Top Quotes: “Lifespan: Why We Age―and Why We Don’t Have To” — David Sinclair

Why We Age

“What’s the upward limit? I don’t think there is one. Many of my colleagues agree. There is no biological law that says we must age. Those who say there is don’t know what they’re talking about. We’re probably still a long way off from a world in which death is a rarity, but we’re not far from pushing it ever farther into the future.”

“Imagine you are a small rodent that is likely to be picked off by a bird of prey. Because of this, you’ll need to pass down your genetic material quickly, as did your parents and their parents before them. Gene combinations that would have provided a longer-lasting body were not enriched in your species because your ancestors likely didn’t escape predation for long (and you won’t, either).

Now consider instead that you are a bird of prey at the top of the food chain. Because of this, your genes — well, actually, your ancestors’ genes — benefited from building a robust, longer lasting body that could breed for decades. But in return, they could afford to raise only a couple of fledglings a year.

Kirkwood’s hypothesis explains why a mouse lives 3 years while some birds can live to 100. It also quite elegantly explains why the American chameleon lizard is evolving a longer lifespan as we speak, having found itself a few decades ago on remote Japanese islands without predators.”

“About a decade ago, the ideas of leading scientists in the aging field began to coalesce around a new model — one that suggested that the reason so many brilliant people had struggled to identify a single cause of aging was that there wasn’t one.

In this more nuanced view, aging and the diseases that come with it are the result of multiple “hallmarks” of aging:

• Genomic instability caused by DNA damage
• Attrition of the protective chromosomal endcaps, the telomeres
• Alterations to the epigenome that controls which genes are turned on and off
• Loss of healthy protein maintenance, known as protestasis
• Deregulated nutrient sensing caused by metabolic changes
• Mitochondrial dysfunction
• Accumulation of senescent zombielike cells that inflame healthy cells
• Exhaustion of stem cells
• Altered intercellular communication and the production of inflammatory molecules

Researchers began to cautiously agree: address these hallmarks, and you can slow down aging. Slow down aging, and you can forestall disease. Forestall disease, and you can push back death.

Take stem cells, which have the potential to develop into many other kinds of cells: if we can keep these undifferentiated cells from tiring out, they can continue to generate all the differentiated cells necessary to heal damaged tissues and battle all kinds of diseases. Meanwhile, we’re improving the rates of acceptance of bone marrow transplants, which are the most common form of stem cell therapy, and using stem cells for the treatment of arthritic joints, type 1 diabetes, loss of vision, and neurodegenerative diseases such as Alzheimer’s and Parkinson’s. These stem cell-based interventions are adding years to people’s lives.

Or take senescent cells, which have reached the end of their ability to divide but refuse to die, continuing to spit out panic signals that inflame surrounding cells: if we can kill off senescent cells or keep them from accumulating in the first place, we can keep our tissues much healthier for longer.

The same can be said for combating telomere loss, the decline in proteostasis, and all of the other hallmarks. Each can be addressed one by one, a little at a time, in ways that can help us extend human healthspans.”

“Yet I believe that such an answer exists — a cause of aging that exists upstream of all the hallmarks. Yes, a singular reason why we age.

Aging, quite simply, is a loss of information.”

“As cloning beautifully proves, our cells retain their youthful digital information even when we are old. To become young again, we just need to find some polish to remove the scratches.

This, I believe, is possible.”

“Mammals, for instance, don’t have just a couple of genes that create a survival circuit, such as those that first appeared in M. superstes. Scientists have found more than two dozen of them within our genome. Most of my colleagues call these “longevity genes” because they have demonstrated the ability to extend both average and maximum lifespans in many organisms. But these genes don’t just make life longer, they make it healthier, which is why they can also be thought of as “vitality genes.”

Together, these genes form a surveillance network within our bodies, communicating with one another between cells and between organs by releasing proteins and chemicals into the bloodstream, monitoring and responding to what we eat, how much we exercise, and what time of day it is. They tell us to hunker down when the going gets tough, and they tell us to grow fast and reproduce fast when the going gets easier.

And now that we know these genes are there and what many of them do, scientific discovery has given us an opportunity to explore and exploit them; to imagine their potential; to push them to work for us in different ways. Using molecules both natural and novel, using technology both simple and complex, using wisdom both new and old, we can read them, turn them up and down, and even change them altogether.”

