AMPK and Aging
“A Technical Review”
By Raegan Linton
The notion that we “die of old age” is a common and misleading myth of modern medicine.
We die not of old age, but of cumulative failures within our cellular machinery. These failures should not be thought of as inevitable breakdowns, but instead as reversible elements of aging.
One such reversible factor is a cellular enzyme called AMPK.
No matter which organ system or underlying disease is involved, if you trace the pathological process far enough back, you will likely encounter a problem related to insufficient AMPK activity.
This is good news for people who believe in significantly extending their life spans. That’s because a growing body of evidence suggests that boosting AMPK activity can prevent, and even reverse,1-4 life-shortening effects of aging. This includes disorders as disparate as cardiovascular disease, diabetes, liver and kidney failure, neurodegenerative diseases (e.g., Alzheimer’s), cancers, and more.5
In fact, scientists are beginning to refer to AMPK as literally a suppressor of aging itself.6
Substantial evidence indicates that restoring AMPK activity not only increases longevity, but works to fight the symptoms of aging in individual body systems.
In this article, we’ll take a closer look at AMPK, what it does, and how its activity level changes with advancing age and unhealthy lifestyles. We’ll then examine evidence showing that restoring AMPK activity can increase healthy longevity.
What Is AMPK?
AMPK stands for adenosine monophosphate-activated protein kinase.7 It is found in every living cell of every living mammal (and most other animals) on Earth.8-12 If you want to avoid the life span-shortening symptoms of aging, you need to maintain optimal AMPK activity.13
AMPK has been referred to as a “metabolic master switch.”14 AMPK controls a gamut of metabolic pathways that enable us to extract energy from food, store and distribute that energy safely through the body, and ultimately use that energy for everything from moving and mating to talking and thinking, and even to understanding these very words as you read them.14,15
The core role of AMPK is to sense each cell’s energy status at every moment, and to trigger responses that maintain the cell’s energy at precisely the optimum level.5,9,14 Too little available energy starves the cell, while too much energy can exhaust and disrupt cellular components.16 In either case (too little or too much energy), the cell (and the tissues, organs, and systems in which it is a part) functions inefficiently. That energy inefficiency ultimately leads to the dysfunctions we identify as the diseases (or symptoms) of aging.
Here’s how AMPK works: Every cell in your body depends absolutely on a steady supply of energy in the form of chemical bonds.17,18 When you eat and absorb nutrients, energy from chemical bonds in food is released and passed down a complex series of enzymes until it is stored again in a molecule called adenosine triphosphate, or ATP. The more ATP that is present in the cell, the higher the cell’s available energy supply. When ATP is broken down to release energy for cellular work, a major end product is adenosine monophosphate, or AMP.5,19
If a cell were to use up all of its energy from ATP, it would rapidly fill up with low-energy AMP molecules. It would then run out of energy, and shortly thereafter, it would collapse and die, unable to sustain even the simplest energy-requiring processes.
And that is precisely where AMPK comes into play.
AMPK is biochemically activated in the presence of rising levels of AMP (and decreasing levels of ATP).5 Activated AMPK, in turn, increases fatty acid oxidation and glucose transport, thereby releasing additional energy from available or stored sources (fats and sugars).14
These processes, detailed in Table 1, all work together to balance cellular metabolism.5,9 The net result is tight control over cellular energy levels so that they never fall low enough to impair cellular activity, but never rise high enough to damage cellular machinery.
The benefit of such tight control of energy levels is evident from studies of fruit flies genetically modified to synthesize high levels of AMP: They live up to one-third longer as a result of precise energy maintenance by activated AMPK.20
A long life span would be predictable from the data in Table 1, which shows that activated AMPK promotes energy-releasing processes while suppressing energy-storing processes. As a result, organisms with high AMPK activity are vigorous, active, and lean, with relatively low blood sugar and fat levels and little fat storage, and a very low risk of heart disease, diabetes, and other metabolic disorders.
AMPK also promotes the cellular “housekeeping” function called autophagy,21,22 in which cells consume themselves and recycle their contents, a process that eliminates damaged DNA23 and misshapen proteins24 that can themselves impair cellular function and even trigger cancers.25-32 As a result, young organisms with higher AMPK activity33 have a very low risk of cancer and degenerative disorders, such as Alzheimer’s disease,33 which stem from misfolded or damaged proteins.
High levels of activated AMPK occur in youth, while low levels of activated AMPK occur in aging.34 We grow old, not simply because time passes, but because our youthful levels of AMPK drop away.
And AMPK activity does decline sharply with age.35 That is why we become less energetic and get fatter as we grow older, while becoming increasingly vulnerable to cancer and diseases associated with impaired DNA and protein function.
But the modern American lifestyle, with its overabundance of nutrients and low level of physical activity, is even worse for the AMPK system than aging alone.
