Effect of dietary restriction on intestinal stem cell aging

饮食限制对肠道干细胞衰老的影响

• 批准号: 10823900
• 负责人: Archana Unnikrishnan
• 金额: $ 23.22万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10823900
• 关键词: Ablation; Acute; Affect; Age; Aging; Biological Aging; Biological Markers; Blood; Bone Marrow; Brain; C57BL/6 Mouse; Cell Count; Cell Differentiation Induction; Cell Differentiation process; Cell Separation; Cell physiology; Cells; Chromatin; Cognition; Cytosine; DNA; DNA Methylation; DNA Modification Methylases; DNA-Binding Proteins; Data; Data Analyses; Deceleration; Development; Diet; Dioxygenases; Disease; Enhancers; Enzymes; Epigenetic Process; Epithelial Cells; Equilibrium; Exposure to; Female; Future; Gene Expression; Genes; Genetic Enhancer Element; Genome; Genomics; Geroscience; Grant; Hippocampus; In Vitro; Intervention; Intestinal Mucosa; Intestines; Invertebrates; Kidney; Knowledge; Laboratories; Life; Liver; Longevity; Maintenance; Measures; Mediating; Memory; Messenger RNA; Methylation; Mitogens; Molecular; Mucous Membrane; Mus; Muscle; Natural regeneration; Neurotensin; Organism; Pathway interactions; Physiological; Physiological Processes; Play; Positioning Attribute; Process; Proliferating; Promoter Regions; Rattus; Regenerative capacity; Regulation; Reporting; Resolution; Rodent; Role; Site; Testing; Time; Tissues; United States National Institutes of Health; Work; adult stem cell; age effect; age related; aged; anti aging; base; data integration; demethylation; dietary restriction; epigenetic regulation; functional decline; genome-wide; improved; insight; intestinal epithelium; male; methylation pattern; mouse genome; nerve stem cell; neurogenesis; nonhuman primate; prevent; promoter; regeneration potential; sex; stem cell aging; stem cell differentiation; stem cell function; stem cell genes; stem cell proliferation; stem cell self renewal; stem cells; theories; transcription factor; transcriptome; transcriptome sequencing; transcriptomics; whole genome

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.

随着年龄的增长，干细胞在维持组织功能和保留其功能方面发挥着关键作用。 再生能力对于这一作用至关重要，与年龄相关的再生能力下降。 由于在许多组织中观察到干细胞数量和功能的丧失， 了解调节干细胞功能的机制对于延缓干细胞功能至关重要 衰老过程和影响干细胞的干预措施有可能成为抗衰老的目标 饮食限制（DR）是一种强有力的抗衰老干预措施，可以延长寿命。 多种生物体的寿命，并已被证明可以防止生理衰退 DR已被证明可以增强多种干细胞的功能和自我更新。 研究表明，长期和短期的 DR 都会对组织（包括肠道干细胞）产生影响。 增加肠道干细胞数量和干细胞再生整个隐窝的能力 尽管 DR 已被证明可以增强肠干的再生能力。 细胞中，这种效应的机制仍不清楚。 更重要的是，DNA在干细胞增殖和分化中发挥着关键作用。 根据这些关键研究和我们的研究，甲基化漂移与干细胞衰老有关。 最近的初步数据显示，DR 增加了相关基因的表达 通过诱导 DNA 甲基化的变化来影响 ISC 的增殖和分化 此外，我们建议短期 DR 将扭转 ISC 的特定基因组位点。 通过修改 DNA 甲基化和基因，导致干细胞衰老与年龄相关的下降 我们将通过以下目标检验我们的假设：(i) 识别 DNA 甲基化。 DR 在 ISC 基因组中引起的变化 (ii) 识别在 DR 效应中发挥作用的关键基因 关于 ISC 功能。