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.
Highlights
In 2000, Franceschi et al [1] coined the term "inflammaging" in order to refer to a low-grade proinflammatory status appearing during the aging process
In the case of Nod‐like receptor 3 (NLRP3), the activated receptor interacts with the adaptor protein ASC which recruits the inflammatory caspase-1 (CASP-1) to the complex which subsequently oligomerizes into pentaor heptameric inflammasomes [16,19]
CASP-1 is the common effector molecule in inflammasomes which cleaves the inactive precursors of two proinflammatory cytokines, i.e. IL-1β and IL-18, into their mature forms which are secreted from cells
Summary
In 2000, Franceschi et al [1] coined the term "inflammaging" in order to refer to a low-grade proinflammatory status appearing during the aging process. The presence of a proinflammatory phenotype in aged mammals is evident by (i) increased expression of genes linked to inflammation and immune responses in the tissues of old humans and rodents [4,5,6], (ii) higher level of cytokines in serum, e.g. IL-6 and TNF-α [7,8], (iii) activation of NF-κB signaling which is the master regulator of inflammatory responses [9,10,11]. Inflammasomes are intracellular multiprotein sensors which can recognize a large set of danger signals, induced either by pathogens or cellular stress, and once activated, they subsequently stimulate inflammatory responses [15,16,17,18].
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