FIVE
A BETTER PILL TO SWALLOW
THE DREAM OF EXTENDING HUMAN lives did not begin in the early twenty-first century any more than the dream of human flight began in the early twentieth. Nothing begins with science; it all begins with stories.
From Gilgamesh the Sumerian king, who is said to have reigned over Uruk for 126 years, to Methuselah the patriarch in Hebrew scriptures, who is said to have lived to the age of 969, humanity’s sacred stories testify to our deep-seated fascination with longevity. Outside myths and parables, though, we had little scientific evidence of anyone succeeding in extending their life far beyond the single century mark.
We had little hope of doing so without a deep understanding of how life works. That is knowledge, albeit still imperfect, that some of my colleagues and I believe we finally possess.
It wasn’t until 1665 that “England’s Leonardo,” Robert Hooke, published Micrographia, in which he reported seeing cells in cork bark. That discovery launched us into the modern era of biology. But centuries would pass before we had any clue about how cells work at the molecular scale. That knowledge could come only from the combination of a series of great leaps in microscopy, chemistry, physics, genetics, nanoengineering, and computing power.
To understand how aging occurs, we must journey down into the subcellular nanoworld, heading down to the cell, piercing the outer membrane, and traveling into the nucleus. From there, we head down to the scale of amino acids and DNA. At this size, it is obvious why we don’t live forever.
Until we understood life at the nanoscale, even why we live was a mystery. The brilliant Austrian theoretical physicist Erwin Schrödinger, the man who developed quantum physics (and yes, that famous thought experiment involving a both-dead-and-alive cat) was flummoxed when he tried to explain life. In 1944, he threw up his hands and declared that living matter “is likely to involve ‘other laws of physics’ hitherto unknown.”1 That was the best he could do at the time.
But things moved quickly in the decades to come. And today, the answer to Schrödinger’s 1944 book, What Is Life?, if not fully answered, is certainly close to being so.
Turns out, there is no new law required to explain life. At the nanoscale, it is merely an ordered set of chemical reactions, concentrating and assembling atoms that would normally never assemble, or breaking apart molecules that would normally never disintegrate. Life does this using proteinaceous Pac-Men called enzymes made up of coils and layered mats of amino acid chains.
Enzymes make life possible by taking advantage of fortuitous molecular movements. Every second you are alive, thousands of glucose molecules are captured within each of your trillions of cells by an enzyme called glucokinase, which fuses glucose molecules to phosphorus atoms, tagging them for energy production. Most of the energy created is used by a multicomponent RNA and protein complex called a ribosome, whose primary job is to capture amino acids and fuse them with other amino acids to make fresh proteins.
Does this sort of talk make your eyes gloss over? You are not alone, and you are not to blame. We teachers have done society a great disservice by making cool science boring. Textbooks and scientific papers depict biology as a static, two-dimensional world. Chemicals are drawn as sticks, biochemical pathways are arrows, DNA is a line, a gene is a rectangle, and enzymes are ovals, drawn thousands of times larger relative to the cell than they actually are.
But once you understand how cells actually work, they are the most amazing things. The problem with conveying this wonder in a classroom is that cells exist in four dimensions and buzz around with speeds and on scales we humans cannot perceive or even conceive. To us, the second and the millimeter are short divisions of time and space, but to an enzyme about 10 nanometers across and vibrating every quadrillionth of a second, a millimeter is the size of a continent and a second is more than a year.2
Consider catalase, a ubiquitous, regular-sized enzyme that can break apart and detoxify 10,000 molecules of hydrogen peroxide per second. A million of them could fit inside an E. coli bacterium, a million of which could fit on the head of a pin.3 These numbers aren’t just hard to imagine; they are inconceivable.
In each cell are a total of 75,000 enzymes like catalase,4 all thrown together, jostling around in a slightly salty sea. At the nanoscale, water is gelatinous, and molecular events are more violent than a category 5 hurricane, with molecules thrown together at speeds we would perceive as a thousand miles per hour. Enzymatic reactions are one-in-a-thousand events, but at the nanoscale one-in-a-thousand events can occur thousands of times a second, enough to sustain life.
If this sounds chaotic, it is, but we need this chaos for order to emerge. Without it, the molecules that must come together to sustain life would not find each other, and they would not fuse. The human sirtuin enzyme called SIRT1 serves as a good example. Precise vibrating sockets on SIRT1 simultaneously clasp onto an NAD molecule and the protein it wants to strip the acetyls from, such as a histone or FOXO3. The two captured molecules immediately lock together, just before SIRT1 rips them apart in a different way, producing vitamin B3 and acetylated adenine ribose as waste products that are recycled back to NAD.
More important is the fact that the target protein has now been stripped of the acetyl chemical group that was holding it at bay. Now the histone can pack DNA more tightly to silence genes, and FOXO3 has had its shackles removed, allowing it to go turn on a defense program of protective genes.
If the chaos ended and our enzymes suddenly stopped doing what they do, we would all be dead within a few seconds. Without energy and cell defenses, there can be no life. M. superstes would never have emerged from the scum and its descendants would never have been capable of comprehending the words on this page.
And so, at the fundamental level, life is rather simple: we exist by the grace of an order created from chaos. When we toast to life, we really should be toasting to enzymes.
By studying life at this level, we’ve also learned something rather important—something the Nobel Prize–winning physicist Richard Feynman expressed succinctly: “There is nothing in biology yet found that indicates the inevitability of death. This suggests to me that it is not at all inevitable and that it is only a matter of time before biologists discover what it is that is causing us the trouble.”5
It’s true: there are no biological, chemical, or physical laws that say life must end. Yes, aging is an increase in entropy, a loss of information leading to disorder. But living things are not closed systems. Life can potentially last forever, as long as it can preserve critical biological information and absorb energy from somewhere in the universe. This doesn’t mean we could be immortal tomorrow—no more than we could have flown to the moon on December 18, 1903. Science moves forward with small steps and big steps, but always one step at a time.
Here’s the remarkable thing: the first steps have actually been available to us since the times of Gilgamesh and Methuselah, and indeed from the time of M. superstes. And, in the past few centuries, and by accident even earlier than that, we have discovered ways to chemically modulate enzymes with molecules we call medicines.