It is now clear that, when caloric intake remains much higher than needed to sustain energy expenditure (think couch potato eating potato chips), AMPK activation is markedly decreased.36 This puts the body into a state exactly the opposite of that shown in Table 1. With reduced AMPK activity, cells decrease their energy-releasing ATP-generating activities, and instead shift to energy-storing processes that generate new fat deposits and make excess new glucosemolecules.
The modern picture of the overweight American, living a sedentary lifestyle and enjoying an overabundance of carbohydrates and calories, is harmful for AMPK activation and therefore deadly. We are literally eating ourselves to death. By suppressing AMPK activation, we develop dangerous fat deposits, especially in the belly region. Burgeoning fat masses reduce insulin sensitivity37-39 and produce systemwide inflammation,40 which may contribute to “metabolic syndrome.”41
Inflammation is intimately involved in many disorders of aging, such as cardiovascular disease, diabetes, and cancer,42 conversely, inflammation further suppresses AMPK activation in a rapidly tightening lethal spiral. These processes can be seen schematically in Figure 1.41,43,44
Activated AMPK Promotes Longevity
The good news, as we’ll now see, is that we can restore our dwindling AMPK activity through a combination of lifestyle, diet, and supplement interventions, with the possibility of significantly increasing life span through mitigation of potentially fatal symptoms of aging.
The most compelling evidence that activating AMPK can help you live longer comes from a study just released in 2014, in which diabetic patients treated with the drug metformin, a potent AMPK activator, lived a median of 15% longer than did matched controls without diabetes.45
Take a moment to read that again: This study showed a longer median life span in diabetics than in healthy people—the only difference was their use of AMPK-activating metformin! By contrast, diabetics treated with drugs in the sulfonylurea category lived on average 38% shorter lives than did the metformin-treated group.45
Metformin is the most commonly used antidiabetic drug,46 but it has also been shown to have life-extending properties closely related to its activation of AMPK.47 Metformin-treated roundworms, for example, have higher AMPK activity and live about 20% longer than untreated control animals.48
Higher animals can also be made to live longer through metformin-induced AMPK activation. Mice supplemented with the drug demonstrated an increase in mean life span of nearly 6% compared with controls.47 As expected with AMPK activation, the supplemented mice also weighed less throughout their lives, which may have contributed to their increased longevity.
In fact, AMPK is so important in maintaining and restoring youthful function that it has been called a “gerosuppressor,” that is, a compound that significantly suppresses, not one or several diseases, but processes of biological aging.7 This is shown by the results of several lines of laboratory investigation.
AMPK activation triggers increased production of mitochondria, the energy-releasing “power plants” found in every cell.49-54 Since a reduction in mitochondrial numbers and function is associated with accelerated aging,55 AMPK-induced “mitochondrial biogenesis” can be expected to slow the aging process.
Activating AMPK in human cells in culture also stimulates production and activation of SIRT1,56 an enzyme that is increased in laboratory animals with extended life spans.57-59 SIRT1 can also be activated by marked calorie restriction, which has been demonstrated to increase life span in some species.60 Research now shows that AMPK activation can trigger the life-extending actions of SIRT1.41
Studies in primitive animals demonstrate that AMPK slows aging by modulating expression of critical transcription factors and enzymes, as would be expected by its effects on SIRT1.21,61,62 In fruit flies engineered to have higher AMP levels (which results in higher AMPK activity), for example, life span was extended by one-third compared with controls.20
One specific area of genetic modulation by AMPK is in control of systemwide inflammation; studies show that AMPK inhibits signaling by the master inflammation regulator called NF-kappaB.13 Reducing inflammation throughout the body is a key target in extending life span by preventing premature death from complications of aging such as cardiovascular and metabolic diseases. Let’s now look at some other aging manifestations, and see how AMPK can influence their outcomes.
Activated AMPK Promotes Systemic Healthy Longevity
AMPK activation has been shown to extend life span in several species.20,63,64 We’ve looked at some of the universal ways it does this, e.g., enhancing energy utilization, promoting new mitochondria, and reducing inflammation. Starting on the next page is a quick rundown on the roles of AMPK in specific body systems, where its activation can reduce the risk of age-related disorders.
