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.

Fig. 1

Schematic illustration of the functional connections of AMPK linked to the inhibition of NF-κB signaling and suppression of inflammation. Green arrows show the activating pathways and red arrows are the inhibitory connections. Several hormones and phytochemicals, physical exercise, and some drugs, e.g., AICAR and metformin, activate AMPK. In contrast, obesity and hyperglycemia inhibit the expression of AMPK. On the downstream, AMPK stimulates SIRT1, PGC-1α, p53, and FoxO factors which can inhibit the NF-κB signaling with different mechanisms. AMPK inhibits the appearance of ER and oxidative stresses which can trigger NF-κB signaling. NF-κB is the key inducer of inflammatory responses which affect the healthspan and lifespan