Now that we know how life works and have the tools to change it at a genetic and epigenetic level, we can build upon this very old wisdom. And when it comes to the goal of extending healthy lifespans, the easiest measures to use are the various drugs that we already know can impact human aging.
THE WORLD’S GREATEST EASTER EGG
Rapa Nui, a remote volcanic island 2,300 miles west of Chile, is commonly known as Easter Island and even better known for the nearly nine hundred giant stone heads that line the island’s perimeter. What should be just as well known—and perhaps one day will be—is the story of how the island came to be the source of the world’s most effective lifespan-extending molecule.
Back in the mid-1960s, a team of scientists traveled to the island. The researchers were not archaeologists seeking answers about the origins of the moai statues but rather biologists looking for endemic microorganisms.
In the dirt beneath one of the island’s famed stone heads, they discovered a new actinobacterium. That single-celled organism was Streptomyces hygroscopicus, and when it was isolated by a pharmaceutical researcher, Suren Sehgal, it soon became clear that the actinobacterium secreted an antifungal compound. Sehgal named that compound rapamycin, in honor of the island where it was discovered, and began looking for ways to process it as a potential remedy for fungal conditions such as athlete’s foot.6 The compound looked promising for that purpose, but when the Montreal lab where Sehgal worked was shuttered in 1983, he was directed to destroy the compound.
He couldn’t bring himself to do that, though. Instead he spirited a few vials of the bacterium out of the lab and kept them in his freezer at home until the late 1980s, when he convinced his bosses at a new lab in New Jersey to let him resume studying it.
It wasn’t long before researchers discovered that the compound was an effective suppressor of the immune system. That would end its potential as an antifungal—there are plenty of remedies for athlete’s foot that don’t come at the cost of lowered immunity—but it gave scientists a new attribute to study.
Even in the 1960s, researchers knew that one of the most common reasons for an organ transplant to fail is that the recipient patient’s body rejects it. Could rapamycin lower the immune response enough to ensure the organ would be accepted? Indeed it could.
It is for this reason that if you were to make a pilgrimage to Rapa Nui, you might come upon a small plaque at the site where S. hygroscopicus was discovered. “At this site,” the plaque reads in Portuguese, “soil samples were obtained in January 1965 that allowed the production of rapamycin, a substance that inaugurated a new era for patients who need organ transplants.”
I suspect that a larger plaque may soon be in order, because the discovery of S. hygroscopicus set into motion a tremendous amount of research, much of which is still ongoing and some of which has the potential to prolong vitality for countless other people. Because in recent years it has become clear that rapamycin isn’t just an antifungal compound and it isn’t just an immune system suppressor; it’s also one of the most consistently successful compounds for extending life.
We know this from experiments on a diverse menagerie of model organisms in labs around the world. And much as my own research began with experiments with yeast, much of the initial work that has been done to understand rapamycin was completed on S. cerevisiae. If you put 2,000 normal yeast cells into a culture, a few will remain viable after six weeks. But if you feed those yeast cells rapamycin, in six weeks about half will still be healthy.7 The drug will also increase the number of daughter cells mothers can produce by stimulating the production of NAD.
Fruit flies fed rapamycin live about 5 percent longer.8 And small doses of rapamycin given to mice when they are already in the final months of their normal lives results in 9 to 14 percent longer lives, depending on whether they are male or female, which translates to about a decade of healthy human life.9
We’ve known for a long time that greater parental age is a risk factor for disease in the next generation. That’s the power of epigenetics. But mice treated with rapamycin buck this trend. When researchers from the German Center for Neurodegenerative Diseases inhibited mTOR in mice born to older fathers, the negative impact of having an old parent went away.10
Want to know what the world’s most prominent arbiters of great science think about the potential of TOR and the molecules that inhibit it to change the world? The three men who discovered TOR in yeast, Joseph Heitman, Michael Hall, and Rao Movva, are on a lot of people’s shortlists for the Nobel Prize in Medicine or Physiology. My colleague across the river at MIT, David Sabatini, who identified mTOR, was named a Clarivate Citation Laureate for having his work cited most frequently in top-tier peer-reviewed journals; the Clarivate list has predicted more than forty Nobel Prize winners since 2002.11
Rapamycin isn’t a panacea. Longer-lived animals might not fare as well on it as shorter-lived ones do; it’s been shown to be toxic to kidneys at high doses over extended periods of time; and it might suppress the immune system over time. That doesn’t mean TOR inhibition is a dead end, though. It might be safe in small or intermittent doses—that worked in mice to extend lifespan12 and in humans dramatically improved the immune responses of elderly people to a flu vaccine.13
There are hundreds of researchers from the TOR inhibition side of the family working in universities and biotech companies to identify “rapalogs,” which are compounds that act on TOR in ways similar to rapamycin but have greater specificity and less toxicity.14
The quality of the people involved in this line of research and development makes it hard to bet against TOR inhibition as a pathway to greater human health and vitality. But even if rapalogs don’t pan out, there’s another pharmaceutical pathway to prolonged vitality that has already proven to be both effective and relatively safe.
PENNIES FOR PROLONGED VITALITY
Galega officinalis is a lovely flower, with stacks of delicate purple petals that seem locked in a reverent bow to the world.
Also known as goat’s rue, a rather unfortunate name, and French lilac, a far more charming sobriquet, it has been used as an herbal medicine in Europe for centuries, owing to a chemical composition rich in guanidine, a small chemical in human urine that serves as an indicator of healthy protein metabolism. In the 1920s, doctors began to prescribe guanidine as a way to lower blood glucose levels in patients with diabetes.
In 1922, a 14-year-old boy named Leonard Thompson, who was dying in a Toronto hospital, became the first diabetic patient to be given an injection of a novel pancreatic peptide hormone that had shown great promise in animal studies. Two weeks later he was given another, and news of his exceptional improvement spread quickly around the world. Type 1 diabetes, which occurs when the pancreas doesn’t produce enough of the hormones needed to alert the body to sugar, is now widely treated by supplemental insulin. But the fight was not over.
The type 2 version of the disease, so-called age-associated diabetes, occurs when the pancreas is able to make enough insulin but the body is deaf to it. The 9 percent of all adults globally with this disease need a drug that restores their body’s sensitivity to insulin so cells take up and use the sugar that’s coursing through their bloodstreams. That’s important for at least two reasons: it gives the overworked pancreas a rest, and it prevents spikes of freely floating sugar from essentially caramelizing proteins in the body. Recent results indicate high blood sugar can also speed up the epigenetic clock.
