Nicotinamide Riboside and NMN Enhance CAR-T Cell Function in Aging: Preclinical Findings

Synopsis

Chimeric antigen receptor (CAR) T cell therapy is a powerful cancer treatment, but its effectiveness declines with aging. This study found that CAR-T cells from aged female mice show mitochondrial dysfunction caused by NAD+ depletion, leading to reduced stem-like traits and weaker tumor-fighting ability. Treatment with nicotinamide mononucleotide (NMN) improved mitochondrial activity in young T cells but had no effect on aged T cells. Similarly, nicotinamide riboside (NR) helped prevent T cell exhaustion in younger cells, but it couldn’t reverse mitochondrial issues or prevent damage in older T cells, highlighting that age-related NAD+ decline is difficult to fix with standard NAD+ boosters. Analysis of human data confirmed that age and NAD+ metabolism strongly influence CAR-T therapy success. Boosting NAD+ pathways restored mitochondrial health and functionality in CAR-T cells from older adults, improving their anti-cancer performance. These findings highlight age-related NAD+ decline as a key metabolic barrier to CAR-T therapy and suggest that replenishing NAD+ could enhance cancer immunotherapy outcomes in elderly patients.

Journal

Nature Cancer