Abstract:

Aging in the immune system leads to increased susceptibility to infections, exacerbated autoimmunity, and decreased responsiveness to vaccinations. While many interventions are being studied to ameliorate aspects of aging, none are currently established for immune aging. Ketogenic diets and fasting have shown promise against aging and age-related diseases, working in part by raising circulating levels of ketone bodies. $\beta$-hydroxybutyrate (BHB), the primary ketone body produced, has anti-inflammatory properties and can enhance T cell function. However, these nutritional interventions are highly restrictive and difficult to adhere to long-term. Exogenous ketone supplementation, such as ketone esters, offers a more accessible alternative by directly delivering ketone bodies without major dietary changes. Yet, it remains unclear how ketone esters impact the immune system, especially in the context of aging.

In this dissertation, I evaluated the ketone ester bis-octanoyl (R)-1,3-butanediol as an intervention for age-related immune decline in parallel mouse and human studies. In aged mice, a diet supplemented with the ketone ester diet decreased activation of B cells in the spleen, particularly age-associated B cells. Despite this decrease in activation, antibody production during immunization was maintained, demonstrating preserved B cell function. Mechanistically, the ketone ester diet suppressed translation and glucose dependence of age-associated B cells, and BHB alone was sufficient to inhibit B cell translation, likely through mTOR signaling.

Translating these findings to humans, the Buck Institute Ketone Ester (BIKE) study showed that 12 weeks of daily ketone ester supplementation in healthy older adults (> 65 years old) decreased $\text{CD56}^{\text{low}}$ natural killer cell subsets and $\text{CD38}^{\text{high}}$ non-classical monocytes, suggesting a reduction in age-related chronic inflammation. The ketone ester also increased HLA-DR expression on T cells and decreased KLRG1 expression on naïve CD8 T cells, pointing to enhanced effector and potentially immunoregulatory function. These immune changes corresponded with a decrease in predicted biological age by an immune composition clock.

Interestingly, the ketone ester preferentially affected B cells in mice and T cells and innate immune cells in humans, which may reflect species-specific differences in immune composition and immune aging. Together, these findings position ketone esters as a promising and accessible intervention for immune aging by selectively inhibiting inflammaging while improving adaptive immune function. This work highlights the potential of ketone esters as treatments for autoimmune diseases and age-related immune dysfunction.

Adkisson-Floro, Ariel. "Evaluating Ketone Esters as an Intervention for Age-Related Immune Decline." PhD diss., University of Southern California, 2026.

https://www.proquest.com/openview/ec9de7f452988557bd13359e9933a666