Thanks to an increasingly sedentary lifestyle and the abundance of sugars and carbohydrates on every supermarket shelf around the globe, high blood sugar is causing the premature deaths of 3.8 million people a year. These deaths do not come quickly and compassionately but in horrific ways, with blindness, kidney failure, stroke, open foot wounds, and limb amputations.
As they considered this disease in the mid-1950s, the pharmacist Jan Aron and the physician Jean Sterne—both Frenchmen who would have been exceptionally familiar with the purple-flowering plant so ubiquitous in their native land—decided to reinvestigate the potential of French lilac derivatives to fight type 2 diabetes in ways insulin doesn’t.15
In 1957, Sterne published a paper demonstrating the effectiveness of oral dimethyl biguanide to treat type 2 diabetes. The drug, now most commonly called metformin, has since become one of the most widely taken and effective medicines on the globe. It’s among the medications on the World Health Organization’s Model List of Essential Medicines, a catalog of the most effective, safe, and cost-effective therapies for the world’s most prevalent medical conditions. As a generic medication, it costs patients less than $5 a month in most of the world. Except for an extremely rare condition called lactic acidosis, the most common of the side effects is some stomach discomfort. Many people mitigate that side effect by taking the medication as a coated tablet or with a glass of milk or a meal, but even when that doesn’t work, the mild upset feeling comes with a bit of a side benefit: it tends to discourage overeating.
What place does a diabetes medication have in a conversation about prolonging vitality? Perhaps it would have no place at all if not for the fact that, a few years ago, researchers noticed a curious phenomenon: people taking metformin were living notably healthier lives—independent, it seemed, of its effect on diabetes.16
In mice, even a very low dose of metformin has been shown by Rafael de Cabo’s lab at the National Institutes of Health to increase lifespan by nearly 6 percent, though some have argued that the effect is due mostly to weight loss.17 Either way, that amounts to the equivalent of five extra healthy years for humans, with an emphasis on healthy—the mice showed reduced LDL cholesterol levels and improved physical performance.18 As the years have gone by, the evidence has mounted. In twenty-six studies of rodents treated with metformin, twenty-five showed protection from cancer.19
Like rapamycin, metformin mimics aspects of calorie restriction. But instead of inhibiting TOR, it limits the metabolic reactions in mitochondria, slowing down the process by which our cellular powerhouses convert macronutrients into energy.20 The result is the activation of AMPK, an enzyme known for its ability to respond to low energy levels and restore the function of mitochondria. It also activates SIRT1, one of my lab’s favorite proteins. Among other beneficial effects, metformin inhibits cancer cell metabolism, increases mitochondrial activity, and removes misfolded proteins.21
A study of more than 41,000 metformin users between the ages of 68 and 81 concluded that metformin reduced the likelihood of dementia, cardiovascular disease, cancer, frailty, and depression, and not by a small amount. In one group of already frail subjects, metformin use over the course of nine years reduced dementia by 4 percent, depression by 16 percent, cardiovascular disease by 19 percent, frailty by 24 percent, and cancer by 4 percent.22 In other studies, the protective power of metformin against cancer has been far greater than that. Though not all cancers are suppressed—prostate, bladder, renal, and esophageal cancer seem recalcitrant—more than twenty-five studies have shown a powerful protective effect, sometimes as great as a 40 percent lower risk, most notably for lung, colorectal, pancreatic, and breast cancer.23
These aren’t just numbers. These are people whose lives were markedly improved by using a single, safe drug that costs less than a cup of bad coffee.
If all metformin could do was reduce cancer incidence, it would still be worth prescribing widely. In the United States, the lifetime risk of being diagnosed with cancer is greater than 40 percent.24 But there’s a dividend beyond preventing cancer directly, a side effect of living longer that most people don’t consider: after age 90, your chances of dying of cancer drop considerably.25 Of course, people will still die of other conditions, but the tremendous pain and costs associated with cancer would be significantly mitigated.
The beauty of metformin is that it impacts many diseases. Through the power of AMPK activation, it makes more NAD and turns on sirtuins and other defenses against aging as a whole—engaging the survival circuit upstream of these conditions, ostensibly slowing the loss of epigenetic information and keeping metabolism in check, so all organs stay younger and healthier.
Most of us assume that the effects of a pill like metformin would take years to produce any appreciable effect on aging, but maybe not. An admittedly small study of healthy volunteers claimed that the DNA methylation age of blood cells is reversed within a week and, astoundingly, only ten hours after taking a single 850 mg pill of metformin.26 But clearly more work is needed with greater numbers of subjects to know for sure if metformin can delay the aging clock over the long run.
In most countries, metformin isn’t yet prescriptible as an antiaging drug, but for the hundreds of millions of people around the world who are diabetic, it’s not a hard prescription to get. In some places, such as Thailand, metformin is even available over the counter at every pharmacy—for just a few cents a pill. In the rest of the world, even if you have prediabetes, it can be challenging to convince a doctor to prescribe you metformin. If you’ve been good to your body, and greater than 93.5 percent of your blood’s hemoglobin isn’t irreversibly bound to glucose—meaning it’s mostly the HbA1 type not HbA1c—you’re out of luck, not just because the majority of physicians don’t know the data I just shared with you, but because even if they did, aging isn’t yet considered a disease.
Among the people taking metformin—and leading the charge to evaluate its long-term effects on aging in humans—is Nir Barzilai, the Israeli American physician and geneticist who, along with his colleagues at Albert Einstein College of Medicine, discovered several longevity gene variants in the insulin-like growth hormone receptor that controls FOXO3, the cholesterol gene CETP, and the sirtuin SIRT6, all of which seem to help ensure that some lucky people with Ashkenazi Jewish ancestry remain healthy beyond 100.
Yes, although genes play a back-seat role to the epigenome, it does seem that some people are genetically primed for longevity at the digital level—enjoying longer lives almost irrespective of how they live, thanks in part to gene variants that stabilize their epigenomes, preventing the loss of analog information over time. But Barzilai doesn’t see these people as winners so much as markers—they represent the potential that most other humans have for long and healthy lives—and he is fond of pointing out that even if we were never to extend lives past 120, we know that 120 is possible. “So for most of us,” he has told me, “there are 40 good years still on the table.”
