How do you achieve anti-aging?
That word has many different definitions.
For a skin care product, anti-aging can mean “looking” younger. While the product may reduce superficial signs, like wrinkles and loss of elasticity, no skin care regimen can actually slow the biological aging process of the skin.
Even if they look better, the rate at which those cells age will remain the same, no matter what serum you’re slathering on.
Yet there might be a way to actually slow the aging process. Not just cosmetically, but perhaps in every way throughout our body.
Calorie restriction is the only thing scientists know of which actually slows the clock.
To date, long term studies have only been done in animals and for that reason, no one knows for sure if the same would happen in humans (1). But consider that this has been observed in every animal tested so far. Life forms as simple as yeast to as complex as fish, rodents, dogs and rhesus monkeys have demonstrated anti-aging while on a calorie-restricted diet.
Calorie restriction (CR) means the animals receive all their essential nutrients without experiencing malnutrition. They’re receiving the bare amount of calories needed, not extra.
Both of those rhesus monkeys are (or should be) at the very end of their life span. One looks the part, the other doesn’t.
Even without knowing further details, it’s clear to see the one on the right has hair which is robust and still rich in color. His posture is obviously better, too. You don’t see under eye bags and wrinkles, but the monkey on the left definitely has those.
Guess what? They’re both the exact same age – 27.6 years. The difference is that the healthier and more youthful monkey has been on a calorie restricted diet since an early age (2). The other just eats normally.
Mimicking calorie restriction?
To be clear, being slim and in-shape is not the same as a calorie restricted diet.
A 6 foot man could consistently weigh 145 lbs, consistently have 6% body fat, and still be eating a diet which is the complete opposite of CR. So don’t confuse being skinny as being on a CR-like diet.
A true calorie restricted diet, like those seen in the animal studies, can be quite dangerous. The scientists calculate out the bare minimum needed for the animal’s daily survival and that’s it.
Imagine eating, but never getting the chance to feel full. You would probably always feel hungry on a calorie restricted diet. It’s misery, daily.
The reason there are potentially dangerous side effects is because it’s borderline starvation. Yes, all the vitamins, minerals, carbohydrates, protein, and other essential nutrients are provided, but there’s not a big margin of a safety – your body is not provided comfortable amounts of energy to use.
In short, a calorie restriction diet would be torture to be on for your entire life, not to mention it could be harmful and result in side effects like muscle loss, reduced bone mineral density, and more.
Between the unpleasantness, the extreme dedication, and the dangers if done wrong, it’s no surprise that controlled long term calorie restriction diets in humans have not been done.
So even though it works in every animal studied, including the closest genetically to humans – which are rhesus monkeys – scientists can’t say for sure whether or not it would work in humans.
But what if it did?
If it works, then the preferred use would probably be to find ways to mimic calorie restriction, rather than actually doing it.
In other words, it would be great to achieve some of the biological processes which are increased during a CR diet, without needing to be on the diet.
Figuring out how to control our anti aging enzymes might be the secret to accomplish that.
What enzymes do is signal your cells to do things. Every activity of a cell is prompted by some type of enzyme. During calorie restriction, certain enzymes are activated which “turn on” anti aging benefits in the cells.
Might they offer the key to slowing down the process of death, which starts when we are born?
Death is guaranteed for all of us, but you probably are not in a hurry to get there!
Or perhaps you’re like us… death of this body is not the fear. Rather, it’s the fear of being alive in this body and suffering long term with terrible diseases like Alzheimer’s and cancer.
Whichever camp you fall into, you have a motive to age gracefully.
What is AMPK?
It’s an abbreviation for 5′ adenosine monophosphate-activated protein kinase. This is an enzyme which is found in every cell of the body. It is believed to serve as a signaling pathway, helping to regulate cell growth, metabolism, and autophagy (the process of scraping old cells and turning them into energy). Activation of our cells’ AMPK pathway declines with age. For that reason, some have coined it as being a “youth enzyme” which might offer anti aging benefits.
If you can remember back to your biology days in high school, the phrase ATP production should ring a bell. ATP is the biochemical way our cells use and store their energy.
You can increase ATP production with AMPK activation (3).