Infections are a leading cause of death among older adults and AMPK activation is critical in the immune system, where it has been shown to:
- Enhance white blood cells’ ability to home in on and kill invading bacteria.65
- Prevent infection with Rift Valley Fever Virus (a potentially lethal virus originating in Africa) by blocking fatty acid synthesis the virus needs to replicate itself.66
Cancer remains the second leading cause of death in the US.67 Its growth and invasiveness are closely related to the loss of regulation of AMPK signaling.68 AMPK activation is critical in:
- Inhibiting tumor cell growth and promoting tumor cell destruction by programmed cell death (apoptosis).69-72
- Increasing cancer cell vulnerability to chemotherapy.73,74
- Switching cancer cells’ metabolism from the unique ability to burn sugar in the absence of glucose toward a more normal oxygen-requiring pathway, thereby inhibiting tumor growth.75,76
Cardiovascular Disease And Atherosclerosis
Heart and blood vessel diseases are the leading causes of death in Americans.77 They are intimately related to AMPK’s functions as an energy regulator, particularly when it comes to fatty acids and cholesterol.78 Activation of AMPK has been shown to:
- Inhibit damage to blood vessel lining (endothelial) cells caused by oxidized LDL (“bad”) cholesterol.79
- Reduce vascular cell death in response to low oxygen levels (which occur during a heart attack or stroke).80
- Reduce the ability of vascular smooth muscle cells to migrate and draw in inflammatory cells to form artery-clogging plaques.81
- Suppress activity of enzymes known to produce large volumes of dangerous reactive oxygen species that damage arterial linings.82
- Regulate oxidative metabolism to reduce inflammation caused by immune system cells in cardiac tissue.83-85
- Reverse the hypertension-inducing effects of angiotensin II, a peptide hormone involved in salt and fluid balance.86
Metabolic Syndrome And Diabetes
Diabetes alone is the seventh leading cause of death in America and like metabolic syndrome, energy balance is dysregulated.87 As a metabolic regulator, AMPK has been shown to:
- Reduce insulin resistance and support glucose transport out of the bloodstream, allowing body cells to utilize available insulin and lower blood sugar.88,89
- Reduce weight gain in diet-induced obesity in animals.90
- Inhibit metabolic syndrome-associated inflammation.13
- Increase utilization of stored fat for energy, potentially helping to reduce both obesity and lipid disorders.91
- Reduce output of glucose from the liver, a major contributor to sustained high blood sugar levels.92,93
- Improve mitochondrial fat-burning94 function and enhance the effect of the anti-obesity hormone adiponectin.95
Fat accumulation in the liver is a major consequence of the metabolic syndrome, and can lead to liver inflammation and scarring that shortens life span.96,97 AMPK activation in liver tissue:
- Reduces the expression of lipogenic genes while increasing the expression of lipolytic genes.98
- Inhibits liver fibrosis, the scarring that leads to life-threatening cirrhosis.99
- Increases the number of mitochondria, thereby enhancing fatty acid oxidation.100
Promoting AMPK Activation Naturally
It is evident that you should do all you can to maintain and even boost your AMPK activity if you want to slow aging throughout your body. You can use drugs, but obtaining prescriptions for drugs like metformin is challenging unless you happen to be a type II diabetic.
More natural ways to boost AMPK involve lifestyle changes. Regular moderate exercise is a good approach, since we know that muscle contractions are potent triggers for AMPK activation.9,14,21 And of course, an exercising body uses up ATP, generating higher AMP levels, activating AMPK.5 As we age past 60, however, the ability of vigorous exercise to increase AMPK diminishes.
Or, you can take the opposite approach, metabolically, by engaging in marked calorie restriction of 30%, which is not the same as the moderate dieting we all try. In this case, low levels of available energy lead to rising AMP levels, and again activation of AMPK. AMPK activation is credited with the remarkable life extension seen in several species, with promising physiological effects in humans.35,48,63,101
But, regardless of which of these strategies you try, or even if you haven’t the discipline to do any of them, there is still plenty you can do to boost your AMPK activity by using certain supplements. Indeed, many supplements originally recognized for their nutritional properties are now being found to increase AMPK activation, which may contribute to their life-extending effects.102
Here are two of the better-documented AMPK-activating ingredients and their beneficial impact on processes that accelerate aging:
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 and speed fat burning. In cultured human fat cells (adipocytes), rose hip extract and trans-tiliroside both prevented new fat accumulation.107
When mice were made obese through a high-fat diet, and then either supplemented with rose hip extract or no supplement, the supplemented animals:
- Gained less body weight and developed less abdominal fat than the control animals.
- Had lower liver weight, indicating less liver fat, than controls.
In a study of obese humans, a daily drink made from rose hip powder, used for six weeks, resulted in:108
- Reduction of systolic blood pressure by 3.4%.
- Reductions in total and LDL (“bad”)cholesterol of 4.9 and 6%, respectively, and of 6.5% in the ratio of LDL to HDL (“good”) cholesterol.
- A 17% reduction in a standardized cardiovascular disease risk score.
It seems certain that many other natural products will emerge as AMPK activators, given the widespread distribution of AMPK throughout the world.
To really understand aging, we have to recognize that it is not an automatic result of time passing, but rather the result of reversible events that occur in all cells, regardless of the tissue or organ system to which they belong.
