标题： 衰老与疾病进化的医学和生命历史视角：权衡、超功能与错配 显示英文标题

标题： An evolutionary medicine and life history perspective on aging and disease: Trade-offs, hyperfunction, and mismatch

摘要： 过去一个世纪慢性疾病发病率的上升在全球范围内带来了显著的健康和经济负担。 在此，我们应用进化医学和生命史理论来更好地理解它们的发展。 我们强调生长与增殖（合成代谢）与维持和休眠（分解代谢）之间不平衡的代谢轴，重点关注包括IGF-1、mTOR、AMPK和Klotho在内的主要机制。 我们还将这一轴线与衰老的超功能理论联系起来，该理论同样指出像mTOR这样的合成代谢机制在衰老和疾病中的作用。 接下来，我们强调脑体能量保护模型，该模型将超功能理论与诱导低功能和分解代谢健康风险（如免疫功能障碍）的能量权衡联系起来。 最后，我们讨论了现代环境错配如何加剧这一过程。 在我们的综述之后，我们讨论了未来的研究方向，以更好地理解健康风险。 这包括研究IGF-1、mTOR、AMPK和Klotho以及它们如何与人类生存群体中的健康和衰老相关，包括生活方式的变化。 它还包括了解它们在健康和疾病发育起源以及健康差异社会决定因素中的作用。 此外，我们讨论了未来研究长寿物种的需求，以理解可能被低估的与长寿相关的权衡和代价。 最后，我们考虑了可能对治疗的启示，包括（1）补偿途径对抗治疗，（2）“恰到好处”区域，在这个区域内过度抑制合成代谢会引入分解代谢健康风险，以及（3）物种限制，在较短寿命且有更大合成代谢失衡的物种中测试的治疗在人类中效果较差。 显示英文摘要

摘要： The rise in chronic diseases over the last century presents a significant health and economic burden globally. Here we apply evolutionary medicine and life history theory to better understand their development. We highlight an imbalanced metabolic axis of growth and proliferation (anabolic) versus maintenance and dormancy (catabolic), focusing on major mechanisms including IGF-1, mTOR, AMPK, and Klotho. We also relate this axis to the hyperfunction theory of aging, which similarly implicates anabolic mechanisms like mTOR in aging and disease. Next, we highlight the Brain-Body Energy Conservation model, which connects the hyperfunction theory with energetic trade-offs that induce hypofunction and catabolic health risks like impaired immunity. Finally, we discuss how modern environmental mismatches exacerbate this process. Following our review, we discuss future research directions to better understand health risk. This includes studying IGF-1, mTOR, AMPK, and Klotho and how they relate to health and aging in human subsistence populations, including with lifestyle shifts. It also includes understanding their role in the developmental origins of health and disease as well as the social determinants of health disparities. Further, we discuss the need for future studies on exceptionally long-lived species to understand potentially underappreciated trade-offs and costs that come with their longevity. We close with considering possible implications for therapeutics, including (1) compensatory pathways counteracting treatments, (2) a Goldilocks zone, in which suppressing anabolic metabolism too far introduces catabolic health risks, and (3) species constraints, in which therapeutics tested in shorter lived species with greater anabolic imbalance will be less effective in humans.