Ketone ester supplementation in aged mice reduces activation of B cell subsets

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. We found that the ketone ester diet decreased activation of B cells, especially age-associated B cells, in the spleen. In spite of this decrease in activation, mice on the ketone ester diet showed no impairment in antibody production after nitrophenyl-ovalbumin immunization. The ketone ester diet also inhibited glucose dependence and translation of age-associated B cells, likely through inhibition of mTOR signaling via ketone bodies. 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.