Barzilai is leading the charge to make metformin the first drug to be approved to delay the most common age-related diseases by addressing their root cause: aging itself. If Barzilai and his colleagues can show metformin has measurable benefits in the ongoing Targeting Aging with Metformin (TAME) study, the US Food and Drug Administration has agreed to consider aging as a treatable condition. That would be a game changer, the beginning of the end for a world in which aging is “just the way it goes.”
Barzilai believes that day is coming. He has predicted that the traditional Hebrew blessing “Ad me’ah ve-essrim shana,” or “May you live until 120,” may soon need updating, for it will be a wish not for a long life but for a very average one.
STAC IT UP
Back in 1999, the story of the sirtuin longevity pathway we discovered in Lenny Guarente’s lab at MIT was about to get even hotter.
We had finally figured out a molecular cause of aging in yeast cells, the first for any species. We were still feeling the glow scientists get when they publish new work that shows how smart they are. In a series of prominent papers that had captured the imagination of the scientific community, we’d reported that the cause of yeast aging was the movement of Sir2 away from the mating-type genes to deal with DNA breaks and a whole lot of ensuing genome instability.27 We’d shown that extra copies of the SIR2 gene could stabilize the rDNA and extend lifespan. We’d linked genetic instability to epigenetic instability and found one of the world’s first true longevity genes—and the yeast hadn’t had to go hungry to receive its benefits.
But splicing extra copies of a gene into a single-celled organism is a much easier endeavor than putting those copies into more complex creatures. It’s also far less ethically complicated. That’s why a few other researchers and I entered a scientific race to find ways to ramp up sirtuin activity in mammals without inserting extra sirtuin genes.
Here is where science becomes a matter of logical guesswork and some good old-fashioned luck. Because there are more than 100 million chemicals known to science. Where do you even start?
Thankfully, Konrad Howitz was on the case. The Cornell-educated biochemist was then the director of molecular biology for Biomol, a Pennsylvania company that was a supplier of molecules for life science researchers. Howitz was looking for chemicals that would inhibit the SIRT1 enzyme, so they could be sold to the growing number of scientists who were starting to study the enzyme. In the process of evaluating different contenders, he found two chemicals that, rather than inhibiting SIRT1, stimulated or “activated” it, making it work ten times as fast. That was a serendipitous discovery, not only because he was expecting to find inhibitors but because activators are very rare in nature. They are so rare, in fact, that most drug companies don’t even bother following up when one is discovered, figuring it must be a mistake.
The first SIRT1-activating compound, or STAC, was a polyphenol called fisetin, which helps gives plants such as strawberries and persimmons their color and is now known to also kill senescent cells. The second was a molecule called butein, which can be found in numerous flowering plants as well as a toxic plant known as the Chinese lacquer tree. Both had a significant effect on SIRT1, though not the sort of pedal-to-the-metal reaction that might make them ripe for further research.
THE THREE MAIN LONGEVITY PATHWAYS, mTOR, AMPK, AND SIRTUINS, EVOLVED TO PROTECT THE BODY DURING TIMES OF ADVERSITY BY ACTIVATING SURVIVAL MECHANISMS. When they are activated, either by low-calorie or low-amino-acid diets, or by exercise, organisms become healthier, disease resistant, and longer lived. Molecules that tweak these pathways, such as rapamycin, metformin, resveratrol, and NAD boosters, can mimic the benefits of low-calorie diets and exercise and extend the lifespan of diverse organisms.
Howitz showed his initial results to Biomol’s founder and scientific director, Robert Zipkin, a brilliant chemist and entrepreneur who has an encyclopedic knowledge of chemical structures. “Fisetin and butein, huh?” Zipkin said. “You know what those two molecules look like? They’ve got an overlapping structure: two phenolic rings connected by a bridge. You know what else has that structure? Resveratrol.”
In 2002, antioxidants were all the rage. They might not have been the antiaging and health panaceas some believed them to be, but that wasn’t yet known. One of the antioxidants, scientists from the Karol Marcinkowski University of Medical Sciences (now Poznan University of Medical Sciences in Poland) had learned, was resveratrol, a natural molecule that is found in red wine and that many plants produce in times of stress.28 A few researchers had suggested that resveratrol might explain the “French paradox,” the fact that the French have lower rates of heart disease, even though their diet is relatively high in foods containing saturated fat, such as butter and cheese.
Zipkin’s guess that resveratrol might have a similar effect as fisetin and butein was right on the money. When I studied it in my lab at Harvard, I saw that it actually far outperformed the other two molecules.
As a reminder, aging in yeast is often measured by the number of times a mother cell divides to produce daughter cells. In most cases, a yeast cell gets to about twenty-five divisions before it dies. Because the experiments required a week of micromanipulation of cells while looking down a microscope, and the fewer times you put the cells in the fridge to get some sleep, the longer the yeast cells live, I assembled a lab at home on my dining room table.
There, I saw something incredible: the resveratrol-fed yeast were slightly smaller and grew slightly more slowly than untreated yeast, getting to an average of thirty-four divisions before dying, as though they were calorie restricted. The human equivalent would be an extra 50 years of life. We saw increases in maximum lifespan, too—on resveratrol, they kept going past 35. We tested resveratrol in yeast cells with no SIR2 gene, and there was no effect. We tested it on calorie-restricted yeast, and saw no further increase in lifespan, suggesting that the same pathway was being activated; this was how calorie restriction was working.
It seemed like a joke’s punch line—not only had we found a calorie-restriction mimetic, something that could extend longevity without hunger, but we’d found it in a bottle of red wine.
