肠干细胞衰老是肠道衰老的核心。我们曾报道衰老肠干细胞干性减低且分化障碍，且限食可延缓造血干细胞衰老（EMBO J, 2015；Stem Cell Rev，2019；J Exp Med，2016），但其能否改善肠干细胞衰老及其机制尚无报道。我们预实验发现衰老小鼠肠道微生态倾向于抑制肠道脂肪酸氧化，限食则可显著上调衰老肠干细胞脂肪酸氧化相关基因表达并改善其功能，清除肠道微生态后该拯救作用消失。据此我们推测：限食通过纠正衰老肠道微生态的异常促进肠干细胞脂肪酸氧化，从而延缓肠干细胞衰老。为此，本课题拟研究：1）限食对衰老小鼠肠道微生态的调控作用，是否使其向年轻小鼠肠道微生态转变；2）肠道微生态对衰老肠干细胞脂肪酸氧化及其功能的调控作用；3）通过干预关键菌种及靶基因明确限食延缓肠干细胞衰老中起关键作用的菌种及脂肪酸氧化靶点。本课题将明确限食延缓肠干细胞衰老的机制，为改善肠道衰老提供新思路。

Intestinal stem cells are the driving force of intestinal homeostasis and regeneration, and therefore play essential roles in intestinal aging. Previously, we reported that aged intestinal stem cells harbor significantly declined stemness and impaired differentiation capacity. Moreover, we found that dietary restriction remarkably delays hematopoietic stem cell aging (EMBO J, 2015; Stem Cell Rev, 2019；J Exp Med, 2016). However, whether and how dietary restriction ameliorates intestinal stem cell aging remain to be delineated. Our preliminary data revealed that dietary restriction significantly up-regulated expressions of genes involved in fatty acid oxidation and improved functions of intestinal stem cells derived from aged mice. Intriguingly, elimination of the intestinal flora by broad-spectrum antibiotics wiped off the rescuing effect on aged intestinal stem cell functions of dietary restriction, suggesting that the rescue of dietary restriction on aged intestinal stem cells was dependent on the gut microbiota. Additionally, we also found an abnormal structural composition of gut microbiota in aged mice which dominantly inhibits fatty acid oxidation in the intestine. Furthermore, recent studies showed that fatty acid oxidation promotes intestinal stem cell functions markedly. Taken together, we hypothesized that dietary restriction ameliorates intestinal stem cell aging via rectifying abnormalities of gut microbiota and promotes fatty acid oxidation. To verify this hypothesis, we plan to: 1) study the effect of dietary restriction on the gut microbiota in aged mice; 2) study the effect of gut microbiota on fatty acid oxidation and functions of intestinal stem cells derived from aged mice; 3) explore key bacterial taxa and target genes which essentially mediate the effect of dietary restriction on intestinal stem cell aging. The current study aims to mechanistically understand how dietary restriction ameliorates intestinal stem cell aging, and will shed new insight into potential ways to delay intestinal aging.