StimulatingS-adenosyl-l-methionine synthesis extends lifespan via activation of AMPK

Dietary restriction (DR), such as calorie restriction (CR) or methionine (Met) restriction, extends the lifespan of diverse model organisms. Although studies have identified several metabolites that contribute to the beneficial effects of DR, the molecular mechanism underlying the key metabolites responsible for DR regimens is not fully understood. Here we show that stimulatingS-adenosyl-l-methionine (AdoMet) synthesis extended the lifespan of the budding yeastSaccharomyces cerevisiae. The AdoMet synthesis-mediated beneficial metabolic effects, which resulted from consuming both Met and ATP, mimicked CR. Indeed, stimulating AdoMet synthesis activated the universal energy-sensing regulator Snf1, which is theS. cerevisiaeortholog of AMP-activated protein kinase (AMPK), resulting in lifespan extension. Furthermore, our findings revealed thatS-adenosyl-l-homocysteine contributed to longevity with a higher accumulation of AdoMet only under the severe CR (0.05% glucose) conditions. Thus, our data uncovered molecular links between Met metabolites and lifespan, suggesting a unique function of AdoMet as a reservoir of Met and ATP for cell survival.

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Faculty of 1000 evaluation for Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy.

F1000 - Post-publication peer review of the biomedical literature ◽

10.3410/f.7796956.8134054 ◽

2011 ◽

Author(s):

Franck Polleux ◽

Julien Courchet

Keyword(s):

Protein Kinase ◽

Energy Sensing ◽

Amp Activated Protein Kinase

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mTOR Inhibitor Therapy and Metabolic Consequences: Where Do We Stand?

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/2640342 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 15

Author(s):

Aleksandra Kezic ◽

Ljiljana Popovic ◽

Katarina Lalic

Keyword(s):

Protein Kinase ◽

Glucose Metabolism ◽

Calorie Restriction ◽

Mtor Inhibitor ◽

Hepatic Glucose Production ◽

Mtor Inhibitors ◽

Glucose Production ◽

Metabolic Effects ◽

Solid Organ ◽

Amp Activated Protein Kinase

mTOR (mechanistic target of rapamycin) protein kinase acts as a central integrator of nutrient signaling pathways. Besides the immunosuppressive role after solid organ transplantations or in the treatment of some cancers, another promising role of mTOR inhibitor as an antiaging therapeutic has emerged in the recent years. Acute or intermittent rapamycin treatment has some resemblance to calorie restriction in metabolic effects such as an increased insulin sensitivity. However, the chronic inhibition of mTOR by macrolide rapamycin or other rapalogs has been associated with glucose intolerance and insulin resistance and may even provoke type II diabetes. These metabolic adverse effects limit the use of mTOR inhibitors. Metformin is a widely used drug for the treatment of type 2 diabetes which activates AMP-activated protein kinase (AMPK), acting as calorie restriction mimetic. In addition to the glucose-lowering effect resulting from the decreased hepatic glucose production and increased glucose utilization, metformin induces fatty acid oxidations. Here, we review the recent advances in our understanding of the metabolic consequences regarding glucose metabolism induced by mTOR inhibitors and compare them to the metabolic profile provoked by metformin use. We further suggest metformin use concurrent with rapalogs in order to pharmacologically address the impaired glucose metabolism and prevent the development of new-onset diabetes mellitus after solid organ transplantations induced by the chronic rapalog treatment.

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Sex Differences in the Metabolic Effects of Testosterone in Sheep

Endocrinology ◽

10.1210/en.2011-1634 ◽

2012 ◽

Vol 153 (1) ◽

pp. 123-131 ◽

Cited By ~ 19

Author(s):

