Late-Life Short-Term Dietary Restriction Improves Intestinal Stem Cell Function and Alters Intestinal Stem Cell...

Area of Science:

• Aging research
• Gastroenterology
• Nutritional science

Background:

• Intestinal regenerative capacity diminishes with age due to declining intestinal stem cell (ISC) function.
• Dietary restriction (DR) is a potent anti-aging intervention known to enhance ISC function in younger animals.

Purpose of the Study:

• To investigate the impact of short-term dietary restriction (stDR) on ISC function when initiated late in life.
• To explore the molecular mechanisms, including gene expression and DNA methylation, underlying stDR's effects on aged ISCs.

Main Methods:

• Utilized aged (21-month-old) and young (2-month-old) male C57BL/6 mice subjected to either ad libitum feeding or 4-month stDR (40% restriction).
• Assessed ISC function via in vitro enteroid-forming assays.
• Analyzed gene expression using RNA sequencing (RNA-seq) and DNA methylation patterns using whole-genome bisulfite sequencing.

Main Results:

• Late-life stDR increased enteroid formation by over 10-fold in aged mice.
• stDR prevented age-related changes in the expression of 38 genes not previously linked to ISC function.
• stDR prevented age-associated alterations in DNA methylation at CG sites in specific gene regulatory regions.

Conclusions:

• Late-life stDR can rejuvenate the function of ISCs in aged mice.
• Nutritional interventions late in life may improve gut function and reduce risks of age-related intestinal disorders.
• DNA methylation likely plays a role in how DR enhances ISC function.