xCT Knockout Modestly Extends Life in Mice

As a general rule, methods that produce 10-20% life extension in mice are unlikely to prove all that interesting in humans. But it depends on what is going on under the hood. In most cases interventions act on life span by upregulating cellular stress response mechanisms, and there is more than enough evidence to suggest that this category of approaches is far more effective at extending life in short-lived species than is the case in long-lived species such as our own. In this case, the mechanism of interest may be anti-inflammatory, a reduction of age-related chronic inflammation. There is not yet a body of evidence to tell us whether or not this is less interesting in long-lived species such as our own, at the same time as there is a great deal of evidence telling us that chronic inflammation drives many age-related diseases in humans.

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.

Link: https://doi.org/10.1038/s41380-022-01470-5

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