High glucose diets are unhealthy, although the mechanisms by which ikelevated glucose is harmful to whole animal physiology are not well understood. In Caenorhabditis elegans, high glucose shortens lifespan, while chemically inflicted glucose restriction promotes longevity. We investigated the impact of glucose metabolism on aging quality (maintained locomotory capacity and median lifespan) and found that, in addition to shortening lifespan, excess glucose negatively impacts locomotory healthspan. Conversely, disrupting glucose utilization by knockdown of glycolysis-specific genes results in large mid-age physical improvements via a mechanism that requires the FOXO transcription factor DAF-16. Adult locomotory capacity is extended by glycolysis disruption, but maximum lifespan is not, indicating that limiting glycolysis can increase the proportion of life spent in mobility health. We also considered the largely ignored role of glucose biosynthesis (gluconeogenesis) in adult health. Directed perturbations of gluconeogenic genes that specify single direction enzymatic reactions for glucose synthesis decrease locomotory healthspan, suggesting that gluconeogenesis is needed for healthy aging. Consistent with this idea, overexpression of the central gluconeogenic gene pck-2 (encoding PEPCK) increases health measures via a mechanism that requires DAF-16 to promote pck-2 expression in specific intestinal cells. Dietary restriction also features DAF-16-dependent pck-2 expression in the intestine, and the healthspan benefits conferred by dietary restriction require pck-2. Together, our results describe a new paradigm in which nutritional signals engage gluconeogenesis to influence aging quality via DAF-16. These data underscore the idea that promotion of gluconeogenesis might be an unappreciated goal for healthy aging and could constitute a novel target for pharmacological interventions that counter high glucose consequences, including diabetes.

高糖饮食是不健康的，尽管人们还不了解高架葡萄糖对整个动物生理的危害机理。在秀丽隐杆线虫中，高葡萄糖会缩短寿命，而化学限制的葡萄糖限制则会延长寿命。我们调查了葡萄糖代谢对衰老质量（维持运动能力和中位寿命）的影响，发现除了缩短寿命外，过量的葡萄糖还会对运动健康产生负面影响。相反，通过敲低糖酵解特异性基因来破坏葡萄糖利用会导致中年人通过要求FOXO转录因子DAF-16的机制获得更大的身体改善。糖酵解破坏可延长成人的运动能力，但最长寿命却无法延长，这表明限制糖酵解可以增加在行动健康中度过的生命比例。我们还考虑了葡萄糖生物合成（糖异生）在成人健康中的作用而被忽略。指定葡萄糖合成的单向酶促反应的糖异生基因的直接扰动降低了机体健康期，表明健康衰老需要糖异生。与这个想法一致，中央糖原异源基因的过表达pck-2（编码PEPCK）通过要求DAF-16促进特定肠道细胞中pck-2表达的机制来增强健康措施。饮食限制还具有肠道中DAF-16依赖性pck-2表达的特征，而饮食限制所带来的健康益处需要pck-2。总之，我们的结果描述了一种新的范例，其中营养信号参与糖异生，从而通过DAF-16影响衰老质量。这些数据强调了糖原异生的促进可能是健康衰老的一个未实现的目标，并可能构成应对高血糖后果（包括糖尿病）的药物干预的新目标。