One of the most fundamental of those events is a decline in activity of AMPK, the universal cellular energy sensor that dictates whether cells store energy as dangerous fats or use energy efficiently to power vital processes. Activated AMPK creates a more youthful energy profile, one with only small amounts of fat stores, a great deal of energy for useful activity, and rapid recycling of old, damaged proteins.
Studies are increasingly revealing the central role of AMPK in maintaining youthful function across the entire spectrum of cell and tissue types, resulting in increased longevity. This “systemic anti-aging” approach is likely to be much more successful than mainstream medicine’s “one disease at a time” strategy, which treats each disease as a separate entity and accounts for America’s destructive addiction to prescription drugs.
It’s critical that you understand AMPK and how to optimize its activation in your body if you want to extend your life span in the best possible state of health.
If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.
- Deji N, Kume S, Araki S, et al. Role of angiotensin II-mediated AMPK inactivation on obesity-related salt-sensitive hypertension. Biochem Biophys Res Commun. 2012 Feb 17;418(3):559-64.
- Chou CC, Lee KH, Lai IL, et al. AMPK reverses the mesenchymal phenotype of cancer cells by targeting the Akt-MDM2-Foxo3a signaling axis. Cancer Res. 2014 Sep 1;74(17):4783-95.
- Grahame Hardie D. AMP-activated protein kinase: a key regulator of energy balance with many roles in human disease. J Intern Med. 2014 May 13.
- Watt MJ, Dzamko N, Thomas WG, et al. CNTF reverses obesity-induced insulin resistance by activating skeletal muscle AMPK. Nat Med. 2006 May;12(5):541-8.
- Coughlan KA, Valentine RJ, Ruderman NB, Saha AK. AMPK activation: a therapeutic target for type 2 diabetes? Diabetes Metab Syndr Obes. 2014;7:241-53.
- William R. Clark. A Means to an End: The Biological Basis of Aging and Health. Oxford University Press. 2002:3-20.
- Menendez JA, Joven J, Aragones G, et al. Xenohormetic and anti-aging activity of secoiridoid polyphenols present in extra virgin olive oil: a new family of gerosuppressant agents. Cell Cycle. 2013 Feb 15;12(4):555-78.
- Towler MC, Hardie DG. AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res. 2007 Feb 16;100(3):328-41.
- Richter EA, Ruderman NB. AMPK and the biochemistry of exercise: implications for human health and disease. Biochem J. 2009 Mar 1;418(2):261-75.
- El-Masry OS, Brown BL, Dobson PR. Effects of activation of AMPK on human breast cancer cell lines with different genetic backgrounds. Oncol Lett. 2012 Jan;3(1):224-8.
- Hardie DG. AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev. 2011 Sep 15;25(18):1895-908.
- Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol. 2012 Mar 22;13(4):251-62.
- Salminen A, Hyttinen JM, Kaarniranta K. AMP-activated protein kinase inhibits NF-kappaB signaling and inflammation: impact on healthspan and life span. J Mol Med (Berl). 2011 Jul;89(7):667-76.
- Winder WW, Hardie DG. AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes. Am J Physiol. 1999 Jul;277(1 Pt 1):E1-10.
- Mirguet O, Sautet S, Clement CA, et al. Discovery of pyridones as oral AMPK direct activators. ACS Med Chem Lett. 2013 Jul 11;4(7):632-6.
- Bekta H, Deniz O, Temel S, Kekliko lu HD, Akyol S. Rhabdomyolysis related to dyskinesia in Parkinson’s disease. J Mov Disord. 2014 Apr;7(1):25-7.
- Deamer D, Weber AL. Bioenergetics and life’s origins. Cold Spring Harb Perspect Biol. 2010 Feb;2(2):a004929.
- Stankov SV. Right identification of the substantial energy source in biochemical processes as a necessary prerequisite for coherent development of medical sciences. Med Hypotheses. 2004;63(4):688-90.
- Berg JM, Tymoczko JL, Stryer L. Biochemistry, 5th Edition. New York: W H Freeman; 2002. Section 14.1 Metabolism Is Composed of Many Coupled, Interconnecting Reactions.
- Stenesen D, Suh JM, Seo J, et al. Adenosine nucleotide biosynthesis and AMPK regulate adult life span and mediate the longevity benefit of caloric restriction in flies. Cell Metab. 2013 Jan 8;17(1):101-12.
- Kohli L, Roth KA. Autophagy: cerebral home cooking. Am J Pathol. 2010 Mar;176(3):1065-71.
- Hardie DG. AMPK and autophagy get connected. EMBO J. 2011 Feb 16;30(4):634-5.
- Rodriguez-Rocha H, Garcia-Garcia A, Panayiotidis MI, Franco R. DNA damage and autophagy. Mutat Res. 2011 Jun 3;711(1-2):158-66.
- Glick D, Barth S, Macleod KF. Autophagy: cellular and molecular mechanisms. J Pathol. 2010 May;221(1):3-12.
