All Current Longevity Roads Lead to AMPK - The Anti-Aging Rome
You may not know the term AMPK but you've definitely heard of the roads that lead there.
- Intermittent fasting
- Cold exposure
- Calorie restriction
- Metformin or berberine
All the big buzz words for anti-aging!
We'll look at each one down below along with supplements that directly stimulate AMPK but this pathway is fascinating in its own right.
That will be our starting point since it drives the whole train until CRISPR or David Sinclair's Yamanaka Factor research hits the market (more on that here).
The MILES study with Metformin actually reversed aging biomarkers so that's our cue and at the heart of it...AMPK.
Here are the topics we'll cover:
- What is AMPK
- AMPK and mitochondria
- AMPK and oxidative stress
- AMPK and systemic inflammation
- AMPK and metabolic complex
- AMPK and cancer
- AMPK and senescent cells
- Intermittent fasting - calorie restriction and AMPK
- Cold and heat exposure and AMPK
- Sirtuins and AMPK
- Resveratrol and AMPK
- Metformin or berberine for AMPK
- Keto diet and AMPK
- Exercise and AMPK
- Supplements for AMPK
Let's get started!
What is AMPK
In its simplest terms, AMPK is an internal nutrient sensor.
AMPK is short for AMP-activated protein kinase.
It's the "AMP" that matters. It's the "currency" of energy production in all known living things. Very very old systems conserved through evolution.
In short, AMPK manages energy use and needs balancing but we have zoom out a bit to see its role in longevity and aging.
Like it or now, from a game theory point of view, the goal of our bodies is to pass on genes that can successfully survive and thrive.
The rest didn't make it!
Here's where things get interesting for AMPK.
In times of severe survivability shock (famine, drought, environmental catastrophe, etc), this pathway will shift our entire biology to survive in the hopes of reproducing later once things settle down.
It's all about available energy:
When cellular energy is low, AMPK is activated and targets a range of physiological processes, the net response of which is an increase in energy production and a coordinated decrease in ATP usage.
Basically, the sensors see signs of extreme stress and say "Okay, batten down the hatches...get our house in order so we can live to play another day".
By play, it means to reproduce.
A whole series of cascading effects occur from this transition.
Cellular housekeeping gets priority with a slew of positive effects.
We'll dive into the individual components but the summary level:
Insufficient AMPK activity may be related to virtually all pathological aging processes. Research indicates that restoring AMPK not only increases longevity, but works to fight the symptoms of aging in individual body systems.
And the original research that got everyone's attention:
Recent reports demonstrated that AMPK can exert pro-longevity effects in several species21. AMPK activation in gastrointestinal tract increases Drosophila melanogaster’s lifespan by 30%, from six weeks to eight weeks
Again, this pathway is highly conserved across all living creatures. Very old indeed.
This all feeds back to the ability to reproduce...no sense in making babies in hard times….keep everything in top shape till this passes.
Interestingly, there are new ways to nudge AMPK pathways without drought and famine.
Temporarily famine (fasting) or shocks to the system will do the trick along with a few shortcuts (supplements, etc).
Let's dive into the core systems affected by AMPK first.
Since AMPK is all about energy, mitochondria seem to be a logical entry point.
AMPK and mitochondria
Mitochondria are the little energy factories of our cells. Everything you do requires them to function!
As with all sources of energy, there's a tremendous amount of waste product in the form of various oxygen constructs.
Free oxygen is highly reactive and destructive to organic tissue (us!!) as they operate like little chemical scissors...slicing and dicing everything they come in contact with including neurons.
Why does this matter?
Macromolecular damage usually occurs via oxidative mechanisms linked to free radicals, including O2−, NO and OH− (hydroxyl ions).
Meaning...tissue damage. Even our own DNA (very close in the cell to the power production).
The brain is a huge producer of energy and confined within tight quarters.
There are two main issues:
- Energy production goes down as we get older (and get less efficient)
- Waste product is more poorly handled
AMPK is a direct controller of this pathway:
Recent studies have revealed that one ancestral function of AMPK is to promote mitochondrial health, and multiple newly discovered targets of AMPK are involved in various aspects of mitochondrial homeostasis, including mitophagy T
First the energy side with AMPK.
Mitochondria with their simple (and separate DNA) may be one of the first links to break with aging.