“Descended from gene B in M. superstes, sirtuins are enzymes that remove acetyl tags from histones and other proteins and, by doing so, change the packaging of the DNA, turning genes off and on when needed. These critical epigenetic regulators sit at the very top of cellular control systems, controlling our reproduction and our DNA repair. After a few billion years of advancement since the days of yeast, they have evolved to control our health, our fitness, and our very survival. They have also evolved to require a molecule called nicotinamide adenine dinucleotide, or NAD. As we will see later, the loss of NAD as we age, and the resulting decline in sirtuin activity, is thought to be a primary reason our bodies develop diseases when we are old but not when we are young.”

“Trading reproduction for repair, the sirtuins order our bodies to “buckle down” in times of stress and protect us against the major diseases of aging: diabetes and heart disease, Alzheimer’s disease and osteoporosis, even cancer. They mute the chronic, overactive inflammation that drives diseases such as atherosclerosis, metabolic disorders, ulcerative colitis, arthritis, and asthma. They prevent cell death and boost mitochondria, the power packs of the cell. They go to battle with muscle wasting, osteoporosis, and macular degeneration. In studies on mice, activating the sirtuins can improve DNA repair, boost memory, increase exercise endurance, and help the mice stay thin, regardless of what they eat. These are not wild guesses as to their power; scientists have established all of this in peer-reviewed studies published in journals such as Nature, Cell, and Science.

And in no small measure, because sirtuins do all of this based on a rather simple program — the wondrous gene B in the survival circuit — they’re turning out to be more amenable to manipulation than many other longevity genes. They are, it would appear, one of the first dominos in the magnificent Rube Goldberg machine of life, the key to understanding how our genetic material protects itself during times of adversity, allowing life to persist and thrive for billions of years.

Sirtuins aren’t the only longevity genes. Two other very well studied sets of genes perform similar roles, which also have been proven to be manipulable in ways that can offer longer and healthier lives.

One of these is called target of rapamycin, or TOR, a complex of proteins that regulates growth and metabolism. Like sirtuins, scientists have found TOR — called mTOR in mammals — in every organism in which they ve looked for it. Like that of sirtuins, mTOR activity is exquisitely regulated by nutrients. And like the sirtuins, mTOR can signal cells in stress to hunker down and improve survival by boosting such activities as DNA repair, reducing inflammation caused by senescent cells, and, perhaps its most important function, digesting old proteins.

When all is well and fine, TOR is a master driver of cell growth. It senses the amount of amino acids that is available and dictates how much protein is created in response. When it is inhibited, though, it forces cells to hunker down, dividing less and reusing old cellular components to maintain energy and extend survival — sort of like going to the junkyard to find parts with which to fix up an old car rather than buying a new one, a process called autophagy. When our ancestors were unsuccessful in bringing down a woolly mammoth and had to survive on meager rations of protein, it was the shutting down of mTOR that permitted them to survive.

The other pathway is a metabolic control enzyme knoWn as AMPK, which evolved to respond to low energy levels. It has also been highly conserved among species and, as with sirtuins and TOR, we have learned a lot about how to control it

These defense systems are all activated in response to biological stress. Clearly, some stresses are simply too great to overcome — step on a snail, and its days are over. Acute trauma and uncontrollable infections will kill an organism without aging that organism. Sometimes the stress inside a cell, such as a multitude of DNA breaks, is too much to handle. Even if the cell is able to repair the breaks in the short term without leaving mutations, there is information loss at the epigenetic level.

Here’s the important point: there are plenty of stressors that will activate longevity genes without damaging the cell, including certain types of exercise, intermittent fasting, low-protein diets, and exposure to hot and cold temperatures. That’s called hormesis. Hormesis is generally good for organisms, especially when it can be induced without causing any lasting damage. When hormesis happens, all is well. And, in fact, all is better than well, because the little bit of stress that occurs when the genes are activated prompts the rest of the system to hunker down, to conserve, to survive a little longer. That’s the start of longevity.

Complementing these approaches are hormesis-mimicking molecules. Drugs in development and at least two drugs on the market can turn on the body’s defenses without creating any damage. It’s like making a prank call to the Pentagon. The troops and the Army Corps of Engineers are sent out, but there’s no war. In this way, we can mimic the benefits of exercise and intermittent fasting with a single pill.”

