Scientists who play by someone else’s rules don’t have much chance of making discoveries.
—Jack Horner
In the fall of 2016, I met three friends at George Bush Intercontinental Airport in Houston to embark on a somewhat unusual vacation. We flew eleven hours overnight to Santiago, Chile, where we drank coffee and ate breakfast before boarding another plane to fly six more hours to the west, across 2,500 miles of open ocean, to Easter Island, the world’s most isolated body of land that is inhabited by humans. We were all men in our forties, but this was not your typical guys’ weekend.
Most people know about Easter Island because of the thousand or so mysterious giant stone heads, called moai, dotting its shoreline, but there’s a lot more to it. The island was named by European explorers who landed there on Easter Sunday in 1722, but the natives call it Rapa Nui. It is an extreme, isolated, spectacular place. The triangle-shaped island of roughly sixty-three square miles is what’s left of a trio of ancient volcanoes that surged up more than two miles from the seabed millions of years ago. One end of the island is ringed by very high cliffs that plunge down into the gorgeous blue ocean. The nearest human settlement is more than one thousand miles away.
We were not there as tourists. We were on a pilgrimage to the source of one of the most intriguing molecules in all of medicine, one that most people have never even heard of. The story of how this molecule was discovered, and how it revolutionized the study of longevity, is one of the most incredible sagas in biology. This molecule, which came to be known as rapamycin, had also transformed transplant medicine, giving millions of patients a second chance at life. But that was not why we had traveled ten thousand miles to this remote spot. We had come because rapamycin had been demonstrated to do something that no other drug had ever done before: extend maximum lifespan in a mammal.
This discovery came about at least in part thanks to the work of one member of our group, David Sabatini, who was then a professor of biology at MIT’s Whitehead Institute. David had helped discover the key cellular pathway that rapamycin acts upon. Also on the trip was another biologist named Navdeep Chandel (Nav to his friends), a friend of David’s who studies metabolism and mitochondria, the little organelles that produce power (and do much more) in our cells, at Northwestern University. Completing our foursome was my close friend Tim Ferriss. Tim is an entrepreneur and author, not a scientist, but he has a knack for asking the right questions and bringing a fresh perspective to something. Plus, I knew that he would be willing to swim in the ocean with me every day, reducing my chances of being eaten by a shark by approximately 50 percent.
One purpose of our trip was to scout out the location for a scientific conference that would be entirely devoted to research about this amazing substance. But mostly, we wanted to make a pilgrimage to the place where this extraordinary molecule had come from and to pay homage to its almost accidental discovery.
After we dropped off our luggage at our thirty-room tourist hotel, our first stop was Rano Kau, the one-thousand-foot-tall extinct volcano that dominates the southwest corner of the island. Our destination was the center of the crater, where there is a large swampy lake, nearly a mile across, that had a certain mystique among the locals. According to a local legend that we had heard, when people were feeling sick or unwell, they would make their way down into the crater, perhaps spending a night in the belly of the volcano, which was believed to have special healing powers.
This is where the story of rapamycin begins. In late 1964, a Canadian scientific and medical expedition arrived on Easter Island, having sailed all the way from Halifax aboard a naval vessel. They spent several weeks conducting research and dispensing much-needed medical care to the local inhabitants, and they brought home numerous specimens of the island’s unusual flora and fauna, including soil samples from the area of the crater. The scientists might have heard the same legend about its healing properties that we did.
A few years later, a jar of Easter Island dirt ended up on the lab bench of a biochemist in Montreal named Suren Sehgal, who worked for a Canadian pharmaceutical company then called Ayerst. Sehgal found that this soil sample was saturated with a strange and potent antifungal agent that was seemingly produced by a soil bacterium called Streptomyces hygroscopicus. Curious, Sehgal isolated the bacterium and grew it in culture, then began testing this mysterious compound in his lab. He named it rapamycin, after Rapa Nui, the native name for Easter Island (mycin is the suffix typically applied to antimicrobial agents). But then Ayerst abruptly closed its Montreal lab, and Sehgal’s bosses ordered him to destroy all the compounds he was researching.
Sehgal disobeyed the order. One day, he smuggled a jar of rapamycin home from work. His son Ajai, who was originally supposed to be the fifth member of our pilgrimage, remembers opening the family freezer to get ice cream when he was a kid and seeing a well-wrapped container in there marked DO NOT EAT. The jar survived the family’s move to Princeton, New Jersey, where Sehgal was ultimately transferred, and when the pharmaceutical giant Wyeth acquired Ayerst in 1987, his new bosses asked Sehgal if he had any interesting projects he’d like to pursue. He pulled the jar of rapamycin out of the freezer and went back to work.
