Effects of 2 years of caloric restriction on oxidative status assessed by urinary F2‐isoprostanes: The CALERIE 2 randomized clinical trial

Calorie restriction (CR) without malnutrition slows aging in animal models. Oxidative stress reduction was proposed to mediate CR effects. CR effect on urinary F2-isoprostanes, validated oxidative stress markers, was assessed in CALERIE, a two-year randomized controlled trial. Healthy volunteers (n = 218) were randomized to prescribed 25% CR (n = 143) or ad libitum control (AL, n = 75) stratifying the randomization schedule by site, sex, and BMI. F2-isoprostanes were quantified using LC-MS/MS in morning, fasted urine specimens at baseline, at 12 and 24 months. The primary measure of oxidative status was creatinine-adjusted 2,3-dinor-iPF(2α)-III concentration, additional measured included iPF(2α)-III, iPF2a-VI, and 8,12-iso-iPF2a-VI. Intention-to-treat analyses assessed change in 2,3-dinor-iPF(2α)-III using mixed models assessing treatment, time, and treatment-by-time interaction effects, adjusted for blocking variables and baseline F2-isoprostane value. Exploratory analyses examined changes in iPF(2α)-III, iPF(2α)-VI, and 8,12-iso-iPF(2α)-VI. A factor analysis used aggregate information on F2-isoprostane values. In CR group, 2,3-dinor-iPF(2α)-III concentrations were reduced from baseline by 17% and 13% at 12 and 24 months, respectively; these changes were significantly different from AL group (p < .01). CR reduced iPF(2α)-III concentrations by 20% and 27% at 12 and 24 months, respectively (p < .05). The effects were weaker on the VI-species. CR caused statistically significant reduction in isoprostane factor at both time points, and mean (se) changes were -0.36 (0.06) and -0.31 (0.06). No significant changes in isoprostane factor were at either time point in AL group (p < .01 between-group difference). We conclude that two-year CR intervention in healthy, nonobese men and women reduced whole body oxidative stress as assessed by urinary concentrations of F2-isoprostanes.