What does this enzyme have to do with calorie restriction? Possibly a lot. Scientists have hailed it as a “key sensor and effector” in longevity effects produced during a CR diet (4):
“AMPK has emerged as a key energy sensor with the ability to transcriptionally reprogram the cell and metabolically adapt to external cues.”
Resveratrol is thought to work mostly through activating SIRT1 versus the AMPK pathway.
What’s the difference between the AMPK and SIRT1 pathway?
They are actually very similar. Research suggests they are involved in the regulation of many common target molecules which influence the aging process (7).
Resveratrol is believed to influence both of those pathways, but mostly via SIRT1.
Unfortunately, resveratrol is easily oxidized by air and is quickly degraded by light and heat. It also has a very short half-life after being absorbed into the human bloodstream.
In short, even if resveratrol works, it’s so unstable and such high dosages would be needed (and frequently at that) in order to possibly replicate the results seen in animal studies.
The ones that got so much press coverage a decade ago used dosages which would be equivalent to drinking a thousand bottles of red wine, per day!
While reviews rarely refer to them as such, you can actually categorize all of the aforementioned as AMPK activation supplements. Nicotinamide riboside foods as well as pterostilbene foods are believed to positively influence that pathway, in addition to the SIRT1.
While SIRT1 remains intriguing, research throughout the past several years seems to infer that it is actually the AMPK pathway which might offer more health advantages. For that reason, learning how to activate it is at the forefront of the anti aging research taking place today.
7 AMPK benefits suggested by science
The history of AMPK is short. It is a somewhat recent discovery. Who discovered AMPK is unclear, since the description of the enzyme was mentioned in various research before being officially named in 1988 (8). In the decades since, it has been studied for possible health benefits and roles in disease progression.
1. Life extension
In research involving fruit flies, the lifespans of both the males and females were extended by approximately 20% versus their sibling controls. The AMPK booster used was a genetic mutation to increase it, rather than a supplemental source (9).
In other published research involving the same species, they dive into the details of what exactly is taking place (10):
- Increased autophagy in the brain and gut, which “slows systemic aging.” As mentioned above, the autophagy is how our cells programmatically self-destruct and get used as fuel by other, healthier cells. That’s a good process, as we want to rid ourselves of the bad cells.
- Effects were linked to “altered insulin-like signaling.” Speaking of insulin, AMPK benefits for diabetics appear to be quite promising, more on that below.
While fruit flies are far different from humans or any primate, they’re often used in research because their entire lifespans can be monitored, as well as successive generations, all within a short period of time. Doing the same with mice and rats is obviously preferred, but takes much longer. Especially when you want to analyze 10 generations or more, as was done in the first study.
2. Exercise and muscle
If you want to know how to activate AMPK naturally, the research as of today suggests you have four options:
- Calorie restriction
- Genetics, if you are naturally so lucky. Changing them would not be a natural process. In studies, such as those with fruit flies, their genes were tinkered with to increase the enzymatic expression.
- Foods, but only a few have demonstrated noteworthy activity. They’re listed below.
- Exercise, but a jog probably won’t suffice. It takes “vigorous” fitness, like intense bodybuilding and other extremely strenuous activities. Even with intensity, this method of activation may not work in the elderly, even if they can safely withstand such a regimen (11).
When you read AMPK supplement reviews, you should be highly skeptical. They have something to sell you, right? But if the idea of influencing this pathway is just a scam, then why does the World Anti-Doping Agency (WADA) ban metabolic modulators designed to increase AMPK?
That’s right, the Olympics and most professional sports ban the use of drugs which have that effect (12).
Shortly before the 2008 Olympics in Beijing, a study came out about how using the AMPK activator AICOR boosted the athletic performance of mice on treadmills, even without any training involved!
That, along with supporting research, led WADA to ban them and for good reason… better athletic performance solely from taking a drug or supplement is an unfair competitive advantage (13).
Now to be clear, WADA has banned AICAR (AICA ribonucleotide) which is an otherwise legitimate medication used to tread cardiac ischemic injury.
They have not yet banned over the counter dietary supplements which purport to be AMPK boosters. Though if future research continues to re-affirm their potential for endurance and muscle growth, it would not be surprising to see those on the list, too. They may end up similar to DHEA supplements, which are still legally sold in the U.S. as a dietary supplement, but professional sports organizations ban their use.
