Arguing a Role for NLRP3 Driven Inflammation in Human Life Span Variation
Chronic inflammation is a feature of aging, driven by a range of mechanisms, and in turn disruptive to tissue structure and function. It might be argued, then, that the regulators of inflammation are likely important in natural variation in human life span, and might be targeted to slow aging. The challenge to date is that the same regulators of inflammation are involved in both the unwanted chronic inflammation of aging and in the necessary short-term inflammation needed to defend against pathogens and coordinate regeneration of injuries. Ways to act upon these regulators to suppress the former without suppressing the latter do not yet exist, and may or may not be very challenging to develop.
This paper presents a novel perspective, amassing substantial evidence that targeting NLRP3 not only converges various aging mechanisms but also exerts regulatory control over them. This unique approach underscores a sophisticated interdependence that is yet to be fully understood. Furthermore, NLRP3 appears to regulate cellular senescence so that its activation does not lead to pyroptosis. This suggests that senescent cells could be a persistent source of IL-1β production, thereby contributing to aging. The significance of NLRP3 in aging is highlighted by studies demonstrating that its knockout endows mice with a phenotype of healthspan and lifespan. Additionally, treatments targeting pathways upstream of NLRP3 have been shown to extend the healthspan of primates and reverse various aging symptoms in humans.
Therefore, NLRP3 is not merely a participant in the aging process but potentially acts as a master regulator. Modulating NLRP3 could significantly alter the health trajectories of individuals experiencing NLRP3-mediated accelerated aging. Since this process is largely driven by autologous components, the term 'auto-aging' is proposed. Further research is essential to understand the role of NLRP3 in accelerated aging entirely and to develop healthspan-extending therapies targeting this key regulator.
A critical question remains: Should interventions aim to completely inhibit NLRP3 activation or selectively target specific activation pathways to maximize health benefits? While there appears to be redundancy among NLRs in defending against pathogen-associated molecular patterns, broad inhibition might increase susceptibility to specific infections by weakening primary defense mechanisms. Additionally, better biomarkers are needed to gauge the impact of such therapies on NLRP3 activity. Assessments often focus on free IL-1β levels in plasma, which are minimal due to neutralization by soluble IL receptors. Alternatives could include measuring total IL-1β or utilizing surrogate markers like IL-6 downstream of IL-1β, which may provide a more accurate reflection of NLRP3-mediated inflammatory status.