Fight Aging!

With advancing age, a wide range of mechanisms act to provoke the immune system into a state of constant inflammatory signaling and activation. Age-related mitochondrial dysfunction leads to mislocalized mitochondrial DNA fragments that trigger the cGAS-STING pathway to provoke inflammation. Senescent cells produce pro-inflammatory signaling, and their numbers increase with age. Visceral fat tissue produces signaling similar that resulting from infected cells. The increased presence of protein aggregates aggravates immune cells inside and outside of the brain. And so forth. Given all of this, actually fixing the issue of age-related chronic inflammation will likely require control over a great deal of the underlying biochemistry of aging itself.

Nonetheless, chronic inflammation is clearly a major problem that produces sizable downstream issues. It is highly disruptive to tissue function, accelerating all of the major fatal age-related conditions. If there are shortcuts to suppress excessive, chronic inflammation without affecting the necessary short-term inflammation required for the immune system to function, then pursing these shortcuts may turn out to be at least as beneficial as, say, control over raised blood pressure. Unfortunately, most of the approaches developed to date do poorly when it comes to avoiding suppression of necessary immune function.

As discussed in today's open access paper, there is the hope that targeting the immune sensors called inflammasomes will produce a better next generation of more discriminatory anti-inflammatory therapies. It remains the case that near all immune reactions, whether excessive and unwanted or transient and necessary, run through the same signaling pathways, however. At some point, given a greater understanding of the detailed mechanisms of immune reaction and signaling, a way to discriminate must emerge - but that has yet to happen and be demonstrated in practice.

The role of inflammasomes in human diseases and their potential as therapeutic targets

Inflammasomes are large protein complexes that play a major role in sensing inflammatory signals and triggering the innate immune response. Each inflammasome complex has three major components: an upstream sensor molecule that is connected to a downstream effector protein such as caspase-1 through the adapter protein ASC. Inflammasome formation typically occurs in response to infectious agents or cellular damage. The active inflammasome then triggers caspase-1 activation, followed by the secretion of pro-inflammatory cytokines and pyroptotic cell death. Aberrant inflammasome activation and activity contribute to the development of diabetes, cancer, and several cardiovascular and neurodegenerative disorders.

As a result, recent research has increasingly focused on investigating the mechanisms that regulate inflammasome assembly and activation, as well as the potential of targeting inflammasomes to treat various diseases. Multiple clinical trials are currently underway to evaluate the therapeutic potential of several distinct inflammasome-targeting therapies. Therefore, understanding how different inflammasomes contribute to disease pathology may have significant implications for developing novel therapeutic strategies. In this article, we provide a summary of the biological and pathological roles of inflammasomes in health and disease. We also highlight key evidence that suggests targeting inflammasomes could be a novel strategy for developing new disease-modifying therapies that may be effective in several conditions.