Mitochondria actually are "kidnapped" bacteria from the beginning of multicellular life.
They have their own DNA and their simple ring form lacks robust error correction as ours do.
AMPK rights the ship:
AMPK promotes mitochondrial biogenesis. Mitochondrial biogenesis occurs in response to increased energy expenditure to produce more ATP
Biogenesis is literally the birth of new and more mitochondria to beef up energy production.
You know...like when you were 20!
What about the oxidative stress that spills out from all this energy production?
AMPK and oxidative stress
Activated AMPK appears to be essential in maintaining intracellular redox status by inhibiting oxidant production by NADPH oxidases, mitochondria, etc. or by increasing the expression of antioxidant enzymes such as SOD (superoxide dismutase)-2 and UCP (uncoupling protein)-2.
Let's translate the word soup.
Just like its role in managing energy balance, it does the same for oxidative stress.
Check out our reviews on CBD and oxidative stress or CBD and glutathione to learn more.
Speaking of which, glutathione is our heavy hitter in addressing the oxidative stress issue.
AMPK's effect there:
Recently, AMPK activation has been reported to increase the expression of antioxidant enzymes in monocytes macrophages , restore glutathione (GSH) depletion and reduce reactive oxygen species (ROS) levels in rat diabetic fibrosis, kidney tissues and humans [11–13], suppress ROS production in bovine endothelial cells
By the way, CBD is a powerful antioxidant...more so than Vitamin E or C!
It's a hop skip and a jump over to immune system inflammation.
AMPK and systemic inflammation
There's a new term on the block...inflammaging.
The steady increase in system-wide inflammation that accompanies the years.
Inflammaging is a highly significant risk factor for both morbidity and mortality in the elderly people, as most if not all age-related diseases share an inflammatory pathogenesis.
Sickness and death.
It is known that AMPK signaling inhibits the activity of the NF-κB system and thus suppresses pro-inflammatory responses.
As our immune system ages, there are distinct changes such as an increase in a specific type of cell called MDSCs:
The numbers of MDSCs also significantly increase during the aging process concurrently with the immunosenescence associated with chronic low-grade inflammation.
AMPK activation inhibits the functions of myeloid-derived suppressor cells (MDSC): impact on cancer and aging
Speaking of cancer…
AMPK and cancer
It's important to understand that we have entire systems to find and remove faulty cells including those that will become cancer.
It resides in the immune system!
There's a reason that most cancer risk rises with age...the immune system is losing control of the situation.
There's a powerful pathway called mTOR.
Most of us in the longevity space have heard of rapamycin. That's the "R" in rapamyacin. Mechanistic target of rapamycin.
mTOR is a powerful player in managing cellular birth/death cycles.
mTOR functions as a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, autophagy, and transcription
This is right up cancer's ally.
The mTOR signaling pathway, which is often activated in tumors, not only regulates gene transcription and protein synthesis to regulate cell proliferation and immune cell differentiation but also plays an important role in tumor metabolism.
This has an immediate bearing on longevity which we can see from rapamycin directly:
rapamycin also prolongs life in normal mice as well as in yeast, worms and flies, and it prevents age-related conditions in rodents, dogs, nonhuman primates and humans.
Basically, too much mTOR is bad for cancer risk and the ailments that accompany aging.
We want to slow it down or "inhibit" its action.
What's the connection with AMPK?
AMPK inhibits mTORC1 through phosphorylation of TSC2 and raptor
This makes sense. mTOR is a growth vector. During hard times, AMPK causes a shift from growth to housekeeping.
There are profound effects from this cross-talk between AMPK and mTOR...especially around cell removal.
Check out turkey tail and CBD for cancer pathways.
Let's look at the cells that are on their way to faulty.
AMPK and senescent cells
There's a type of cell just slightly worse than a cancerous cell.
Senescent or so-called "zombie cells".
Errors have accumulated to the point where the cells are no longer functioning correctly.
Typically, our immune system will detect this and remove the cell in a process called autophagy (literally to eat oneself).
As we get older, our immune system flounders in this endeavor and these cells are allowed to accumulate and leak out inflammation and nonsense to surrounding tissue.
It's a big part of frailty and aging in the body.