Howitz and I were fascinated by the fact that resveratrol is produced in greater quantities by grapes and other plants experiencing stress. We also knew that many other health-promoting molecules, and chemical derivatives of them, are produced in abundance by stressed plants; we get resveratrol from grapes, aspirin from willow bark, metformin from lilacs, epigallocatechin gallate from green tea, quercetin from fruits, and allicin from garlic. This, we believe, is evidence of xenohormesis—the idea that stressed plants produce chemicals for themselves that tell their cells to hunker down and survive. Plants have survival circuits, too, and we think we might have evolved to sense the chemicals they produce in times of stress as an early-warning system, of sorts, to alert our bodies to hunker down as well.29
What this means, if it’s true, is that when we search for new drugs from the natural world we should be searching the stressed-out ones: in stressed plants, in stressed fungi, and even in the stressed microbiome populations in our guts. The theory is also relevant to the foods we eat; plants that are stressed have higher concentrations of xenohormetic molecules that may help us engage our own survival circuits. Look for the most highly colored ones because xenohormetic molecules are often yellow, red, orange, or blue. One added benefit: they tend to taste better. The best wines in the world are produced in dry, sun-exposed soil or from stress-sensitive varietals such as Pinot Noir; as you might guess, they also contain the most resveratrol.30 The most delectable strawberries are those that have been stressed by periods of limited water supply. And as anyone who has grown leaf vegetables can attest, the best heads of lettuce come when the plants are exposed to a one-two combo punch of heat and cold.31 Ever wonder why organic foods, which are often grown under more stressful conditions, might be better for you?
Resveratrol extended the lifespan of simple yeast cells, but would it do the same for other organisms? When my fellow researcher Marc Tatar of Brown University visited me in Boston, I gave him a small vial of white, fluffy resveratrol powder—marked only with the letter R—to try on insects in his lab. He took it back to Rhode Island, mixed it with some yeast paste, and fed it to his fruit flies.
A few months later, I got a call from him. “David!” he said. “What is this R stuff?”
Under lab conditions, the fruit fly Drosophila melanogaster typically lives for an average of forty or so days. “We added a week to their lives and sometimes more than that,” Tatar told me. “On average, they’re living for more than fifty days.”
In human terms, that’s an additional fourteen years.
In my lab, resveratrol-fed roundworms also lived longer, an effect that required the worm sirtuin gene to be engaged. And when we gave resveratrol to human cells in culture dishes, they became resistant to DNA damage.
Later, when we fed resveratrol to obese mice at one year of age, something interesting happened: the mice stayed fat, causing postdoctoral fellow Joseph Baur, now a professor at the University of Pennsylvania, to conclude that I’d wasted more than a year of his time, jeopardizing his scientific career with a harebrained experiment. But when he and Rafael de Cabo, our collaborator at the NIH, opened up the mice, they were shocked. The resveratrol mice looked identical to mice on a normal diet, with healthy hearts, livers, arteries, and muscles. They also had more mitochondria, less inflammation, and lower blood sugar levels. The ones they didn’t dissect wound up living about 20 percent longer than normal.32
Other researchers went on to show in hundreds of published studies that resveratrol protects mice against dozens of diseases, including a variety of cancers, heart disease, stroke and heart attacks, neurodegeneration, inflammatory diseases, and wound healing, and generally makes mice healthier and more resilient.33 And in collaboration with de Cabo, we discovered that when resveratrol is combined with intermittent fasting, it can greatly extend both average and maximum lifespan even beyond what fasting alone accomplishes. Out of fifty mice, one lived more than 3 years—in human terms, that would amount to about 115 years.34
The first paper on resveratrol’s effects on aging went on to be one of the most highly cited papers of 200635 and was widely circulated in the mainstream media, too. We were all over TV, and I was starting to be recognized in public. I ran off to the little German village called Burlo, where my wife was born, and the news had even made it there. Sales of red wine reportedly went up 30 percent. If you like red wine but needed a good excuse to imbibe, you can thank Rob Zipkin.36
On our kitchen wall hangs a variety of cartoons from the day. My favorite is one by Tom Toles. In it, a wife tries to downplay the enthusiasm of her very large husband, who covers most of a couch.
“The study said that to get the same dose as they gave the mice you’d have to drink between 750 and 1,000 glasses of red wine every day,” the wife says.
“The news just keeps getting better and better,” the husband replies.
As it turned out, resveratrol wasn’t very potent and wasn’t very soluble in the human gut, two attributes that most medicines need to be effective at treating diseases. Despite its limitations as a drug, it did serve as an important first proof that a molecule can give the benefits of calorie restriction without the subject having to go hungry, and it set off a global race to find other molecules that might delay aging. Finally, at least in scientific circles, slowing aging with a drug was no longer considered bonkers.
By studying resveratrol, we also learned that it is possible to activate sirtuins with a chemical. This prompted a flood of research into other sirtuin-activating compounds, called STACs, that are many times more potent than resveratrol at stimulating the survival circuit and extending healthy lifespans in animals. They go by names such as SRT1720 and SRT2104, both of which extend the healthy lifespan of mice when given to them late in life.37 There are, today, hundreds of chemicals that have been demonstrated to have an effect on sirtuins that are even more effective than resveratrol’s and some that have already been demonstrated in clinical trials to lower fatty acid and cholesterol levels, and to treat psoriasis in humans.38
Another STAC is NAD, sometimes written as NAD+.39 NAD has an advantage over other STACs because it boosts the activity of all seven sirtuins.
NAD was discovered in the early twentieth century as an alcoholic fermentation enhancer. That was fortuitous: if it hadn’t had the potential to improve the way we make booze, scientists might not have been so enamored by it. Instead they worked on it for decades, and in 1938 they had a breakthrough: NAD was able to cure black tongue disease in dogs, the canine equivalent of pellagra. It turned out that NAD is a product of the vitamin niacin, a severe lack of which causes inflamed skin, diarrhea, dementia, skin sores, and ultimately death. And because NAD is used by over five hundred different enzymes, without any NAD, we’d be dead in thirty seconds.
By the 1960s, however, researchers had concluded that all the interesting research on NAD had been done. For decades to come, NAD was simply a housekeeping chemical that teenage biology students had to learn about—with all the enthusiasm of a teenager doing housekeeping. That all changed in the 1990s, when we began to realize that NAD wasn’t just keeping things running; it was a central regulator of many major biological processes, including aging and disease. That’s because Shin-ichiro Imai and Lenny Guarente showed that NAD acts as fuel for sirtuins. Without sufficient NAD, the sirtuins don’t work efficiently: they can’t remove the acetyl groups from histones, they can’t silence genes, and they can’t extend lifespan. And we sure wouldn’t have seen the lifespan-extending impact of the activator resveratrol. We and others also noticed that NAD levels decrease with age throughout the body, in the brain, blood, muscle, immune cells, pancreas, skin, and even the endothelial cells that coat the inside of microscopic blood vessels.
