The Anti-Aging Pathways of AMPK

Today, we take a look at AMPK, a fascinating enzyme that acts as sort of our body’s fuel gauge.

In my book on everything evidence-based in weight loss, How Not to Diet, I had a section entitled “Amping AMPK.” AMPK is an enzyme that acts as a universal fuel gauge for plants and animals, revving up when it detects a depletion of the universal fuel. The universal energy currency in all of biology is a molecule called adenosine triphosphate, commonly known as ATP. The tri in triphosphate means three, as in tricycle or, in this case, ATP’s three phosphates where energy is stored. Plants make ATP with energy from the sun, and animals make it by burning fat, carbohydrates, and protein. The energy is spent by releasing the phosphates, which transforms ATP to AMP—adenosine monophosphate, with mono meaning one—which then can be juiced up with two more phosphates back to ATP, and the cycle continues. In this way, every cell in our bodies and in every living thing is like a little rechargeable battery. AMP molecules are charged up with phosphates to ATP using sunlight or food, and then drained back down to AMP to do the cell’s work. This brings us to AMPK, or AMP-activated protein kinase.

A kinase is a type of enzyme. What might be the function of an enzyme activated by AMP? A buildup of AMP means the rechargeable battery is running low. It’s akin to the fuel gauge in your car reading empty. As the needle creeps toward the E, what do you do? Add more fuel. But instead of having an extra gas can in your trunk, you may have junk in the trunk—fat stores on your body. So that’s what AMPK does: It flips the switch in your body from storing fat to burning fat. That’s why AMPK is not only known as the “master energy sensor” in our body but the “fat controller.” No wonder I featured it in How Not to Diet. But it can also control aging, and so also plays a starring role in How Not to Age.

To sustain life, each of our cell “batteries” needs to stay fully charged. This means maintaining a ratio of about 100 ATP for every AMP. So, our body needs to perfectly balance cellular activities that consume energy with cellular processes that generate energy. In times of plenty, our cells can plow full steam ahead. However, in lean times, which for animals means not enough food, and for plants means not enough light (darkness is like starvation for plants), AMPK kicks in to reorient the cell into conservation mode and start tapping into our energy stores, like burning off body fat. Our cells can also institute a recycling program called autophagy.

Autophagy comes from the Greek words auto, meaning “self,” and phagein meaning “to eat.” So, autophagy literally means “self-eating.” It’s a housekeeping process by which defective cellular components, like misfolded proteins that had been allowed to wastefully build up in times of surplus, are broken down and scrapped for spare parts. This doubles as both salvage operation and quality control, scavenging raw materials in scarce supply as well as clearing away some of the buildup of damaged debris that is implicated in the aging process. As one review put it, “The janitor is the undercover boss.”

This is one of the reasons AMPK is increasingly recognized as a pro-longevity factor. AMPK induces autophagy, which cleans house, sweeps away accumulated waste, and effectively institutes a sort of cellular “reset.”

There are three main ways longevity researchers establish an aging pathway: Does the factor worsen with age? If you amplify it, does it accelerate aging? And if you dampen it, does it slow aging, and thereby extend lifespan? The loss of AMPK activity as we age fits all three criteria. Our levels of AMPK drop as we grow older, and it gets harder to activate. When this decline is exacerbated, aging is hastened (at least in the hearts of mice). And when this process is reversed, when AMPK activation is boosted, lifespan is extended in model organisms—as much as 38 percent in a type of microscopic roundworm known as C. elegans.

Up and down the evolutionary tree of life, one of the most reliable ways to extend lifespan may be long-term food restriction. And AMPK activation is thought to be one of the mechanisms for this longevity boost. What was remarkable about the AMPK-boosting experiments, though, is that animal lives can be extended even though they were allowed to eat as much as they want. So, AMPK activators can effectively fool the body into thinking it is starving, flipping it into protective housecleaning mode without having to suffer the pangs of deprivation. AMPK activators can thereby be considered calorie restriction mimetics, or imitators. No wonder AMPK is considered a “druggable” target for longevity. But is there a way we can naturally boost AMPK activation to slow aging without starving ourselves? The answer is yes, which we’ll explore next.

