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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.

 
Impact Of AMPK Activation In Selected Human Tissues

TABLE 1: Impact Of AMPK Activation In Selected Human Tissues5

 

Effect

Energy-Releasing Processes

Energy-Storing Processes

Glucose Uptake

Fat Burning

Glucose Burning

New
Mitochondria

Fat and/or
Cholesterol
Synthesis

Fat Storage
and Release

Glucose
Synthesis

Tissue

Skeletal Muscle

Cardiac Muscle

Liver

Adipose (Fat) Tissue

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.

What You Need To Know
Slow Aging With AMPK

Slow Aging With AMPK

  • Although we seem to age by losing function in each organ or organ system separately, the truth is that aging largely results from universal processes that are common to all cells in the body.
  • Management of energy from food to power cellular activity is one such process, and it is regulated by an enzyme called AMPK.
  • Activated AMPK promotes all the processes we look for to maintain a youthful profile: rapid, efficient release of energy, with little energy storage as fat or new sugar molecules.
  • Thus, activated AMPK keeps us lean and active, with a steady renewal of cellular components.
  • AMPK activity fades with age. Just as importantly, when excessive calories are available, the result is accelerated tissue aging.
  • You can boost AMPK activity through exercise and/or calorie restriction, but should also make use of natural supplements that support AMPK activity.
  • Boosting AMPK activity will keep your tissues young and slow aging throughout your body.

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

Lifestyle And Genetic Factors Impair AMPK Activation

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.

ADENOSINE MONOPHOSPHATE-ACTIVATED PROTEIN KINASE

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.

Immune Function

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

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  

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
Why It’s Difficult To Lose Weight By Cutting Calories Without Exercise
Why It’s Difficult To Lose Weight By Cutting Calories Without Exercise

If metabolism were as simple as accounting, overweight and obese people could readily lose weight simply by cutting their calorie intake and changing nothing else. For example, if you ate 2,500 calories a day, but only burned 1,800, you would gain weight. If you ate exactly 1,800 calories/day, you would maintain weight, and you could lose weight simply by cutting your caloric intake modestly, to, say 1,500/day, because your caloric intake would then be less than you burned.

As anyone who has tried dieting knows, it simply doesn’t work that way. You can cut calories painfully, but lose very little weight unless you add a program of moderate exercise. Now that we understand how AMPK works, we can see why.

An American who has been enjoying a surfeit of calories for a long time has suppressed the AMPK system sharply.36 That leaves the person’s body in a state of continued energy storage and reduced energy utilization. Cutting calories forces the body to activate AMPK to make more of its own glucose and fat, and to sustain fat stores inappropriately.

Exercise, we now know, is a powerful AMPK-activating strategy.9,41,51,109 So it is only when adding exercise, or some other AMPK-activating factor, that regular dieting becomes effective. Activated AMPK puts the whole body back on its youthful track, effectively burning off energy, while draining fat stores instead of refilling them.

Sustained exercise programs, of course, are hard for most people to manage. Drug companies are rushing to manufacture synthetic molecules to activate AMPK, 110 but these are years in the future and likely to be fraught with high costs and safety issues. Fortunately, a growing number of naturally occurring molecules show potent and safe AMPK-activating properties, and are available now at a low cost.5

Liver Disease

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.

Summary

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.

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