Sehgal believed he had found a cure for athlete’s foot, which would have been a big enough deal. At one point, his son Ajai recalls, he prepared a homemade ointment containing rapamycin for a neighbor who had developed some sort of weird body rash; her rash cleared up almost immediately. But rapamycin turned out to be so much more than the next Dr. Scholl’s foot spray. It proved to have powerful effects on the immune system, and in 1999 it was approved by the US Food and Drug Administration (FDA) to help transplant patients accept their new organs. As a surgical resident, I used to give it out like Tic Tacs to kidney and liver transplant patients. Sometimes referred to as sirolimus, rapamycin is also used as a coating on arterial stents because it prevents the stented blood vessels from reoccluding. The hits kept coming, even after Sehgal died in 2003: In 2007, a rapamycin analog[*1] called everolimus was approved for use against a type of kidney cancer.
The compound was deemed so important that in the early 2000s Wyeth-Ayerst placed a plaque on Easter Island, not far from the volcano crater, honoring the place where rapamycin had been discovered. But when we went looking for the plaque, we found to our dismay that it had been stolen.
The reason rapamycin has so many diverse applications is thanks to a property that Sehgal had observed, but never explored, which is that it tends to slow down the process of cellular growth and division. David Sabatini was one of a handful of scientists who picked up the baton from Sehgal, seeking to explain this phenomenon. Understanding rapamycin became his life’s work. Beginning when he was a graduate student, working from a sheaf of papers that Sehgal himself had photocopied, Sabatini helped to elucidate how this unique compound worked on the cell. Ultimately, he and others discovered that rapamycin acted directly on a very important intracellular protein complex called mTOR (pronounced “em-tor”), for “mechanistic target of rapamycin.”[*2]
Why do we care about mTOR? Because this mechanism turns out to be one of the most important mediators of longevity at the cellular level. Not only that, but it is highly “conserved,” meaning it is found in virtually all forms of life, ranging from yeast to flies to worms and right on up to us humans. In biology, “conserved” means that something has been passed on via natural selection, across multiple species and classes of organisms—a sign that evolution has deemed it to be very important.
It was uncanny: this exotic molecule, found only on an isolated scrap of land in the middle of the ocean, acts almost like a switch that inhibits a very specific cellular mechanism that exists in nearly everything that lives. It was a perfect fit, and this fact still blows my mind every time I think about it.
The job of mTOR is basically to balance an organism’s need to grow and reproduce against the availability of nutrients. When food is plentiful, mTOR is activated and the cell (or the organism) goes into growth mode, producing new proteins and undergoing cell division, as with the ultimate goal of reproduction. When nutrients are scarce, mTOR is suppressed and cells go into a kind of “recycling” mode, breaking down cellular components and generally cleaning house. Cell division and growth slow down or stop, and reproduction is put on hold to allow the organism to conserve energy.
“To some extent, mTOR is like the general contractor for the cell,” Sabatini explains. It lies at the nexus of a long and complicated chain of upstream and downstream pathways that basically work together to regulate metabolism. It senses the presence of nutrients, especially certain amino acids, and it helps assemble proteins, the essential cellular building blocks. As he put it, “mTOR basically has a finger in every major process in the cell.”
On July 9, 2009, a brief but important science story appeared in The New York Times: “Antibiotic Delayed Aging in Experiments with Mice,” the headline read. Yawn. The “antibiotic” was rapamycin (which is not really an antibiotic), and according to the study, mice that had been given the drug lived significantly longer on average than controls: 13 percent longer for females, 9 percent for males.
The story was buried on page A20, but it was a stunning result. Even though the drug had been given late in life, when the mice were already “old” (six hundred days, roughly the equivalent of humans in their sixties), it had still boosted the animals’ remaining life expectancy by 28 percent for males and 38 percent for females. It was the equivalent of a pill that could make a sixty-year-old woman live to the age of ninety-five. The authors of the study, published in Nature, speculated that rapamycin might extend lifespan “by postponing death from cancer, by retarding mechanisms of aging, or both.” The real headline here, however, was that no other molecule had been shown to extend lifespan in a mammal. Ever.
The results were especially convincing because the experiment had been run by three different teams of researchers in three separate labs, using a total of 1,901 genetically diverse animals, and the results had been consistent across the board. Even better, other labs quickly and readily reproduced these results, which is a relative rarity, even with much-ballyhooed findings.