How can we naturally boost the enzyme AMPK to slow aging without starving ourselves? AMPK is activated by a fuel shortage. If we don’t want to limit the amount of energy going in through our mouths, then we have to ramp up the amount of energy going out through our muscles. Put people on a bike and start taking muscle biopsies while they cycle, and you can detect a near tripling of AMPK activation within twenty minutes in both diabetics and nondiabetics. That makes sense. The muscles use up the ATP to contract, so AMP builds up and AMPK is activated. That may be one of the ways exercise leads to weight loss.

AMPK activation also leads to mitochondrial biogenesis, meaning the formation of extra mitochondria, the power plants within our cells where fat is burned and ATP is created. So, AMPK doesn’t just cause more fat to be shoveled into the furnace—it also causes more furnaces to be built. In this way, AMPK helps explain why endurance training eventually enables us to run faster and farther. So, might an AMPK activator be like the fabled exercise-in-a-pill? Indeed, AMPK activation can dramatically enhance performance. An AMPK-activator drug given to sedentary mice for a month boosted their running endurance by 44 percent. After one such drug was discovered at the famed Tour de France, AMPK activators were banned by the World Anti-Doping Agency.

So, not just fasting in a pill, but an exercise mimetic too? People are often “unwilling to perform even a minimum of physical activity…” wrote a group of pharmacologists, “thus, indicating that drugs mimicking endurance exercise are highly desirable.” The “mass appeal” of such a pill may tempt “’Big Pharma’ to view physical inactivity as a market to be medicalized for profit.” But that vision pales in comparison to the universal market for an anti-aging remedy.

In his essay ‘‘On youth and old age,” the Greek philosopher Aristotle described death as the loss of inner heat. Indeed, the progressive loss of function of the estimated 10 million billion mitochondria spread throughout the body is considered a core tenet of the biology of aging. But mitochondrial dysfunction isn’t just a consequence of aging, but one of its causes. Dysfunctional mitochondria are thought to actively contribute to the aging process––an insight illustrated by a pioneering experiment published over 30 years ago.

If you inject mitochondria from a young animal into a human cell, nothing happens. The cell doesn’t appear to notice. Human skin cells average about 300 mitochondria each, and adding 10 to 15 extras from a young rat didn’t appear to have any effect. But add the same number of mitochondria from an old rat, and the human cells start to show signs of degeneration within just a few days. Even just having a few percent of those old mitochondria was enough to drive the human cells to an early grave. So, age-impaired mitochondria don’t just become less efficient, but may become actively harmful. So, if centenarian-equivalent rat mitochondria are so toxic, how do centenarian human cells survive? A group of Italian researchers took some centenarian skin biopsies to find out.

Skin samples taken from the forearms of young individuals were compared to those of elderly individuals. As expected, each mitochondrial mite from the older cells was comparatively defective—less efficient, leaking free radicals. But to the scientists’ surprise, the total amount of ATP the centenarian cells were pumping out was even greater than that of the younger cells. How is that possible? Because of a bulked up mitochondrial mass. It’s like if an older Mike Tyson took on a featherweight. Even if pound-for-pound, the whippersnapper’s biceps were more energy-generating, Mike’s sheer muscular mass might prevail. So, how did the centenarian mitochondria get swole? AMPK.

Mitochondria can take up anywhere between 2 percent and 50 percent of the volume of a cell, and are in constant motion, merging together and splitting apart like the molten wax of a lava lamp. In times of starvation or stress, the fusing of individual mitochondria together into a large tubular network can be advantageous, in part by diluting the effects of damaged mitochondria by mixing their contents in with others. AMPK appears to accomplish this by tipping the lava lamp balance from fission to fusion by blocking one of the proteins necessary to break mitochondria back apart. This is thought to be one of the routes by which endurance exercise can rejuvenate mitochondrial function. Thanks to AMPK, working out may magnify your mitochondria as well as your muscles.

Our mitochondrial function does decline with age, in part through the impaired ability of AMPK to generate new mitochondria. But AMPK can build new cellular power plants, expand existing ones, and decommission old ones (so-called mitophagy). AMPK is said to serve as a “mitochondrial guardian,” and in that role may help guard against the ravages of age-related disease.

If an AMPK-activating drug really could help us reap the fat-burning and health-promoting benefits of fasting and exercise without the hunger and sweat, one could imagine how it would become one of the best-selling drugs on the planet. And it is. It’s called metformin, prescribed more than 90 million times a year in the U.S. alone.