(OR25-03-23) The Effects of Time Restricted Eating on AGE-RAGE Signaling in Women at High Risk for Breast Cancer

Objectives: It has been estimated that breast cancer risk can be reduced by 30% through lifestyle change. Time restricted eating (TRE) is an eating pattern that prolongs the overnight fasting duration and may be associated with reduced breast cancer and recurrence risk, however the underlying mechanistic aspects of TRE and the relationship to breast cancer risk is not yet known. Advanced glycation end products (AGEs) are reactive metabolites that accumulate in tissues as we grow older. We now consume copious amounts of AGEs as part of the modern diet. A role for dietary derived AGEs in breast cancer is supported by our recent collaborative population studies that positively correlate a high intake of dietary-AGE with breast cancer risk in both the ‘NIH-AARP Diet and Health Study’ and the ‘PLCO Cancer Screening Trial’. The objective of this study is to investigate the link between dietary AGE and TRE with breast cancer risk and outcomes.

Methods: Mice are weaned at 3 weeks of age and started on a high AGE diet. At 8 weeks of age, mice are orthotopically injected with mammary tumor-derived Met1 cells, with subsequent access to diet ad lib or time restriction for 6 hours each day. Water is available at all times in both groups. Tumor growth is measured twice weekly by digital calipers. Blood is collected at the end of the study to measure circulating levels of AGE and RAGE by ELISA.

Results: Previous studies showed that consumption of a high AGE diet led to accelerated and aggressive tumor growth. This study found that TRE led to a decrease in dietary-AGE mediated tumor growth. This was accompanied by a significant increase in sRAGE, a decoy receptor for AGE found in the circulation that has been identified as clinically important in diabetes and breast cancer.

Conclusions: Our data support the hypothesis that TRE induced increases in sRAGE may represent a cancer risk modification by reducing AGE-RAGE toxicity. Therefore, we are also conducting a pilot Randomized Controlled Trial (RCT) designed to measure the effect of TRE on AGE-RAGE toxicity in postmenopausal women with pre-diabetes, a high risk group for breast cancer development. As the epidemic of diabetes continues to expand, increasing the number of women at high risk of breast cancer, identifying the mechanism and type of sRAGE increased in response to TRE will provide a platform for larger intervention studies.

Funding Sources: NIH/NCI