The plasticity of gastric chief cells is exemplified by their ability to transdifferentiate into Spasmolytic Polypeptide-expressing Metaplasia (SPEM) after parietal cell loss. We sought to determine if chief cell maturity is a limiting factor in the capacity to transdifferentiate. Mist1^-/- mice, previously shown to form only immature chief cells, were treated with DMP-777 or L635 to study the capability of these immature chief cells to transdifferentiate into a proliferative metaplastic lineage after acute parietal cell loss. Mist1^-/- mice treated with DMP-777 showed fewer chief cell to SPEM transitions. Mist1^-/- mice treated with L635 demonstrated significantly fewer proliferative SPEM cells compared to control mice. Thus, immature chief cells were unable to transdifferentiate efficiently into SPEM after acute parietal cell loss. To determine whether chief cell age affects transdifferentiation into SPEM, we used tamoxifen to induce YFP expression in chief cells of Mist1^CreER/+;Rosa^YFP mice and subsequently treated with L635 to induce SPEM at 1 to 3.5 months after tamoxifen treatment. After L635 treatment to induce acute parietal cell loss, 43% of all YFP-positive cells at 1 month post-tamoxifen were SPEM cells, of which 44% of these YFP-positive SPEM cells were proliferative. By 2 months after tamoxifen induction, only 24% of marked SPEM cells were proliferating. However, by 3.5 months after tamoxifen induction, only 12% of marked chief cells transdifferentiated into SPEM and none were proliferative. Thus, as chief cells age, they lose their ability to transdifferentiate into SPEM and proliferate. Therefore, both functional maturation and age limit chief cell plasticity.