- Liao LZ, Chen YL, Lu LH, Zhao YH, Guo HL, Wu WK. Polysaccharide from Fuzi likely protects against starvation-induced cytotoxicity in H9c2 cells by increasing autophagy through activation of the AMPK/mTOR pathway. Am J Chin Med. 2013;41(2):353-67.
- Ryu HW, Choi SH, Namkoong S, et al. Simulated microgravity contributes to autophagy induction by regulating AMP-activated protein kinase. DNA Cell Biol. 2014 Mar;33(3):128-35.
- Wang LT, Chen BL, Wu CT, Huang KH, Chiang CK, Hwa Liu S. Protective role of AMP-activated protein kinase-evoked autophagy on an in vitro model of ischemia/reperfusion-induced renal tubular cell injury. PLoS One. 2013;8(11):e79814.
- Xiao K, Jiang J, Guan C, et al. Curcumin induces autophagy via activating the AMPK signaling pathway in lung adenocarcinoma cells. J Pharmacol Sci. 2013;123(2):102-9.
- Yu HC, Lin CS, Tai WT, Liu CY, Shiau CW, Chen KF. Nilotinib induces autophagy in hepatocellular carcinoma through AMPK activation. J Biol Chem. 2013 Jun 21;288(25):18249-59.
- Yun SM, Jung JH, Jeong SJ, Sohn EJ, Kim B, Kim SH. Tanshinone IIA induces autophagic cell death via activation of AMPK and ERK and inhibition of mTOR and p70 S6K in KBM-5 leukemia cells. Phytother Res. 2014 Mar;28(3):458-64.
- Zhang Q, Yang YJ, Wang H, et al. Autophagy activation: a novel mechanism of atorvastatin to protect mesenchymal stem cells from hypoxia and serum deprivation via AMP-activated protein kinase/mammalian target of rapamycin pathway. Stem Cells Dev. 2012 May 20;21(8):1321-32.
- Zou MH, Xie Z. Regulation of interplay between autophagy and apoptosis in the diabetic heart: new role of AMPK. Autophagy. 2013 Apr;9(4):624-5.
- Hsu CY, Chuang YL. Changes in energy-regulated molecules in the trophocytes and fat cells of young and old worker honeybees (Apis mellifera). J Gerontol A Biol Sci Med Sci. 2014 Aug;69(8):955-64.
- McCarty MF. AMPK activation—protean potential for boosting healthspan. Age (Dordr). 2014 Apr;36(2):641-63.
- Salminen A, Kaarniranta K. AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Res Rev. 2012 Apr;11(2):230-41.
- Xu XJ, Balon TW, Brandon A, Kraegen EW, Ruderman NB. Insulin resistance due to nutrient excess: is it a consequence of AMPK downregulation? Cell Cycle. 2011 Oct 15;10(20):3447-51.
- Frayn KN. Adipose tissue and the insulin resistance syndrome. Proc Nutr Soc. 2001 Aug;60(3):375-80.
- Lann D, LeRoith D. Insulin resistance as the underlying cause for the metabolic syndrome. Med Clin North Am. 2007 Nov;91(6):1063-77.
- Gallagher EJ, Leroith D, Karnieli E. Insulin resistance in obesity as the underlying cause for the metabolic syndrome. Mt Sinai J Med. 2010 Sep-Oct;77(5):511-23.
- Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity. Annu Rev Immunol. 2011;29:415-45.
- Ruderman NB, Carling D, Prentki M, Cacicedo JM. AMPK, insulin resistance, and the metabolic syndrome. J Clin Invest. 2013 Jul 1;123(7):2764-72.
- Aggarwal BB, Prasad S, Reuter S, et al. Identification of novel anti-inflammatory agents from Ayurvedic medicine for prevention of chronic diseases: reverse pharmacology and bedside to bench approach. Curr Drug Targets. 2011 Oct;12(11):1595-653.
- Kamoshita M, Ozawa Y, Kubota S, et al. AMPK-NF-kappaB axis in the photoreceptor disorder during retinal inflammation. PLoS One. 2014;9(7):e103013.
- Sun Y, Li J, Xiao N, et al. Pharmacological activation of AMPK ameliorates perivascular adipose/endothelial dysfunction in a manner interdependent on AMPK and SIRT1. Pharmacol Res. 2014 Aug 7.
- Bannister CA, Holden SE, Jenkins-Jones S, et al. Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. Diabetes Obes Metab. 2014 Jul 7.
- Avci CB, Harman E, Dodurga Y, Susluer SY, Gunduz C. Therapeutic potential of an anti-diabetic drug, metformin: alteration of miRNA expression in prostate cancer cells. Asian Pac J Cancer Prev. 2013;14(2):765-8.
- Martin-Montalvo A, Mercken EM, Mitchell SJ, et al. Metformin improves healthspan and life span in mice. Nat Commun. 2013;4:2192.
