AMP-activated protein kinase inhibits NF-κB signaling and inflammation: impact on healthspan and lifespan

Abstract

Adenosine monophosphate-activated protein kinase (AMPK) is a crucial regulator of energy metabolic homeostasis and thus a major survival factor in a variety of metabolic stresses and also in the aging process. Metabolic syndrome is associated with a low-grade, chronic inflammation, primarily in adipose tissue. A low-level of inflammation is also present in the aging process. There are emerging results indicating that AMPK signaling can inhibit the inflammatory responses induced by the nuclear factor-κB (NF-κB) system. The NF-κB subunits are not direct phosphorylation targets of AMPK, but the inhibition of NF-κB signaling is mediated by several downstream targets of AMPK, e.g., SIRT1, PGC-1α, p53, and Forkhead box O (FoxO) factors. AMPK signaling seems to enhance energy metabolism while it can repress inflammatory responses linked to chronic stress, e.g., in nutritional overload and during the aging process. AMPK can inhibit endoplasmic reticulum and oxidative stresses which are involved in metabolic disorders and the aging process. Interestingly, many target proteins of AMPK are so-called longevity factors, e.g., SIRT1, p53, and FoxOs, which not only can increase the stress resistance and extend the lifespan of many organisms but also inhibit the inflammatory responses. The activation capacity of AMPK declines in metabolic stress and with aging which could augment the metabolic diseases and accelerate the aging process. We will review the AMPK pathways involved in the inhibition of NF-κB signaling and suppression of inflammation. We also emphasize that the capacity of AMPK to repress inflammatory responses can have a significant impact on both healthspan and lifespan.

Cardiac Myocyte-Derived Follistatin-Like 1 Prevents Renal Injury in a Subtotal Nephrectomy Model

“…Because AMP-activated protein kinase (AMPK) has been reported to have anti-inflammatory and antioxidative stress properties in a variety of cell types, 17,[20][21][22][23][24] we investigated the effects of Fstl1 on the AMPK signaling pathway in mesangial cells. Treatment with FSTL1 protein, at 250 ng/ml, increased the phosphorylation levels of AMPK and its downstream target acetyl-CoA carboxylase (ACC) in human mesangial cells in a time-dependent manner ( Figure 5A).…”

Repurposing of Metformin and Aspirin by Targeting AMPK-mTOR and Inflammation for Pancreatic Cancer Prevention and Treatment

“…Recently, metformin has also been shown to increase the sensitivity of resistant cells to cisplatin by suppressing STAT3 activity without activation of AMPKa (76). It has been suggested that AMPK suppresses NFkB signaling indirectly via its downstream mediators, such as sirtuin 1, forkhead box protein O (FoxO) family, peroxisome proliferative activated receptor gamma coactivator 1a, and p53; these factors can subsequently repress the expression of inflammatory factors (77). However, whether inhibition of NFkB and STAT3 by metformin in pancreatic cancer cells requires AMPK activation needs further investigation.…”

The SNF1 Kinase Ubiquitin-associated Domain Restrains Its Activation, Activity, and the Yeast Life Span

“…An evolutionarily conserved stress response network utilizing AMPK and Forkhead proteins has been described (53,55,57). In yeast, it was shown that the Forkhead protein Hcm1, but not Fkh1 or Fkh2, was phosphorylated by Snf1 under stress conditions (55).…”