Keywords: inflammation, aging, spermidine , mitochondria
Mitochondria are independent organelles with their own mini-chromosomes and DNA, responsible for producing the chemical energy needed to maintain life and health. When stressed or dysfunctional, mitochondria excrete oxidized and fragmented DNA (mtDNA) into the cytoplasm, where it can enter the bloodstream and trigger inflammation.
In autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis , the amount of oxidized mtDNA in the circulation is related to the severity of the disease. An open question plaguing the field is whether oxidized mtDNA is simply a biomarker of disease or an inducer in the pathology of aging.
In a new study published in the journal Immunity in July 2022, researchers at the University of California, San Diego School of Medicine describe the biochemical pathway that leads to the production of oxidized mtDNA and how it triggers a damaging inflammatory response.
When macrophages (a type of white blood cell that detect infection and tissue damage and direct other immune system cells to respond) are exposed to metabolic danger signals, one of the immediate responses of mitochondria is to rapidly uptake them from the cytoplasm calcium ions promote the production of reactive oxygen species , leading to the formation of oxidized mtDNA. This oxidized mtDNA is very large. When it is cut off by an enzyme called FEN1, it will enter the cytoplasm and combine with the multi-protein complex of the inflammasome to activate the inflammatory response .
In autoimmune diseases, inflammation often gets out of control, causing the immune system to attack and destroy healthy cells and tissues. This finding highlights the critical role of FEN1 in promoting autoinflammation, and researchers have shown that blocking signaling with FEN1 inhibitors prevents the inflammatory process from occurring.
As we all know, chronic low-grade inflammation is one of the key factors in accelerating aging. Delaying aging and related diseases by controlling inflammation has become an important way to extend life in the anti-aging circle, such as spermidine, rapamycin and other popular life-extending supplements. The agent also relies heavily on its anti-inflammatory mechanism to function.
[Reference]
1. Hongxu Xian et al, Oxidized DNA fragments exit mitochondria via mPTP- and VDAC-dependent channels to activate NLRP3 inflammasome and interferon signaling, Immunity (2022).
2. Liu R, Li X, Ma H, et al. al. Spermidine endows macrophages anti-inflammatory properties by inducing mitochondrial superoxide-dependent AMPK activation, Hif-1α upregulation and autophagy. Free Radic Biol Med. 2020 Dec;161:339-350.
3. Desler C, Lillenes MS, Tønjum T, Rasmussen LJ. The Role of Mitochondrial Dysfunction in the Progression of Alzheimer's Disease. Curr Med Chem. 2018;25(40):5578-5587.
