An acetylation switch of the NLRP3 inflammasome

Abstract

It is well documented that the rate of aging can be slowed, but it remains unclear to which extent aging-associated conditions can be reversed. How the interface of immunity and metabolism impinges upon the diabetes pandemic is largely unknown.

Here, we show that NLRP3, a pattern recognition receptor, is modified by acetylation in macrophages and is deacetylated by SIRT2, an NAD +-dependent deacetylase and a metabolic sensor.

We have developed a cell-based system that models aging-associated inflammation, a defined co-culture system that simulates the effects of inflammatory milieu on insulin resistance in metabolic tissues during aging, and aging mouse models; and demonstrate that SIRT2 and NLRP3 deacetylation prevent, and can be targeted to reverse, aging-associated inflammation and insulin resistance.

These results establish the dysregulation of the acetylation switch of the NLRP3 inflammasome as an origin of aging-associated chronic inflammation and highlight the reversibility of aging-associated chronic inflammation and insulin resistance.

FULL TEXT: Cell Metabolism

EDITOR’S NOTE: the deacetylation step, performed by SIRT2, is switched ‘on’ in healthy cells. This is one more part of the NAD+ / sirtuin puzzle. The goal is to keep NAD+ and sirtuins functioning normally.



Niacin: an old lipid drug in a new NAD + dress

Abstract

Niacin, the first antidyslipidemic drug, has been at the center stage of lipid research for many decades before the discovery of statins. However, to date, despite its remarkable effects on lipid profiles, the clinical outcomes of niacin treatment on cardiac events is still debated.

In addition to its historically well-defined interactions with central players of lipid metabolism, niacin can be processed by eukaryotic cells to synthesize a crucial cofactor, NAD+. NAD+ acts as a cofactor in key cellular processes, including oxidative phosphorylation, glycolysis, and DNA repair.

More recently, evidence has emerged that NAD+ also is an essential cosubstrate for the sirtuin family of protein deacylases and thereby has an impact on a wide range of cellular processes, most notably mitochondrial homeostasis, energy homeostasis, and lipid metabolism. NAD+ achieves these remarkable effects through sirtuin-mediated deacetylation of key transcriptional regulators, such as peroxisome proliferator-activated receptor gamma coactivator 1-α, LXR, and SREBPs, that control these cellular processes.

Here, we present an alternative point of view to explain niacin’s mechanism of action, with a strong focus on the importance of how this old drug acts as a control switch of NAD+/sirtuin-mediated control of metabolism.

FULL TEXT: Journal of Lipid Research


Sirtuin signaling in cellular senescence and aging

Abstract

Sirtuin is an essential factor that delays cellular senescence and extends the organismal lifespan through the regulation of diverse cellular processes. Suppression of cellular senescence by sirtuin is mainly mediated through delaying the age-related telomere attrition, sustaining genome integrity and promotion of DNA damage repair.

In addition, sirtuin modulates the organismal lifespan by interacting with several lifespan regulating signaling pathways including insulin/IGF-1 signaling pathway, AMP-activated protein kinase, and forkhead box O. Although still controversial, it is suggested that the prolongevity effect of sirtuin is dependent with the level of and with the tissue expression of sirtuin. Since sirtuin is also believed to mediate the prolongevity effect of calorie restriction, activators of sirtuin have attracted the attention of researchers to develop therapeutics for age-related diseases.

Resveratrol, a phytochemical rich in the skin of red grapes and wine, has been actively investigated to activate sirtuin activity with consequent beneficial effects on aging. This article reviews the evidences and controversies regarding the roles of sirtuin on cellular senescence and lifespan extension, and summarizes the activators of sirtuin including sirtuin-activating compounds and compounds that increase the cellular level of nicotinamide dinucleotide (NAD).

FULL TEXT: BMB Reports