NAD⁺ supplementation prevents STING-induced senescence in CD8⁺ T cells by improving mitochondrial homeostasis

Understanding the connection between senescence phenotypes and mitochondrial dysfunction is crucial in aging and premature aging diseases. Loss of mitochondrial function leads to a decline in T cell function, which plays a significant role in this process. However, more research is required to determine if improving mitochondrial homeostasis alleviates senescence phenotypes. Our research has shown an association between NAD(+) and senescent T cells through the cGAS-STING pathway, which can lead to an inflammatory phenotype. Further research is needed to fully understand the role of NAD(+) in T-cell aging and how it can be utilized to improve mitochondrial homeostasis and alleviate senescence phenotypes. We demonstrate here that mitochondrial dysfunction and cellular senescence with a senescence-associated secretory phenotype (SASP) occur in senescent T cells and tumor-bearing mice. Senescence is mediated by a stimulator of interferon genes (STING) and involves ectopic cytoplasmic DNA. We further show that boosting intracellular NAD(+) levels with nicotinamide mononucleotide (NMN) prevents senescence and SASP by promoting mitophagy. NMN treatment also suppresses senescence and neuroinflammation and improves the survival cycle of mice. Encouraging mitophagy may be a useful strategy to prevent CD8(+) T cells from senescence due to mitochondrial dysfunction. Additionally, supplementing with NMN to increase NAD(+) levels could enhance survival rates in mice while also reducing senescence and inflammation, and enhancing mitophagy as a potential therapeutic intervention.