Moderate restriction of dietary energy intake, referred to here as dietary restriction (DR), delays aging and extends lifespan in experimental animals compared with a diet of ad libitum feeding (AL) control animals. Basic knowledge of the mechanisms underlying the effects of DR could be applicable to extending the healthspan in humans. This review highlights the importance of forkhead box O (FoxO) transcription factors downstream of the growth hormone-insulin-like growth factor 1 signaling in the effects of DR. Our lifespan studies in mice with heterozygous Foxo1 or Foxo3 gene knockout indicated differential roles of FoxO1 and FoxO3 in the tumor-inhibiting and life-extending effects of DR. Subsequent studies suggested a critical role of FoxO3 in metabolic and mitochondrial bioenergetic adaptation to DR. Our studies also verified hypothalamic neuropeptide Y (Npy) as a vital neuropeptide showing pleiotropic and sexually dimorphic effects for extending the healthspan in the context of nutritional availability. Npy was necessary for DR to exert its effects in male and female mice; meanwhile, under AL conditions, the loss of Npy prevented obesity and insulin resistance only in female mice. Overnutrition disrupts FoxO- and Npy-associated metabolic and mitochondrial bioenergetic adaptive processes, causing the acceleration of aging and related diseases.

中文翻译：

---

饮食能量限制延缓衰老的机制


与随意喂养（AL）对照动物的饮食相比，适度限制膳食能量摄入（此处称为饮食限制（DR））可以延缓实验动物的衰老并延长寿命。 DR 影响机制的基本知识可用于延长人类的健康寿命。这篇综述强调了生长激素-胰岛素样生长因子 1 信号下游的叉头框 O (FoxO) 转录因子在 DR 影响中的重要性。我们对Foxo1或Foxo3杂合基因敲除小鼠的寿命研究表明，FoxO1 和 FoxO3 在 DR 的肿瘤抑制和延长寿命作用中发挥着不同的作用。随后的研究表明 FoxO3 在代谢和线粒体生物能适应 DR 中发挥着关键作用。我们的研究还证实下丘脑神经肽 Y (Npy) 是一种重要的神经肽，具有多效性和性二态性效应，可在营养充足的情况下延长健康寿命。 Npy是DR在雄性和雌性小鼠中发挥作用所必需的；同时，在 AL 条件下，Npy 的缺失仅能预防雌性小鼠的肥胖和胰岛素抵抗。营养过剩会破坏 FoxO 和 Npy 相关的代谢和线粒体生物能适应过程，导致衰老和相关疾病的加速。