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. We identified an age-related link between altered basal lipid metabolism and impaired antigen responsiveness in the naive CD8+ T cell compartment. These abnormalities were associated with an enhanced susceptibility to activation-induced apoptosis and could be recapitulated in vitro by exposure to the homeostatic cytokine interleukin (IL)-7. Importantly, reversal of the bioenergetic anomalies with lipid-altering drugs, such as rosiglitazone, almost completely restored the functional capabilities of naive CD8+ T cells. Interventions that favor lipid catabolism may therefore find utility as adjunctive therapies in the elderly to promote vaccine-induced immunity against emerging pathogens, such as seasonal influenza viruses and SARS-CoV-2. ### Competing Interest Statement The authors have declared no competing interest.

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