“Studies of identical twins place the genetic influences on longevity at between 10 and 25 percent which, by any estimation, is surprisingly low.”

“Youth — broken DNA — genome instability — disruption of DNA packaging and gene regulation (the epigenome) — loss of cell identity — cellular senescence — disease — death.

The implications were profound: if we could intervene in any of these steps, we might help people live longer.

But what if we could intervene in all of them? Could we stop aging?”

Stopping Aging

“Our DNA is constantly under attack. On average, each of our forty-six chromosomes is broken in some way every time a cell copies its DNA, amounting to more than 2 trillion breaks in our bodies per day. And that’s just the breaks that occur during replication. Others are caused by natural radiation, chemicals in our environment, and the X-rays and CT scans that we’re subjected to.

If we didn’t have a way to repair our DNA, we wouldn’t last long. That’s why, way back in primordium, the ancestors of every living thing on this planet today evolved to sense DNA damage, slow cellular growth, and divert energy to DNA repair until it was fixed — what I call the survival circuit.”

“When they’re home, those folks take care of the typical business of being at home: paying bills, mowing lawns, coaching baseball, whatever. But when they’re away, helping keep places like the Gulf Coast from descending into anarchy — a condition that would have had disastrous results for the rest of the nation — a lot of those things have to be put on hold.

When sirtuins shift from their typical priorities to engage in DNA repair, their epigenetic function at home ends for a bit. Then, when the damage is fixed and they head back to home base, they get back to doing what they usually do: controlling genes and making sure the cell retains its identity and optimal function.

But what happens when there’s one emergency after another to tend to? Hurricane after hurricane? Earthquake after earthquake? The repair crews are away from home a lot. The work they normally do piles up. The bills come due, then overdue, and then the folks from collections start calling.”

“One of the most important things they do while at home — reproducing — doesn’t get done. This form of hormesis, the original survival circuit, works fine to keep organisms alive in the short term. But unlike longevity molecules that simply mimic hormesis by tweaking sirtuins, mTOR, or AMPK, sending out the troops on fake emergencies, these real emergencies create life-threatening damage. What could cause so many emergencies? DNA damage. And what causes that? Well, over time, life does. Malign chemicals. Radiation. Even normal DNA copying.

These are the things that we’ve come to believe are the causes of aging, but there is a subtle but vital shift we have to make in that manner of thinking. It’s not so much that the sirtuins are overwhelmed, though they probably are when you are sunburned or get an X-ray; what’s happening every day is that the sirtuins and their coworkers that control the epigenome don’t always find their way back to their original gene stations after they are called away. It’s as if a few emergency workers who came to address the damage done in the Gulf Coast by Katrina had lost their home address. Then disaster strikes again and again, and they must redeploy.

Wherever epigenetic factors leave the genome to address damage, genes that should be off, switch on and vice versa. Wherever they stop on the genome, they do the same, altering the epigenome in ways that were never intended when we were born.

Cells lose their identity and malfunction. Chaos ensues. The chaos materializes as aging.”

“All of the symptoms of aging — the conditions that push mice, like humans, farther toward the precipice of death — were being caused not by mutation but by the epigenetic changes that come as a result of DNA damage signals.

We hadn’t given the mice all of those ailments. We had given them aging.

And if you can give something, you can take it away.”

“Bristlecones are, after all, our eukaryotic cousins — about half of their genes are close relatives of ours.

Yet they do not age.

Oh, they add years to their lives — thousands upon thousands of them, marked by the nearly microscopic ings hidden in their dense heartwood, which also record their size, shape, and chemical composition climate events long past.”

“Yet even over the course of many thousands of years, their cells do not appear to have undergone any decline n function. Scientists call this “negligible senescence.” ndeed, when a team from the Institute of Forest Genetics went looking for signs of cellular aging — studying bristlecones from 23 to 4,713 years old — they came up empty-handed. Between young and old trees, their 2001 study found, there were no meaningful differences in the chemical transportation systems, in the rate of shoot growth, in the quality of the pollen they produced, in the size of their seeds, or in the way those seeds germinated.

