Time-restricted eating to entrain circadian rhythms, increase physiological responsiveness, and prevent stressor-induced frailty: A pilot randomized controlled trial.

INTRODUCTION: Treatments for advanced and metastatic cancer can cause fatigue and accelerate the progression to frailty, a condition that increases vulnerabilities to stressors. Time-restricted eating (TRE) entails consuming food within a defined time window every day. TRE may help strengthen circadian rhythms and improve physiology. We present findings from a pilot study assessing the feasibility of TRE, when aligned with the daytime hours, as well as measures of fatigue, frailty, diurnal rhythms, and physiological responsiveness among people living with cancer. MATERIALS AND METHODS: Participants were eligible if they were ≥ 55 years old and had prostate cancer receiving androgen deprivation therapy (ADT) or metastatic breast cancer receiving CDK4/6 inhibitors plus an aromatase inhibitor. All participants met with a licensed dietitian/nutritionist and were provided with personalized nutrition counseling fortnightly for 12 weeks. After baseline assessments, participants were randomized 1:1 to TRE, with a self-selected 10-h eating window, or control. The primary outcomes were retention and adherence. Secondary outcomes included fatigue (FACIT-F fatigue subscale), frailty (Fried's frailty criteria), rest-activity rhythms using actigraphy, 24-h urinary hormone fluctuations (e.g., cortisol, melatonin, epinephrine, norepinephrine; dynamic range assessed as maximum-minimum), and orthostatic blood pressure change. For future hypothesis generation, effect of group was assessed using linear regression; correlations between outcomes were assessed using linear mixed models controlling for relevant confounding factors. RESULTS: Participants (n = 30, 93% male) were 68.8 ± 6.4 years old (range 57.4-81.0 y); 24 were randomized and 20 completed the intervention (83.3% retention). The average eating window was 11.6 ± 2.4 h at baseline (all participants). From weeks 1-12, the average eating window was 9.2 ± 1.4 h for the TRE group and 13.3 ± 1.5 for the control group (t-test, p < 0.001). There were no between-group effects for fatigue, frailty, or rhythm measures (p > 0.05). However, relative amplitude of rest-activity rhythms was associated with less fatigue (b ± SE = -6.3 ± 2.8, p = 0.03). Also, frailty was negatively associated with the dynamic range in urinary norepinephrine (b ± SE = -0.033 ± 0.016, p = 0.06). DISCUSSION: TRE is a feasible nutritional program for older adults living with cancer. A greater dynamic range of several circadian rhythm parameters was associated with better supportive care outcomes, suggesting that entrainment of circadian rhythms may help alleviate fatigue and frailty. A larger, phase II preliminary efficacy study is warranted. TRIAL REGISTRATION: NCT05968144.