AMPK Pathway

Put in central postulate  and honing in

Not to be confused with cAMP-activated protein kinase.

5′ AMP-activated protein kinase or AMPK or 5′ adenosine monophosphate-activated protein kinase is an enzyme (EC 2.7.11.31) that plays a role in cellular energy homeostasis. It belongs to a highly conserved eukaryotic protein family and its orthologues are SNF1 and SnRK1 in yeast and plants, respectively. It consists of three proteins (subunits) that together make a functional enzyme, conserved from yeast to humans. It is expressed in a number of tissues, including the liver, brain, and skeletal muscle. The net effect of AMPK activation is stimulation of hepatic fatty acid oxidation, ketogenesis, stimulation of skeletal muscle fatty acid oxidation and glucose uptake, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipolysis and lipogenesis, and modulation of insulin secretion by pancreatic beta-cells.[1]

It should not be confused with cyclic AMP-activated protein kinase (protein kinase A).[2]

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Winder WW, Hardie DG (July 1999). “AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes”. Am. J. Physiol. 277 (1 Pt 1): E1–10. PMID 10409121.

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Hallows KR, Alzamora R, Li H, Gong F, Smolak C, Neumann D, Pastor-Soler NM (April 2009). “AMP-activated protein kinase inhibits alkaline pH- and PKA-induced apical vacuolar H+-ATPase accumulation in epididymal clear cells”. Am. J. Physiol., Cell Physiol. 296 (4): C672–81. doi:10.1152/ajpcell.00004.2009. PMC 2670645pastedGraphic.png. PMID 19211918.

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a b Stapleton D, Mitchelhill KI, Gao G, Widmer J, Michell BJ, Teh T, House CM, Fernandez CS, Cox T, Witters LA, Kemp BE (January 1996). “Mammalian AMP-activated protein kinase subfamily”. J. Biol. Chem. 271 (2): 611–4. doi:10.1074/jbc.271.2.611. PMID 8557660.

Chronic, age-associated diseases are already among the leading causes of morbidity and death in the world, a problem exacerbated by the rapidly rising proportion of elderly in the global population. This emergent epidemic represents the next great challenge for biomedical science and public health. Fortunately, decades of studies into the biology of aging have provided a head start by revealing an evolutionarily conserved network of genes that controls the rate and quality of the aging process itself and which can thereby be targeted for protection against age-onset disease. A number of dietary, genetic, and pharmacological interventions, including dietary restriction (DR) and the biguanide metformin, can extend healthy lifespan and reduce the incidence of multiple chronic conditions. Many of these interventions recurrently involve a core network of nutrient sensors: AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), the insulin/insulin-like growth factor signaling pathway (IIS), and the sirtuins. Here, we will summarize how AMPK acts downstream of these pro-longevity interventions and within this network of nutrient sensors to control the cell and physiological processes important for defining how well we age.

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AMPK activity is key for mitochondrial biogenesis and declines with age.  The 2010 publication Regulation of mitochondrial biogenesis points this out.  “Mitochondrial dysfunction is an important component

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Essays Biochem. 2010;47:69-84. doi: 10.1042/bse0470069.

Regulation of mitochondrial biogenesis.

Jornayvaz FR1, Shulman GI.

Author information

Abstract

Although it is well established that physical activity increases mitochondrial content in muscle, the molecular mechanisms underlying this process have only recently been elucidated. Mitochondrial dysfunction is an important component of different diseases associated with aging, such as Type 2 diabetes and Alzheimer’s disease. PGC-1alpha (peroxisome-proliferator-activated receptor gamma co-activator-1alpha) is a co-transcriptional regulation factor that induces mitochondrial biogenesis by activating different transcription factors, including nuclear respiratory factor 1 and nuclear respiratory factor 2, which activate mitochondrial transcription factor A. The latter drives transcription and replication of mitochondrial DNA. PGC-1alpha itself is regulated by several different key factors involved in mitochondrial biogenesis, which will be reviewed in this chapter. Of those, AMPK (AMP-activated protein kinase) is of major importance. AMPK acts as an energy sensor of the cell and works as a key regulator of mitochondrial biogenesis. AMPK activity has been shown to decrease with age, which may contribute to decreased mitochondrial biogenesis and function with aging. Given the potentially important role of mitochondrial dysfunction in the pathogenesis of numerous diseases and in the process of aging, understanding the molecular mechanisms regulating mitochondrial biogenesis and function may provide potentially important novel therapeutic targets.

https://www.ncbi.nlm.nih.gov/pubmed/20533901

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EXS. 2016;107:227-256.

