Ketone ester supplementation reduces age-associated B cell activation in aged mice without impairing antibody responses

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Abstract Background Aging in the immune system results in increased susceptibility to infections, exacerbated autoimmunity, and reduced responsiveness to vaccines. However, there are no current established interventions for immune aging. Ketogenic diets and fasting have been researched as interventions against other aspects of aging and age-related diseases, and they work in part by increasing circulating levels of ketone bodies, which have anti-inflammatory properties and can boost T cell function. Exogenous ketones, such as ketone esters, are currently being studied as a more accessible approach to obtain the benefits of ketone bodies through direct supplementation. Here, we investigated whether ketone ester supplementation improves immune function during aging. Aged (19-month-old) C57BL/6JN mice were given a diet supplemented with the ketone ester or a control diet for 15 weeks. Results We found that the ketone ester diet decreased activation of B cells, especially age-associated B cells, in the spleen. The diet also reduced the proportion of age-associated B cells defined by CD11b and CD11c expression, though not of the broader CD21 − CD23 − population. Despite this decrease in activation, there was no impairment in antibody production, as mice on the ketone ester diet mounted a normal response to nitrophenyl-ovalbumin immunization. The ketone ester diet also reduced glucose dependence and translation in subsets of age-associated B cells. Treating splenocytes from aged mice with β-hydroxybutyrate was sufficient to suppress B cell translation and reduced mTORC1 signaling, indicating that ketone bodies act directly on B cells. β-hydroxybutyrate also decreased expression of T-bet, the signature transcription factor driving the autoimmune functions of age-associated B cells. Conclusions Our study elucidates the effect of ketone esters on B cells in the context of aging and unveils a new immunoregulatory role of ketone bodies on B cells.

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