- De Haes W, Frooninckx L, Van Assche R, et al. Metformin promotes life span through mitohormesis via the peroxiredoxin PRDX-2. Proc Natl Acad Sci USA. 2014 Jun 17;111(24):E2501-9.
- Dugan LL, You YH, Ali SS, et al. AMPK dysregulation promotes diabetes-related reduction of superoxide and mitochondrial function. J Clin Invest. 2013 Nov 1;123(11):4888-99.
- Kristensen JM, Larsen S, Helge JW, Dela F, Wojtaszewski JF. Two weeks of metformin treatment enhances mitochondrial respiration in skeletal muscle of AMPK kinase dead but not wild type mice. PLoS One. 2013;8(1):e53533.
- O’Neill HM, Holloway GP, Steinberg GR. AMPK regulation of fatty acid metabolism and mitochondrial biogenesis: implications for obesity. Mol Cell Endocrinol. 2013 Feb 25;366(2):135-51.
- Wang L, Brautigan DL. alpha-SNAP inhibits AMPK signaling to reduce mitochondrial biogenesis and dephosphorylates Thr172 in AMPKalpha in vitro. Nat Commun. 2013;4:1559.
- Wu SB, Wu YT, Wu TP, Wei YH. Role of AMPK-mediated adaptive responses in human cells with mitochondrial dysfunction to oxidative stress. Biochim Biophys Acta. 2014 Apr;1840(4):1331-44.
- Yan W, Zhang H, Liu P, et al. Impaired mitochondrial biogenesis due to dysfunctional adiponectin-AMPK-PGC-1alpha signaling contributing to increased vulnerability in diabetic heart. Basic Res Cardiol. 2013;108(3):329.
- Zhu J, Wang KZ, Chu CT. After the banquet: mitochondrial biogenesis, mitophagy, and cell survival. Autophagy. 2013 Nov 1;9(11):1663-76.
- Ruderman NB, Xu XJ, Nelson L, Cacicedo JM, Saha AK, Lan F, Ido Y. AMPK and SIRT1: a long-standing partnership? Am J Physiol Endocrinol Metab. 2010 Apr;298(4):E751-60.
- Satoh A, Brace CS, Rensing N, et al. Sirt1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH. Cell Metab. 2013 Sep 3;18(3):416-30.
- Mercken EM, Mitchell SJ, Martin-Montalvo A, et al. SRT2104 extends survival of male mice on a standard diet and preserves bone and muscle mass. Aging Cell. 2014 Oct;13(5):787-96.
- Suchankova G, Nelson LE, Gerhart-Hines Z, et al. Concurrent regulation of AMP-activated protein kinase and SIRT1 in mammalian cells. Biochem Biophys Res Commun. 2009 Jan 23;378(4):836-41.
- Chen D, Bruno J, Easlon E, et al. Tissue specific regulation of SIRT1 by calorie restriction. Genes Dev. 2008 Jul 1;22(13):1753-7.
- Mair W. Tipping the energy balance toward longevity. Cell Metab. 2013 Jan 8;17(1):5-6.
- Mair W, Morantte I, Rodrigues AP, et al. Life span extension induced by AMPK and calcineurin is mediated by CRTC-1 and CREB. Nature. 2011 Feb 17;470(7334):404-8.
- Greer EL, Dowlatshahi D, Banko MR, et al. An AMPK-FOXO pathway mediates longevity induced by a novel method of dietary restriction in C. elegans. Curr Biol. 2007 Oct 9;17(19):1646-56.
- Lu JY, Lin YY, Sheu JC, et al. Acetylation of yeast AMPK controls intrinsic aging independently of caloric restriction. Cell. 2011 Sep 16;146(6):969-79.
- Park DW, Jiang S, Tadie JM, et al. Activation of AMPK enhances neutrophil chemotaxis and bacterial killing. Mol Med. 2013;19:387-98.
- Moser TS, Schieffer D, Cherry S. AMP-activated kinase restricts Rift Valley fever virus infection by inhibiting fatty acid synthesis. PLoS Pathog. 2012;8(4):e1002661.
- Anand P, Kunnumakkara AB, Sundaram C, et al. Cancer is a preventable disease that requires major lifestyle changes. Pharm Res. 2008 Sep;25(9):2097-116.
- Namiki T, Tanemura A, Valencia JC, et al. AMP kinase-related kinase NUAK2 affects tumor growth, migration, and clinical outcome of human melanoma. Proc Natl Acad Sci USA. 2011 Apr 19;108(16):6597-602.
- Shao JJ, Zhang AP, Qin W, Zheng L, Zhu YF, Chen X. AMP-activated protein kinase (AMPK) activation is involved in chrysin-induced growth inhibition and apoptosis in cultured A549 lung cancer cells. Biochem Biophys Res Commun. 2012 Jul 6;423(3):448-53.
