Abstract
The cystine/glutamate antiporter system xc− 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 xc− deletion would negatively affect life- and healthspan. Still, till now the role of system xc− 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 xc− is thus not only a promising strategy to prevent cognitive decline, but also to promote healthy aging.
Highlights
The cystine/glutamate antiporter system xc− exchanges intracellular glutamate for extracellular cystine and has been identified as modulator of both glutamatergic neurotransmission in the central nervous system (CNS) of mice [1–3] and ofinflammation [4, 5]
The oxidative shift reported by Sato et al in the plasma cystine/cysteine balance of adult xCT−/− mice led to the hypothesis that xCT deletion would accelerate the aging process [6], in line with the increasing cystine/cysteine ratio that is observed over the lifespan in humans [12]
RESULTS xCT deletion extends lifespan without major effects on general health parameters In our survival study, xCT deletion resulted in a prolonged median lifespan (Fig. 1A) and a strong trend for an increased maximum lifespan (Fig. 1B), despite an increased cystine/cysteine ratio in the plasma of aged xCT−/− mice, compared to age-matched xCT+/+ mice and adult mice (Fig. 1C–E)
Summary
The cystine/glutamate antiporter system xc− exchanges intracellular glutamate for extracellular cystine and has been identified as modulator of both glutamatergic neurotransmission in the central nervous system (CNS) of mice [1–3] and of (neuro)inflammation [4, 5]. The oxidative shift reported by Sato et al in the plasma cystine/cysteine balance of adult xCT−/− mice led to the hypothesis that xCT deletion would accelerate the aging process [6], in line with the increasing cystine/cysteine ratio that is observed over the lifespan in humans [12]. With age, increased levels of pro-inflammatory factors promote the onset of frailty, and the occurrence of agerelated disorders, including dementia and cognitive aging [14]. These seemingly conflicting hypotheses regarding the role of system xc− in aging warrant a more in-depth study
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