Scott D. Clarke ◽

Iain J. Clarke ◽

Alexandra Rao ◽

Michael A. Cowley ◽

Belinda A. Henry

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

Uncoupling Protein ◽

Specific Effect ◽

Metabolic Effects ◽

Mrna Levels ◽

Nonesterified Fatty Acids ◽

Glucose Levels ◽

Amp Activated Protein Kinase ◽

The Brain

Adiposity is regulated in a sexually divergent manner. This is partly due to sex steroids, but the differential effects of androgens in males and females are unclear. We investigated effects of testosterone on energy balance in castrated male (n = 6) and female sheep (n = 4), which received 3 × 200 mg testosterone implants for 2 wk or blank implants (controls). Temperature probes were implanted into retroperitoneal fat and skeletal muscle. Blood samples were taken to measure metabolites and insulin. In males, muscle and fat biopsies were collected to measure uncoupling protein (UCP) mRNA and phosphorylation of AMP-activated protein kinase and Akt. Testosterone did not change food intake in either sex. Temperature in muscle was higher in males than females, and testosterone reduced heat production in males only. In fat, however, temperature was higher in the castrate males compared with females, and there was no effect of testosterone treatment in either sex. Preprandial glucose levels were lower, but nonesterified fatty acids were higher in females compared with males, irrespective of testosterone. In males, the onset of feeding increased UCP1 and UCP3 mRNA levels in skeletal muscle, without an effect of testosterone. During feeding, testosterone reduced glucose levels in males only but did not alter the phosphorylation of AMP-activated protein kinase or Akt in muscle. Thus, testosterone maintains lower muscle and fat temperatures in males but not females. The mechanism underlying this sex-specific effect of testosterone is unknown but may be due to sexual differentiation of the brain centers controlling energy expenditure.

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Pentamethylquercetin generates beneficial effects in monosodium glutamate-induced obese mice and C2C12 myotubes by activating AMP-activated protein kinase

Diabetologia ◽

10.1007/s00125-012-2519-z ◽

2012 ◽

Vol 55 (6) ◽

pp. 1836-1846 ◽

Cited By ~ 26

Author(s):

J. Z. Shen ◽

L. N. Ma ◽

Y. Han ◽

J. X. Liu ◽

W. Q. Yang ◽

...

Keyword(s):

Protein Kinase ◽

Monosodium Glutamate ◽

C2c12 Myotubes ◽

Obese Mice ◽

Beneficial Effects ◽

Amp Activated Protein Kinase

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AMP-Activated Protein Kinase (AMPK) and Energy-Sensing in the Brain

Experimental Neurobiology ◽

10.5607/en.2012.21.2.52 ◽

2012 ◽

Vol 21 (2) ◽

pp. 52-60 ◽

Cited By ~ 33

Author(s):

Santosh Ramamurthy ◽

Gabriele Ronnett

Keyword(s):

Protein Kinase ◽

Energy Sensing ◽

Amp Activated Protein Kinase ◽

The Brain

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AMP-activated protein kinase pathway: a potential therapeutic target in cardiometabolic disease

Clinical Science ◽

10.1042/cs20080066 ◽

2009 ◽

Vol 116 (8) ◽

pp. 607-620 ◽

Cited By ~ 109

Author(s):

Aaron K. F. Wong ◽

Jacqueline Howie ◽

John R. Petrie ◽

Chim C. Lang

Keyword(s):

Protein Kinase ◽

Metabolic Diseases ◽

Elongation Factor ◽

Cardiometabolic Disease ◽

Acid Oxidation ◽

Ampk Activation ◽

Atp Production ◽

Beneficial Effects ◽

Eukaryotic Elongation Factor ◽

Amp Activated Protein Kinase

AMPK (AMP-activated protein kinase) is a heterotrimetric enzyme that is expressed in many tissues, including the heart and vasculature, and plays a central role in the regulation of energy homoeostasis. It is activated in response to stresses that lead to an increase in the cellular AMP/ATP ratio caused either by inhibition of ATP production (i.e. anoxia or ischaemia) or by accelerating ATP consumption (i.e. muscle contraction or fasting). In the heart, AMPK activity increases during ischaemia and functions to sustain ATP, cardiac function and myocardial viability. There is increasing evidence that AMPK is implicated in the pathophysiology of cardiovascular and metabolic diseases. A principle mode of AMPK activation is phosphorylation by upstream kinases [e.g. LKB1 and CaMK (Ca2+/calmodulin-dependent protein kinase], which leads to direct effects on tissues and phosphorylation of various downstream kinases [e.g. eEF2 (eukaryotic elongation factor 2) kinase and p70 S6 kinase]. These upstream and downstream kinases of AMPK have fundamental roles in glucose metabolism, fatty acid oxidation, protein synthesis and tumour suppression; consequently, they have been implicated in cardiac ischaemia, arrhythmias and hypertrophy. Recent mechanistic studies have shown that AMPK has an important role in the mechanism of action of MF (metformin), TDZs (thiazolinediones) and statins. Increased understanding of the beneficial effects of AMPK activation provides the rationale for targeting AMPK in the development of new therapeutic strategies for cardiometabolic disease.

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