- Chen MB, Zhang Y, Wei MX, et al. Activation of AMP-activated protein kinase (AMPK) mediates plumbagin-induced apoptosis and growth inhibition in cultured human colon cancer cells. Cell Signal. 2013 Oct;25(10):1993-2002.
- Son HS, Kwon HY, Sohn EJ, et al. Activation of AMP-activated protein kinase and phosphorylation of glycogen synthase kinase3 beta mediate ursolic acid induced apoptosis in HepG2 liver cancer cells. Phytother Res. 2013 Nov;27(11):1714-22.
- Shen M, Zhang Z, Ratnam M, Dou QP. The interplay of AMP-activated protein kinase and androgen receptor in prostate cancer cells. J Cell Physiol. 2014 Jun;229(6):688-95.
- Fumarola C, Caffarra C, La Monica S, et al. Effects of sorafenib on energy metabolism in breast cancer cells: role of AMPK-mTORC1 signaling. Breast Cancer Res Treat. 2013 Aug;141(1):67-78.
- Rocha GZ, Dias MM, Ropelle ER, Osório-Costa F, Rossato FA, Vercesi AE, et al. Metformin amplifies chemotherapy-induced AMPK activation and antitumoral growth. Clin Cancer Res. 2011 Jun 15;17(12):3993-4005.
- Russo GL, Russo M, Ungaro P. AMP-activated protein kinase: a target for old drugs against diabetes and cancer. Biochem Pharmacol. 2013 Aug 1;86(3):339-50.
- Faubert B, Boily G, Izreig S, et al. AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab. 2013 Jan 8;17(1):113-24.
- Coulter SA. Epidemiology of cardiovascular disease in women: risk, advances, and alarms. Tex Heart Inst J. 2011;38(2):145-7.
- Lee WH, Kim SG. AMPK-dependent metabolic regulation by PPAR agonists. PPAR Res. 2010.
- Dong Y, Zhang M, Wang S, et al. Activation of AMP-activated protein kinase inhibits oxidized LDL-triggered endoplasmic reticulum stress in vivo. Diabetes. 2010 Jun;59(6):1386-96.
- Nagata D, Hirata Y. The role of AMP-activated protein kinase in the cardiovascular system. Hypertens Res. 2010 Jan;33(1):22-8.
- Vigetti D, Clerici M, Deleonibus S, et al. Hyaluronan synthesis is inhibited by adenosine monophosphate-activated protein kinase through the regulation of HAS2 activity in human aortic smooth muscle cells. J Biol Chem. 2011 Mar 11;286(10):7917-24.
- Song P, Zou MH. Regulation of NAD(P)H oxidases by AMPK in cardiovascular systems. Free Radic Biol Med. 2012 May 1;52(9):1607-19.
- Steinberg GR, Schertzer JD. AMPK promotes macrophage fatty acid oxidative metabolism to mitigate inflammation: implications for diabetes and cardiovascular disease. Immunol Cell Biol. 2014 Apr;92(4):340-5.
- Galic S, Fullerton MD, Schertzer JD, et al. Hematopoietic AMPK β1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity. J Clin Invest. 2011 Dec;121(12):4903-15.
- Sag D, Carling D, Stout RD, Suttles J. Adenosine 5’-monophosphate-activated protein kinase promotes macrophage polarization to an anti-inflammatory functional phenotype. J Immunol. 2008 Dec 15;181(12):8633-41.
- Deji N, Kume S, Araki S, et al. Role of angiotensin II-mediated AMPK inactivation on obesity-related salt-sensitive hypertension. Biochem Biophys Res Commun. 2012 Feb 17;418(3):559-64.
- Giovannucci E, Harlan DM, Archer MC, et al. Diabetes and cancer: a consensus report. Diabetes Care. 2010 Jul;33(7):1674-85.
- Buettner R, Bettermann I, Hechtl C, et al. Dietary folic acid activates AMPK and improves insulin resistance and hepatic inflammation in dietary rodent models of the metabolic syndrome. Horm Metab Res. 2010 Oct;42(11):769-74.
- Ong KW, Hsu A, Tan BK. Chlorogenic acid stimulates glucose transport in skeletal muscle via AMPK activation: a contributor to the beneficial effects of coffee on diabetes. PLoS One. 2012;7(3):e32718.
- Nguyen PH, Le TV, Kang HW, et al. AMP-activated protein kinase (AMPK) activators from Myristica fragrans (nutmeg) and their anti-obesity effect. Bioorg Med Chem Lett. 2010 Jul 15;20(14):4128-31.
- Chen WL, Kang CH, Wang SG, Lee HM. alpha-Lipoic acid regulates lipid metabolism through induction of sirtuin 1 (SIRT1) and activation of AMP-activated protein kinase. Diabetologia. 2012 Jun;55(6):1824-35.
