032.19. System xc- - deficiency extends life-span and modulates aging of the immune system in mice

The cystine/glutamate antiporter, with xCT as specific subunit, is mainly expressed in the central nervous system and tissues related to the immune system. Although system xc- has been proposed as therapeutic target for the treatment of cancer as well as several (age-related) neurological disorders, the function of system xc- in ‘healthy’ aging has never been studied. We confirmed the oxidative shift that was reported by Sato et al. (2005) to occur in the plasma of mice with a genetic deletion of xCT (xCT-/-mice) and this seemed to be even more pronounced in aged xCT-/-mice, compared to age-matched xCT+/+littermates. Cystine plasma levels were not only increased in young xCT-/-mice compared to xCT+/+ littermates, but also significantly increased with aging in xCT-/- mice, contrary to xCT+/+ mice. Moreover, cysteine levels significantly dropped with aging in xCT-/- mice, inducing a shift towards a more oxidative state. However, despite this oxidative shift that suggests accelerated aging, we observed a significantly increased median life-span in xCT-/- mice, compared to xCT+/+ mice. The peripheral immune system and the central nervous system communicate in a bidirectional way. The functioning of both systems is affected by aging and can be modulated by system xc- We therefore investigated the effect of system xc- - deficiency on age-related hippocampal impairment (Verbruggen et al., sfn 2019 poster) as well as on exacerbation of the inflammatory response and immune senescence. Whereas aging induces an overall increase in the systemic response to a low-dose LPS injection (0.2mg/kg, i.p.), this effect was attenuated by the genetic deletion of xCT: aged xCT-/- mice have a smaller maximum drop in body temperature as seen at 4h and 6h after LPS administration and show reduced levels of peripheral pro-inflammatory cytokines at 3h post-LPS injection. Whether this can be translated to reduced neuroinflammation is currently being investigated. Aging also results in a disturbance of relative proportions of cells of both the innate and the adaptive immune system. Preliminary data show that the absence of system xc- during the aging process affects some of these age-related changes.To conclude, the positive effects of absence of system xc- during the aging process - both on life-span and hippocampal function - might in part be mediated by a reduced age-related systemic pro-inflammatory environment.