You might find this surprising, but many of the most headline-grabbing studies, the ones you read about in the newspaper or see reported on the news, are never repeated. Case in point: the well-publicized finding from 2006 that a substance found in the skins of grapes (and in red wine), resveratrol, extended lifespan in overweight mice. This generated countless news articles and even a long segment on 60 Minutes about the benefits of this amazing molecule (and, by extension, red wine). Resveratrol supplement sales shot through the roof. But other labs could not reproduce the initial findings. When resveratrol was subjected to the same sort of rigorous testing as rapamycin, as part of a National Institute on Aging program to test potential antiaging interventions, it did not extend lifespan in a similar diverse population of normal mice.
The same is true of other well-hyped supplements such as nicotinamide riboside, or NR: it, too, failed to extend lifespan consistently in mice. Of course, there are no data showing that any of these supplements lengthen life or improve health in humans. But study after study since 2009 has confirmed that rapamycin can extend mouse lifespans pretty reliably. It has also been shown to do so in yeast and fruit flies, sometimes alongside genetic manipulations that reduced mTOR activity. Thus, a reasonable person could conclude that there was something good about turning down mTOR, at least temporarily—and that rapamycin may have potential as a longevity-enhancing drug.
To scientists who study aging, the life-extending effect of rapamycin was hugely exciting, but it also wasn’t exactly a surprise. It appeared to represent the culmination of decades, if not centuries, of observations that how much food we eat correlates somehow with how long we live. This idea goes all the way back to Hippocrates, but more modern experiments have demonstrated, over and over, that reducing the food intake of lab animals could lengthen their lives.
The first person to really put the idea of eating less into practice, in a rigorous, documented way, was not an ancient Greek or a modern scientist but a sixteenth-century Italian businessman named Alvise Cornaro. A self-made real estate developer who had become tremendously wealthy by draining swamps and turning them into productive farmland, Cornaro (whose friends called him “Luigi”) had a beautiful young wife and a villa outside Venice with its own theater. He loved to throw parties. But as he neared forty, he found himself suffering from “a train of infirmities,” as he put it—stomach pains, weight gain, and continual thirst, a classic symptom of incipient diabetes.
The cause was obvious: too much feasting. The cure was also obvious: knock off the huge meals and parties, his doctors advised him. Not-Thin Luigi balked. He didn’t want to give up his lavish lifestyle. But as his symptoms became more and more unbearable, he realized that he had to make a hard course correction or he would never get to see his young daughter grow up. Summoning all his willpower, he cut himself back to a Spartan diet that consisted of about twelve ounces of food per day, typically in the form of some sort of chicken-based stew. It was nourishing, but not overly filling. “[I] constantly rise from the table with a disposition to eat and drink still more,” he wrote later.
After a year on this regimen, Cornaro’s health had improved dramatically. As he put it, “I found myself…entirely freed from all my complaints.” He stuck to the diet, and by the time he reached his eighties he was so thrilled to have lived so long in such good health that he felt compelled to share his secret with the world. He penned an autobiographical tract that he called “Discourses on the Sober Life,” although it was emphatically not a teetotaler’s screed, for he washed down his longevity stew with two generous glasses of wine each day.
Cornaro’s prescriptions lived on long after he died in 1565. His book was reprinted in several languages over the next few centuries, lauded by Benjamin Franklin, Thomas Edison, and other luminaries, making it perhaps the first bestselling diet book in history. But it was not until the mid-twentieth century that scientists would begin rigorously testing Cornaro’s notion that eating less can lengthen one’s life (or at least, the lives of laboratory animals).
We’re not talking about simply putting animals on Weight Watchers. Caloric restriction without malnutrition, commonly abbreviated as CR, is a precise experimental method where one group of animals (the controls) are fed ad libitum, meaning they eat as much as they want, while the experimental group or groups are given a similar diet containing all the necessary nutrients but 25 or 30 percent fewer total calories (more or less). The restricted animals are then compared against the controls.
The results have been remarkably consistent. Studies dating back to the 1930s have found that limiting caloric intake can lengthen the lifespan of a mouse or a rat by anywhere from 15 to 45 percent, depending on the age of onset and degree of restriction. Not only that, but the underfed animals also seem to be markedly healthier for their age, developing fewer spontaneous tumors than normally fed mice. CR seems to improve their healthspan in addition to their lifespan. You’d think that hunger might be unhealthy, but the scientists have actually found that the less they feed the animals, the longer they live. Its effects seem to be dose dependent, up to a point, almost like a drug.
