Update publication information. Human saliva is a protein-rich, easily accessible source of potential biomarkers for the diagnosis of oral and systemic diseases. However, little is known about the changes in salivary proteome associated with aging of patients with dental caries. Herein, we applied iTRAQ-based quantitative approach to explore the salivary proteome profile of different aged subjects, with and without caries, aiming to identify age-related markers for dental caries. Unstimulated whole saliva samples were collected from 40 caries-free and caries-susceptible young adults and elderly individuals, and then analyzed by combining iTRAQ isobaric labeling with MRM. Among 658 salivary proteins identified by tandem mass spectrometry, 435 proteins exhibited altered expressions in different age groups with and without caries. Of these, 96 were found to be age-specific among caries-susceptible adults and elders, mainly associated with salivary secretion pathway, while 110 age-specific proteins were identified among the healthy individuals. It was found that the age factor caused significant variations and played an important role in both healthy and cariogenic salivary proteome. Subsequently, a total of 136 target proteins with complex protein-protein interactions, including 14 age-specific proteins associated with caries, were further successfully validated using MRM analysis. Moreover, non-age-specific proteins (histatin-1 and BPI fold-containing family B member 1) were verified to be important candidate biomarkers for common dental caries. Our proteomic analysis established by discovery-through-verification pipeline demonstrated distinct variations caused by age factor in both healthy and cariogenic salivary proteome, highlighting the significance of age in the great potential of saliva for caries diagnosis and biomarker discovery.