In any case, at the time Longo was less interested in the association between diet and longevity than in what he considered to be a fascinating by-product of extreme calorie restriction (fasting).
Longo discovered that when he starved bacteria and yeast, they not only lived far longer than their well-fed counterparts but entered a protective state that seemed to shield them from environmental stress. When exposed to hydrogen peroxide, yeast in starvation mode were between 60 and 100 times more resistant to cellular damage than yeast that had been taken from an environment rich in glucose to feed on.
That was surprising. Wouldn’t a cell weakened by starvation become less resistant to damage, rather than more? But in the years that followed, a consensus emerged that explained both Longo’s discovery and other researchers’ findings that lab animals fed a calorie-restricted diet lived longer.
In a well-fed state, our cells and those of other multicellular organisms invest energy in reproduction and regeneration. But when food is scarce, those functions shut down, and the cell diverts its energy to feeding and protecting itself; it takes far less energy to protect the cells you already have than to build new ones.
To do so, the body revs up a host of protective pathways. In the case of Longo’s yeast and bacteria (and eventually mice), he and others would later show, the organisms make enzymes that neutralize free radicals—molecules with unpaired electrons that can damage other cells. Other proteins and enzymes are produced that ensure proteins don’t misfold, and in every cell, the cellular machinery devoted to repairing its own DNA kicks into overdrive.
In more complex organisms like mice or humans, the body still needs calories to keep the heart beating, the brain thinking, and the muscles contracting. To get them, it engages in a process called autophagy (an ancient Greek word that means “self-consumption”), breaking down the body’s own cells and recycling their components. But this autophagy is not random.
“It tends to begin by eating proteins that are misfolded or denatured,” explains Eric Verdun, the president and CEO of the Buck Institute for Research on Aging. “There is a house-cleaning aspect to it. It consumes itself, but it consumes the proteins that need to be cleaned out first.”
Forced to turn inward for energy sources, the body hunts down, eats, and recycles its own cellular garbage, in the process removing debris that can prevent cells from operating efficiently.
Longo was fascinated by this process, and he would spend the next two decades helping to identify the genes and biological pathways at work. As he did so, he began to recognize something unexpected. Many of the genes involved were also prominent in the cancer literature.
In the cancer field, they were known as “proto-oncogenes”—the very same genes that, when mutated, had the power to transform a normal cell into a cancerous one, by essentially wedging the cell’s regeneration machinery permanently into the “on” position and causing it to divide and proliferate uncontrollably.
That gave Longo an idea. He had already shown that starvation could cause all an organism’s normal cells to enter a protective state. But cancer cells aren’t normal cells. One of the hallmarks of cancer is that the cells do not respond to biochemical signals suppressing their growth. What would happen, Longo wondered, if he put mice into starvation mode before exposing them to chemotherapy? If the normal cells went into a protective state but the cancerous ones did not, drugs could kill the cancer with less risk of damaging normal tissue.
Longo administered high doses of the chemotherapy drug doxorubicin to yeast. He found that under starvation conditions, normal yeast cells became a thousand times more resistant to stress, while cancer cells were exposed to the full brunt of the poisons. When Longo repeated the test on mice, starving one group for 60 hours prior to the chemo, the results were dramatic. Every single one of the normal mice died. Every single one of the starved mice lived.
But when Longo began reaching out to clinicians who worked with cancer patients, he encountered unexpected resistance. “We thought, ‘Of course. Everybody is going to do it. It’s going to be easy,’” Longo recalls. “It took us five years to recruit 18 patients. It was water-only fasting. Completely free. Don’t eat. Just drink.
Nobody wanted to do it.
Everybody thought it was a disaster.”
Facing defeat, Longo and his team groped for alternatives and quickly hit on a better idea: perhaps they could design a diet that aimed to trick the body into thinking it was fasting, without actually starving. Longo knew that if he made a low-carbohydrate diet lacking glucose and certain key amino acids—in other words, most proteins and all carbs were out—the body would still enter its protective state.
Longo created a company, L-Nutra. By 2014, his lab had produced its first prototype. And in 2015, he published a study demonstrating that middle-aged mice on the fast-mimicking diet had far fewer tumors and were protected against cognitive decline. By then researchers in Leiden in the Netherlands had finally signed up enough volunteers to show that water-only fasting helped protect human patients from the ravages of chemotherapy.
Longo says more than 40 trials are currently under way, at a wide variety of institutions. Not all of them are for cancer; there are also studies for Crohn’s disease, Alzheimer’s, and Parkinson’s.
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