What Doesn't AMPK Control?

AMPK (adenosine-monophosphate activated protein kinase) is one amazing enzyme.

It's found in every cell and it serves as the body's master regulating switch, determining how fat you'll be and even how long you'll live.

AMPK

Here are a few of the things that could happen in your body if you're in short supply of AMPK or have an AMPK signaling deficit:

  • Abdominal obesity
  • Loss in insulin sensitivity
  • Excess glucose
  • Chronic inflammation
  • High triglycerides
  • High LDL
  • Mitochondrial dysfunction
  • Accumulation of cellular debris
  • Accumulation of senescent cells
  • Increased cellular stress
  • Unfavorable gene expression
  • Heart failure

And, of course, cancer.

Cancer is why I started looking at AMPK again.

The molecule has long been of interest to people who study the chemistry of lifting and body comp because it can de-sensitize fat cells to insulin's effect so fat cells can't store nutrients as easily. Instead, muscles get bigger while fat stores get smaller.

So the molecule has always been on the front burner of muscle-building, fat-burning chemicals, but when a recent study came out appraising the effects of a prescription drug's AMPK modulating effects on cancer, I sat up and took notice.

In one of the largest studies of its kind, a group of scientists pored over the 10-year case histories of 8,000 type II diabetics who'd been taking a drug to lower blood sugar.

They found that users of the drug had an incredible 54% lower incidence of all cancers compared to the general population.

Not only did the glucose-disposal agent exhibit a preventative effect, but users who developed cancer had a much higher survival rate, including those with malignant tumors of the lung, colon, and breast.

The earlier they started using the drug, the longer they continued to fight off cancer.

The effect was so profound that the results, along with the drug's glucose-control properties, prompted the influential Life Extension Foundation (LEF) to recommend that its members – diabetic or not – take it every day.

And, based on editorials in some of the medical journals, at least a few physicians are contemplating giving the same advice.

So why would a blood-sugar lowering drug, or other drugs in the same class, protect against cancer?

One reason is that they reduce obesity, which is a risk factor for more than a dozen cancers. (Generally, there's a 59% increase in the incidence of cancer for every 5-unit increase in body mass index, or BMI.)

Secondly, AMPK, in addition to being a fuel sensor and metabolic master switch, regulates cell growth and replication. It can literally tell cells to stop sucking on the energy teat. Once AMPK is activated, cancer cells end up starving themselves because the energy lifeline's been cut.

But those are just a couple of intriguing things about AMPK and AMPK modulating drugs.

Most of humanity, or at least most of the fairly affluent part of humanity, suffers from nutritional overload. We eat too much of nearly everything. We're part homo sapiens and part locust.

As such, many of us (most?) suffer from improper uptake of glucose and fat. As a result, our fat, slack-muscled bodies are filled with celluar waste and damaged proteins, much of it directly caused by low levels of AMPK or improper AMPK signaling.

Fortunately, this can be treated. Increasing AMPK mimics the effects of calorie restriction and is associated with a 20-30% increase of lifespan in laboratory models.

When switched on, AMPK triggers the use of stored energy from fat, enhances the removal of sugar and fats from the blood, reduces cellular inflammation, cleans up cellular junk, and even leads to the formation of new mitochondria, which is of huge importance.

If you could control the growth and health of mitochondria, you could theoretically double your lifespan without any of the diseases typically associated with old age. You could avoid metabolic diseases like syndrome X that afflict some 47 million Americans and simultaneously retain the energy of youth well into codger-dom.

From an athletic perspective, controlling the vitality and number of mitochondria in your muscle cells could lead to huge improvements in strength endurance that didn't decline with the passing of years.

Clearly, AMPK is one amazing chemical.

So, why aren't we all taking these AMPK modulating drugs? Well, they're problematic in a couple of ways.

One, they potentially cause lactic acidosis, a potentially fatal condition that occurs when lactic acid builds up in the bloodstream faster than it can be removed. In fact, lactic acidosis was the main reason the diet drug phenformin was taken off the market.

Secondly, they might not work so well for bodybuilders and strength athletes because in addition to all the great things that most AMPK modulators do, they also inhibit muscle protein synthesis during resistance exercise. Oh-oh.

