The Inflammasome in Aging

The inflammasome is an important piece of molecular machinery in the processes that initiate the inflammatory response, vital in protecting the body from pathogens and in recovery from injury, at least for so long as it only lasts for a short time. The inflammasome is also associated with a form of programmed cell death related to inflammation, known as pyroptosis, and with the oxidative stress that occurs with aging. Researchers here investigate the inflammasome in the context of inflammation in later life.

Unfortunately inflammation becomes chronic in old age, and the sweeping cellular changes of inflammation, optimized for short term operation, cause damage when constantly activated. This inflammation is a significant aspect of aging, seated somewhere in the middle of the long chains of cause and consequence that determine our aging biochemistry. It is produced by upstream molecular damage to cells and tissues, such as that leading to the accumulation of senescent cells and their inflammatory signals, and causes a wide range of downstream dysfunction and disruption.

Inflammation is a major factor in a myriad of diseases, and inflammaging is part of the normal process in an individual's life cycle. It has been previously shown that the inflammasome is a key contributor to the innate immune response seen in the aging population. We have previously shown that inflammasome signaling proteins are elevated in the brain of aged rats when compared to young. In this study, we extend these findings to show that NLRC4, caspase-1, ASC, and IL-18 are elevated in the cytosolic fraction of cortical lysates in the aged brain when compared to young. This suggests a role for the NLRC4 inflammasome in the innate immune response of the aging brain.

We have previously shown that the inflammasome-mediated cell death mechanism of pyroptosis occurs in cortical neurons. Here we show that pyroptosome formation as determined by oligomerization of the inflammasome adaptor protein ASC is evident in cortical and hippocampal lysates of the brain of aged mice when compared to young. These findings suggest that in the aging brain, there is a natural process of cell death that is in part mediated by the inflammasome, which is consistent with previous findings indicating that indeed in the aging brain there is a cell death process. Taken together, this highlights the potential for inflammasome-mediated naturally occurring cell death associated with inflammaging as a precursor to the development of neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease.

Most degenerative conditions are characterized by low-grade inflammation. Moreover, mitochondrial dysfunction is at the core of many diseases in addition to aging. The brain consumes about 20 to 25% of the body's total energy. Thus it is an organ that undergoes major metabolic demands. Most of this energy is spent in the process of neurotransmission and is spent by mitochondria. As we age, mitochondrial electron transport chain function declines, as the production of free radicals increases.

In this study, we show that ASC is elevated in the mitochondrial fraction of the cortex and hippocampus of aged mice when compared to young, consistent with previous reports indicating a role for mitochondria in inflammasome signaling. To further study the role of oxidative stress and the aging process as it pertains to inflammasome signaling, we obtained fibroblasts from a subject who donated his cells at three different ages (49, 52 and 64 years) and discovered that caspase-1 and ASC protein levels were higher at the oldest time-point analyzed than at the other two younger time-points. Moreover, the cells at 52 were more prone to cell death when subjected to oxidative stress when compared to the cells at 49. Thus, highlighting the vulnerability of cells to oxidative stress due to the aging process.

Importantly, when the inflammasome was inhibited with a caspase-1 inhibitor in these cells following oxidative stress, the amount of free radicals produced was decreased. In conclusion, this is the first report to show that pyroptotic cell death occurs in the aging brain and that the inflammasome can be a viable target to decrease the oxidative stress that occurs as a result of aging.



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