Lifespan extension with preservation of hippocampal function in aged system xc−-deficient male mice
Lise Verbruggen, Gamze Ates, Olaya Lara, Jolien De Munck, Agnès Villers, Laura De Pauw, Sigrid Ottestad‐Hansen, Sho Kobayashi, Pauline Beckers, Pauline Janssen, Hideyo Sato, Yun Zhou, Emmanuel Hermans, Rose Njemini, Lut Arckens, Niels C. Danbolt, Dimitri De Bundel, Joeri L. Aerts, Kurt Barbé, Benoît Guillaume, Laurence Ris, Eduard Bentea, Ann Massie
Abstract
Abstract The cystine/glutamate antiporter system x c − has been identified as the major source of extracellular glutamate in several brain regions as well as a modulator of neuroinflammation, and genetic deletion of its specific subunit xCT (xCT −/− ) is protective in mouse models for age-related neurological disorders. However, the previously observed oxidative shift in the plasma cystine/cysteine ratio of adult xCT −/− mice led to the hypothesis that system x c − deletion would negatively affect life- and healthspan. Still, till now the role of system x c − in physiological aging remains unexplored. We therefore studied the effect of xCT deletion on the aging process of mice, with a particular focus on the immune system, hippocampal function, and cognitive aging. We observed that male xCT −/− mice have an extended lifespan, despite an even more increased plasma cystine/cysteine ratio in aged compared to adult mice. This oxidative shift does not negatively impact the general health status of the mice. On the contrary, the age-related priming of the innate immune system, that manifested as increased LPS-induced cytokine levels and hypothermia in xCT +/+ mice, was attenuated in xCT −/− mice. While this was associated with only a very moderate shift towards a more anti-inflammatory state of the aged hippocampus, we observed changes in the hippocampal metabolome that were associated with a preserved hippocampal function and the retention of hippocampus-dependent memory in male aged xCT −/− mice. Targeting system x c − is thus not only a promising strategy to prevent cognitive decline, but also to promote healthy aging.