Inflammaging: disturbed interplay between autophagy and inflammasomes

Abstract

Inflammaging refers to a low-grade pro-inflammatory phenotype which accompanies aging in mammals. The aging process is associated with a decline in autophagic capacity which impairs cellular housekeeping, leading to protein aggregation and accumulation of dysfunctional mitochondria which provoke reactive oxygen species (ROS) production and oxidative stress. Recent studies have clearly indicated that the ROS production induced by damaged mitochondria can stimulate intracellular danger-sensing multiprotein platforms called inflammasomes. Nod-like receptor 3 (NLRP3) can be activated by many danger signals, e.g. ROS, cathepsin B released from destabilized lysosomes and aggregated proteins, all of which evoke cellular stress and are involved in the aging process. NLRP3 activation is also enhanced in many age-related diseases, e.g. atherosclerosis, obesity and type 2 diabetes. NLRP3 activates inflammatory caspases, mostly caspase-1, which cleave the inactive precursors of IL-1β and IL-18 and stimulate their secretion. Consequently, these cytokines provoke inflammatory responses and accelerate the aging process by inhibiting autophagy. In conclusion, inhibition of autophagic capacity with aging generates the inflammaging condition via the activation of inflammasomes, in particular NLRP3. We will provide here a perspective on the current research of the ROS-dependent activation of inflammasomes triggered by the decline in autophagic cleansing of dysfunctional mitochondria.

Figure 1. The interplay between autophagy and inflammasomes in the generation of inflammaging

Normally, the autophagic uptake of dysfunctional mitochondria prevents the excessive ROS production and in that way the activation of inflammasomes. However, during aging, the autophagic capacity declines and increased ROS production and aggregated proteins activate inflammasomes which provoke a low-grade inflammation in several tissues and in that way inhibit autophagy and accelerate the aging process. There are several activators of autophagy which can delay the aging process. It is known that mTOR inhibitors and AMPK activators can extend lifespan in certain conditions.