Age plays a major role in tumor incidence and is an important consideration when modeling the carcinogenesis process or estimating cancer risks. Epidemiological data show that from adolescence through middle age, cancer incidence increases with age. This effect is commonly attributed to a lifetime accumulation of cellular, particularly DNA, damage. However, during middle age the incidence begins to decelerate and, for many tumor sites, it actually decreases at sufficiently advanced ages. We investigated if the observed deceleration and potential decrease in incidence could be attributed to a decreased capacity of older hosts to support tumor progression, and whether HZE [high atomic number (Z), high energy (E)] radiation differentially modulates tumor progression in young vs. middle-age hosts, issues that are relevant to estimating carcinogenesis risk for astronauts. Lewis lung carcinoma (LLC) cells were injected into syngeneic mice (143 and 551 days old), which were then subject to whole-body (56)Fe irradiation (1 GeV/amu). Three findings emerged: (1) among unirradiated animals, substantial inhibition of tumor progression and significantly decreased tumor growth rates were seen for middle-aged mice compared to young mice, (2) whole-body (56)Fe irradiation inhibited tumor progression in both young and middle-aged mice (with greater suppression seen in case of young animals), with little effect on tumor growth rates, and (3) (56)Fe irradiation suppressed tumor progression in young mice to a degree that was not significantly different than transiting from young to middle-aged. Thus, (56)Fe irradiation acted similar to aging with respect to tumor progression. We further investigated the molecular underpinnings driving the radiation modulation of tumor dynamics in young and middle-aged mice. Through global gene expression analysis, the key players, FASN, AKT1 and the CXCL12/CXCR4 complex, were determined to be contributory. In sum, these findings demonstrated a reduced capacity of middle-aged hosts to support the progression phase of carcinogenesis and identify molecular factors that contribute to HZE radiation modulation of tumor progression as a function of age.