Associations between exercise capacity, p16INK4a expression and inflammation among adult survivors of childhood cancer

Abstract

Background: Over 50% of childhood cancer survivors are exercise intolerant, with maximal aerobic capacities comparable to individuals decades older, suggesting early physiologic ageing. In addition, 36% of survivors are obese. Optimal exercise capacity provides a foundation to support daily function and healthy body habitus and is associated with benefits to cognition, cardiovascular health, and longevity. Cellular senescence and inflammation are key mechanisms that drive age-related disease, quantifiable as biomarkers in peripheral blood.

Aims: This study aimed to evaluate associations between p16^INKa, a biomarker of cellular senescence, and inflammation and exercise capacity among adult survivors of childhood cancer.

Materials and methods: Eligible survivors were recruited from the St. Jude Lifetime (SJLIFE) Cohort Study. Exercise capacity was assessed by maximal oxygen uptake (VO₂, ml/kg/min) obtained via cardiopulmonary exercise testing using a modified Bruce protocol. Body fat (%) was determined from dual energy x-ray absorptiometry (DEXA). Peripheral blood samples were used to evaluate log₂ p16^INK4a mRNA expression, a biomarker of cellular senescence, and inflammation with high sensitivity C-reactive protein (hs-CRP) levels. Multivariable regression evaluated associations between p16^INK4a, hs-CRP, body fat, and exercise capacity.

Results: Participants included 185 five-year childhood cancer survivors (mean age 36.6 [range 20.1 - 55.7] years, 44% male, 77% non-Hispanic white, 53% leukemia/lymphoma). Compared to males, females had lower peak VO₂ (mean ± SD, 22.5 ± 8.2 vs. 28.8 ± 7.7 ml/kg/min, p<0.01), higher p16^INK4a expression (9.6 ± 1.2 vs. 9.2 ± 1.2 fold, p=0.02), and hs-CRP concentration (5.9 ± 8.4 vs. 3.3 ± 3.9 mg/L, p=0.01). Among females (n=103), hs-CRP concentration (β -0.2, 95% CI -0.34 to -0.05, p=0.01) and p16^INK4a expression (β-5.32, 95% CI 10.42 to -0.22, p=0.04) were inversely associated and statistically significant with peak exercise capacity, with a significant interaction between p16^INK4a expression and body fat (β 0.15, 95% CI 0.02 to 0.28, p=0.03). Among males (n=82), p16^INK4a expression (β -1.01, 95% CI -2.14 to 0.12, p=0.08), and body fat (β -0.54, 95% CI -0.70 to -0.38, p<0.01) were inversely associated with peak exercise capacity.

Conclusion: Inflammation and p16^INK4a expression, a biomarker of cellular senescence, are associated with lower exercise capacity in childhood cancer survivors, suggesting potential targets or outcome measures for interventions designed to prevent or remediate accelerated physiologic ageing in this population.

Keywords: cellular senescence; childhood cancer surivor; exercise capacity; inflammation; p16.

Figure 1

Participant flow.

Figure 2

Distribution of biomarkers of inflammation and cellular senescence by sex. (A) hs-CRP concentration (mg/L) (B) p16 ^INK4A expression. * denotes statistical significance at p<0.05

Figure 3

Results of sex-stratified multivariable models. (A, B) hs-CRP concentration (mg/L), (C, D) p16 ^INK4A expression. Regression lines represent the linear associations between individual biomarkers and exercise capacity, adjusted for covariates

Figure 4

Association of p16^INK4A expression and exercise capacity by body fat percent in female survivors.