But because it’s so central to so many fundamental cellular processes, no researchers in the twentieth century had any interest in testing the effects of boosting levels of NAD. “Bad stuff will happen if you mess with NAD,” they thought. But not even having tried to manipulate it, they didn’t really know what would happen if they did.
The benefit of working with yeast, though, is that the worst-case scenario in any experiment is a yeast massacre.
There was little risk in looking for ways to boost NAD in yeast. So that’s what my lab members and I did. The easiest way was to identify the genes that make NAD in yeast. We first discovered a gene called PNC1, which turns vitamin B3 into NAD. That led us to try boosting PNC1 by introducing four extra copies of it into the yeast cells, giving them five copies in total. Those yeast cells lived 50 percent longer than normal, but not if we removed the SIR2 gene. The cells were making extra NAD, and the sirtuin survival circuit was being engaged!
Could we do this in humans? Theoretically, yes. We already have the technology to do it in my lab, using viruses to deliver the human equivalent of the PNC1 gene called NAMPT. But turning humans into transgenic organisms requires more paperwork and considerably more knowledge about safety—for the stakes are higher than a yeast massacre.
That’s why we once again began searching for safe molecules that would achieve the same result.
Charles Brenner, who is now the head of biochemistry at the University of Iowa, discovered in 2004 that a form of vitamin B3 called nicotinamide riboside, or NR, is a vital precursor of NAD. He later found that NR, which is found in trace levels in milk, can extend the lifespan of yeast cells by boosting NAD and increasing the activity of Sir2. Once a rare chemical, NR is now sold by the ton each month as a nutraceutical.
Meanwhile, on a parallel path, researchers, including us, were homing in on a chemical called nicotinamide mononucleotide, or NMN, a compound made by our cells and found in foods such as avocado, broccoli, and cabbage. In the body, NR is converted into NMN, which is then converted into NAD. Give an animal a drink with NR or NMN in it,40 and the levels of NAD in its body go up about 25 percent over the next couple of hours, about the same as if it had been fasting or exercising a great deal.
My friend from the Guarente lab Shin-ichiro Imai demonstrated in 2011 that NMN could treat the symptoms of type 2 diabetes in old mice by restoring NAD levels. Then researchers in my lab at Harvard showed we could make the mitochondria in old mice function just like mitochondria in young mice after just a week of NMN injections.
In 2016, my other lab at the University of New South Wales collaborated with Margaret Morris to demonstrate that NMN treats a form of type 2 diabetes in obese female mice and their diabetes-prone offspring. And back at Harvard, we found that NMN could give old mice the endurance of young mice and then some, leading to the Great Mouse Treadmill Failure of 2017, when we had to reset the tracking program on our lab’s miniature exercise machines because no one had expected that an elderly mouse, or any mouse, could run anywhere near three kilometers.
This molecule doesn’t just turn old mice into ultramarathoners; we have used NMN-treated mice in studies that tested their balance, coordination, speed, strength, and memory, too. The difference between the mice that were on the molecule and the mice that were not was astounding. Were they human, those rodents would long since have been eligible for senior citizen discounts. Nicotinamide mononucleotide turned them into the equivalent of contenders on American Ninja Warrior. Other labs have shown that NMN can protect against kidney damage, neurodegeneration, mitochondrial diseases, and an inherited disease called Friedreich’s ataxia that lands active 20-year-olds in wheelchairs.
As I write this, a group of mice that were put on NMN late in life are getting very old. In fact, only seven out of the original forty mice are still alive, but they are all healthy and still moving happily around the cage. The number of mice alive that didn’t get the NMN?
Zero.
Every day I’m asked by members of the public, “Which is the superior molecule: NR or NMN?” We find NMN to be more stable than NR and see some health benefits in mouse experiments that aren’t seen when NR is used. But it’s NR that has been proven to extend the lifespan of mice. NMN is still being tested. So there’s no definitive answer, at least not yet.
Human studies with NAD boosters are ongoing. So far, there has been no toxicity, not even a hint of it. Studies to test its effectiveness in muscle and neurological diseases are in progress or about to begin, followed by super-NAD-boosting molecules that are a couple of years behind them in development.
But a lot of people haven’t been content to wait for these studies, which can take years to play out. And that has given us some interesting leads about where these molecules, or ones like them, might take us.
FERTILE GROUND
We know that NAD boosters are an effective treatment for a wide variety of ailments in mice and that they extend their lifespan even when given late in life. We know that emerging research strongly suggests they could have a similar, if not duplicative, effect on human health.
We also know that the way it does this, in terms of the epigenetic landscape, is by creating the right level of stress—just enough to push our longevity genes into action to suppress epigenetic changes to maintain the youthful program. In doing so, NMN and other vitality molecules, including metformin and rapamycin, reduce the buildup of informational noise that causes aging, thus restoring the program.
How do they do this? We are still working to understand how epigenetic noise is dampened at a molecular level, but we know in principle how it works. When we give silencing proteins such as sirtuins a boost, they can maintain the youthful epigenome even with DNA damage occurring, like the long-lived yeast cells with extra copies of the SIR2 gene. Somehow they can cope with it. Perhaps they are just superefficient at repairing DNA breaks and head home before they get lost, or if half the sirtuins head off, the remaining enzymes can hold down the fort.
Either way, the increased activity of the sirtuins may prevent Waddington’s marbles from escaping their valleys. And even if they have started to head out of the valley, molecules such as NMN may push them back down, like extra gravity. In essence, this would be age reversal in some parts of the body—a small step, but age reversal nonetheless.
One of the first clues this might be true in an animal larger than a mouse came when a student who works in my lab at Harvard came into my office one afternoon.
“David,” he said quietly, “do you have a moment? There is something I need to discuss. It’s about my mother.”
Given the expression on his face and the tone of his voice, I immediately worried that my student, who came from another country, would tell me his mother was sick. Having been half a planet away from my mother when she was dying, I very much knew how that felt.
“Whatever you need,” I blurted out.
The student seemed taken aback—and I realized I hadn’t yet posed the most pertinent question. “Is your mother all right?” I asked.
“Yes,” he said. “Well . . . I mean, yes . . . well . . . mostly.”
He reminded me that his mother had been taking supplemental NMN, as some of my students and their family members do. “The thing is, well”—his voice lowered to a whisper—“she has started her, um . . . cycle again.”
It took me a few seconds to realize what cycle he was talking about.
