AMPK: The Cellular Energy Sensor and What Switches It On
AMP-activated protein kinase (AMPK) is a sensor of cellular energy status: when energy runs low, it switches on processes that generate ATP and turns down processes that consume it.1,4 Exercise and fasting, which lower cellular energy, are thought to engage it. Here is how AMPK works and what is, and is not, known about its role in ageing.
- When a cell's energy runs low, AMPK restores balance by stimulating ATP-generating processes and turning down ATP-consuming ones that are not needed for immediate survival.4
- AMPK is activated by rises in AMP and ADP, which signal that ATP is being used faster than it is made.1
- Beyond metabolism, AMPK regulates the production and disposal of mitochondria, autophagy and cell growth.1
- In ageing human muscle, levels of the mitochondrial regulator PGC-1α were about half those in young adults, and mitochondrial respiration was lower in less physically able older people.5
- Exercise and fasting both lower cellular energy and engage AMPK, which may explain some of their shared effects, but AMPK is only one of several pathways involved.
AMPK was first identified in the 1980s and is now understood as a sensor of cellular energy status that arose very early in the evolution of complex cells, perhaps as a response to starvation. It is activated by rises in both AMP and ADP, and besides metabolism it regulates the production and disposal of mitochondria, autophagy, cell polarity and cell growth.1
How AMPK Detects Energy Status
AMPK senses energy through its gamma subunit, which binds AMP and ATP in competition. Under normal conditions it exists mostly in an inactive form bound to Mg.ATP, which is far more abundant than AMP; as AMP rises, AMPK activity increases.2
Because ATP is normally abundant and AMP scarce, relatively small shifts in energy balance change the AMP-to-ATP ratio enough to switch AMPK on.
AMPK's Downstream Longevity Effects
AMPK links energy status to growth and renewal. It helps switch on autophagy (see our autophagy article),1 and it acts on PGC-1α, described as a master regulator of mitochondrial biogenesis, by phosphorylation, while another fuel sensor, SIRT1, acts on PGC-1α by deacetylation.3
AMPK and SIRT1 regulate each other and share many target molecules, with similar effects on fuel metabolism, inflammation and mitochondrial function, and disturbances in this partnership may predispose to type 2 diabetes and atherosclerotic cardiovascular disease.4
AMPK in People: Exercise Intensity and Metformin
In human muscle, how hard you exercise matters. In biopsies from healthy adults, an hour of cycling at about 75% of maximal oxygen uptake activated the main muscle form of AMPK three- to four-fold, while 90 minutes at about 50% did not activate it, and the effect had reversed three hours after exercise.6 That is one reason to be wary of claims that gentle endurance exercise works by switching on AMPK.
Metformin was shown to activate AMPK in liver cells, which was proposed to explain how it lowers blood glucose,7 but mice whose livers lacked AMPK still responded to metformin, so how much of the drug’s effect runs through AMPK is still debated.8
AMPK, Mitochondria and Ageing Muscle
Ageing muscle shows signs of failing energy machinery. In one study, low-functioning older adults had 38% less muscle mass and 41% lower mitochondrial respiration than young adults, and levels of PGC-1α and SIRT3 were about 50% lower in older participants.5 Whether falling AMPK activity drives these changes in people has not been established.
The practical message is simple: regular exercise and avoiding chronic overeating are worth doing for their proven benefits, whether or not they act mainly through AMPK.
References
- 1Hardie DG. "AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function." Genes Dev. 2011;25(18):1895-908. PubMed · DOI
- 2Xiao B, et al. "Structural basis for AMP binding to mammalian AMP-activated protein kinase." Nature. 2007;449(7161):496-500. PubMed · DOI
- 3Cantó C, Auwerx J. "PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure." Curr Opin Lipidol. 2009;20(2):98-105. PubMed · DOI
- 4Ruderman NB, et al. "AMPK and SIRT1: a long-standing partnership?" Am J Physiol Endocrinol Metab. 2010;298(4):E751-60. PubMed · DOI
- 5Joseph AM, et al. "The impact of aging on mitochondrial function and biogenesis pathways in skeletal muscle of sedentary high- and low-functioning elderly individuals." Aging Cell. 2012;11(5):801-9. PubMed · DOI
- 6Wojtaszewski JF, et al. "Isoform-specific and exercise intensity-dependent activation of 5'-AMP-activated protein kinase in human skeletal muscle." J Physiol. 2000;528 Pt 1(Pt 1):221-6. PubMed · DOI
- 7Zhou G, et al. "Role of AMP-activated protein kinase in mechanism of metformin action." J Clin Invest. 2001;108(8):1167-74. PubMed · DOI
- 8Foretz M, et al. "Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state." J Clin Invest. 2010;120(7):2355-69. PubMed · DOI