The researchers also looked for deleterious mutations — the sorts of which many scientists at the time expected to be a primary cause of aging. They found none. I expect that if they were to look for epigenetic changes, they would similarly come up empty-handed.

Bristlecones are outliers in the biological world, but they are not unique in their defiance of aging. The freshwater polyp known as Hydra vulgaris has also evolved to defy senescence. Under the right conditions, these tiny cnidarians have demonstrated a remarkable refusal to age. In the wild they might live for only a few months, subject to the powers of predation, disease, and desiccation. But in labs around the world they have been kept alive for upward of 40 years — with no signs that they’ll stop there — and indicators of health don’t differ significantly between the very young and the very old.

A couple of species of jellyfish can completely regenerate from adult body parts, earning them the nickname “immortal jellies.” Only the elegant moon jelly Aurelia aurita from the US West Coast and the centimeter-long Turritopsis dohrni from the Mediterranean are currently known to regenerate, but I’m guessing the majority of jellies do. We just need to look. If you separate one of these amazing animals into single cells, the cells jostle around until they form clumps that then assemble back into a complete organism, like the T-1000 cyborg in Terminator 2, most likely resetting their aging clock.”

“Though it’s not immortal, the Greenland shark is still an impressive animal and far more closely related to us. About the size of a great white, it does not even reach sexual maturity until it is 150 years old. Researchers believe the Arctic Ocean could be home to Greenland sharks that were born before Columbus got lost in the New World. Radiocarbon dating estimated that one very large individual may have lived more than 510 years.”

Biological Age

“These FOXO3 variants likely turn on the body’s defenses against diseases and aging, not just when times are tough but throughout life. If you’ve had your genome analyzed, you can check if you have any of the known variations of FQXO3 that are associated with a long life. For example, having a C instead of a T variant at position rs2764264 is associated with longer life.

Two of our children, Alex and Natalie, inherited two Cs at this position, one from Sandra and one from me, so all other genes being equal, and as long as they don’t live terribly negative lifestyles, they should have greater odds of living longer.”

“There are some simple tests to determine how biologically old you probably are. The number of push-ups you can do is a good indicator. If you are over 45 and can do more than twenty, you are doing well. The other test of age is the sitting-rising test (SRT). Sit on the floor, barefooted, with legs crossed. Lean forward quickly and see if you can get up in one move. A young person can. A middle-aged person typically needs to push off with one of their hands. An elderly person often needs to get onto one knee. A study of people 51 to 80 years found that 157 out of 159 people who passed away in 75 months had received less than perfect SRT scores.”

Diseases

“Sometimes, in fact, the treatment for one disease can be an aggravating factor for another. Chemotherapy can cure some forms of cancer, for instance, but it also makes people’s bodies more susceptible to other forms of cancer. And as we learned in the case of my grandmother Vera, something as seemingly routine as orthopedic surgery can make patients more susceptible to heart failure.”

“If we could stop all cardiovascular disease — every single case, all at once — we wouldn’t add many years to the average lifespan; the gain would be just 1.5 years. The same is true for cancer; stopping all forms of that scourge would give us just 2.1 more years of life on average, because all other causes of death still increase exponentially.”

“Your chance of developing a lethal disease increases by a thousandfold between the ages of 20 and 70, so preventing one disease makes little difference to lifespan.”

“So prevalent is the combined problem of early mortality and morbidity that there is a statistic for it: the disability-adjusted life year, or DALY, which measures the years of life lost from both premature death and poor state of health. The Russian DALY is the highest in Europe, with twenty-five lost years of healthy life per person. In Israel, it is an impressive ten years. In the United States, the number is a dismal twenty-three.”

“One study found that 85-year-old men are diagnosed with an average of four different diseases, with women of that age suffering from five. Heart disease and cancer. Arthritis and Alzheimer’s. Kidney disease and diabetes.”

“Being 50 years old increases your cancer risk a hundredfold. By the age of 70, it is a thousandfold.

Such exponentially increasing odds also apply to heart disease. And diabetes. And dementia. The list goes on and on. Yet there is not a country in the world that has committed any significant resources to help its citizens combat aging. In a world in which we seem to agree on very little, the feeling that “it’s just the way it goes” is almost universal.”

