Caloric restriction reduced 1, 2-dimethylhydrazine-induced aberrant crypt foci and induces the expression of Sirtuins in colonic mucosa of F344 rats.
BACKGROUND
Caloric restriction (CR), a lowering of caloric intake without malnutrition, is associated with longevity. CR also decreases incidences of age-related diseases including cancer. The sirtuins (SIRTs) have been implicated as a key mediator for the beneficial effects of CR on longevity. However, the underlying mechanisms by which CR decreases cancer risk have not yet been fully elucidated.


METHODS
The present study was conducted to determine whether CR would modify the growth of preneoplastic colonic aberrant crypt foci (ACF). We also analyzed the expression of SIRTs to elucidate the molecular mechanisms of cancer-preventive effects of CR. F344 rats were fed a CR diet (60% of ad libitum diet) or a basal diet ad libitum. Then, the animals were given subcutaneous injection of either 1, 2-dimethylhydrazine (DMH) that enhances cell proliferation of colonic mucosa or saline. All animals were sacrificed at 5 weeks after the beginning of the experiment.


RESULTS
The number of ACF in colonic mucosa was significantly decreased in DMH-treated rats with CR as compared to in those without CR. No ACF was found in DMH-untreated animals with or without CR. Also, we found that CR decreased the cell proliferation of colonic mucosa in DMH-treated rats. The expressions of anti-apoptotic gene, Survivin, and cell cycle progression-associated gene, Cyclin D1, were increased by DMH-treatment. Both of the genes expressions were declined by CR in those of DMH-treated rats. The expressions of all SIRT1-7 mRNAs were significantly increased by CR in DMH-treated rats.


CONCLUSIONS
As previous studies demonstrated that SIRT1 down-regulates Survivin and Cyclin D1, our findings suggest that at least SIRT1 protect colonic mucosa from formation and development of ACF by increasing apoptosis and reducing excessive cell growth in colon epithelial cells.
Department of Pathology and Oncology, Graduate School of Medical Science, University of the Ryukyus, Okinawa- 903-0215, Japan.
Mariko
M
Tomita