For now at least, the popularity of the over the counter supplemental versions continue to grow with bodybuilders and those seeking better physical endurance and stamina.
3. Weight Loss
In the future, will this become the next diet pill superstar?
You will see many sources already hailing it as a belly fat burner, but such claims are premature. Human clinical studies to evaluate AMPK weight loss have not yet occurred. What can be said though is this (14):
“A strong correlation between low activation state of AMPK and metabolic disorders associated with insulin resistance, obesity and sedentary activities has been established in a variety of rodent models with aspects of the metabolic syndrome.”
The question though is whether the cart goes before the horse. Low glucose AMPK activation is seen in those who are overweight, don’t work out much, and have related lifestyle diseases like type 2 diabetes. But are the low levels contributing to those? Or is that the diseases cause the low AMPK?
For the answer, metformin provides a good clue.
Sold under the brand name Glucophage, metformin is such an important diabetic drug that it’s on the World Health Organization’s List of Essential Medicines. It’s been FDA approved for over 20 years (since 1995) and elsewhere, its use dates back even earlier. In France, it’s been used since 1957. For a long time, they couldn’t say exactly why metformin was good for diabetes, but they knew it worked.
The discovery of why metformin works didn’t really happen until 2001, with the role of AMP-activated protein kinase in the mechanism of metformin action.
The following year in the prestigious Diabetes Journal, published by the American Diabetes Association, there was a rebuttal of exactly how and where that occurs, but their conclusion was the same; Metformin works by increasing AMPK activity (15).
Within this last decade, studies have evaluated metformin for safety and other basic metabolic measurements, including weight loss or gain.
There was 10 year long randomized clinical trial of metformin versus placebo, to evaluate the drug (16). Some quotes from it:
“…metformin participants had reduced body weight and waist circumference compared with placebo (weight by 2.06 ± 5.65% vs. 0.02 ± 5.52%, P < 0.001, and waist circumference by 2.13 ± 7.06 cm vs. 0.79 ± 6.54 cm, P < 0.001 in metformin vs. placebo, respectively)”
“Throughout the unblinded follow-up, weight loss remained significantly greater in the metformin group than in the placebo group (2.0 vs. 0.2%, P < 0.001), and this was related to the degree of continuing metformin adherence.”
Gastrointestinal side effects were seen in 28% of the users, compared to 16% in the placebo group. This included symptoms like abdominal discomfort, diarrhea, and painful/difficult urination. Whether those side effects were as an AMPK activator or something else specific to the drug is unknown. Either way, it was stated that:
“These symptoms are generally transient, resolve spontaneously, and can often be avoided by gradual escalation of dosage.”
The chart below shows that, as you see the side effects diminish as time went on in this 10 year trial.
Going back to the fat burning and decrease in waist size, remember the prescription drug metformin is for type 2 diabetics. Whether healthy individuals would experience that same effect is unknown. Most important of all, a natural AMPK activator would probably not be as effective.
A prescription drug which boosts this enzyme also caused weight loss as a side effect, as confirmed in a decade-long, well designed human clinical trial. It’s still unknown if other compounds and/or foods could offer similar perks of shedding pounds and inches. Either way, this is strong evidence to suggest that increased expression of this enzymatic activity might help with losing weight.
4. Diabetes and blood sugar
It’s possible there may be other ways in which metformin is helping, but if there are, they remain unknown.
So as of today, the reason why metformin helps blood sugar is understood to be AMPK. That really puts it front and center in the quest for diabetes treatments, or at least in the type 2 form of the disease, which is self-induced by lifestyle choices.
Type 1 diabetes is an auto-immune process which permanently destructs the pancreatic islet cells, something entirely different which can occur in even the skinniest of people, often during their childhood.
Given the out of control rates of obesity, research for type 1 diabetics is far less than it is for type 2. However, better blood sugar control is what’s need for both types, regardless of what originally caused the disease and for that reason, this pathway appears to be important for both.
Is there evidence that the mechanism of activating the AMPK pathway can do the same thing – increase insulin sensitivity – even when caused by something other than metformin?
As it turns, there is.