“If you are not yet convinced that aging is a disease, I want to let you in on a secret. I have a window into the future. In 2028, a scientist will discover a new virus, called LINE-1. It will turn out that we are all, infected with it. We get it from our parents. It will turn out that the LINE-1 virus is responsible for most other major diseases: diabetes, heart disease, cancer, dementia. It causes a slow, horrible chronic disorder, and all humans eventually succumb to it, even if they have a low-grade infection. Fortunately, the world pours billions of dollars into finding a cure. In 2033, a company will succeed in making a vaccine that prevents LINE-1 infections. New generations who are vaccinated, at birth will live fifty years longer than their parents did — it will turn out that that’s our natural lifespan and we had no idea. The new generation of healthy humans will pity previous generations, who blindly accepted that physical decline at 50 was natural and an 80-year life was a life well lived.

Of course, this is a science fiction story I just invented. But it might be truer than you think.

A few recent studies have suggested that the so-called selfish genes we all carry in our genome, actually called LINE-1 elements, replicate and cause cellular havoc as we get older, accelerating our physical demise.”

“Most middle-aged and older adults in the United States report feeling ten to twenty years younger than their age, because they still feel healthy. And feeling younger than your age predicts lower mortality and better cognitive abilities later in life.”

Calorie Restriction

“In animal studies, the key to engaging the sirtuin program appears to be keeping things on the razor’s edge through calorie restriction — just enough food to function in healthy ways and no more. This makes sense. It engages the survival circuit, telling longevity genes to do what they have been doing since primordial times: boost cellular defenses, keep organisms alive during times of adversity, ward off disease and deterioration, minimize epigenetic change, and slow down aging.”

“In 1978 on the island of Okanawa, lamed for its large number of centenarians, bioenergetics researcher Yasuo Kagawa learned that the total number of calories consumed by schoolchildren was less than two-thirds of what children were getting in mainland Japan. Adult Okinawans were also leaner, taking in about 20 percent fewer calories than their mainland counterparts. Kagawa noted that not only were the lifespans of Okinawans longer, but their healthspans were, too — with significantly less cerebral vascular disease, malignancy, and heart disease.

In the early 1990s, the Biosphere 2 research experiment provided another piece of evidence. For two years, from 1991 to 1993, eight people lived inside a three-acre, closed ecological dome in southern Arizona, where they were expected to be reliant on the food they were growing inside. Green thumbs they weren’t, though, and the food they farmed turned out to be insufficient to keep the participants on a typical diet. The lack of food wasn’t bad enough to result in malnutrition, but it did mean that the team members were frequently hungry.

One of the prisoners (and by “prisoners” I mean “experimental subjects”) happened to be Roy Walford, a researcher from California whose studies on extending life in mice are still required reading for scientists entering the aging field. I have no reason to suspect that Walford sabotaged the crops, but the coincidence was rather fortuitous for his research; it gave him an opportunity to test his mouse-based findings on human subjects. Because they were thoroughly medically monitored before, during, and after their two-year stint inside the dome, the participants gave Walford and other researchers a unique opportunity to observe the numerous biological effects of calorie restriction. Tellingly, the biochemical changes they saw in their bodies closely mirrored those Walford had seen in his long-lived calorie-restricted mice, such as decreased body mass (15 to 20 percent), blood pressure (25 percent), blood sugar level (21 percent), and cholesterol levels (30 percent), among others.”

“It sought to limit 145 adults to a diet of 25 percent fewer calories than is typically recommended for a healthy lifestyle. People being people, the actual calorie restriction achieved was, on average, about 12 percent over two years. Even that was enough, however, for the scientists to see a significant improvement in health and a slowdown in biological aging based on changes in blood biomarkers.”

“He didn’t look much younger than his age, though; in large part I suspect this was because a lack of fat exposes wrinkles, but his blood biochemistry suggested otherwise. On his 70th birthday, his health indicators, from blood pressure and LDL cholesterol to resting heart rate to visual acuity were typical of those of a much younger person.”

“Since the 1980s, a long-term study of calorie restriction in rhesus monkeys — our close genetic cousins — has produced stunningly compelling results. Before the study, the maximum known lifespan for any rhesus monkey was 40 years. But of twenty monkeys in the study that lived on calorie-restricted diets, six reached that age, which is roughly equivalent to their reaching 120 in human terms.

