NLRP3 inflammasome suppression improves longevity and prevents cardiac aging in male mice

Abstract

While NLRP3-inflammasome has been implicated in cardiovascular diseases, its role in physiological cardiac aging is largely unknown. During aging, many alterations occur in the organism, which are associated with progressive impairment of metabolic pathways related to insulin resistance, autophagy dysfunction, and inflammation.Here, we investigated the molecular mechanisms through which NLRP3 inhibition may attenuate cardiac aging. Ablation of NLRP3-inflammasome protected mice from age-related increased insulin sensitivity, reduced IGF-1 and leptin/adiponectin ratio levels, and reduced cardiac damage with protection of the prolongation of the agedependent PR interval, which is associated with atrial fibrillation by cardiovascular aging and reduced telomere shortening. Furthermore, old NLRP3 KO mice showed an inhibition of the PI3K/AKT/mTOR pathway and autophagy improvement, compared with old wild mice and preserved Nampt-mediated NAD + levels with increased SIRT1 protein expression. These findings suggest that suppression of NLRP3 prevented many age-associated changes in the heart, preserved cardiac function of aged mice and increased lifespan.

Inhibition of the NLRP3 inflammasome prevents ovarian aging

“…Nlrp3 ablation also showed an increase in autophagy in aged ovaries consistent with previous data in other tissues (8,24). It is known that autophagy efficiency is reduced during aging in many tissues (25).…”

“…Increased systemic inflammation is commonly associated with metabolic alterations, including the appearance of increased adiposity, insulin resistance, and dyslipidemia, responses that are likely critical determinants in the shortening of lifespan and overall health. Many of these metabolic alterations have been associated to NLRP3-inflammassome activation (1,(8)(9)(10). However, little is known about the role of NLRP3 during female aging and fertility.…”

“…The NLRP3 inflammasomes is activated by a range of danger and stress signals (7), many of which rise during aging (1). Genetic deletion of Nlrp3 in mice has been shown to improve lifespan and health by attenuating multiple age-related degenerative changes such as cardiac aging, insulin sensitivity with glycemic control, and bone loss (8,9). However, the role of the NLRP3 inflammasome in ovarian aging and female age-related fertility decline has not been studied.…”

The Aging Heart: Mitophagy at the Center of Rejuvenation

“…NLRP3-deficient mice have improved health span and attenuated age-related functional decline, including reduced bone loss, improved memory and cognitive performance, and motor performance (78). Recently, it was reported that aged NLRP3-deficient mice have reduced cardiac hypertrophy and fibrosis and increased life spans compared to wild type mice (14). This study linked the NLRP3-deficiency in aged mice to reduced mTOR suppression resulting in increased autophagic activity (14).…”

“…It is also a key pathway in cellular quality control by eliminating dysfunctional or unwanted organelles and protein aggregates. However, there is strong evidence that autophagy is decreased with age in tissues, including the heart (5,(9)(10)(11)(12)(13)(14)(15).…”