As women approach and go through menopause, the menstrual cycle can become quite irregular, which is why a year with no periods must go by before most doctors will confirm that menopause has occurred.
After that, such bleeding can be a cause for concern, as it could be a sign of cancer, fibroid tumors, infections, or an adverse reaction to a medication.
“Has she been seen by a doctor?” I asked.
“Yes,” my student said again. “The doctors say there is nothing wrong. They said this just looks like a normal period.”
I was intrigued. “Okay,” I said. “What we really need is more information. Can you give your mom a call to ask her some more questions?”
I’ve never seen the color so quickly wash away from someone’s face.
“Oh, David,” he pleaded, “please, please, pleeease don’t make me ask my mother any more questions about that!”
Since that conversation, which took place in the fall of 2017, I have known a couple of other women and read the accounts of others claiming to have had similar experiences. These cases could, perhaps, be the result of a placebo effect. But a trial in 2018 to test whether an NAD booster could restore the fertility of old horses was successful, surprising the skeptical supervising veterinarian. As far as I know, horses don’t experience the placebo effect.
Still, these stories and clinical results could be random chance. These matters will be studied in much greater detail. If, however, it turns out that mares and women can become fertile again, it will completely overturn our understanding of reproductive biology.
In school, our teachers taught us that women were born with a set number of eggs (perhaps as many as 2 million). Most of the eggs die off before puberty. Almost all the rest are either released during menstruation throughout the course of a woman’s life or just die off along the way, until there are no more. And then, we were told, a woman is no longer fertile. Period.
These anecdotal reports of restored menstruation and fertile horses are early but interesting indicators that NAD boosters might restore failing or failed ovaries. We also see that NMN is able to restore the fertility of old mice that have had all their eggs killed off by chemotherapy or have gone through “mousopause.” These results, by the way, even though they were done multiple times and reproduced in two different labs by different people, are so controversial that almost no one on the team voted to publish them. I was the exception. They remain unpublished, for now.
To me it is clear that we biologists are missing something. Something big.
In 2004, Jonathan Tilly—a highly controversial figure in the reproductive biology community—claimed that human stem cells that can give rise to new eggs, late in life, exist in the ovaries. Controversial though this theory is, it would explain how it is possible to restore fertility even in mice that are old or have undergone chemotherapy.41,42
Whether or not “egg precursor” cells exist in the ovary, there’s no doubt in my mind that we are moving with staggering speed toward a world in which women will be able to retain fertility for a much longer portion of their lives and possibly regain it if it is lost.
All of this, of course, is good for people who wish to have a child but haven’t been able to for any number of social, economic, or medical reasons. But what does it have to do with aging?
To answer that question, we need to remember what an ovary is. It’s not just, as so many of us were taught in school, a slow-release mechanism for human eggs. It’s an organ—just like our hearts, kidneys, or lungs—that has a day-to-day function, both holding on to eggs that were created during embryonic development and potentially being a repository for additional eggs derived from precursor cells later in life.
The ovary is also the first major organ to break down as a result of aging, in humans and animal models alike. What that means in mice is that, instead of waiting for two years for a mouse to reach “old age,” we can start to see and investigate the causes and cures for aging in about 12 months, at the age female mice typically lose their ability to reproduce.
We also have to remember what NMN does: it boosts NAD, and this boosts the activity of the SIRT2 enzyme, a human form of yeast Sir2 found in the cytoplasm. SIRT2, we’ve found, controls the process by which an immature egg divides so that only one copy of the mother’s chromosomes remain in the final egg in order to make way for the father’s chromosomes. Without NMN or additional SIRT2 in old mice, their eggs were toast. Pairs of chromosomes were ripped apart from numerous directions, instead of exactly two. But if the old female mice were pretreated with NMN for a few weeks, their eggs looked pristine, identical to those of young mice.43
All of this is why early indicators of restored ovarian function in humans, anecdotal as they may be, are so fascinating. If true, the mechanisms that work to prolong, rejuvenate, and reverse aging in ovaries are pathways we can use to do the same thing in other organs.
One more thing that is important to bear in mind: NMN is hardly the only longevity molecule showing promise in this area. Metformin is already widely used to improve ovulation in women with infrequent or prolonged menstrual periods as a result of polycystic ovary syndrome.44 Meanwhile, emerging research is demonstrating that the inhibition of mammalian target of rapamycin, or mTOR, may be able to preserve ovarian function and fertility during chemotherapy,45 while the same gene pathway plays an important role in male fertility, as a central player in the production and development of sperm.46
LIFE WITH FATHER
Most of the time, rodent studies come long before formal human studies. That was the case for NAD boosters. But the early indicators of the safety and effectiveness of the molecules in yeast, worms, and rodents are such that many people have already begun their own private human experiments.
My father is among them.
Though he trained as a biochemist, my dad’s passion was computing. He was a computer guy at a pathology company. That meant he spent a lot of his time sitting in front of a screen and on his behind—another thing experts say is devastatingly bad for our health. Some researchers have even suggested it could be as bad for us as smoking.
By the time my mother died in 2014, my father’s health had also begun its seemingly inexorable decline. He had retired at 67 and was in his mid-70s, still fairly active. He liked to travel and garden. But he had passed the type 2 diabetes threshold, was losing his hearing, and his eyes were starting to go bad. He would tire fast. He repeated himself. He was grumpy. He was hardly a picture of exuberant life.
He started taking metformin for his borderline type 2 diabetes. The next year he started taking NMN.
My father has always been a skeptic. But he is also insatiably curious and was fascinated by what he heard from me about what was happening to the mice in my lab. NMN isn’t a regulated substance; it’s available as a supplement. So he tried it out, starting with small doses.
He knew quite well, though, that there are very big differences between mice and humans. At first he would say to me and to anyone else who asked, “Nothing has changed. How would I know?”
So the statement that came about six months into his NMN tryout was telling.
“I don’t want to get carried away,” he said, “but something is happening.”
He was feeling less tired, he told me. Less sore. More mentally aware. “I’m outpacing my friends,” he said. “They’re complaining about feeling old. They can’t even come for bushwalks with me anymore. I’m no longer feeling that way. I don’t have aches or pains. I’m beating much younger people at rowing exercises at the gym.” His doctor, meanwhile, was struck by the fact that his liver enzymes normalized after twenty years of being abnormal.