If you want the jargon-filled explanation of why, just turn to the animal studies which tell you precisely what they see going on when they boost it (17):
“AMPK stimulates Ser372 phosphorylation, suppresses SREBP-1c cleavage and nuclear translocation, and represses SREBP-1c target gene expression in hepatocytes exposed to high glucose, leading to reduced lipogenesis and lipid accumulation.”
Translated to plain English, greater expression of the enzyme means greater insulin sensitivity. That means more balanced blood sugar.
5. Alzheimer’s, Parkinson’s, and brain health
Amyloid plaques in the brain are a trademark sign of Alzheimer’s disease. Published in 2010, a study involving cultured neurons from mice found that resveratrol supplements lowered their amyloid deposits (18). This was basically using cells in a Petri dish and why the reduction was happening, the scientists couldn’t say.
Next, they gave actual living mice resveratrol supplements and it led them to say this:
“Finally, orally administered resveratrol in mice was detected in the brain where it activated AMPK and reduced cerebral Abeta [amyloid] levels and deposition in the cortex. These data suggest that resveratrol and pharmacological activation of AMPK have therapeutic potential against Alzheimer disease.”
This another cart before the horse scenario. If the activation is happening, is that what’s benefiting the amyloid plaques and neurofibrillary tangles? Or is that occurring from something else the resveratrol was doing, if it was responsible. No one can say for sure yet.
While purely theoretical, if it was the activation of the AMPK that was helping, then presumably an even more potent activator than resveratrol might be even better.
Another unknown is what causes Alzheimer’s. Even if AMPK benefits the amyloid deposits and brain tangles which are seen in Alzheimer’s, Huntington’s disease, and some other neurodegenerative conditions, no one knows if those are what’s causing the problem.
In a 2014 study, researchers created a Parkinson’s like disease model in fruit flies and then tested what happened with greater expression of the enzyme (19). Based on their findings, they said this:
“…loss of AMPK activity exacerbates neuronal loss and associated phenotypes in parkin and LRRK mutant flies. Together, our results suggest the relevance of mitochondrial-associated pathway in LRRK2 and parkin-related pathogenesis, and that AMPK activation may represent a potential therapeutic strategy for these familial forms of PD [Parkinson’s disease].”
While exciting, it’s important to remember we know almost nothing regarding the causes of these horrible neurodegenerative diseases. Correlation does not equal causation and for that reason, we really just don’t know whether higher or lower levels of this enzyme being expressed can help, hurt, or have no effect on those diseases.
In 2003, the first research was published which suggested a “clear link” between AMPK and cancer (20).
How it is believed to work is by blocking pathways which cancer cells need for growth.
Other ways it might benefit cancer is through autophagy (21). Remember, autophagy is the natural process our cells use to systematically destroy and recycle the old ones which are not desired. Imagine if the process could be controlled to do that for cancer cells?
Despite those possible advantages, the theory of it helping cancer remains controversial (22).
On one hand, AMPK might be a “tumor suppressor” but on the other, some suggest the enzyme might end up promoting cancer growth. How so? Because if the AMPK puts aggressive types of cancer cells under metabolic stresses (like starving them access to glucose and reducing how much oxygen they get) then it may actually backfire and cause the cancer to fight back even harder.
That may be true, but common sense tells you that the same thing could also be said about many cancer treatments… since they put the cancer cells under stress.
There have been clinical trials taking place looking at metformin for cancer (23). As far as research on the broad topic of cancer and AMPK, if you search for those two words on the NIH’s PubMed database, you get back over 2,400 medical reviews, studies, and articles. AMPK is of immense interest to those fighting this awful disease.
When it comes to the topic of antioxidants, almost everything you read about them involves food and other natural compounds which exhibit antioxidant activity. However, the best antioxidants are those which are body makes internally.
The reason you don’t hear them discussed much is because until recently, the consensus was that little could be done to control how our body makes and uses them. The prevailing mindset was that genetics largely controlled them.
Within the past couple of decades, scientists are starting to discover there may be compounds which are not antioxidants on their own, but they may trigger our body to produce more of them. Knowing how to increase AMPK may be one secret in doing so. A paper published in 2016 describes why (24):
“Because metabolism is interconnected with redox regulation, AMPK has a crucial role in regulating antioxidant defense during oxidative stress. AMPK upregulates several antioxidant genes, such as those encoding superoxide dismutase…”
In other words, AMPK may turn on the “antioxidant genes” which are responsible for your body’s natural production of antioxidants.
