The current study is based on the hypothesis that aging predisposes gastric mucosa to carcinogenesis through altered expression and/or mutations of genes involved in cell growth. To test this hypothesis, we investigated the age-associated changes in mutation of APC, DCC, p53 and K-ras genes in the gastric mucosa of 19 healthy subjects of varying ages (25-91 years). Specifically, we studied the loss of heterozygosity (LOH) of these genes in cardia, body, and antrum of the stomach. We observed that 3 out of 19 subjects (16%), who are over 60 years of age, show LOH of at least one of the tumor suppressor genes. Among the subjects over 60 years of age, the incidence of LOH is 38% (3/8). Two out of three subjects had mutations in more than one tumor suppressor genes. In all three affected subjects, mutation in APC, DCC or p53 was located mainly in the body of the stomach suggesting increased susceptibility of this region to neoplastic changes. However, no LOH of K-ras was observed in these subjects. Our observation that subjects over 60 years of age show mutation in one or more of the tumor suppressor genes suggest an age-related increase in predisposition of the stomach to neoplasia.