Body Composition, Energetics, and Longevity

描述（由申请人提供）：尽管已知热量限制可延长寿命，并且已知肥胖可缩短许多物种（包括许多哺乳动物物种）的寿命，但在基础生物学水平和公共卫生/临床水平上仍有许多问题没有答案。出于实践、理论和伦理方面的原因，不可能将人类随机分配到不同的体重、肥胖或脂肪分布水平，或者不同程度的体重稳定性，然后在整个生命周期中跟踪它们。然而，关于这些体重和成分变量的影响的问题仍然存在。模式生物研究是全部证据的一个关键方面，可以通过提供严格控制的全寿命实验来解决这些问题，这些实验可以补充可以在人类中进行的其他类型的研究。这项研究提出的问题包括：在肥胖的生物体中，减肥必须持续才能对寿命有益吗？反复发作的体重减轻和恢复（即，“体重循环”）有益、有害还是中性？在多大程度上，肥胖生物体的体重减轻的有益效果是由于总脂肪、内脏脂肪、代谢率或脂肪细胞大小的减少。这些问题将在饮食性肥胖小鼠的随机寿命实验中解决，该实验使用最先进的身体组成、代谢评估和统计分析方法，并辅以小型靶向机制子研究。这些问题对基础科学有着重要的意义，因为它们可以开辟和优先考虑途径，以探索减肥和热量限制的有益健康作用的介体，并对加强、削弱或完善有关可能延长肥胖人群寿命的行为和解剖学改变类型的临床建议产生影响。 公共卫生相关性：超过5000万美国人肥胖，因此预计他们的寿命会比其他情况下短。肥胖者总体肥胖或特定肥胖方面的减少是否会延长寿命仍然是积极辩论和争论的主题。拟议的研究将有助于提供信息，为这一对话提供信息。

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.