Role of NLRP3-inflammasone in functional decline in physiological aging. Implications for cardio-metabolic events

Resumen

Aging constitutes the major risk factor for metabolic disabilities onset and cardiovascular disease. Clinically, is associated with an increase in IL1β and IL18, which are cytokines released after inflammasome-dependent caspase-1 activation. This suggests that prevalence and severity of age-related diseases is partly due to chronic inflammasome activation and its contribution to increased inflammatory state. Age-related systemic inflammation is overall produced in numerous organs, including the heart and metabolic tissues such as liver. It is widely believed that a common mechanism drives to several declining disorders triggering adverse impact on healthy aging and affecting therefore, the quality of life and healthspan. This common nexus is termed inflamm-aging. The idea of inflammaging refers to a progressive increase of a proinflammatory state, a systemic low-grade inflammatory process that contributes to the onset and development of chronic diseases and degenerative changes as we age. Interestingly, age-related chronic low-grade inflammation leads to functional decline in many organs even in the absence of a particular disease. Inflammation could be defined as an acute reaction in response to infection or tissue damage to point out a particular injury. Nonetheless, when inflammation becomes chronic, it may trigger collateral damage and in some cases, autoimmune pathologies. Sometimes, inflammatory responses are stress-associated or host-derived signals that are known as damage-associated molecular patterns (DAMPs), which are released as a result of tissue homeostasis imbalance, such as self-derived ATP, cholesterol crystals, uric acid, glucose or environment-derived silica, among others. The inflammasome is a complex of multimeric proteins that consist of an intracellular sensor protein, the Nod-like receptor (NLR); the adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and, the proinflammatory caspase-1 precursor. The most in depth studied inflammasome is NLRP3, which is activated by a wide spectrum of stress and danger signals. Additionally, NLRP3 is special among innate immunity sensors, since is the only inflammasome that can be activated in response to a diverse gamut of host-derived metabolic “danger signals” to trigger “sterile inflammation”, which means an inflammatory response not caused by microbes. NLRP3- inflammasome mediated processes are therefore, crucial for both immunological and metabolic regulation. Importantly, it has been demonstrated that a large number of host-derived NLRP3-inflammasome activators tend to accumulate during the aging process, such as cholesterol crystals, resulting from acquired dietary patterns that maintain the chronic inflammatory state over time, together with the chronic lowgrade inflammation that aging itself involves, highly contribute to cardiometabolic diseases prevalence and severity. Autophagy is the main mechanism in charge of damaged organelles accumulation clearance, and its regulation depends on both intracellular and extracellular signals. AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) are genes involved in longevity and central regulators of autophagic machinery. Under nutrient limiting conditions autophagy becomes active by AMPK, via various mechanisms. However, when mTOR is activated autophagy gets inhibited. Both longevity genes are masters’ regulators of metabolism and there is existing evidence reporting that rather the activation of AMPK or mTOR attenuation enhance cardiac function. AMPK is essential to maintain cardio-metabolic homeostasis. This kinase has shown to be cardioprotective during ischemia. According to some research, mouse models lacking AMPK functionality, had exarcebated myocardial infarction. Activation of AMPK by metformin reduced overload- induced cardiac hypertrophy. Interestingly, it has been recently reported that nutraceutical compounds, including resveratrol, hydroxytyrosol or some flavonols among others, have AMPK-mediated therapeutic effects on diabetes mellitus and CVD, which gives a natural approach to AMPK pathway activation and cardio-metabolic events control. Cardio-metabolic events, such as type 2 diabetes mellitus, insulin resistance, metabolic syndrome, or cardiovascular disease, are determined by an individual’s age. Age-associated chronic inflammatory responses together with western-type lifestyle and certain acquired behavioral habits may induce autophagy impairment, shortened healthspan and a bad quality of life during aging. Data from the World Health Organization (WHO), estimate that by 2050 the proportion of the world’s population over 60 years old, will nearly double, which will represent an increase of 10%. Getting older is the major risk factor for the development of chronic diseases and represents an extraordinary financial burden on the health care systems, constituting a sanitary and a socioeconomic matter. Developing new strategies to attenuate chronic inflammatory state during aging might be a potential target to avoid many age-related cardiometabolic diseases. Here, we demonstrate that either the ablation of NLRP3-inflammasome or its specific pharmacological inhibition with the molecule MCC950, not only might contribute to lifespan, but also to extend healthspan, which is ultimately, the most appealing interest of becoming older.