Adult-onset calorie restriction and fasting delay spontaneous tumorigenesis in p53-deficient mice
Adult-onset calorie restriction and fasting delay spontaneous tumorigenesis in p53-deficient mice
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DOI：
10.1093/carcin/23.5.817
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发表时间：
2002-05-01
期刊：
影响因子：
4.7
通讯作者：
Hursting, SD
中科院分区：
文献类型：
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作者：
Berrigan, D;Perkins, SN;Hursting, SD
杂合p53缺陷（p53（+/-））小鼠是人类李 - 佛美尼综合征的一种潜在模型，其p53肿瘤抑制基因有一个功能性等位基因。这些小鼠容易自发产生肿瘤，最常见的是肉瘤和淋巴瘤；p53+/-小鼠的中位死亡时间为18个月。我们先前已表明，幼年期开始的热量限制（CR）至随意采食量（AL）的60%，通过一种不依赖p53且与胰岛素样生长因子1（IGF - 1）相关的机制，延缓了年轻的p53缺失（-/-）小鼠的肿瘤发展。为了确定在成年p53缺陷小鼠中开始热量限制是否有效，并比较慢性热量限制与间歇性禁食方案，将雄性p53+/-小鼠（7 - 10个月大，每组31 - 32只小鼠）随机分配到以下方案中：（i）随意采食（AIN - 76A饮食），（ii）热量限制至随意采食量的60%，或（iii）每周禁食1天。在非禁食日控制食物供应量以防止补偿性过度进食。与随意采食组相比，热量限制显著延缓（P = 0.001）了成年小鼠肿瘤的发生，而每周禁食1天则造成了适度的延缓（P = 0.039）。各处理组内寿命和最大体重的显著差异与个体小鼠生长特征的差异无关。在另一组接受4周处理的p53+/-小鼠中（每种处理n = 5只小鼠），与随意采食小鼠相比，热量限制小鼠的血浆IGF - 1水平降低了20%（P < 0.01），瘦素水平降低了71%（P < 0.01）；禁食小鼠的瘦素和IGF - 1水平处于中间水平。我们的研究结果表明，热量限制或每周禁食1天抑制了致癌作用——即使是在因p53基因剂量减少而注定会发生肿瘤的小鼠生命后期开始，这支持了寻找合适的干预措施来影响人类能量平衡作为癌症预防工具的努力。
Heterozygous p53-deficient (p53(+/-)) mice, a potential model for human Li-Fraumeni Syndrome, have one functional allele of the p53 tumor suppressor gene. These mice are prone to spontaneous neoplasms, most commonly sarcoma and lymphoma; the median time to death of p53+/- mice is 18 months. We have shown previously that juvenile-onset calorie restriction (CR) to 60% of ad libitum (AL) intake delays tumor development in young p53-null (-/-) mice by a p53-independent and insulin-like growth factor 1 (IGF-1)-related mechanism. To determine whether CR is effective when started in adult p53-deficient mice, and to compare chronic CR with an intermittent fasting regimen, male p53+/- mice (7-10 months old, 31-32 mice/group) were randomly assigned to the following regimens: (i) AL (AIN-76A diet), (ii) CR to 60% of AL intake or (iii) 1 day/week fast. Food availability on non-fasting days was controlled to prevent compensatory over feeding. Relative to the AL group, CR significantly delayed (P = 0.001) the onset of tumors in adult mice, whereas the 1 day/week fast caused a moderate delay (P = 0.039). Substantial variation in longevity and maximum body weight within treatments was not correlated with variation in growth characteristics of individual mice. In a separate group of p53 +/- mice treated for 4 weeks (n = five mice per treatment), plasma IGF-1 levels in CR versus AL mice were reduced by 20% (P < 0.01) and leptin levels were reduced by 71% (P < 0.01); fasted mice had intermediate levels of leptin and IGF-1. Our findings that CR or a 1 day/week fast suppressed carcinogenesis-even when started late in life in mice predestined to develop tumors due to decreased p53 gene dosage support efforts to identify suitable interventions influencing energy balance in humans as a tool for cancer prevention.