miR-146a impedes the anti-aging effect of AMPK via NAMPT suppression and NAD+/SIRT inactivation

Abstract

Nicotinamide adenine dinucleotide (NAD+) is indispensable for the anti-aging activity of the sirtuin (SIRT) family enzymes. AMP-activated protein kinase (AMPK) upregulates NAD+ synthesis and SIRT activity in a nicotinamide phosphoribosyltransferase (NAMPT)-dependent manner. However, the molecular mechanisms that affect AMPK-driven NAMPT expression and NAD+/SIRT activation remain unclear. In this study, we tried to identify senescence-associated microRNAs (miRNAs) that negatively regulate the cascade linking AMPK and NAMPT expression. miRNA-screening experiments showed that the expression of miR-146a increased in senescent cells but decreased following AMPK activation. Additionally, miR-146a overexpression weakened the metformin-mediated upregulation of NAMPT expression, NAD+ synthesis, SIRT activity, and senescence protection, whereas treatment with the miR-146a inhibitor reversed this effect. Importantly, these findings were observed both in vitro and in vivo. Mechanistically, miR-146a directly targeted the 3′-UTR of Nampt mRNA to reduce the expression of NAMPT. AMPK activators metformin and 5-aminoimidazole-4-carboxamide (AICAR) hindered miR-146a expression at the transcriptional level by promoting IκB kinase (IKK) phosphorylation to attenuate nuclear factor-kappaB (NF-κB) activity. These findings identified a novel cascade that negatively regulates the NAD+/SIRT pathway by suppressing miR-146a-mediated NAMPT downregulation. Furthermore, our results showed that miR-146a impedes the anti-aging effect of AMPK. This mutual inhibitory relationship between miR-146a and AMPK enriches our understanding of the molecular connections between AMPK and SIRT and provides new insight into miRNA-mediated NAD+/SIRT regulation and an intervention point for the prevention of aging and age-related diseases.

Dental pulp stem cell secretome ameliorates d‐galactose induced accelerated aging in rat model

“…Accelerated aging models are preferred over natural models due to shorter duration of study and higher survival rate of animals during the study period. Chronic exposure to high concentrations of d ‐galactose ( d ‐gal) is a well‐established accelerated aging model 5,6 . d ‐Gal is an aldohexose, which at higher concentration reacts with free amines and form advanced glycation end products which build‐up in the serum and tissues such as brain, liver, and skin 7 .…”

“…Chronic exposure to high concentrations of D-galactose (D-gal) is a well-established accelerated aging model. 5,6 D-Gal is an aldohexose, which at higher concentration reacts with free amines and form advanced glycation end products which build-up in the serum and tissues such as brain, liver, and skin. 7 It is also oxidized into hydrogen peroxide by the action of galactose oxidase forming reactive oxygen species (ROS) or is metabolized into galactitol which gets accumulated in the cells and leads to further build-up of free radicals, thereby disturbing the osmotic and redox potential of the cells.…”

NAD+metabolism is a key modulator of bacterial respiratory epithelial infections

“…To evade this defense mechanism, several viruses synthesize macrodomains which counteract the function of NAD + -consuming PARP by hydrolyzing ADP ribosylation sites of host proteins (Chen et al, 2011;Shang et al, 2021). Direct interference of viruses with NAMPT expression was suggested to be mediated by the induction of miRNA expression, which prevents NAMPT translation (Chen et al, 2013;Gong et al, 2022). During bacterial infections, several bacterial pathogens, among them Shigella flexneri and the lung pathogens NTHi and Mycobacterium tuberculosis, were shown to utilize host-produced NAD + for their own energy metabolism (Mantis and Sansonetti, 1996;Kemmer et al, 2001;Boshoff et al, 2008).…”

Interactions between Intestinal Homeostasis and NAD+ Biology in Regulating Incretin Production and Postprandial Glucose Metabolism

“…This suggests that intestinal NAD + biosynthesis plays a critical role in intestinal homeostasis. Although the molecular mechanism(s) underlying the association between intestinal NAD + biology and homeostasis remains enigmatic, AMPK has been demonstrated to upregulate NAMPT, boosting NAD + biosynthesis and SIRT activity [ 88 , 89 , 90 ]. AMPK, an energy sensor that regulates whole-body energy balance [ 91 ], is expressed in several metabolic organs, including the liver, brain, adipose tissues, skeletal muscle, and intestine [ 92 , 93 ].…”