Effect of dietary restriction on intestinal stem cell aging

随着年龄的增长，干细胞在维持组织功能方面发挥着关键作用 再生能力对这一角色至关重要。与年龄相关的再生能力下降 由于干细胞数量和功能的丧失，在许多组织中都可以观察到。因此， 了解干细胞功能的调节机制(S)对于延缓 影响干细胞的衰老过程和干预措施有可能成为抗衰老的目标 干预措施。饮食限制(DR)是一种强有力的抗衰老干预措施，它延长了 多种生物体的寿命，并已被证明可以防止生理上的衰退 功能。DR已被证明能增强干细胞的功能和自我更新能力 包括肠道干细胞在内的组织。研究表明，无论是长期还是短期DR 增加肠道干细胞数量和干细胞再生整个隐窝的能力 在试管中。虽然DR已被证明可以增强肠道干细胞的再生能力 细胞，这种效应背后的机制尚不清楚。DNA甲基化已被证明 在干细胞增殖和分化中起关键作用。更重要的是，DNA 甲基化漂移与干细胞老化有关。基于这些关键研究和我们的 最近的初步数据，我们假设，DR增加了相关基因的表达 通过诱导DNA甲基化改变在ISCs增殖和分化中的作用 ISCs的特定基因组位置。此外，我们建议短期DR将逆转 通过改变DNA甲基化和基因来降低干细胞的老化程度 表情。我们将通过这些目标来检验我们的假设：(I)识别DNA甲基化 ISC基因组中DR引起的变化(II)确定在DR效应中起作用的关键基因 论ISC的功能。

Stem cells play a critical role in the maintenance of tissue function with age and retention of their regenerative capacity is essential to this role. An age-related decline in regenerative capacities due to loss of stem cell number and function is observed in many tissues. Therefore, understanding the mechanism(s) that regulates stem cell function is essential for retarding the aging process and interventions that affect stem cells have the potential to be a target for antiaging interventions. Dietary restriction (DR) is a robust anti-aging intervention that extends the lifespan of a variety of organisms and has been shown to prevent the decline in physiological function. DR has been shown to enhance the function and self-renewal of stem cells in various tissues including the intestinal stem cells. Studies indicate that both long and short term DR increases intestinal stem cell number and the ability of the stem cells to regenerate an entire crypt in vitro. Although DR has been shown to enhance the regenerative capacity of intestinal stem cells, the mechanism underlying this effect remains unknown. DNA methylation has been shown to have a critical role in stem cell proliferation and differentiation. More importantly, DNA methylation drift has been associated with stem cell aging. Based on these key studies and our recent preliminary data, we hypothesize that, DR increases the expression of genes involved in ISCs proliferation and differentiation by inducing changes in DNA methylation at specific genomic sites of the ISCs. Further, we propose that short term DR will reverse the age-related decline in stem cell aging by modifying both DNA methylation and gene expression. We will test our hypothesis through these aims: (i) Identify DNA methylation changes induced by DR in the ISC genome (ii) Identify key genes that play a role in DR’s effect on ISC function.