AMPK as a Pro-longevity Target.

Burkewitz K1, Weir HJ2, Mair WB3.

Author information

Abstract

Chronic, age-associated diseases are already among the leading causes of morbidity and death in the world, a problem exacerbated by the rapidly rising proportion of elderly in the global population. This emergent epidemic represents the next great challenge for biomedical science and public health. Fortunately, decades of studies into the biology of aging have provided a head start by revealing an evolutionarily conserved network of genes that controls the rate and quality of the aging process itself and which can thereby be targeted for protection against age-onset disease. A number of dietary, genetic, and pharmacological interventions, including dietary restriction (DR) and the biguanide metformin, can extend healthy lifespan and reduce the incidence of multiple chronic conditions. Many of these interventions recurrently involve a core network of nutrient sensors: AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), the insulin/insulin-like growth factor signaling pathway (IIS), and the sirtuins. Here, we will summarize how AMPK acts downstream of these pro-longevity interventions and within this network of nutrient sensors to control the cell and physiological processes important for defining how well we age.

KEYWORDS:

AMPK; Aging; FOXO; Longevity; Metabolism; Mitochondria; Sirtuins; TOR

https://www.ncbi.nlm.nih.gov/pubmed/27812983

1. Gynostemma pentaphyllum, a traditional Vietnamese herb, activates AMPK to dramatically reshape the way human bodies handle excess glucose and fat.103-106 A study of human type II diabetics, taking no medications, showed that daily supplementation with G. pentaphyllum tea for 12 weeks:103

•Reduced fasting blood sugar levels by a significant 54.1 mg/dL, compared with just 10.8 mg/dL in the control group.

•Lowered hemoglobin A1c levels, a measure of chronic glucose elevation, by a 2% unit reduction, which accounts for a 10-fold improvement over controls.

•Significantly reduced insulin resistance in the supplemented group, while insulin resistance rose in the control subjects.

A similar study in type II diabetics already on therapy with a common antidiabetic drug, gliclazide, showed that G. pentaphyllum extract could add significantly to the drug’s effects:105

•A further reduction in fasting blood sugar of 52.2 mg/dL in subjects who added the supplement, compared with just 16.2 mg/dL in patients on the drug alone.

•A 2% unit reduction in hemoglobin A1c in supplemented patients, compared with only 0.7-unit reduction in controls.

A study of obese people with elevated waist-to-hip ratio showed that daily supplementation with G. pentaphyllum extract for 12 weeks:106

•Significantly reduced body weight, total abdominal fat area, body fat mass, percentage of body fat, and body mass index, compared to a placebo group of similarly obese patients.

2. Trans-tiliroside, a bioactive obtained from rose hips, adds additional AMPK activation to sharply curtail fat accumulation an

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Introduction

As a cellular energy sensor, AMP-activated protein kinase (AMPK) is activated in response to a variety of conditions that deplete cellular energy levels, such as nutrient starvation (especially glucose), hypoxia and exposure to toxins that inhibit the mitochondrial respiratory chain complex.1, 2

Another important aspect of AMPK biology is the role of AMPK in autophagy, a lysosome-dependent catabolic program that maintains cellular homeostasis.43, 44, 45, 46

References

1Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 2012; 13: 251–262. [PMC free article] [PubMed]

2Mihaylova MM, Shaw RJ. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol 2011; 13: 1016–1023. [PMC free article] [PubMed]

42Budanov AV, Karin M. p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 2008; 134: 451–460. [PMC free article] [PubMed]

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