Background: Aging is associated with functional deficits in the naive T cell compartment, which compromise the generation of de novo immune responses against previously unencountered antigens. The mechanisms that underlie this phenomenon have nonetheless remained unclear. Methods: Biochemical and functional properties of naive CD8+ T cells were characterized and compared between middle aged and older individuals. Findings: We identified an age-related link between altered basal lipid metabolism in naive CD8+ T cells and their impaired responsiveness to stimulation, characterized by low proliferative potential and susceptibility to apoptosis. Reversal of the bioenergetic anomalies with lipid-altering drugs, such as rosiglitazone, improved the functional capabilities of naive CD8+ T cells in elderly subjects. Interpretation: Interventions that favor lipid catabolism may find utility as adjunctive therapies in the elderly to promote vaccine-induced immunity against emerging pathogens or tumors. Funding: A full list of the funding sources is detailed in the Acknowledgment section of the manuscript.

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