Health plus autophagy,mitophagy minus Inflamasome.
At the largest fractal level thus far revealed by all the blog posts before, the above is the current grand strategy. Thus there is the same dual aim of increasing the good and inhibiting the bad as cellular homeostasis.
In article below clock gene disruption is related to Sirt-1 decline in ability to deacetylate or inactivate the NLRP3 pathway.
Ursolic acid increases Sirt-1 and Sirt-3 and elevated levels are associated with longevity.
Ursolic acid increases intracellular BHB
Autophagy and mitophagy are increased by BHB.
Autophagy and mitophagy inhibit NLRP3 by removing toxic ROS producing mitochondria.
Melatonin promotes autophagy and mitophagy.
Melatonin counters only sepsis related NLRP3 activation.
BHB and melatonin counter NLRP3 activation in Both aging, sepsis and sterile inflammation from LPS and other triggers of autoimmune disease.
Increasing BHB and melatonin slows aging, neuroinflammation, autoimmune inflammation and degenerative age related diseases likely including cancer, stroke, heart attack, sarcopenia,heart failure, cognitive impairment and dementia.
Same molecule but different expression: aging and sepsis trigger NLRP3 inflammasome activation, a target of melatonin
The connection between the innate immune system, clock genes, and mitochondrial bioenergetics was analyzed during aging and sepsis in mouse heart. Our results suggest that the sole NF-κB activation does not explain the inflammatory process underlying aging; the former also triggers the NLRP3 inflammasome that enhances caspase-1-dependent maturation of IL-1β. In this way, aged mice enter into a vicious cycle as IL-1β further activates the NF-κB/NLRP3 inflammasome link. The origin of NF-κB activation was related to the age-dependent Bmal1/Clock/RORα/Rev-Erbα loop disruption, which lowers NAD+ levels, reducing the SIRT1 deacetylase ability to inactivate NF-κB. Consequently, NF-κB binding to DNA increases, raising the formation of proinflammatory mediators and inducing mitochondrial impairment. The cycle is then closed with the subsequent NLRP3 inflammasome activation. This paired contribution of the innate immune pathways serves as a catalyst to magnify the response to sepsis in aged compared with young mice. Melatonin administration blunted the septic response, reducing inflammation and oxidative stress, and enhancing mitochondrial function at the levels of nonseptic aged mice, but it did not counteract the age-related inflammation. Together, our results suggest that, although with different strengths, chronoinflammaging constitutes the biochemical substrate of aging and sepsis, and identifies the NLRP3 inflammasome as a new molecular target for melatonin, providing a rationale for its use in NLRP3-dependent diseases.
Joseph Thomas (Tony) Liverman,
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