To develop effective strategies for prevention of aging-associated diseases, there is an urgent need for increased understanding of the mechanisms underlying age-related increase in homeostatic disorders. In conjunction with various mouse models, tissue culture studies enabled us to obtain following findings:

(1) In mice lacking Bmi-1 gene, an essential gene for the maintenance of the adult stem cells, p16 expression is increased prematurely in the submandibular gland (SMG) throughout aging, accompanied by a significant reduction of saliva production.
(2) The levels of p16 expression are inversely correlated with the activities of cultured SMG stem/progenitor cells.
(3) Age-related decline of SMG stem/progenitor cell-activity appears to be caused by the modulation of Bmi-1 function through p16 up-regulation in mice.