The immune system declines with age, and older people are more susceptible to infections and cancers, and PD-1 inhibition, a commonly used treatment, is often less effective in older people than in younger people. Studies have shown that there is a biological polyamine spermidine in the human body that decreases with age, and supplementation with spermidine can improve or delay some age-related diseases, including immune system diseases. However, the relationship between spermidine deficiency that accompanies aging and senescence-induced T cell immunosuppression is unclear.
Recently, researchers from Kyoto University in Japan published a research paper entitled “Spermidine activates mitochondrial trifunctional protein and improves antitumor immunity in mice” in Science. This study reveals that spermidine directly binds and activates the mitochondrial trifunctional protein MTP, triggers fatty acid oxidation, and ultimately leads to enhanced mitochondrial metabolism in CD8+ T cells and promotes anti-tumor immunity. The results showed that combined treatment with spermidine and anti-PD-1 antibody enhanced the proliferation, cytokine production and mitochondrial ATP production of CD8+ T cells, and spermidine effectively enhanced mitochondrial function and significantly increased mitochondrial fatty acid oxidation metabolism within 1 hour .
To explore whether spermidine directly activates fatty acid oxidase (FAO) in mitochondria, the research team determined by biochemical analysis that spermidine binds to mitochondrial trifunctional protein (MTP), a central enzyme in fatty acid β-oxidation. MTP consists of α and β subunits, both of which bind spermidine. Experiments using MTPs synthesized and purified from E. coli showed that spermidine binds MTPs with strong affinity [binding affinity (dissociation constant, Kd) = 0.1 μM] and enhances their enzymatic fatty acid oxidation activity. Specific depletion of the MTPα subunit in T cells abrogated the potentiation effect of spermidine on PD-1-suppressive immunotherapy, suggesting that MTP is required for spermidine-dependent T cell activation.
In conclusion, spermidine enhances fatty acid oxidation by directly binding and activating MTP. Supplementation with spermidine can enhance fatty acid oxidation activity, improve mitochondrial activity and cytotoxic function of CD8+ T cells. The research team has a new understanding of the properties of spermidine, which may help develop strategies to prevent and improve the outcome of age-related immune diseases and combat non-responsiveness to PD-1 inhibitory therapy in cancer, regardless of age size.