The effects of time restricted feeding on AGE-RAGE signaling in women at high risk for breast cancer

糖尿病前期与乳腺癌风险增加有关。最近的研究已经认识到， 间歇性禁食，以早期限制进食(TRF)的形式，避免昼夜节律不同步 改善胰岛素抵抗。TRF是一种饮食模式，通过协调来延长隔夜的禁食时间 卡路里摄入量有昼夜昼夜节律。夜间禁食时间延长可能与 降低乳腺癌和复发风险。持续整夜禁食的潜在机制 目前尚不清楚持续时间和与乳腺癌风险的关系。 晚期糖基化终末产物(AGEs)是随着我们年龄的增长而在组织中积累的反应性代谢物。 作为现代饮食的一部分，我们现在消耗了大量的AGE。AGEs的致病作用 通过应激反应的异常激活导致胰岛素抵抗、糖尿病和癌症 小路。我们的动物研究的一个重要发现是，饮食年龄导致乳腺癌的增加 生长受到TRF的限制。饮食-年龄调节的乳腺肿瘤生长的增加取决于 跨膜AGE受体(RAGE)的间质表达。可溶愤怒是一个宽泛的术语 用来定义在循环中发现的各种截断形式的全长愤怒。它包含一个 一组肿瘤抑制变异的致癌基因，被认为通过隔离年龄在循环中 充当诱饵感受器。伴随TRF介导的饮食年龄诱导的肿瘤生长减少 是斯雷格的显著增加。 我们推测，TRF诱导的sRAGE增加可能代表着通过减少 糖尿病前期患者的年龄毒性。这项研究的目的是评估扶轮基金会对 乳腺癌高危女性的年龄毒性，并探讨TRF的机制意义 在饮食年龄的小鼠肿瘤模型中诱导sRAGE。我们提出了两个具体目标：进行试点 随机对照试验(RCT)旨在测量TRF对小鼠年龄毒性的影响 目的：探讨绝经后糖尿病前期妇女(SA1)的SRAGE上调机制。 体内对TRF的反应(SA2)。 为了改进旨在降低乳腺癌风险的治疗方法，必须确定疾病风险因素。 在脆弱的人群中。SRAGE已被确定为对糖尿病和乳腺癌具有临床重要意义。AS 糖尿病的流行继续扩大，增加了乳腺癌高危女性的数量， 确定应对TRF而增加的SRAGE的机制和类型将为更大规模的 干预研究。这类研究的目的是进一步确定以环境为目标的潜力 年龄作为一种通过禁食预防癌症的策略。

Pre-diabetes is associated with increased breast cancer risk. Recent studies have recognized a role for intermittent fasting, in the form of early time restricted feeding (TRF), in avoiding circadian de-synchrony to improve insulin resistance. TRF is an eating pattern that prolongs the overnight fasting duration by coordinating caloric intake with light-dark circadian rhythm. Prolonged nighttime fasting duration may be associated with reduced breast cancer and recurrence risk. The underlying mechanistic aspects of prolonged overnight fasting duration and 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. The pathogenic effects of AGEs contribute to insulin resistance, diabetes and cancer through the aberrant activation of stress response pathways. A high impact finding of our animal studies is that dietary-AGE induced increases in breast tumor growth are restricted by TRF. Dietary-AGE mediated increases in breast tumor growth were dependent upon the stromal expression of the transmembrane receptor for AGE (RAGE). Soluble RAGE (sRAGE) is a broad term used to define various truncated forms of full length RAGE that are found in the circulation. It encompasses a group of tumor suppressive variants of the oncogenic full RAGE, thought to sequester AGE in the circulation by acting as a decoy receptor. Accompanying the TRF mediated decreases in dietary-AGE induced tumor growth was a significant increase in sRAGE. We hypothesize that TRF induced increases in sRAGE may represent a cancer risk modification by reducing AGE-RAGE toxicity in patients with pre-diabetes. The objective of this study is to assess the impact of TRF on AGE-RAGE toxicity in women at higher risk of breast cancer, and explore the mechanistic implications of TRF induced sRAGE in dietary-AGE mouse tumor models. We propose two specific aims; To conduct a pilot Randomized Controlled Trial (RCT) designed to measure the effect of TRF on AGE-RAGE toxicity in postmenopausal women with pre-diabetes (SA1) and to examine the mechanism of sRAGE upregulation in response to TRF in vivo (SA2). It is essential to identify disease risk factors in order to modify therapies aimed at decreasing breast cancer risk in vulnerable populations. sRAGE has been identified as clinically important in diabetes and breast cancer. 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 TRF will provide a platform for larger intervention studies. Such studies would be aimed at further defining the potential of targeting environmental AGE as a cancer prevention strategy through fasting.