- Boon H, Bosselaar M, Praet SF, et al. Intravenous AICAR administration reduces hepatic glucose output and inhibits whole body lipolysis in type 2 diabetic patients. Diabetologia. 2008 Oct;51(10):1893-900.
- Viollet B, Foretz M, Guigas B, et al. Activation of AMP-activated protein kinase in the liver: a new strategy for the management of metabolic hepatic disorders. J Physiol. 2006 Jul 1;574(Pt 1):41-53.
- Misra P. AMP activated protein kinase: a next generation target for total metabolic control. Expert Opin Ther Targets. 2008 Jan;12(1):91-100.
- Coletta DK, Sriwijitkamol A, Wajcberg E, et al. Pioglitazone stimulates AMP-activated protein kinase signalling and increases the expression of genes involved in adiponectin signalling, mitochondrial function and fat oxidation in human skeletal muscle in vivo: a randomised trial. Diabetologia. 2009 Apr;52(4):723-32.
- Svegliati-Baroni G, Saccomanno S, Rychlicki C, et al. Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high-fat diet in nonalcoholic steatohepatitis. Liver Int. 2011 Oct;31(9):1285-97.
- Stepanova M, Rafiq N, Makhlouf H, et al. Predictors of all-cause mortality and liver-related mortality in patients with non-alcoholic fatty liver disease (NAFLD). Dig Dis Sci. 2013 Oct;58(10):3017-23.
- Yang SY, Zhao NJ, Li XJ, Zhang HJ, Chen KJ, Li CD. Ping-tang recipe improves insulin resistance and attenuates hepatic steatosis in high-fat diet-induced obese rats. Chin J Integr Med. 2012 Apr;18(4):262-8.
- Zhang W, Wu R, Zhang F, et al. Thiazolidinediones improve hepatic fibrosis in rats with non-alcoholic steatohepatitis by activating the adenosine monophosphate-activated protein kinase signalling pathway. Clin Exp Pharmacol Physiol. 2012 Dec;39(12):1026-33.
- Heeboll S, Thomsen KL, Pedersen SB, Vilstrup H, George J, Gronbaek H. Effects of resveratrol in experimental and clinical non-alcoholic fatty liver disease. World J Hepatol. 2014 Apr 27;6(4):188-98.
- To K, Yamaza H, Komatsu T, et al. Down-regulation of AMP-activated protein kinase by calorie restriction in rat liver. Exp Gerontol. 2007 Nov;42(11):1063-71.
- Mor V, Unnikrishnan MK. 5’-adenosine monophosphate-activated protein kinase and the metabolic syndrome. Endocr Metab Immune Disord Drug Targets. 2011 Sep 1;11(3):206-16.
- Huyen VT, Phan DV, Thang P, Hoa NK, Ostenson CG. Antidiabetic effect of Gynostemma pentaphyllum tea in randomly assigned type 2 diabetic patients. Horm Metab Res. 2010 May;42(5):353-7.
- Huyen VT, Phan DV, Thang P, Hoa NK, Ostenson CG. Gynostemma pentaphyllum tea improves insulin sensitivity in type 2 diabetic patients. J Nutr Metab. 2013;2013:765383.
- Huyen VT, Phan DV, Thang P, Ky PT, Hoa NK, Ostenson CG.Antidiabetic Effects of Add-On Gynostemma pentaphyllumextract therapy with sulfonylureas in type 2 diabetic patients. Evid Based Complement Alternat Med. 2012;2012:452313.
- Park SH, Huh TL, Kim SY, et al. Antiobesity effect of Gynostemma pentaphyllum extract (actiponin): a randomized, double-blind, placebo-controlled trial. Obesity (Silver Spring). 2014 Jan;22(1):63-71.
- Nagatomo A, Nishida N, Matsuura Y, Shibata N. Rosehip extract inhibits lipid accumulation in white adipose tissue by suppressing the expression of peroxisome proliferator-activated receptor gamma. Prev Nutr Food Sci. 2013 Jun;18(2):85-91.
- Andersson U, Berger K, Hogberg A, Landin-Olsson M, Holm C. Effects of rose hip intake on risk markers of type 2 diabetes and cardiovascular disease: a randomized, double-blind, cross-over investigation in obese persons. Eur J Clin Nutr. 2012 May;66(5):585-90.
- Sriwijitkamol A, Coletta DK, Wajcberg E, et al. Effect of acute exercise on AMPK signaling in skeletal muscle of subjects with type 2 diabetes: a time-course and dose-response study. Diabetes. 2007 Mar;56(3):836-48.
- Tang HC, Chen CY. In silico design for adenosine monophosphate-activated protein kinase agonist from traditional chinese medicine for treatment of metabolic syndromes. Evid Based Complement Alternat Med. 2014;2014:928589.