Accelerated aging among childhood, adolescent, and young adult cancer survivors is evidenced by increased expression of p16 INK4a and frailty

Cancer. 2020 Nov 15;126(22):4975-4983. doi: 10.1002/cncr.33112. Epub 2020 Aug 24.

Abstract

Background: Cellular senescence, measured by expression of the cell cycle kinase inhibitor p16INK4a , may contribute to accelerated aging in survivors of childhood, adolescent, and young adult cancer. The authors measured peripheral blood T-lymphocyte p16INK4a expression among pediatric and young adult cancer survivors, hypothesizing that p16INK4a 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 p16INK4a expression and frailty. Newly diagnosed pediatric patients underwent prospective measurements of p16INK4a 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 p16INK4a was higher among survivors compared with controls (9.6 vs 8.9 log2 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 log2 p16 units; 2-sided P = .002). Nine survivors (16%) were frail and had higher p16INK4a expression compared with robust survivors (10.5 [frail] vs 9.5 [robust] log2 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 p16INK4a , suggesting that cellular senescence may be associated with early aging in survivors.

Keywords: p16 INK4a; adolescents; aging; cancer survivorship; frailty; pediatrics; young adults.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Aging / physiology*
  • Cancer Survivors
  • Cross-Sectional Studies
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics*
  • Frailty / physiopathology*
  • Humans
  • Young Adult

Substances

  • Cyclin-Dependent Kinase Inhibitor p16