Chapter 5
Exercise as a Pill
Researchers define a cascade of events that promotes aging mainly by three criteria: Does the factor worsen with age? If you increase it, does it then accelerate the aging process? And does it slow aging if you brake it, thereby extending lifespan? The lower AMPK activity with age meets all three criteria. As we get older, AMPK levels decline, and it becomes harder to activate them, harder to flip the switch to recharge the batteries. If the breakdown is intensified, aging accelerates (at least in mice), but if this process is reversed and AMPK activation is boosted, lifespan is extended in model organisms— in C. elegans, a roundworm that I introduce at see.nf/models, by up to 38 percent.
Across the tree of life, long-term food restriction is the most reliable way to extend lifespan. Presumably thanks to AMPK activation. But what was remarkable in the experiments with increased AMPK was that the animals lived longer even though they were allowed to eat as much as they wanted. AMPK activators can successfully trick the body into thinking it is starving and shift it into protective housecleaning mode without it having to suffer the pain of deprivation. In this way, AMPK activators can be considered mimetic for food deprivation; that is, they imitate it. For that reason, AMPK is viewed as a potential “drug candidate” for longevity, and pharmaceutical companies produce a wide variety of AMPK activators.
Exercise as a Pill
Do we have a way to naturally increase AMPK activation without starving, in order to age more slowly? Since AMPK is activated by lack of fuel, if we don’t want to take in less energy through our mouths, we have to expend more energy through our muscles. If you put people on bicycles and take a muscle biopsy while they’re pedaling, after 20 minutes you find nearly threefold higher AMPK activity. That’s also why you lose weight through exercise.
AMPK activation also leads to mitochondrial biogenesis, the formation of additional mitochondria, the power plants that burn fat. So AMPK not only shovels more fat into the furnace—it also builds more furnaces to burn it. That explains why endurance training enables us, over time, to run faster and farther. So could an AMPK activator be an “exercise pill”? When sedentary mice were given an AMPK activator for a month, their running endurance actually increased by 44 percent. When such an agent was detected at the Tour de France, AMPK activators were banned by the World Anti-Doping Agency.
So are we talking not only about a fasting pill, but also an agent that mimics movement? A way to make the body believe it is starving without feelings of hunger, while at the same time becoming more capable? People with obesity are often “unwilling to engage in even the slightest physical activity,” wrote a group of pharmacologists, “therefore we would very much like drugs that imitate endurance exercise.” The “broad appeal” of such a pill could tempt the pharmaceutical industry to “medicalize physical inactivity and profit from it,” but that pales in comparison with the universal market for an anti-aging agent.
Power Plant Maintenance
In his treatise On Youth and Old Age, the Greek philosopher Aristotle described death as the loss of inner heat. Well, the progressive loss of function of the estimated ten quadrillion mitochondria distributed throughout our bodies is understood as a foundation of the biology of aging, as one of its nine established hallmarks. But mitochondrial malfunction is not only a consequence of aging; it is also one of its causes. Dysfunctional mitochondria are believed to actively contribute to the aging process, an insight illustrated by a landmark experiment published in the early 1990s.
If you inject mitochondria from a young rat into a human cell, nothing happens. The cell seems to take no notice of it. In each human skin cell there are, on average, about 300 mitochondria, and 10 to 15 additional mitochondria from a young rat apparently remain without effect. But if you introduce the same number of mitochondria from an old rat— in human years, a 100-year-old— the human cells begin to show signs of degeneration within just a few days. Just a few percent of these old mitochondria were enough to send the human cells to an early grave. So age-damaged mitochondria don’t just lose their performance—they become actively harmful. This is where AMPK enters the picture.
With age, mitochondrial function declines, but AMPK could promote our survival by building new cellular power plants, expanding existing ones, and taking old ones out of service (through so-called mitophagy). AMPK is the “guardian of the mitochondria” and in this role could help protect against age-related diseases.
If a drug that activates AMPK really helps provide us with the fat-burning and health-promoting benefits of fasting and exercise without hunger and sweat, you could imagine it becoming one of the world’s best-selling agents.
And that is exactly how it was.
Metformin
Metformin, originally sold under the name Glucophage (“sugar eater”), is prescribed over 85 million times annually in the United States alone. Despite all advances in biotechnology, the pharmaceutical industry has not yet found a safer and more effective baseline treatment for type 2 diabetes than an AMPK-promoting drug whose sale price per tablet is in the cents range. At see.nf/metformin I discuss the interesting story of its origin and all its other benefits, including the spectacular finding that diabetics on metformin sometimes live longer than people who never had diabetes. From the standpoint of longevity, it is as if their diabetes diagnosis had been something good, because it gave them access to this life-extending drug. If metformin has the power to more than offset a diagnosis as feared as diabetes, shouldn’t everyone take it?
At see.nf/metformindownsides I cover its common but mild side effects, as well as one that is rare but potentially fatal. Another downside of metformin is less a side effect than a main effect. It increases AMPK, but it impairs the body’s ability to produce energy, because it acts like a mild poison on the mitochondria, so it is, unsurprisingly, detrimental to physical fitness performance, including aerobic capacity and muscle growth.
To determine whether metformin’s benefits in extending healthspan and lifespan in nondiabetics outweigh its risks, it has to be tested accordingly. This is where the emerging TAME trial comes in (Targeting Aging with Metformin, “targeting aging with metformin”), which I introduce at see.nf/tame. The bottom line is that we should dial back our expectations. Metformin does extend the average lifespan of certain mice by 5 percent, but at a higher dose it even shortens life expectancy. Further reservations about its potential as a cure-all arise from the groundbreaking Diabetes Prevention Program study, in which only those at the highest risk seemed to benefit from the drug. A small study even found that metformin does lessen insulin resistance in diabetics, but in overweight nondiabetics with no family history of diabetes, the agent actually made things worse. Healthier people, then, do not get the benefit of metformin that we try to infer from longevity studies in diabetics.
Foods That Can Impair AMPK
A saturated fat called palmitic acid suppresses AMPK. Although palmitic acid was originally discovered in palm oil, it is found most concentrated in meat and milk fat. Palmitic acid appears to be more pathogenic than other saturated fats with respect to metabolic disorders, cardiovascular disease, cancer, neurodegenerative diseases, and inflammation, which is due at least in part to the inhibition of AMPK. Presumably, this is why saturated fats are so toxic to the liver.