The life-extending effect of CR seems to be almost universal. Numerous labs have found that restricting caloric intake lengthens lifespan not only in rats and mice (usually) but also in yeast, worms, flies, fish, hamsters, dogs, and even, weirdly, spiders. It has been found to extend lifespan in just about every model organism on which it has been tried, with the odd exception of houseflies. It seems that, across the board, hungry animals become more resilient and better able to survive, at least inside a well-controlled, germ-free laboratory.
That doesn’t mean that I will be recommending this kind of radical caloric restriction as a tactic for my patients, however. For one, CR’s usefulness remains doubtful outside of the lab; very lean animals may be more susceptible to death from infection or cold temperatures. And while eating a bit less worked for Luigi Cornaro, as well as for some of my own patients, long-term severe caloric restriction is difficult if not impossible for most humans to sustain. Furthermore, there is no evidence that extreme CR would truly maximize the longevity function in an organism as complex as we humans, who live in a more variable environment than the animals described above. While it seems likely that it would reduce the risk of succumbing to at least some of the Horsemen, it seems equally likely that the uptick in mortality due to infections, trauma, and frailty might offset those gains.
The real value of caloric restriction research lies in the insights it has contributed to our understanding of the aging process itself. CR studies have helped to uncover critical cellular mechanisms related to nutrients and longevity. Reducing the amount of nutrients available to a cell seems to trigger a group of innate pathways that enhance the cell’s stress resistance and metabolic efficiency—all of them related, in some way, to mTOR.
The first of these is an enzyme called AMP-activated protein kinase, or AMPK for short. AMPK is like the low-fuel light on the dashboard of your car: when it senses low levels of nutrients (fuel), it activates, triggering a cascade of actions. While this typically happens as a response to lack of nutrients, AMPK is also activated when we exercise, responding to the transient drop in nutrient levels. Just as you would change your itinerary if your fuel light came on, heading for the nearest gas station rather than Grandma’s house, AMPK prompts the cell to conserve and seek alternative sources of energy.
It does this first by stimulating the production of new mitochondria, the tiny organelles that produce energy in the cell, via a process called mitochondrial biogenesis. Over time—or with disuse—our mitochondria become vulnerable to oxidative stress and genomic damage, leading to dysfunction and failure. Restricting the amount of nutrients that are available, via dietary restriction or exercise, triggers the production of newer, more efficient mitochondria to replace old and damaged ones. These fresh mitochondria help the cell produce more ATP, the cellular energy currency, with the fuel it does have. AMPK also prompts the body to provide more fuel for these new mitochondria, by producing glucose in the liver (which we’ll talk about in the next chapter) and releasing energy stored in fat cells.
More importantly, AMPK works to inhibit the activity of mTOR, the cellular growth regulator. Specifically, it seems to be a drop in amino acids that induces mTOR to shut down, and with it all the anabolic (growth) processes that mTOR controls. Instead of making new proteins and undergoing cell division, the cell goes into a more fuel-efficient and stress-resistant mode, activating an important cellular recycling process called autophagy, which means “self-eating” (or better yet, “self-devouring”).
Autophagy represents the catabolic side of metabolism, when the cell stops producing new proteins and instead begins to break down old proteins and other cellular structures into their amino acid components, using the scavenged materials to build new ones. It’s a form of cellular recycling, cleaning out the accumulated junk in the cell and repurposing it or disposing of it. Instead of going to Home Depot to buy more lumber and drywall and screws, the cellular “contractor” scavenges through the debris from the house he just tore down for spare materials that he can reuse, either to build and repair the cell or to burn to produce energy.
Autophagy is essential to life. If it shuts down completely, the organism dies. Imagine if you stopped taking out the garbage (or the recycling); your house would soon become uninhabitable. Except instead of trash bags, this cellular cleanup is carried out by specialized organelles called lysosomes, which package up the old proteins and other detritus, including pathogens, and grind them down (via enzymes) for reuse. In addition, the lysosomes also break up and destroy things called aggregates, which are clumps of damaged proteins that accumulate over time. Protein aggregates have been implicated in diseases such as Parkinson’s and Alzheimer’s disease, so getting rid of them is good; impaired autophagy has been linked to Alzheimer’s disease–related pathology and also to amyotrophic lateral sclerosis (ALS), Parkinson’s disease, and other neurodegenerative disorders. Mice who lack one specific autophagy gene succumb to neurodegeneration within two to three months.
