Immunosenescence is the remodeling of immunological responses; mitochondria and mitochondrial metabolism are considered to be key players in this process. Nevertheless, there is a shortage of information about the cytokine-inducing chemicals and the mitochondrial stress response's function in this remodeling.
The data suggests that these cytokines have an anti-inflammatory function and increase over time, while many unanswered questions about their biology remain.
Further research is required to establish the exact function of cytokines and the mitochondrial stress response in immune responses other than inflammation. This is especially true within the context of immunosenescence and the interplay between the immune system and other tissues like the liver and adipose tissue. Future research should clarify the specific function of mitochondrial dysfunction and other stressors in regulating immunological responses via cytokine synthesis, as other forms of stress, such as endoplasmic reticulum stress, may also induce the creation of certain cytokines. Additionally, it would be great if scientists tried to explain how cytokines directly react to the immune system or inflammatory triggers. But if the idea that cytokines are trying to control inflammatory reactions, both short-term and long-term, turns out to be true, specialists need to rethink their role in aging-related diseases and cell death and think about how they can use them (by regulating their expression positively) in targeted research.
The many systems that detect and react to mitochondrial malfunction are at the epicenter of adapting and remodeling the various cell types and organs that contribute to the successful or failed cell aging that occurs.
Specifically, GDF15 may mediate cancer cachexia, according to gain and loss-of-function studies in mice models. Furthermore, GDF15 is thought to be a marker of all-cause mortality. Consistent with earlier research, researchers suggested that GDF15 is the mitokine most linked to death in aged research models. Thus, GDF15's function may be more nuanced and perhaps contradictory than first thought (this could be because inflammation is necessary for proliferation, but too much of it might cause cellular damage).
Potential Impact of Mitokines on Inflammation
As mentioned, GDF15, FGF21, and HN have been suggested as molecules with anti-inflammatory properties in several experimental settings. Like many pro-inflammatory mediators, their blood levels seem to rise over time. This raises the possibility that they are part of a molecular immune-metabolic machinery or network that can respond to mitochondrial stress and create a coordinated systemic anti-inflammatory response in acute and chronic conditions. Here, the cytokine response may be considered a component of an "anti-inflammation" mechanism that has been postulated as a result of inflammation in the past.
The capacity to suppress inflammatory reactions, whether acute or chronic, has been deemed essential for a state of homeostasis and to prevent or delay the onset of age-related disorders such as cardiovascular disease, type 2 diabetes, neuro-inflammation, cancer, and many more, as researchers purport.
MOTS-c Peptide and Mitokines
A decrease in MOTS-c levels has been suggested in aged mice's skeletal muscle and plasma. This suggests that insulin-sensitive tissues, including fat and skeletal muscle, may be important targets of MOTS-c. Because of this, some have hypothesized that MOTS-c could be a mitokine associated with aging. It has been suggested that cytokines, peptides generated by mitochondria, function in endocrine cytoprotection and constitute an important retrograde communication mechanism between mitochondria and the rest of the cell.
A few years ago, Lee et al. found a peptide of 16 amino acids called MOTS-c. MOTS-c is found in the bloodstream and is expressed in other tissues, including skeletal muscle and adipose tissue. Recent research has pointed to MOTS-c as a possible inflammation and cellular metabolism modulator. Research has suggested that MOTS-c may mitigate inflammation by decreasing quantities of cytokines that promote inflammation, such as IL-6, IL-1β, and TNFα, and raising quantities of IL-10, a cytokine that inhibits inflammation. Specifically, MOTS-c has been theorized to improve survival rates in sepsis-stricken mice by lowering bacterial loads and increasing macrophage bactericidal ability. In addition, the NF-κB and STAT1 pathways might be regulated by MOTS-c, which further reduces inflammation, investigations purport. There seems to be a correlation between aging and a decline in MOTS-c circulating levels.
In a functional cell aging state, stress triggers the mitochondrial unfolded protein response (UPRmt) and the production of cytokines (HN, FGF21, GDF15). These cytokines inhibit the production and activity of inflammatory cytokines (such as IL-1β, IL-18, IL-6, type I IFN, and TNF-α) through mechanisms that have not been fully explained. As a result, a balance between inflammatory and specific immune responses is maintained. In dysfunctional cell aging, however, there is an imbalance between these two types of responses, leading to excess inflammatory cytokines. This is accompanied by an increase in danger-associated molecular patterns (DAMPs) and a high production of reactive oxygen species (ROS), contributing to the onset of ARDs.
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[i] Conte, Maria, et al. “Mitochondria, Immunosenescence and Inflammaging: A Role for Mitokines?” Seminars in Immunopathology, vol. 42, no. 5, 5 Aug. 2020, pp. 607–617, 10.1007/s00281-020-00813-0.
[ii] Zhai, Dongsheng, et al. “MOTS-c Peptide Increases Survival and Decreases Bacterial Load in Mice Infected with MRSA.” Molecular Immunology, vol. 92, 1 Dec. 2017, pp. 151–160, pubmed.ncbi.nlm.nih.gov/29096170/, 10.1016/j.molimm.2017.10.017.
[iii] Yin, Xinqiang, et al. “The Intraperitoneal Administration of MOTS-c Produces Antinociceptive and Anti-Inflammatory Effects through the Activation of AMPK Pathway in the Mouse Formalin Test.” European Journal of Pharmacology, vol. 870, 5 Mar. 2020, p. 172909, pubmed.ncbi.nlm.nih.gov/31926126/, 10.1016/j.ejphar.2020.172909.
[iv] D’Souza, Randall F., et al. “Increased Expression of the Mitochondrial Derived Peptide, MOTS-c, in Skeletal Muscle of Healthy Aging Men Is Associated with Myofiber Composition.” Aging (Albany NY), vol. 12, no. 6, 17 Mar. 2020, pp. 5244–5258, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138593/, 10.18632/aging.102944.