Ageassociated Nicotinamide Adenine Dinucleotide Decline Drives Cart Cell Failure Helen Carrasco Hope 1 by Helen Carrasco Hope  1, 2, Jana De Sostoa3, 4, 5, 6, 10, Pierpaolo Ginefra  1, 2, 10, instant download after payment.

Chimeric antigen receptor (CAR) T cell therapy is one of the most promising cancer treatments. However, diferent hurdles are limiting its application and efcacy. In this context, how aging infuences 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 ftness 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.