To hit that mark, the monkeys didn’t need to live on a calorie-restricted diet for their entire lives. Some of the test subjects were started on a 30 percent reduction regimen when they were middle-aged monkeys.”

“The earlier the mice start on CR, the greater the lifespan extension. What these and other animal studies tell us is that it’s hard to “age out” of the longevity benefits of calorie restriction, but it’s probably better to start earlier than later, perhaps after age 40, when things really start to go downhill, molecularly speaking.”

“Today, human studies are confirming that once-in-a-while calorie restriction can have tremendous health results, even if the times of fasting are quite transient.

In one such study, participants ate a normal diet most of the time but turned to a significantly restricted diet consisting primarily of vegetable soup, energy bars, and supplements for five days each month. Over the course of just three months, those who maintained the “fasting mimicking” diet lost weight, reduced their body fat, and lowered their blood pressure, too. Perhaps most important, though, the participants had lower levels of a hormone made primarily in the liver called insulin-like growth factor 1, or IGF-1. Mutations in IGF-1 and the IGF-1 receptor gene are associated with lower rates of death and disease and found in abundance in females whose families tend to live past 100.

Levels of IGF-1 have been closely linked to longevity.”

“As it turns out, there is a strong correlation between fasting behavior and longevity in Blue Zones such as Ikaria, Greece, “the island where people forget to die,” where one-third of the population lives past the age of 90 and almost every older resident is a staunch disciple of the Greek Orthodox church and adheres to a religious calendar that calls for some manner of fasting more than half the year. On many days, that means no meat, dairy products, or eggs and sometimes no wine or olive oil, either — for some Greeks, that’s just about everything. Additionally, many Greeks observe periods of total fasting before taking Holy Communion. Other longevity hot spots, such as Bama County in southern China, are places where people have access to good, healthy food but choose to forgo it for long periods each day. Many of the centenarians in this region have spent their lives eschewing a morning meal. They generally eat their first small meal of the day around noon, then share a larger meal with their families at twilight. In this way, they typically spend sixteen hours or more of each day without eating.”

“Over time, some of these ways of limiting food will prove to be more effective than others. A popular method is to skip breakfast and have a late lunch (the 16:8 diet). Another is to eat 75 percent fewer calories for two days a week (the 5:2 diet).”

Plant-Based Diets

“When we substitute animal protein with more plant protein, studies have shown, all-cause mortality falls significantly.

From an energy perspective, the good news is that there isn’t a single amino acid that can’t be obtained by consuming plant-based protein sources. The bad news is that, unlike most meats, weight for weight, any given plant usually delivers limited amounts of amino acids.

From a vitality perspective, though, that’s great news. Because a body that is in short supply of amino acids overall, or any single amino acid for a spell, is a body under the very sort of stress that engages our survival circuits.

You’ll recall that when the enzyme known as mTOR is inhibited, it forces cells to spend less energy dividing and more energy in the process of autophagy, which recycles damaged and misfolded proteins. That act of hunkering down ends up being good for prolonged vitality in every organism we’ve studied. What we’re coming to learn is that mTOR isn’t impacted only by caloric restriction. If you want to keep TOR from being activated too much or too often, limiting your intake of amino acids is a good way to start, so inhibiting this particular longevity gene is really as simple as limiting your intake of meat and dairy.

It’s also increasingly clear that all essential amino acids aren’t equal. Rafael de Cabo at the National Institutes of Health, Richard Miller at the University of Michigan, and Jay Mitchell at Harvard Medical School have found over the years that feeding mice a diet with low levels of the amino acid methionine works particularly well to turn on their bodily defenses, to protect organs from hypoxia during surgery, and to increase healthy lifespan by 20 percent. One of my former students, Dudley Lamming, who now runs a lab at the University of Wisconsin, demonstrated that methionine restriction causes obese mice to shed most of their fat — and fast. Even as the mice, which Lamming called “couch potatoes, continued to eat as much as they wanted and shun exercise, they still lost about 70 percent of their fat in a month, while also lowering their blood glucose levels.

We can’t live without methionine. But we can do a better job of restricting the amount of it we put into our bodies. There’s a lot of methionine in beef, lamb, poultry, pork, and eggs, whereas plant proteins, in general, tend to contain low levels of that amino acid-enough to keep the light on, as it were, but not enough to let biological complacency set in.

