Hope, Helen Carrascode Sostoa, JanaGinefra, PierpaoloAndreatta, MassimoChiang, Yi-HsuanRonet, CatherinePich-Bavastro, ChristineCorría-Osorio, JesúsKuonen, FrançoisAuwerx, JohanD’Amelio, PatriziaHo, Ping‐ChihCarmona, Santiago J.Coukos, GeorgeMigliorini, DenisVannini, Nicola2025-05-262025-05-262025-05-232025-05-2010.1038/s43018-025-00982-7https://infoscience.epfl.ch/handle/20.500.14299/250450Chimeric antigen receptor (CAR) T cell therapy is one of the most promising cancer treatments. However, different hurdles are limiting its application and efficacy. In this context, how aging influences CAR-T cell outcomes is largely unknown. Here we show that CAR-T cells generated from aged female mice present a mitochondrial dysfunction derived from nicotinamide adenine dinucleotide (NAD) depletion that leads to poor stem-like properties and limited functionality in vivo. Moreover, human data analysis revealed that both age and NAD metabolism determine the responsiveness to CAR-T cell therapy. Targeting NAD pathways, we were able to recover the mitochondrial fitness and functionality of CAR-T cells derived from older adults. Altogether, our study demonstrates that aging is a limiting factor to successful CAR-T cell responses. Repairing metabolic and functional obstacles derived from age, such as NAD decline, is a promising strategy to improve current and future CAR-T cell therapies.entext::journal::journal article::research article