title: Age-related changes in AMPK activation: Role for AMPK phosphatases and inhibitory phosphorylation by upstream signaling pathways.
abstract: AMP-activated protein kinase (AMPK) is a fundamental regulator of energy metabolism, stress resistance, and cellular proteostasis. AMPK signaling controls an integrated signaling network which is involved in the regulation of healthspan and lifespan e.g. via FoxO, mTOR/ULK1, CRCT-1/CREB, and SIRT1 signaling pathways. Several studies have demonstrated that the activation capacity of AMPK signaling declines with aging, which impairs the maintenance of efficient cellular homeostasis and enhances the aging process. However, it seems that the aging process affects AMPK activation in a context-dependent manner since occasionally, it can also augment AMPK activation, possibly attributable to the type of insult and tissue homeostasis. Three protein phosphatases, PP1, PP2A, and PP2C, inhibit AMPK activation by dephosphorylating the Thr172 residue of AMPKα, required for AMPK activation. In addition, several upstream signaling pathways can phosphorylate Ser/Thr residues in the β/γ interaction domain of the AMPKα subunit that subsequently blocks the activation of AMPK. These inhibitory pathways include the insulin/AKT, cyclic AMP/PKA, and RAS/MEK/ERK pathways. We will examine the evidence whether the efficiency of AMPK responsiveness declines during the aging process. Next, we will review the mechanisms involved in curtailing the activation of AMPK. Finally, we will elucidate the potential age-related changes in the inhibitory regulation of AMPK signaling that might be a part of the aging process.
authors.affiliation: Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland. Electronic address: antero.salminen@uef.fi.
authors.forename: Antero
authors.initials: A
authors.lastname: Salminen
authors.affiliation: Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland; Department of Ophthalmology, Kuopio University Hospital, P.O. Box 100, FI-70029 KYS, Finland.
authors.forename: Kai
authors.initials: K
authors.lastname: Kaarniranta
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
authors.forename: Anu
authors.initials: A
authors.lastname: Kauppinen
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000375:Aging / Q000378:metabolism*; D000818:Animals; D004734:Energy Metabolism; D006801:Humans; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D055372:AMP-Activated Protein Kinases; D010744:Phosphoric Monoester Hydrolases
keywords: AMPK; Ageing; Cyclic AMP; Lifespan; Longevity; Protein phosphatase