Constant, unresolved inflammatory signaling is a feature of aging. It occurs in absence of the usual provocations of infection and injury, and is disruptive to tissue structure and function. Normal, short-term inflammation is useful and necessary, but long-term inflammation is harmful. It changes cell behavior for the worse, causes the normal processes of tissue maintenance to run awry, degrades the effectiveness of the immune system, encourages growth of cancers, and contributes to the onset and progression of all of the common fatal diseases of aging.
Much of this unwanted inflammation of aging is caused by the reaction of inflammasomes to the molecular damage present in an aged cell. Inflammasomes are protein complexes that evolved to react to the presence of molecules characteristic of infectious agents such as viruses by inducing inflammatory signaling that will then be amplified by the immune system. Unfortunately, this means that they will also react to age-related cell dysfunction that leads to the escape of fragments of nuclear DNA from the nucleus and mitochondrial DNA from mitochondria into the body of the cell. Analogous maladaptive activation of inflammasomes also takes place as a result of other dysfunctions that occur in aged cells.
Researchers are interested in targeting inflammasomes to prevent this induction of inflammation in aged tissues. The challenge here is that, so far, it appears that distinguishing between unwanted activation and desirable activation will be challenging. Efforts to suppress inflammatory signaling will not just suppress the harmful chronic inflammation, but also suppress useful short-term inflammation, further impairing immune function. It remains to be seen as to whether there are clever ways around this problem; one or two possible paths forward have been found in recent years, but these approaches may or may not work out. It is too early to say.
Potential Role of Inflammasomes in Aging
Inflammaging is a term used to describe the physiological changes in the immune system associated with aging that play a significant role in the onset and progression of complex aging-related diseases. These changes affect various conditions, including skin aging, cardiovascular disease, neurodegenerative disease, periodontal disease, and other chronic illnesses. Molecular and cellular mechanisms linking aging and chronic inflammation have been studied extensively, focusing on increased cytokine expression related to inflammasomes and their sustained activation in inflammatory diseases.
Inflammasomes are protein complexes observed within the cell cytoplasm, serving as critical molecular platforms that induce inflammatory responses. Inflammasomes recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), leading to the secretion of pro-inflammatory cytokines, such as interleukin (IL)-1β and IL-18, as well as the initiation of pyroptosis, a form of cell death. The activation of inflammasomes involves various sensors, including nucleotide-binding oligomerization domain and leucine-rich repeat-containing receptor (NLR) proteins, pyrin, absent in melanoma 2 (AIM2), and gamma-interferon-inducible protein Ifi-16 (IFI16). These sensors activate the protease enzyme caspase-1, which cleaves pro-IL-1β and pro-IL-18, generating mature IL-1β and IL-18. Furthermore, inflammasome activation leads to the cleavage of gasdermin-D, resulting in N-terminal fragments that form pores in the cell membrane. This process induces pyroptosis while releasing various DAMPs and cytokines.
Inflammasomes play a fundamental role in enhancing innate immune responses and promoting pathogen clearance and tissue repair. However, their activation can be context-dependent, and excessive activation may exacerbate inflammatory conditions. Conversely, insufficient cytokine activation could contribute to chronic inflammation. Therefore, the precise regulation of inflammasome activity is essential for maintaining physiological homeostasis.
The targeting of inflammasomes offers a promising avenue for mitigating inflammaging and age-related diseases. Given the distinct yet overlapping roles of various inflammasome sensors, the development of selective and broad-spectrum inflammasome inhibitors is critical. While many studies have focused on NLRP3 inhibition, the involvement of other inflammasomes in inflammaging suggests that a more comprehensive approach is necessary. Each inflammasome sensor responds to different activation signals, meaning that a single-target strategy may be insufficient to fully mitigate chronic inflammation and its systemic effects in aging. Further research is needed to determine how targeting multiple inflammasomes simultaneously could impact the inflammaging process and whether dual or multi-inflammasome inhibition can provide synergistic benefits without compromising immune surveillance.
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