A team of Chinese researchers has outlined the cellular link between age-related inflammation (inflammaging) and the physical aging of heart muscle cells (cardiomyocytes).
NLRP3 and why it matters
We have previously discussed the NLRP3 inflammasome, which releases inflammatory cytokines upon exposure to irritants , including reactive oxygen species (ROS) . The researchers hypothesized that ROS, in addition to its direct effects, triggers NLRP3 and thus contributes to inflammaging of the heart.
In order to induce premature aging, the researchers exposed cells to D-galactose. As expected, the senescence markers ß-galactosidase, p53, and p21 were increased, as were the inflammatory cytokines IL-1ß and IL-18. Lactate dehydrogenase (LDH), an indicator of cell toxicity, was also increased.
The researchers found that NLRP3 was increased, showing its role in at least this model of accelerated aging. ROS was also found to be increased with D-gal exposure.
The team then tested cells pre-treated with MCC950, a known inhibitor of NLRP3. As expected, treatment with this compound reduced ß-gal, p53, and p21, providing evidence that NLRP3 is responsible for generating these compounds.
The role of ROS
Previous research has linked NLRP3 to ROS , and this study aimed to better flesh out the relationship. In this vein, one of the first things the researchers did was to inhibit NLRP3 with MCC950 and then measure ROS production. This gave a negative result, implying that while ROS may affect NLRP3, the relationship is not bidirectional.
The researchers then confirmed the relationship between ROS and NLRP3 by using NAC, a well-known scavenger of ROS. They pre-administered NAC to cells slated to be given D-gal and then observed ROS and NLRP3 production. As expected, both ROS and NLRP3 were decreased.
Stimulating NLRP3 directly
While D-gal is a stimulator of NLRP3, its other effects may have confounded the results. Therefore, the researchers also used a compound called nigericin to directly stimulate NLRP3 and observed its effects. ß-galactosidase, p53, and p21 were all upregulated in response, as were IL-1ß, IL-18, and LDH. Therefore, the researchers conclude that NLRP3 itself is responsible for these effects.
This study is instrumental in bringing a few disparate concepts in aging research together. While this is only a cellular in vitro study and was not conducted in living organisms, it shows exactly how an inflammatory response that is beneficial in the short term can be constantly triggered by long-term damage (the accmulation ROS) and lead to further damage (inflammaging) on its own.
With this knowledge comes the opportunity to develop treatments that might directly interfere with this process and so curb inflammaging. If a treatment can be developed to minimize the impact of the NLRP3 inflammasome on cardiac tissue, it could potentially have significantly beneficial effects for people at risk of heart disease.
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 Swanson, K. V., Deng, M., & Ting, J. P. Y. (2019). The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nature Reviews Immunology, 19(8), 477-489.
 Tschopp, J., & Schroder, K. (2010). NLRP3 inflammasome activation: The convergence of multiple signalling pathways on ROS production?. Nature reviews immunology, 10(3), 210-215.
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