Senescent cells accumulate with age. This may result in higher levels of certain senescence-associated secretory phenotype (SASP) proteins, which researchers believe drive aging-related processes and promote aging-related diseases
AMPK and mTOR work together to remove these cells when functioning correctly.
In fact, one reason these cells can even escape may be due to their effects on AMPK:
The results showed that AMPK was inactivated in senescent cells. However, pharmacological activation of AMPK by metformin and berberine significantly prevented the development of senescence and, accordingly, inhibition of AMPK by Compound C was accelerated.
Goodness...AMPK gets turned off in these cells.
We did deep dives on both metformin here and berberine here.
A big push in longevity is so-called senolytics...compounds that spur the immune system to remove these zombie cells.
We'll cover them below in our tools section.
Let's turn to the real star of the show with AMPK.
AMPK and metabolic complex
As we mentioned, AMPK is an energy sensor and manager. Point.
All other effects stem from this role.
We're basically looking at the following plus the multiple pathways that cascade out:
Insulin and sugar management
Hormones related to metabolism
Gut microbiome interaction
Goodness...you just listed about 2/3rds of big pharma's breadbasket (diabetes, statins, autoimmune, etc).
Most of this chemical magic takes place in the liver.
All of these have direct implications on aging and illness associated with aging.
Let's take some examples.
The entire insulin complex is directly tied to aging and health.
In fact, IGF1 (insulin growth factor 1) is a well-known biomarker for actual aging in the body.
The insulin-like growth factor 1 (IGF1) signaling pathway has emerged as a major regulator of the aging process, from rodents to humans.
IGF1 goes down as we get older. What's the connection with AMPK?
Insulin-like growth factor-1 activates AMPK to augment mitochondrial function and correct neuronal metabolism in sensory neurons in type 1 diabetes
And vice versa...look what happens when AMPK is genetically knocked out:
Knockout of AMPK caused activation of the IGF1 receptor (IGF1R)–protein kinase B (PKB; also known as Akt) pathway in hepatocytes, which was mediated by hypersecretion of IGF1
Another metric that tracts age as a result...obesity:
Chronic genetic AMPK activation results in protection against diet-induced obesity due to an increase in whole-body energy expenditure, most probably because of a substantial increase in the oxygen consumption rate of white adipose tissue.
Then there's brown fat, the good kind that actually burns more energy:
AMPK plays an important role in the development and maintenance of brown and beige adipose tissue. Adipose tissue AMPK is reduced in people with insulin resistance, consistent with findings that mice lacking adipocyte AMPK develop greater NAFLD and insulin resistance
The benefit for exercise on blood sugar comes from…
The benefit of exercise in diabetic patients is well known and recent research indicates that AMP activated protein kinase (AMPK) plays a major role in this exercise related effect. AMPK is considered as a master switch regulating glucose and lipid metabolism.
When cholesterol levels are high in the cells, AMPK phosphorylation deactivates phosphorylation of HMG-CoA reductase.
Guess what class of drugs are HMG-CoA inhibitors? Statins.
But without the gut changes, muscle deterioration, and depletion of key nutrients (COQ10, vitamin D, calcium, potassium, etc).
Don't get us started on statin's effects on acetylcholine, the lunch pin for dementia and brain function:
However long-term statin treatment showed a significant decrease in serum cholesterol level as well as brain AChE level.
Check out CBD and dementia or Acetylcholine review.
What about hormones tied to the metabolic complex?
AMPK has been shown to mediate the metabolic effects of hormones such as leptin, ghrelin, adiponectin, glucocorticoids and insulin as well as cannabinoids.
Leptin and ghrelin literally shape your appetite. Cannabinoids?
That's our wheelhouse and yes, anandamide and other constituents balance other key systems including metabolism and appetite (hence the connection between THC and increased appetite - see CBD versus THC).
We can't talk about metabolic effects (which is key to aging) without discussing the gut microbiome.
It functions almost like a separate organ which we covered at our microbiome and anxiety, autoimmune and CBD, and CBD and the gut barrier.
First...look at the metformin (a known powerhouse of AMPK signaling) effect:
We observed changes in various microbiome, including Akkermansia, Escherichia, Intestinibacter, Clostridium, and Romboutsia, a finding that is in agreement with results reported in previous studies
We're currently testing a source for Akkermensia munipallis which has fascinating effects on the metabolism and AMPK.
