The loss of methionine sulfoxide reductases significantly suppresses tumor development and exacerbates kidney pathology in male quadruple Msr knockout mice

Abstract

To investigate the effects of the loss of methionine sulfoxide reductase (Msr) on aging, we have conducted the survival and end-of-life pathological analyses using male quadruple Msr knockout (KO) mice lacking MsrA, MsrB1, MsrB2, and MsrB3. Our study demonstrated that the loss of Msr in male mice resulted in a similar lifespan compared to wild-type (WT) mice. The end-of-life pathology data obtained from male mice showed a significantly higher severity of glomerulonephritis in quadruple Msr KO compared to WT mice, although the incidence of fatal glomerulonephritis was similar between quadruple Msr KO and WT mice. More importantly, the incidence of fatal lymphoma and neoplastic lesions (all fatal tumors), and tumor burden were significantly less in male quadruple Msr KO than WT mice. The comorbidity index was similar between quadruple Msr KO and WT mice. Our study suggests that the loss of four Msrs did not change lifespan in male quadruple Msr KO mice compared to WT mice. The end-of-life pathology showed paradoxical results for the non-neoplastic and neoplastic lesions in male quadruple Msr KO mice. The loss of four Msrs resulted in deleterious effects on the non-neoplastic lesion, i.e., severe kidney pathology, whereas cancer development was significantly suppressed. These results call for further study into the pathophysiological roles of the loss of four Msrs in aging and age-related pathology. Among our findings, the anti-cancer effects due to the loss of four Msrs was the most striking observation that could lead us to seek the underlying mechanisms and potential discovery of new preventive and/or therapeutic methods for certain human cancers.

Keywords: Methionine sulfoxide reductase, aging, cancer, lymphoma, glomerulonephritis, Msr KO mice