dc.description.abstract | 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. | es |