By cleansing our cells of damaged proteins and other cellular junk, autophagy allows cells to run more cleanly and efficiently and helps make them more resistant to stress. But as we get older, autophagy declines. Impaired autophagy is thought to be an important driver of numerous aging-related phenotypes and ailments, such as neurodegeneration and osteoarthritis. Thus, I find it fascinating that this very important cellular mechanism can be triggered by certain kinds of interventions, such as a temporary reduction in nutrients (as when we are exercising or fasting)—and the drug rapamycin. (The Nobel Committee shares this fascination, having awarded the 2016 Nobel Prize in Physiology or Medicine to Japanese scientist Yoshinori Ohsumi for his work in elucidating the genetic regulation of autophagy.)
Yet its autophagy-promoting effect is only one reason why rapamycin may have a future as a longevity drug, according to Matt Kaeberlein, a researcher at the University of Washington. Kaeberlein, who has been studying rapamycin and mTOR for a couple of decades, believes that the drug’s benefits are much more wide-ranging and that rapamycin and its derivatives have huge potential for use in humans, for the purpose of extending lifespan and healthspan.
Even though rapamycin is already approved for use in humans for multiple indications, there are formidable obstacles to launching a clinical trial to look at its possible impact on human aging—mainly, its potential side effects in healthy people, most notably the risk of immunosuppression.
Historically, rapamycin was approved to treat patients indefinitely following organ transplantation, as part of a cocktail of three or four drugs meant to suppress the part of their immune system that would otherwise attack and destroy their new organ. This immune-suppressing effect explains why there has been some reluctance to consider using (or even studying) rapamycin in the context of delaying aging in healthy people, despite ample animal data suggesting that it might lengthen lifespan and healthspan. Its purported immune-suppressing effects just seemed to be too daunting to overcome. Thus, it has seemed unlikely that rapamycin could ever realize its promise as a longevity-promoting drug for humans.
But all that started to change in late December 2014 with the publication of a study showing that the rapamycin analog everolimus actually enhanced the adaptive immune response to a vaccine in a group of older patients. In the study, led by scientists Joan Mannick and Lloyd Klickstein, who then worked at Novartis, the group of patients on a moderate weekly dose of everolimus seemed to have the best response to the flu vaccine, with the fewest reported side effects. This study suggested that rapamycin (and its derivatives) might actually be more of an immune modulator than an “immunosuppressor,” as it had almost always been described before this study: that is, under some dosing regimens it can enhance immunity, while under completely different dosing regimens it may inhibit immunity.
Until this study appeared, I (like many others) had largely given up on the possibility that rapamycin could ever be used as a preventive therapy in healthy people. I had assumed that its apparent immunosuppressive effects were too serious. But this very well-done and well-controlled study actually suggested the opposite. It appeared that the immune suppression resulted from daily use of rapamycin at low to moderate doses. The study subjects had been given moderate to high doses followed by a rest period, and this cyclical administration had had an opposite, immune-enhancing effect.
It seems odd that giving different doses of the same drug could have such disparate effects, but it makes sense if you understand the structure of mTOR, which is actually composed of two separate complexes, called mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The two complexes have different jobs, but (at risk of oversimplifying) the longevity-related benefits seem to result from inhibiting complex 1. Giving the drug daily, as is typically done with transplant patients, appears to inhibit both complexes, while dosing the drug briefly or cyclically inhibits mainly mTORC1, unlocking its longevity-related benefits, with fewer unwanted side effects. (A rapamycin analog or “rapalog” that selectively inhibited mTORC1 but not mTORC2 would thus be more ideal for longevity purposes, but no one has successfully developed one yet.)
As it is, its known side effects remain an obstacle to any clinical trial of rapamycin for geroprotection (delaying aging) in healthy people. To get around these objections, Kaeberlein is doing a large clinical trial of rapamycin in companion (pet) dogs, which are not a bad proxy for humans—they’re large, they’re mammals, they share our environment, and they age in ways similar to us. In a preliminary phase of this study, which he calls the Dog Aging Project, Kaeberlein found that rapamycin actually seemed to improve cardiac function in older animals. “One thing that’s been surprising to me,” he says, “is the different ways that rapamycin not only seems to delay the decline but seems to make things better. There clearly seems to be, at least in some organs, a rejuvenating function.”
