diagnosed patients from matched pretreatment to posttreatment samples (7.3-8.9 log 2 p16 units; 2-sided P = .002). Nine survivors (16%) were frail and had higher p16 INK4a expression compared with robust survivors (10.5 [frail] vs 9.5 [robust] log 2 p16 units; 2-sided P = .055), representing a 35-year age acceleration among frail survivors. CONCLUSIONS: Chemotherapy is associated with increased cellular senescence and molecular age in pediatric and young adult cancer survivors. Frail survivors, compared with robust survivors, exhibit higher levels of p16 INK4a , suggesting that cellular senescence may be associated with early aging in survivors. Cancer 2020;126:4975-4983.

BACKGROUND:Young adult cancer survivors experience frailty and decreased muscle mass at rates equivalent to much older noncancer populations, which indicate accelerated aging. Although frailty and low muscle mass can be identified in survivors, their implications for health-related quality of life are not well understood. METHODS: Through a cross-sectional analysis of young adult cancer survivors, frailty was assessed with the Fried frailty phenotype and skeletal muscle mass in relation to functional and quality of life outcomes measured by the Medical Outcomes Survey Short-Form 36 (SF-36). z tests compared survivors with US population means, and multivariable linear regression models estimated mean SF-36 scores by frailty and muscle mass with adjustments made for comorbidities, sex, and time from treatment. RESULTS: Sixty survivors (median age, 21 years; range, 18-29) participated in the study. Twenty-five (42%) had low muscle mass, and 25 were either frail or prefrail. Compared with US population means, survivors reported worse health and functional impairments across SF-36 domains that were more common among survivors with (pre)frailty or low muscle mass. In multivariable linear modeling, (pre)frail survivors (vs nonfrail) exhibited lower mean scores for general health (−9.1; P = .05), physical function (−14.9; P < .01), and overall physical health (−5.6; P = .02) independent of comorbid conditions. CONCLUSIONS: Measures of frailty and skeletal muscle mass identify subgroups of young adult cancer survivors with significantly impaired health, functional status, and quality of life independent of medical comorbidities. Identifying survivors with frailty or low muscle mass may provide opportunities for interventions to prevent functional and health declines or to reverse this process.

Background Young adult cancer survivors experience early aging‐related morbidities and mortality. Biological aging biomarkers may identify at‐risk survivors and increase our understanding of mechanisms underlying this accelerated aging. Methods Using an observational study design, we cross‐sectionally measured DNA methylation‐based epigenetic age in young adult cancer survivors at a tertiary, academic state cancer hospital. Participants were a convenience sample of consecutively enrolled survivors of childhood, adolescent, and young adult cancers treated with either an anthracycline or alkylating agent, and who were at least 3 months post‐treatment. Similarly aged healthy comparators were consecutively enrolled. Cancer treatment and treatment intensity were compared to DNA methylation‐based epigenetic age and pace of aging. Results Sixty survivors (58 completing assessments, mean age 20.5 years, range 18–29) and 27 comparators (mean age 20 years, range 17–29) underwent DNA methylation measurement. Survivors were predominantly female (62%) and white (60%) and averaged nearly 6 years post‐treatment (range 0.2–25 years). Both epigenetic age (AgeAccelGrim: 1.5 vs. −2.4, p < 0.0001; AgeAccelPheno 2.3 vs. −3.8, p = 0.0013) and pace of aging (DunedinPACE 0.99 vs. 0.83, p < 0.0001) were greater in survivors versus comparators. In case–case adjusted analysis, compared to survivors with normal muscle mass, myopenic survivors had higher AgeAccelGrim (2.2 years, 95% CI 0.02–4.33, p = 0.02), AgeAccelPheno (6.2 years, 2.36–10.09, p < 0.001), and DunedinPACE (0.11, 0.05–0.17, p < 0.001). Conclusions Epigenetic age is older and pace of aging is faster in young adult cancer survivors compared to noncancer peers, which is evident in the early post‐therapy period. Survivors with physiological impairment demonstrate greater epigenetic age advancement. Measures of epigenetic age may identify young adult survivors at higher risk for poor functional and health outcomes.

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10556 Background: The mechanism of accelerated aging among survivors of childhood, adolescent, and young adult cancer is not clearly understood. Cellular senescence may contribute to this process. We measured peripheral blood T lymphocyte p16INK4a expression, a biomarker of cellular senescence and aging, among pediatric and young adult cancer survivors hypothesizing that p16INK4a expression is higher due to chemotherapy exposure and among frail survivors. Methods: Two cohorts were enrolled from January 2018 to December 2019 at an academic medical center. One, a cross-sectional cohort of young adult cancer survivors and age-matched, cancer-free controls in whom we assessed p16INK4a expression and clinical frailty. Frailty was measured with the modified Fried Frailty Index that evaluates skeletal muscle index, weakness, slowness, leisure energy expenditure, and exhaustion. A second cohort underwent prospective measurement of p16INK4a expression before and after cancer chemotherapy. Eligibility among survivors and newly diagnosed patients required treatment with an alkylating agent, an anthracycline / anthracenedione, or both. Multivariable linear regression was used to model expression of p16INK4a by patient age at assessment, treatment intensity, and frailty status. Results: The cross-sectional cohort enrolled 60 young adult survivors and 29 age-matched, cancer-free controls with median age 21 years and range 17-29 years for both groups. Survivors were a median of 5.5 years from end of treatment. The prospective cohort enrolled nine newly diagnosed patients (range 1-18 years). Expression of p16INK4a was higher among young adult cancer survivors as compared to age-matched controls (9.6 v. 8.9 log2 p16 units, p < 0.01) representing a 25-year age acceleration in the survivors. Expression of p16INK4a increased among newly diagnosed patients from matched pre- to post-treatment samples (7.3 to 8.9 log2 p16 units, p = 0.002). Nine survivors (16%) met criteria for being frail and had higher p16INK4a expression as compared to robust survivors (10.5 [frail] v. 9.5 [robust] log2 p16 units, p = 0.055). Conclusions: Chemotherapy is associated with increased cellular senescence in pediatric and young adult cancer survivors as reflected in expression of p16INK4a indicating an increase in molecular age following chemotherapy exposure. The large proportion of frail survivors in this study also exhibited higher levels of p16INK4a suggesting that cellular senescence may be associated with early aging observed among these survivors.