For Your Health

[basserdan]

Forget the Blood of Teens. This Pill Promises to Extend Life for a Nickel a Pop.

By Sam Apple
July 1, 2017



The following is an excerpt from this lengthy article:

With so many potential uses, it can be difficult to avoid the conclusion that metformin is too good to be true, and some of the hype may yet prove to be overblown. Many of the most exciting cancer findings linked to the drug, for instance, come from observational studies of diabetics. They show a correlation between metformin and lower cancer rates, but don’t prove that the compound is responsible for those outcomes or that they extend to nondiabetics. It’s possible that, rather than metformin lowering cancer risk, the other diabetes medications are increasing it.

It’s also possible that, as some metformin skeptics have argued, a lack of statistical rigor has exaggerated some of the most sensational cancer findings. And while evidence from observational studies of cancer patients has been supported by animal experiments as well as by human trials that measure markers of cancer, when it comes to the most important test of a cancer treatment—whether a drug actually extends life—metformin has thus far been a bust. In two controlled trials involving patients with advanced pancreatic cancer, a notoriously difficult cancer to treat, metformin failed to provide any benefit.

But while it’s possible that metformin won’t live up to the excitement it has generated, it’s also possible that the compound, or a very closely related one, may turn out to be even more promising than the current scientific literature suggests. Because it’s no longer under patent, metformin is widely studied, and yet, for the same reason, it doesn’t benefit from the rigorous (and expensive) multistage pharmaceutical drug development process that could determine the most effective dose for cancer or which patients are most likely to respond to treatment. “I don’t think the trials have been done in a very rational way,” says Navdeep S. Chandel, a metabolism researcher at Northwestern University who studies metformin. “The antidiabetic dose that you give to patients might not be enough metformin” for cancer.

If researchers don’t yet know the best way to treat cancer with metformin, they are making real progress on the long-standing question of how it works inside our cells. After a patient takes a metformin tablet, much of the drug ends up in the liver, where it disrupts the process by which cells break down and burn nutrients with oxygen for energy.

If metformin shut down the oxygen reactions completely, it would be deadly—that’s how cyanide works. But the drug merely interferes with one stage of the multistage process by which the energy from nutrients makes its way to oxygen. Michael Pollak, a cancer researcher at McGill University who has studied metformin, compares it to water that’s sprinkled on flames—the fire slows down but doesn’t get extinguished.

It’s possible that metformin treats cancer and other conditions directly by interfering with energy production and, in the process, reducing inflammation. But the cascade of metabolic changes that follow may be even more important. When liver cells are in a state of energy stress, they begin sending out less glucose. “If you’re running out of energy yourself, you don’t want to give it to the rest of your body,” Pollak says.

Lower glucose, in turn, means that the pancreas needs to send out less insulin, the hormone that tells cells to take up and store nutrients. And it’s this indirect influence on insulin that many researchers now point to as a possible explanation for many of metformin’s remarkable range of benefits. Too much insulin has been linked to almost every condition metformin appears to treat, including aging.

The biological logic of the link among glucose, insulin, and aging wasn’t hard for researchers to unravel. Insulin sends a message to our cells that nutrients are available, meaning it’s time to grow and proliferate. When the levels of the hormones drop, it’s a signal to cells that its time to enter a life-extending mode of conservation. Such a system makes evolutionary sense. It would have allowed an organism to survive periods of food scarcity with the hope of reproducing when better times arrived. It could also explain why very low-calorie diets can significantly extend life in animals. Metformin is often said to mimic the effects of a low-calorie diet—a pill that offers the benefits of eating less, without leaving you hungry.

Aging in humans is considerably more complicated than aging in microscopic worms and other model organisms, including fruit flies and mice. But evolution builds on what comes before, and the mechanisms have fundamental similarities across species. “Cancer in each individual is a different and specific disease. The genome of the cancer is different,” Barzilai says. “A lot of aging is the same in yeasts and in flies and in nematodes and in mice and in rats and in humans.” Barzilai’s English begins to falter under the weight of his enthusiasm. “We’re not going to prevent every disease in the world,” he says. But we can target “this risk factor of aging that is so important, and take it out of the table.”

When Barzilai’s Vatican panel ended, the conference paused for a scheduled break and the attendees surged forward to ask him about metformin. He told a man in an expensive-looking suit that if he didn’t want to pay $20 a month in the US, he could get metformin for $2 a month in Mexico. When another man asked Barzilai what dosage he should take, Barzilai turned to the woman by his side and asked her how much longer she wanted him to remain alive.

Barzilai seemed entirely in his element as he whizzed around the room, shaking hands and cracking jokes. But when it was just the two of us, he looked momentarily deflated. I asked him what was wrong. He told me that the moderator had cut the session short before he’d had a chance to mention the most important thing about his plan to change health care with his groundbreaking metformin study: “I wanted to say what it costs, and ask if somebody here is ready to fund it.”

Sam Apple (@samuelapple) teaches science writing at the University of Pennsylvania. He is working on a book about cancer and nutrition.

https://www.wired.com/story/this-pill-promises-to-extend-life-for-a-nickel-a-pop/