Foods that activate AMPK?
While preliminary, after understanding the exciting research about this enzyme, it’s easy to understand why both scientists as well as laymen are looking for ways to increase AMPK naturally. Foods are the best place to start.
First, let’s talk about the foods which are bad.
High fat diets = bad idea
Heart healthy nuts and oils are good for you, right?
We regularly hammer home how liquefied fats like olive oil are linked to atherosclerosis. Like refined sugars, these purified oils are not found in nature, so it’s no surprise our can body go haywire when we ingest them (25).
Now you have another reason to consider an oil free diet or greatly reducing intake. High fat diets have been linked to lower AMPK in several animal models (26).
Does this mean you should cut out nuts? Not at all, but going overboard where 20% or more of your daily calories come from fat is probably a lipid overload.
Now that you know what you should be limiting, which foods should you increasing?
Viscous dietary fiber
Aside from being more likely to live an active lifestyle, there’s another reason why greater AMPK expression is seen in healthy people when compared to type 2 diabetics.
Better sensitivity to insulin = better AMPK expression.
Diabetics are the opposite of sensitive, they experience insulin resistance.
Whether you’re healthy or diabetic, you may be able to improve insulin sensitivity by increasing your intake of viscous dietary fiber (27).
What is that? Well not all fiber is equal. Viscous is a water-soluble fiber which is plentiful in many vegetables and fruits. Some of the best sources are legumes (like beans and lentils), oats, apples, and psyllium seed husks. A vegan diet, if based on whole foods instead of processed junk, will provide the greatest amount of this fiber.
Among all dietary fibers, the patented PGX (PolyGlycopleX) blend is the most viscous by percentage. What is PGX fiber made of? A blend of highly viscous natural fibers coming from:
- konjac powder, which is a Japanese root vegetable
- sodium alginate, from brown algae
- xanthan gum, which typically comes from corn. It can be made from wheat but since PGX is gluten free, it’s safe to conclude they’re not using that source.
This patented blend is not marketed for anti-aging, but rather for weight loss through appetite control. Whatever your motive, you can buy PGX supplements which may be a good solution if you’re unable to squeeze in large amounts of veggies with every meal. PGX’s benefit of appetite suppression is icing on the cake for those who are overweight.
Even though it’s not the most potent source, this is one of the best foods for activating the enzyme because green tea is affordable and readily available.
The specific compound in green tea responsible for this is EGCG (Epigallocatechin-3-Gallate).
A human study from way back in 1999 found that over a 24 hour period, those consuming green tea experienced a 4% increase in metabolism. Since then, it has been touted as a natural way how to increase metabolism. It’s why still to this day, it remains a popular diet pill ingredient.
Yet no one knew why it seemed to boost metabolism.
You might assume it was the caffeine content, but the amount in green tea (or any tea for that matter) is not that high relative to coffee, which does not demonstrate that same weight loss benefit. Nor do other caffeine supplements which are equal or higher than a green tea dosage.
Only recently were scientist given a plausible reason as to why green tea works for weight loss. In 2015, research found the polyphenols were an AMPK activator (28). In this study involving rats, the conclusion was:
“Our study identified that metabolic changes caused by GT [green tea] intake induced AMPK activation and modulate the expression of genes involved in metabolism, particularly in adipose tissue, thus offering a therapeutic strategy to combat insulin resistance, dyslipidemia, and obesity in rats.”
The drawback with this food source is that it has high tannin content and can cause digestive upset in many people. If you can’t handle drinking large quantities of green tea, you may want to consider EGCG extract capsules.
On average, only 3.14% of turmeric is curcumin (29).
Despite being such a minuscule amount, it’s the curcumin which is the reason why turmeric is one of the most studied foods throughout the world.
Among the laundry list of health benefits it can offer, a few years ago it was discovered that curcumin is also an AMPK supplement (30).
The bad news is that turmeric has poor bioavailability.
Eating turmeric with black pepper does boost the absorption. Due to the peperine content, bioavailability is increased up to 2,000% (31). Sounds impressive, but it can’t hold a candle to the patented versions on the market which are dozens of times more potent. See our in-depth review of curcumin supplement formulations.