Upon his next visit to the United States, I noticed that something else was different, something very subtle. It dawned on me: for the first time since my mother’s death, the smile had returned to his face.
These days, he runs around like a teenager. Hiking for six days through wind and snow to reach the peak of the highest mountain in Tasmania. Riding three-wheelers through the Aussie bush. Hunting remote waterfalls in the American West. Zip-line touring through the forest in northern Germany. Whitewater rafting in Montana. Ice cave exploring in Austria.
He’s “aging in place,” but he’s rarely at his place.47
And because he missed working, he took on a new career at one of Australia’s largest universities, where he sits on the ethics committee that approves human research studies, taking full advantage of his knowledge about scientific rigor, medical practice, and data security.
You might expect this sort of behavior from someone who had lived his whole life this way, but he is definitely not a guy who has lived his whole life this way. Dad used to say he wasn’t looking forward to getting old. He isn’t outgoing or optimistic by nature; he’s more like Eeyore from Winnie-the-Pooh. He expected to have a decent ten years of retirement, then go into a nursing home. The future was clear. He had seen what had happened to his mother. He had watched helplessly as her health had declined in her 70s and 80s and as she had suffered from pain and dementia in the final decade of her life.
With all of that fresh in mind, the idea of living much past his 70s wasn’t very interesting to him. In fact, it was pretty scary. But he’s pretty happy with how it’s turning out and wakes up every morning with a deep-seated desire to fill his life with new, exciting experiences. To that end, he faithfully takes his metformin and his NMN each morning and gets nervous when they start to run low. The turnaround in his energy, enjoyment of life, and perspective on growing old has been remarkable. It could all be unrelated to the molecules he’s taking. I suppose his physical and mental transformation may just be how some people age. But it sure wasn’t that way for any of my other relatives.
My father is also wondering what to think. We are a family of scientists, after all. “I can’t be sure that the NMN is responsible,” he told me recently. He thought about his life for a moment, then smiled and shrugged his shoulders, “but there’s really no other explanation.”
Recently, after touring much of the East Coast of the United States, Dad was heading home to Australia. I sheepishly asked him if he could fly back to the United States for an event being held the following month. I had been named an Officer of the Order of Australia, an honor bestowed “for distinguished service to medical research into the biology of ageing, to biosecurity initiatives, and as an advocate for the study of science,” and there was going to be a ceremony at the Australian Embassy in Washington, DC.
“Sandra says it’s not fair of me to ask for you to come back,” I told him. “It’s only four weeks from now, and you’re almost eighty, and it’s a long journey back, and—”
“I would love to come,” he said, “but I’m just not sure I can fit it into my schedule.”
He canceled some meetings and did fit the trip into his schedule, and having him there, along with Sandra and the kids, ensured that it was one of the best days of my life. As I looked at Dad, standing with my family, I thought, “This is what longer life is all about—having your parents there for life’s important moments.”
And as he stood there, he later told me, he thought, “This is what longer life is all about—being around for your children’s important moments.”
My father’s story of reinvigoration is, of course, completely anecdotal. I won’t be publishing it in a scientific journal anytime soon—a placebo can be a powerful drug, after all. There’s simply no way to know if the combo of NMN and metformin is the reason he’s feeling better or is simply what he started taking at the time he decided, subconsciously, that it was time for a big change in his approach to life.
Compelling evidence that the clock of aging is reversible will come when well-planned double-blind human clinical studies are completed. Until then, I remain very proud of my father, an average guy who grabbed life by the horns in his late 70s to start his life anew—a shining example of what life can be like if we don’t accept aging as “just the way it goes.”
Still, it’s hard for me and anyone else who has seen what has happened to my father to not suspect that something special might be going on.
It’s also hard to know what I know, to see what I’ve seen—the results of experiments and other clinical trials around the world years before the rest of the world learns about them—and not believe that something profound is about to happen to humanity.
COME WHAT MAY
By engaging our bodies’ survival mechanisms in the absence of real adversity, will we push our lifespans far beyond what we can today? And what will be the best way to do this? Could it be a souped-up AMPK activator? A TOR inhibitor? A STAC or NAD booster? Or a combination of them with intermittent fasting and high-intensity interval training? The potential permutations are virtually endless.
Maybe the research under way on any one of these molecular approaches to battling aging will provide half a decade of additional good health. Maybe a combination of these compounds and an optimal lifestyle will be the elixir that gets us a couple of extra decades. Or maybe, as time goes by, our enthusiasm for these molecules will be dwarfed by what we discover next.
The discovery of the molecules I have described here can be credited to a lot of serendipity. But imagine what the world will discover now that we’re actively and intentionally looking for molecules that engage our in-built defenses. Armies of chemists are now working to create and analyze natural and synthetic molecules that have the potential to be even better at suppressing epigenomic noise and resetting our epigenetic landscape.
There are hundreds of compounds that have already shown potential in this area and hundreds of thousands more that are waiting to be researched. And it’s very possible that there is an as-yet-undiscovered chemical out there, hiding in a microorganism such as S. hygroscopicus or in a flower such as G. officinalis, that is just waiting to show us another way to help our bodies stay healthier longer. And that’s just the natural chemicals—which are typically many times less effective than the synthetic drugs they inspire. Indeed, the emerging analogs of the molecules I’ve already described are demonstrating tremendous potential in early-stage human clinical trials.
It will take some time to sort out which of these molecules are best, when, and for whom. But we’re getting closer every day. There will come a time in which significantly prolonged vitality is indeed only a few pills away; there are too many promising leads, too many talented researchers, and too much momentum for it to be otherwise.
Will any of these be a “cure” for aging? No. What’s likely is that researchers will continue to identify molecules that are better and better at promoting both a reduction of epigenetic noise and a rejuvenation of cellular tissue. As we do, we’ll be buying time for other advances that will also lead to significantly prolonged vitality.
But let’s say that doesn’t happen. For the sake of argument, not to mention emphasis, let’s pretend we live in a world in which none of these molecules had ever been discovered and no one had ever thought to address aging with a pharmaceutical.
That would not change the inevitability of longer and healthier lives. Not at all. For drugs that engage the ancient survival mechanisms within us are just one of the many ways that scientists, engineers, and entrepreneurs are setting the stage for the most significant shift in the evolution of our species since . . .
. . . well, since . . .
. . . forever.