Including enough spermidine in a diet or taking spermidine supplements may positively affect human health. Better yet, it might affect aging and promote healthy longevity. Spermidine levels decrease with aging in immune cells. In a variety of organisms, spermidine slows down age-related diseases. Aged animals with inadequate immunotherapy against tumors were treated with spermidine supplementation, which improved mitochondrial function by stimulating CD8+ T cells. The mechanism behind spermidine’s anticancer potential is supported by improved antitumor immune cell metabolism. Because spermidine exerts its action by several mechanisms, the relation between spermidine deficit and T cells is still unclear. In addition, we will focus on the major key e.g how spermidine can help in antitumor immunity.
Spermidine promotes antitumor immune cell metabolism
Spermidine impacts changes in several tissues in mice such as the liver, and muscle, that was caused by calorie restriction, autophagy, and other mechanisms. With aging, the amount of spermidine in CD8+ T cells that fight cancer decreases by half. The researchers analyzed spermidine levels in CD8+ T cells, in young and old mice to establish that spermidine levels decline with age in anticancer immune cells. They found that the concentrations of total and free spermidine in CD8+ T cells from aged mice were almost half that of those in young mice.
Al-Habsi M, Chamoto K, Matsumoto K, Nomura N, Zhang B, Sugiura Y, Sonomura K, Maharani A, Nakajima Y, Wu Y, Nomura Y, Menzies R, Tajima M, Kitaoka K, Haku Y, Delghandi S, Yurimoto K, Matsuda F, Iwata S, Ogura T, Fagarasan S, Honjo T. Spermidine activates mitochondrial trifunctional protein and improves antitumor immunity in mice. Science. 2022 Oct 28;378(6618):eabj3510. doi: 10.1126/science.abj3510. Epub 2022 Oct 28. PMID: 36302005.
(When compared to young mice, older mice had roughly half the spermidine in their antitumor immune cells.)
Furthermore, they investigate how spermidine supplementation can increase CD8+ activity. Through the enhancement of effector and mitochondrial activity in CD8+ T cells, SPD improves the effectiveness of PD-1/PD-L1 antibody-blocking therapy in old mice. Spermidine alone does not have antitumor activity. Increased rates and quantities of CD8+ T cells with a non-exhausted PD-1 Tim3 phenotype were seen in response to SPD combo therapy.
Al-Habsi M, Chamoto K, Matsumoto K, Nomura N, Zhang B, Sugiura Y, Sonomura K, Maharani A, Nakajima Y, Wu Y, Nomura Y, Menzies R, Tajima M, Kitaoka K, Haku Y, Delghandi S, Yurimoto K, Matsuda F, Iwata S, Ogura T, Fagarasan S, Honjo T. Spermidine activates mitochondrial trifunctional protein and improves antitumor immunity in mice. Science. 2022 Oct 28;378(6618):eabj3510. doi: 10.1126/science.abj3510. Epub 2022 Oct 28. PMID: 36302005.
(The anti-cancer benefits of antibody therapy are enhanced by spermidine.)
Spermidine increases the mitochondrial FAO activity of CD8+ T cells
Because there is a correlation between spermidine and mitochondrial FAO activity, the effect of SPD on FAO was next examined in vitro using etomoxir, a particular inhibitor of carnitine palmitoyltransferase 1a (CPT1a). They assessed the bioenergetic states of naive CD8+ T lymphocytes in vitro with anti-CD3 and -CD28 mAb-coated beads stimulation, in the presence and absence of spermidine and etomoxir. After 44 hours, ATP levels were increased by boosting mitochondrial function.
Spermidine directly binds with the mitochondrial trifunctional protein (MTP), which is the main enzyme of FAO. For that purpose, the researchers isolated SPD-binding proteins and separated them by electrophoresis.
Al-Habsi M, Chamoto K, Matsumoto K, Nomura N, Zhang B, Sugiura Y, Sonomura K, Maharani A, Nakajima Y, Wu Y, Nomura Y, Menzies R, Tajima M, Kitaoka K, Haku Y, Delghandi S, Yurimoto K, Matsuda F, Iwata S, Ogura T, Fagarasan S, Honjo T. Spermidine activates mitochondrial trifunctional protein and improves antitumor immunity in mice. Science. 2022 Oct 28;378(6618):eabj3510. doi: 10.1126/science.abj3510. Epub 2022 Oct 28. PMID: 36302005.
(In the presence or absence of SPD, naive CD8+ T cells from old mice were activated after 44 hours with anti-CD3 and anti-CD28 coated beads.)
Spermidine benefits
By directly activating MTP in CD8+ T cells, they demonstrated how SPD abruptly boosted FAO and ATP production. Increased mitochondrial metabolism may result from a chain of events that may be started by SPD binding and MTP activation.
Numerous studies conducted on model organisms suggest that spermidine prevents aging and increases lifespan. For instance, spermidine increased survival in a fly Parkinson’s disease model. Another study on B12-deficient worms demonstrated spermidine can increase their life span. Moreover, spermidine is being tested in a number of clinical studies to examine its effects on mood and sleep quality or to lower blood pressure.
The key findings
To test if spermidine prevents tumor growth, mice were injected with tumor cells, spermidine, and anticancer antibodies. Since the antibodies identify and attach to cancer cells before presenting them to “killer” CD8+ T cells for extermination, they decided to use anticancer antibody therapy. Since certain cancer patients have difficulty responding to this immunotherapy, the team wondered if spermidine deficiency would be a significant contributing factor. These findings confirm that, at least in mice, spermidine supplementation can improve the effects of antitumor antibody therapies by boosting anticancer immune cell and mitochondrial metabolism.
The study discovered that spermine, a different polyamine derived from SPD with significant cellular protective properties, also directly binds to MTP and competitively inhibits SPD’s FAO activity. This means that the balance between spermidine and spermine is important for FAO assessment in aging cells.
To sum up
These findings support the theory that SPD’s first and most effective function is MTP activation. The spermidine activity in CD8+ T cells provides antiaging characteristics and may help with the development and preventive measures for age-related immunological disorders. Spermidine achieves these results by causing autophagy together with calorie restriction.
Even though aging is a natural process, there are biological, genetic, medical, lifestyle, and environmental factors that might influence it. Spermidine has been shown to be essential for extending lifetime, and excessive changes in spermidine levels have been connected to both aging and the development of disease.
References:
- Al-Habsi, M., Chamoto, K., Matsumoto, K., Nomura, N., Zhang, B., Sugiura, Y., Sonomura, K., Maharani, A., Nakajima, Y., Wu, Y., Nomura, Y., Menzies, R., Tajima, M., Kitaoka, K., Haku, Y., Delghandi, S., Yurimoto, K., Matsuda, F., Iwata, S., … Honjo, T. (2022). Spermidine activates mitochondrial trifunctional protein and improves antitumor immunity in mice. In Science (Vol. 378, Issue 6618). American Association for the Advancement of Science (AAAS). https://doi.org/10.1126/science.abj3510