Kaeberlein has also observed that rapamycin seems to reduce systemic inflammation, perhaps by tamping down the activity of so-called senescent cells, which are “older” cells that have stopped dividing but have not died; these cells secrete a toxic cocktail of inflammatory cytokines, chemicals that can harm surrounding cells. Rapamycin seems to reduce these inflammatory cytokines. It also improves cancer surveillance, the ways in which our body, most likely the immune system, detects and eliminates cancer cells. In another recent study, Kaeberlein’s group found that rapamycin appeared to improve periodontal (gum) health in older dogs.
The main phase of the Dog Aging Project, involving some 600 pet dogs, is now under way; results from this larger clinical trial are expected in 2026. (Disclosure: I am a partial funder of this research.) The dogs in this study are also following a weekly, cyclical dosing schedule with rapamycin, similar to the protocol in the 2014 immune study in humans. If the results are positive, it would not surprise me if the use of rapamycin for longevity purposes becomes more common. A small but growing number of people, including me and a handful of my patients, already take rapamycin off-label for its potential geroprotective benefits. I can’t speak for everyone, but taking it cyclically does appear to reduce unwanted side effects, in my experience.
Even so, the hurdles it would have to clear to gain approval for broader human use remain daunting. The vast majority of people who currently take rapamycin comprise transplant patients who already have serious health issues and multiple comorbidities. In populations like this, rapamycin’s side effects seem less significant than they might in healthier people.
“There is a very low tolerance for side effects, by the public and by regulatory agencies, if you’re talking about treating a healthy person,” says Kaeberlein. “The intent is to slow aging in people before they get sick, to keep them healthy longer, so in many ways it is the opposite of the traditional biomedical approach, where normally we wait until people are sick and then we try to cure their diseases.”
The real obstacle here is a regulatory framework rooted in Medicine 2.0, which does not (yet) recognize “slowing aging” and “delaying disease” as fully legitimate end points. This would represent a Medicine 3.0 use for this drug, where we would be using a drug to help healthy people stay healthy, rather than to cure or relieve a specific ailment. Thus, it would face much more scrutiny and skepticism. But if we’re talking about preventing the diseases of aging, which kill 80 percent of us, then it’s certainly worth having a serious conversation about what level of risk is and isn’t acceptable in order to achieve that goal. Part of my aim in writing this book is to move that conversation forward.
This may already be starting to happen. The FDA has given the green light for a clinical trial of another drug with potential longevity benefits, the diabetes medication metformin. This trial is called TAME (Targeting Aging with Metformin), and it came about in a very different way. Metformin has been taken by millions of people for years. Over time, researchers noticed (and studies appeared to confirm) that patients on metformin appeared to have a lower incidence of cancer than the general population. One large 2014 analysis seemed to show that diabetics on metformin actually lived longer than nondiabetics, which is striking. But none of these observations “prove” that metformin is geroprotective—hence the need for a clinical trial.
But aging itself is difficult—if not impossible—to measure with any accuracy. Instead, TAME lead investigator Nir Barzilai, whom we met in the previous chapter, decided to look at a different endpoint: whether giving metformin to healthy subjects delays the onset of aging-related diseases, as a proxy for its effect on aging. I’m hopeful that someday, maybe in the near future, we could attempt a similar human trial of rapamycin, which I believe has even greater potential as a longevity-promoting agent.[*3]
For the moment, though, let’s think about the fact that all of what we’ve talked about in this chapter, from mTOR and rapamycin to caloric restriction, points in one direction: that what we eat and how we metabolize it appear to play an outsize role in longevity. In the next chapter, we will take a much more detailed look at how metabolic disorders help to instigate and promote chronic disease.
*1 A drug analog is a compound with similar but not identical molecular structure; e.g., oxycodone is an analog of codeine.
*2 This is where the nomenclature gets a bit confusing. Briefly, the drug rapamycin blocks or inhibits the activity of mTOR, mechanistic target of rapamycin, the protein complex found in cells. Adding to the confusion, mTOR was originally called mammalian target of rapamycin, to distinguish it from a version of target of rapamycin, TOR, that had first been discovered in yeast. TOR and mTOR are essentially the same, meaning this same basic mechanism is found up and down the tree of life, across a billion years of evolution.
*3 Before leaving Rapa Nui, the four of us vowed to replace the missing plaque honoring the discovery of rapamycin with a new one saluting the island’s unique contribution to molecular biology and the role of Suren Sehgal in preserving and elucidating the importance of this molecule.