An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice
Notice how some people can eat whatever they want and not put on weight or better yet, just pick at their food?
The gut microbiome and prior interactions with antibiotics, especially longer-term or frequent use directly shape this.
We could spend an entire article on this but we have to move on.
Let's turn to all the big pushes in longevity.
Intermittent fasting - calorie restriction and AMPK
Remember the famine connection above?
Caloric restriction, i.e., reducing calorie availability by ~20–50%, is one of the rare known strategies that can extend lifespan. In short-lived species such as rodents, caloric restriction can increase maximal lifespan up to 50%1 while improving general health and decreasing aging-associated diseases
Intermittent famine, shall we say.
The main mechanism that confers this effect is….AMPK!
Newer research (which needed CRISPR for gene editing) is finally teasing out the direct connection:
Genetic deletion of AMPKβ1 and 2 subunits only in dopamine neurons prevented ghrelin-induced AMPK phosphorylation and neuroprotection. Hence, ghrelin signaling through AMPK in SN dopamine neurons mediates CR's neuroprotective effects
To translate, by blocking AMPK function genetically, the "hunger" hormone lost its ability to protect the brain from calorie restriction.
CR is short for calorie restriction.
That's a top-level behavior...let's drill down into the pathways more.
Starting with a big star of longevity research...sirtuins.
Sirtuins and AMPK
This is a good jumping point from calorie restriction:
It has been shown that SIRT1 null mice have a shorter lifespan than their wild-type (WT) littermates and do not benefit from CR to increase their lifespan
So...when they block SIRT1 gene activity, calorie restriction benefits go away.
So what do SIRT1 genes do?
They manage the histone complex which guides the folding, unfolding, and exposing of our DNA for protein synthesis.
The net result:
SIRT1 protects cells against oxidative stress, regulates glucose/lipid metabolism, and promotes DNA stability by binding to and deacetylating several substrates
Goodness...most of what we touch upon above.
AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity
It shows us who's the boss (AMPK).
Speaking of which, there's a well-known sirtuin that's popular in longevity.
Resveratrol and AMPK
From the red wine buzz, we have resveratrol.
resveratrol markedly increased the protein expression of SIRT1 in a dose-dependent manner.
As with any good sirtuin, resveratrol also calmed inflammation (the inflamaging piece).
To tie it all together with a bow:
Here, we show that resveratrol activated AMPK in Neuro2a cells and primary neurons in vitro as well as in the brain.
These are system-wide pathways...old old pathways we share even with bacteria!
So you can zero in on a particular area and see the effects:
Resveratrol protects ROS-induced cell death by activating AMPK in H9c2 cardiac muscle cells
That's brain and heart but everything is "managed" by AMPK in times of energy stress.
See...all roads lead to AMPK!
What about the current supplemental stars...metformin and it's natural analog...berberine.
Metformin or berberine for AMPK
Just check out the MILE (Metformin in longevity study) here.
In fact, a new study (TAME) may allow metformin to be the first FDA approved drug for aging.
Read that back over...the FDA hasn't ever see aging as an ailment.
This was really the first big blockbuster moment in longevity where it looked like aging might be a malleable thing!
It was actually shown to reverse markers of aging after 12 months of use. This accelerated in the last 3 months.
We covered it in our Metformin review here.
A big review of all pathways can be found here:
You'll notice shared attributes between metformin's effects and everything we discussed above so…
Metformin inhibits mitochondrial complex I and thereby oxidative phosphorylation leading to an increased AMP:ATP ratio, causing a direct activation of AMPK
Metformin is a side-door way to stimulate AMPK!
Berberine is a similar analog for metformin (minus the need for prescription):
Berberine significantly increased the AMPK activation and mitigated high glucose and/or the AMPK inhibitor, compound C-mediated mTOR activation and apoptosis in podocytes.
We have a full review on berberine here.
A great deal of this may be mediated by effects in the microbiome in the gut.
Speaking of the gut…
Keto diet and AMPK
Keto is a form of selective famine...famine of carbohydrates.
This forces the body to make sugar (the basic building block of our immediate energy pathway) from different means.
Our human ancestors regularly entered ketosis due to limited food availability and periods of fasting, a practice that has evolutionarily programmed us to derive immense health benefits from this metabolic process.