Barberry, goldenseal, and other berberines
A berberine is a specific type of quaternary ammonium salt which is naturally found in the roots, bark, stems, and rhizomes of certain plants:
- Barberry (Berberis vulgaris)
- Tree turmeric (Berberis aristata, not to be confused with turmeric from Curcuma longa)
- Goldenseal (Hydrastis Canadensis)
- Prickly poppy (Argemone mexicana)
- Oregon grap (Mahonia aquifolium)
- Amur cork tree (Phellodendron amurense)
- Chinese goldthread (Coptis chinensis)
- Yellowroot (Xanthorhiza simplicissima)
- Californian poppy (Eschscholzia californica)
- Guduchi (Tinospora cordifolia)
Some of these have been used for generations in herbal medicinal practices, like Ayurveda and Traditional Chinese Medicine.
The oral bioavailability of berberine is low (32). For that reason and since they’re not ranked as a particularly potent activator, you don’t really hear much about berberine for benefiting this enzyme.
They probably make more sense for other purposes, like goldenseal possibly being a natural antibiotic.
There is a supplement on the market by a very small company, Journey Naturals, called LongeviTrim. It uses berberine, gynostemma, and quercetin. However it’s a “proprietary blend” of those along with and curcumin, trans-resveratrol and niacin. All great things, but you don’t know how much you’re getting of each, only their combined dosage per capsule, which is 525 mg. For that reason, we don’t recommended LongeviTrim and have no personal reviews to share of it.
Instead, your best bet will be to focus on concentrated sources of the last two items on the list. We saved the two best foods for last…
GynostemmaIn Asian cultures, this plant is known as jiaogulan and southern ginseng. Here in the U.S. most refer to it as gynostemma, which comes from its scientific name.
The Gynostemma pentaphyllum plant is in the same family as the cucumber. Due to the belief that it helped longevity, it has been used in Traditional Chinese Medicine for centuries (33).
Recent findings have found there might be something to that; it appears to be one of the most potent activators. It’s not being ignored for that, either.
On PubMed there are nearly 300 results containing the name of the plant, Gynostemma pentaphyllum. You will find research suggesting anti-cancer and antioxidant properties (34). Aside from those topics, some are talking about the AMP-activated protein kinase, or benefits which suggest the pathway may be influenced by this herb (35).
For example, one human study involved randomly giving type 2 diabetics either Gynostemma pentaphyllum tea or another type of tea, which was used as a placebo for comparison (36). When compared to the placebo group, those receiving the G. pentaphyllum tea had:
- Almost 3x the decrease in insulin resistance.
- 5x greater reduction in fasting glucose.
- 10x greater reduction in HbA1c levels, which is the best way of measuring high blood sugar over time.
While still very preliminary, there is a fair amount of research out there to suggest the G. pentaphyllum compounds may be useful for blood sugar levels (37) (38) (39) (40) (41). If it is helping with insulin sensitivity, then the AMPK gynostemma link would make sense.
Last but certainly not least we come to rose hips, which seems to offer the most promise thanks to its high content of trans-tiliroside.
How powerful might it be? Well consider that in a lab study using cultured human liver cells, the beneficial effect seen when they were treated with trans-tiliroside were comparable to when they were treated with metformin (42).
In a study involving rats who were given trans-tiliroside, the conclusion stated (43):
“Trans-tiliroside, a constituent from Potentilla chinesis, revealed significant anti-hyperglycemic, anti-hyperlipidemic and antioxidant activities.”
They used a different source of tiliroside, the Potentilla chinesis plant. However it involved a patented extraction process. Research suggests that rose hips is a superior natural source.
In addition to the apparent enzymatic boosting on the cellular level, a study involving mice found that tiliroside reduced their glucose uptake in the digestive tract, after the mice ate carbs (44).
No one eats rose hips, but it is used in tea. None of the Whole Foods in the Los Angeles area sell it last we checked, but a good specialty health grocer should. You can also buy rose hips tea in bulk on Amazon.
The best AMPK activator might actually be a supplement sold under that very name, which the brand Life Extension makes. Why? Because its two ingredients are concentrated gynostemma and trans-tiliroside from rose hips. When you don’t have the time or inclination for tea, their capsules are the best choice.
These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.