Effect of dietary restriction on intestinal stem cell aging

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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.