The keto pathway is really a response to food scarcity which we know is firmly under the umbrella of AMPK.
As for direct effects of keto on AMPK:
AMPK activation adapts rRNA synthesis away from fed-state growth/storage toward energy production/release, common to fasted-states. Research suggests that induced and controlled dietary ketogenesis, a fasting mimetic, transcriptionally modifies gene expression thereby attenuating metabolic diseases
The three specific ketone molecules directly drive this boost to AMPK:
ketone bodies (KB) seem to be able
to increase food intake through AMP-activated protein kinase (AMPK) phosphorylation,
gamma-aminobutyric acid (GABA) and the release and production of adiponectin
What about other shocks outside calorie-related ones?
Cold and heat exposure and AMPK
We've leaned heavily on the famine piece of AMPK since it has such powerful metabolic effects but really, it's any potentially calamitous shock.
Brown fat (part of the metabolic milieu) does come into play:
We conclude that chronic cold not only increases AMPK activity in brown and white adipose tissue, but that it does so via distinct signalling pathways.
It's not just metabolic though...any systemic threat including heat shock:
Immediately following a single 2-h heating session, we observed increased phosphorylation of AMP-activated protein kinase and ERK1/2 but not of p38 MAPK or JNK
Even lack of oxygen:
These findings reveal that hypoxia can trigger AMPK activation in the apparent absence of increased [AMP] through ROS-dependent CRAC channel activation, leading to increases in cytosolic calcium that activate the AMPK upstream kinase CaMKKβ.
So...pick a shock. We can probably find AMPK connection.
It's THAT basic in its function.
Again, we share it with bacteria so a few billion years old?
What about exercise?
Exercise and AMPK
Exercise is good for almost every pathway in the body (I'm leaving knees out) but it is interesting since the practice results in a massive dump of inflammation.
Should be negative to our health, right?
Think of it as a demand side energy shock now as opposed to supply (caloric intake).
Our energy needs far outstretch our baseline needs.
AMP-activated protein kinase (AMPK) is a phylogenetically conserved fuel-sensing enzyme that is present in all mammalian cells. During exercise, it is activated in skeletal muscle in humans, and at least in rodents, also in adipose tissue, liver and perhaps other organs by events that increase the AMP/ATP ratio.
You can see effects all down the chain including rapamycin (mTOR):
An increase in AMP-activated protein kinase (AMPK) activity has recently been shown to decrease mammalian target of rapamycin (mTOR) signaling to key regulators of translation initiation.
It gets stranger. What about mindful meditation (see mindful meditation and neurogenesis)?
New Harvard Study shows for the first time that meditation upregulates genes in the AMPK pathway similar to metformin
We're constantly surprised by the power of mindful meditation. It's like a secret gift drop to us down here on Earth (think Hunger Games).
Let's look at other tricks.
Supplements for AMPK
We've looked at a few above but there are some cheats we can use to spur AMPK activity.
Here's the shortlist:
Metformin - you can do this now with online doctors like AgelessRX
Berberine - powerful effects on the gut
Resveratrol - we liked it but felt revved up on it
Vitamin D - steroid we get from the sun!
CBD - supports the endocannabinoid system which balances the metabolic system!
A few notes. We covered, metformin, berberine, and resveratrol already.
Vitamin D is a powerful player in every pathway including...:
We have shown that vitamin D3 has a modulating role in steroidogenesis pathway of granulosa cells by regulation of AMP-activated protein kinase (AMPK) as an underlying molecular mechanism in mouse polycystic ovary.
It depends...are we looking at a normal cell or a cancerous cell?
Cannabinoids inhibit energetic metabolism and induce AMPK-dependent autophagy in pancreatic cancer cells
Remember that AMPK triggers changes in mTOR which "eats up" (autophagy) cancerous and virally infected cells.
It doesn't do this to surrounding healthy tissue which speaks to the underlying system's impact on the immune system (key to cellular birth/death cycle).
The net effect of CBD?:
CBD increases phosphorylation of AMPK signaling proteins at early time points.
Check out CBD and longevity tools here.
Okay...we've covered a lot. This will tide us over till the Yamanaka factor research kicks in (Bezos just signed on to the company exploring it). Read up on that here...total game changer.
Be well. Take care of each other. Take care of yourself.