Research co-led by Ludwig Lausanne’s Helen Carrasco Hope and Nicola Vannini reported in a May publication in Nature Cancer that the metabolic decline that accompanies aging promotes mitochondrial dysfunction and impairs the efficacy of CAR-T cell therapy. That dysfunction, they showed, stems from the age-related depletion of nicotinamide adenine dinucleotide (NAD+), a molecule of critical importance to energy production, metabolism and mitochondrial function. They found that CAR-T cells produced from the T cells of aged mice tend to lack “stemness”, or the capacity to persist long-term in vivo and efficiently control tumor growth. These capabilities could be restored by NAD+-boosting compounds currently under clinical investigation for other conditions—which means that the strategy may be readily translated for clinical evaluation. Notably, parallel analyses of clinical datasets by the researchers confirmed that both chronological age and NAD+-related gene expression correlate with outcomes of CAR-T therapy in patients. The findings underscore how fundamentally aging alters the function and metabolism of immune cells, ultimately compromising immunotherapy efficacy. The authors highlight the need to better model age in preclinical studies of immunotherapy, as three-quarters of patients eligible for such treatments are over 65 years old. Interventions that address age as a limiting factor of therapeutic response could improve outcomes for patients receiving immunotherapy.
Age-associated nicotinamide adenine dinucleotide decline drives CAR-T cell failure
Nature Cancer, 2025 May 20