Research Article: Inflammaging: disturbed interplay between autophagy and inflammasomes

Date Published: March 7, 2012

Publisher: Impact Journals LLC

Author(s): Antero Salminen, Kai Kaarniranta, Anu Kauppinen.

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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.

Partial Text

In 2000, Franceschi et al. [1] coined the term “inflammaging” in order to refer to a low-grade pro-inflammatory status appearing during the aging process. They emphasized the role of macrophages as well as cellular stress and genetic factors in the generation of the inflammaging condition. In addition, they hypothesized that this inflammatory environment could predispose the organism to the development of several age-related diseases. During recent years, this scenario has been confirmed by a plethora of experimental evidence. However, it seems that concurrently with the chronic, low-level inflammation one encounters several symptoms of immunosenescence, both in the innate and adaptive immune systems [2,3]. The presence of a pro-inflammatory 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 [4-6], (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 [9-11]. There are tissue specific differences in the production of age-related inflammatory factors as well as in the onset and level of pathological changes [12].

The aging process jeopardizes the maintenance of cellular homeostasis leading to the activation of a variety of host defence systems. 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 [15-18]. There are several subfamilies of NOD-like receptors (NLR) but emerging data indicates that the NLRP subfamily, in particular the NLRP3 member, is the major sensor for “intracellular danger-associated molecular patterns” (DAMPs). Inflammasomes are signaling platforms which are assembled after the recognition of DAMP by the receptor protein. In the case of 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 penta- or 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 then secreted from cells. In addition to CASP-1, some other inflammatory caspases, e.g. CASP-4, CASP-5 and CASP-12, can also process the proforms of these cytokine [16,20]. In general, the expression levels of NLRP3 receptor as well as the precursors of IL-1β and IL-18 remain low and activation of NLRP3 inflammasomes requires a priming phase while the expression of these proteins is clearly induced [17,21,22]. Interestingly, NF-κB signaling is a crucial inducer of NLRP3 expression [21]. It should be noted that different cellular stresses and the aging process can stimulate NF-κB signaling [11,23] and probably enhance the priming and potentiation of the inflammasome activation.

Autophagy is an ancient housekeeping mechanism which controls the cellular homeostasis by facilitating the removal of misfolded proteins and dysfunctional organelles, e.g. mitochondria and endoplasmic reticulum, for degradation in lysosomal system [39,40]. There are three pathways which can deliver cytoplasmic material for autophagic degradation, i.e. macro- and microautophagy as well as chaperone-mediated autophagy. Macroautophagy, segregating organelles like mitochondria, is the major type of autophagy associated with innate immunity [41,42] and it is hereafter shortly called “autophagy”. In addition to the cleansing function, autophagy can regulate cellular energy balance, e.g. during starvation it can trigger energy production from its own components [43]. Autophagy may also be involved in lipid metabolism by sequestering lipid droplets [44]. In conjunction with this increased knowledge on inflammasomes, the role of autophagy in the regulation of inflammatory responses has started to emerge.

The aging process involves a progressive decline in cellular and organismal function. The major hallmark of aging is the deficient maintenance of proteostasis which permits the accumulation of damaged and defective cellular components, e.g. lipofuscin, within cells. Brunk and Terman [66] called this cellular status as “garbage can” hypothesis of aging. They proposed that lipofuscin accumulation would disturb lysosomal degradation thus inhibiting the cleansing of dysfunctional mitochondria. After ten years of experimental work, this hypothesis still seems to be valid since different research approaches have demonstrated that autophagy clearly declines with aging and the number of dysfunctional mitochondria augments. In particular, defects in mitochondrial uptake and degradation could increase ROS production and stimulate inflammasomes. Recently, this research topic has been extensively reviewed in detail elsewhere [67-72].

As Cuervo [67] outlined, the role of autophagy is to “keep that old broom working” with aging. As discussed above, there is much evidence that caloric restriction can activate autophagy and also extend lifespan, probably via its beneficial health effects. Currently, there are a number of drug discovery programs aimed at finding safe chemicals which would be able to activate autophagy. There are two potential groups of compounds acting in this way; mTOR inhibitors [103,104] and AMPK activators [105,106] (Figure 1). mTOR is the major inhibitor of autophagy and is involved in aging [107,108]. Rapamycin and other mTOR inhibitors are either used or under investigation for therapy of cancer and many age-related diseases [107-110]. mTOR is a key protein kinase which couples nutritional and growth factor signaling to protein synthesis, transcription and critical responses in cellular growth, proliferation and survival. Moreover, many studies have reported that lifespan extension induced by CR is associated with the down-regulation of mTOR activity [108,111]. Harrison et al. [79] observed that rapamycin, a recognized inhibitor of mTOR, could extend lifespan in mice if fed late in their life. Recently, Anisimov et al. [112] demonstrated that the lifelong administration of rapamycin extended lifespan in inbred female mice. Moreover, rapamycin could also increase maximal lifespan in cancer-prone mice [113]. Cao et al. [114] observed that rapamycin treatment reversed the senescent phenotype of Hutchinson-Gilford progeria cells in culture by stimulating autophagy. Rapamycin treatment has also been reported to be able to reduce age-related cognitive defects. Majumder et al. [115] demonstrated that life-long administration of rapamycin improved the spatial learning and memory performance in aging mice. Interestingly, this was associated with a decrease in the brain level of IL-1β but not that of TNF-α which could be interpreted to imply that the inflammasomal activity had been reduced by rapamycin therapy. This suggestion is in agreement with the results of Mawhinney et al. [116] which indicated that increased inflammasome activation was linked to age-related cognitive impairment in rats. Rapamycin, also called sirolimus in clinical use, has been intensively studied as an anti-cancer agent [109]. Rapamycin is a macrolide antibiotic and powerful immunosuppressant which causes some serious complications, e.g. lung toxicity. Currently, there are intensive drug discovery programs planned at developing rapalogues, i.e. rapamycin analogues, such as everolimus and temsirolimus [104].

 

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