Accelerated aging among childhood, adolescent, and young adult cancer survivors is evidenced by increased expression of p16<sup>INK4a</sup> and frailty
Andrew B. Smitherman, William A. Wood, Natalia Mitin, Vanessa L. Ayer Miller, Allison M. Deal, Ian J. Davis, Julie Blatt, Stuart Gold, Hyman B. Muss
Abstract
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.