Luckily, there are chemicals found in nature that also affect AMPK, one of which is Cyanidin-3 Glucoside (sold as Indigo-3G®) a naturally occurring anthocyanidin found in blueberries, blackberries, acai berries, and many other berries and fruits.

C3G

It's actually a pigment that gives these fruits and others their characteristic indigo color. Plants are of course exposed to harsh UV light for long periods so they evolved to produce C3G and other polyphenols to protect themselves from free-radical damage.

C3G conveys much of this free-radical protection to anyone or anything that ingests it. When C3G is isolated and taken in larger quantities, though, it also has powerful blood-glucose lowering properties that rival pharmaceutical versions.

One of several laboratory experiments using C3G showed two dosage-related drops in blood glucose of 33% and 51%, prompting the authors of the study themselves to remark how favorably it compared to glucose-disposal drugs.

Bodybuilders love C3G because it allows them to put on more muscle and simultaneously lose fat. Nutrients are specifically shuttled towards muscle cells, resulting in better pumps, more strength, better performance, and ultimately more muscle.

That way, lifters can eat more (actually, they're encouraged to eat more) without worrying about fat storage.

And, like these glucose-disposal drugs, C3G also raises adipokinectin levels while decreasing leptin levels. It does these things the same way that the glucose-disposal drugs do, which is by raising levels of AMPK with the downstream effects of increasing glucose and lipid uptake directly into muscle cells.

Users of the compound can literally ingest more calories and see it partitioned to muscle instead of fat.

However, unlike prescription glucose-disposal agents, C3G doesn't inhibit muscle protein synthesis.

C3G's effects on AMPK activations on muscle growth are diminished via FOX01 (a protein that plays a role in insulin resistance), and AMPK works through FOX01 to hinder muscle protein synthesis.

That's terrific news.

There are probably four known ways to boost AMPK.

  1. Prescription drugs. Sure, you could take prescription glucose-disposal agents. However, as described earlier, these drugs might cause the potentially lethal condition called lactic acidosis and they also interfere with workout-induced muscle protein synthesis.
  2. Calorie restriction. Eating a lot less over the course of years or even a lifetime increase AMPK, which is probably the reason that calorie restriction seems to work in extending life span, at least in laboratory models. Unfortunately, the practice of calorie restriction is difficult, joyless, and is a contradictory to adding muscle.
  3. Exercise. Most exercise increases AMPK, too, making the chemical one of the likely factors involved in exercise-induced muscle growth and fat reduction. Unfortunately, the increases in AMPK are short-lived and irregular and cease some time after exercise is over.
  4. Botanical extracts. Plant alternatives, particularly C3G, work exceptionally well in raising AMPK, seemingly as well or better than prescription drugs. They can be taken throughout the day to keep levels high, and they don't interfere in muscle protein synthesis.

If, as seems logical, you choose the botanical extract route, your impulse might be to just add some berries to your diet, but unfortunately it isn't that easy.

You'd have to eat bushels – or at least baskets – full of dark berries to get the muscle building, fat burning, cancer fighting, and heart protective (though reducing inflammation, triglycerides, and LDL) effects of C3G.

Besides, nature doesn't guarantee that the dosages in her products are standardized. For effective doses, you need to go the supplement route.

  1. Dreyer HC et al. Resistance exercise increases AMPK activity and reduces 4E-BP1 phosphorylation and protein synthesis in human skeletal muscle. J Physiol. 2006 Oct 15;576(Pt 2):613-24. PubMed.
  2. Grace MH et al. Hypoglycemic activity of a novel Anthocyanin-rich formulation from Lowbush Blueberry, Vacciniumangustifolium Aiton. Phytomedicine. 2009 May;16(5):406-15. PubMed.
  3. Yun-Kyoung L et al. Anthocyanins target AMPK/mTOR and AMPK/Wnt pathways in exerting anti-tumor effects in colon cancer or hepatocarcinoma cells. The FASEB Journal. 2010 Apr;24(S1);lb259.
  4. Libby G et al. New Users of Metformin are at a Low Risk of Incident Cancer. Diabetes Care 2009;32(9):1620–1625. PubMed.
  5. Liu X et al. The role of AMPK/mTOR/S6K1 signaling axis in mediating the physiological process of exercise-induced insulin sensitization in skeletal muscle of C57BL/6 mice. Biochim Biophys Acta. 2012 Nov;1822(11):1716-26. PubMed.