Body Composition, Energetics, and Longevity

描述（由申请人提供）：尽管已知热量限制可以延长包括许多哺乳动物在内的许多物种的寿命，肥胖可以缩短寿命，但在基础生物学和公共卫生/临床水平上仍有许多问题未得到解答。出于实践、理论和伦理的原因，不可能随机将人类分配到不同的体重、肥胖程度、脂肪分布或不同程度的体重稳定性，然后跟踪他们的整个生命周期。然而，关于这些体重和成分变量的影响的问题仍然存在。通过提供严格控制的全生命周期实验，模型生物研究是解决这些问题的全部证据的一个关键方面，这些实验可以补充其他类型的人类研究。该研究提出了以下问题：在肥胖生物中，减肥必须持续才能对寿命有益吗？反复的体重减轻和恢复（即“体重循环”）是有益的、有害的还是中性的？在肥胖生物体中，减肥的有益效果在多大程度上源于总脂肪、内脏脂肪、代谢率或脂肪细胞大小的减少？这些问题将在饮食肥胖小鼠的随机寿命实验中得到解决，使用最先进的身体组成，代谢评估和统计分析方法，并辅以小目标机制子研究。这些问题对基础科学具有启示意义，可以打开和优先探索作为减肥和热量限制的健康效应介质的途径，并对加强、削弱或改进有关可能延长肥胖人群寿命的行为和解剖改变类型的临床建议具有启示意义。

DESCRIPTION (provided by applicant): Although caloric restriction is known to prolong life and obesity is known to shorten life in many species including many mammalian species, many questions remain unanswered at both the level of basic biology and the public health/clinical level. For practical, theoretical, and ethical reasons it is impossible to randomly assign humans to different levels of body weight, fatness, or fat distribution or different degrees of weight stability and to then follow them for the entire lifespan. Yet, questions about the effects of such body weight and composition variables remain. Model organism studies are a key aspect of the totality of evidence that can be brought to bear on such questions by offering rigorously controlled full-lifespan experiments that can complement other types of studies that can be done in humans. The research proposed addresses questions such as: Among obese organisms, must weight loss be sustained to be beneficial with respect to lifespan? Are repeated bouts of weight loss and regain (i.e., 'weight cycling') beneficial, harmful, or neutral? To what extent do the beneficial effects of weight loss among obese organisms result from reductions in total fat, visceral fat, metabolic rate, or adipocyte size. These questions will be addressed in a randomized lifespan experiment in dietary obese mice using state-of-the-art body composition, metabolic assessment, and statistical analysis methods, supplemented with small targeted mechanistic sub-studies. These questions have implications for basic science in terms of opening and prioritizing pathways to explore as mediators of the salubrious effects of weight loss and caloric restriction and implications for strengthening, weakening, or refining clinical recommendations concerning the types of behavioral and anatomic alterations likely to enhance longevity among obese humans. PUBLIC HEALTH RELEVANCE: Over 50 million Americans are obese and are therefore predicted to live less long than they would otherwise live. Whether reductions in overall obesity or selected aspects of fatness among obese persons will prolong life remains the subject of active debate and controversy. The proposed research will help provide information to inform that dialogue.