The same is true for arginine and the three branched-chain amino acids, leucine, isoleucine, and valine, all of which can activate mTOR. Low levels of these amino acids correlate with increased lifespan and in human studies, a decreased consumption of branched-chain amino acids has been shown to improve markers of metabolic health significantly.

We can’t live without them, but most of us can definitely stand to get less of them, and we can do that by lowering our consumption of foods that many people consider to be the “good animal proteins,” chicken, fish, and eggs — particularly when those foods aren’t being used to recover from physical stress or injury.

All of this might seem counterintuitive; amino acids, after all, are often considered helpful. And they can be. Leucine, for instance, is well known to boost muscle, which is why it’s found in large quantities in the protein drinks that bodybuilders often chug before, during, and after workouts. But that muscle building is coming in part because leucine is activating mTOR, which essentially calls out to your body, “Times are good right now, let’s disengage the survival circuit.” In the long run, however, protein drinks may be preventing the mTOR pathway from providing its longevity benefits. Studies in which leucine is completely eliminated from a mouse’s diet have demonstrated that just one week without this particular amino acid significantly reduces blood glucose levels, a key marker of improved health. So a little leucine is necessary, of course, but a little goes a long way.

All of these findings may explain why vegetarians suffer significantly lower rates of cardiovascular disease and cancer than meat eaters. The reduction of amino acids — and thus the inhibition of mTOR — isn’t the only thing at play in that equation. The lower calorie content, increased polyphenols, and feeling of superiority over your fellow human beings are also helpful. All of these, except the last, are valid explanations for why vegetarians live longer and stay healthier.”

Exercise

“Yes, exercise improves blood flow. Yes, it improves lung and heart health. Yes, it gives us bigger, stronger muscles. But more than any of that — and indeed, what is responsible for much of that — is a simple thing that happens at a much smaller scale: the cellular scale.

When researchers studied the telomeres in the blood cells of thousands of adults with all sorts of different exercise habits, they saw a striking correlation: those who exercised more had longer telomeres. And according to one study funded by the Centers for Disease Control and Prevention and published in 2017, individuals who exercise more — the equivalent of at least a half hour of jogging five days a week — have telomeres that appear to be nearly a decade younger than those who live a more sedentary life. But why would exercising delay the erosion of telomeres?

If you think about how our longevity genes work — employing those ancient survival circuits — this all makes sense. Limiting food intake and reducing the heavy load of amino acids in most diets aren’t the only ways to activate longevity genes that order our cells to shift into survival mode. Exercise, by definition, is the application of stress to our bodies. It raises NAD levels, which in turn activates the survival network, which turns up energy production and forces muscles to grow extra oxygen-carrying capillaries. The longevity regulators AMPK, mTOR, and sirtuins are all modulated in the right direction by exercise, irrespective of caloric intake, building new blood vessels, improving heart and lung health, making people stronger, and, yes, extending telomeres. SIRT1 and SIRT6, for example, help extend telomeres, then package them up so they are protected from degradation. Because it’s not the absence of food or any particular nutrient that puts these genes into action; instead it is the hormesis program governed by the survival circuit, the mild kind of adversity that wakes up and mobilizes cellular defenses without causing too much havoc.

There’s really no way around this. We all need to be pushing ourselves, especially as we get older, yet only 10 percent of people over the age of 65 do. The good news is that we don’t have to exercise for hours on end. One recent study found that those who ran four to five miles a week — for most people, that’s an amount of exercise that can be done in less than 15 minutes per day — reduce their chance of death from a heart attack by 40 percent and all-cause mortality by 45 percent. That’s a massive effect.

In another study, researchers reviewed the medical records of more than 55,000 people and cross-referenced those documents with death certificates issued over fifteen years. Among 3,500 deaths, they weren’t particularly surprised to see that those who had told their doctors they were runners were far less likely to die of heart disease. Even when the researchers adjusted for obesity and smoking, the runners were less likely to have died during the years of the study. The big shock was that the health benefits were remarkably similar no matter how much running the people had done. Even about ten minutes of moderate exercise a day added years to their lives.

There is a difference between a leisurely walk and a brisk run, however. To engage our longevity genes fully, intensity does matter. Mayo Clinic researchers studying the effects of different types of exercise on different age groups found that although many forms of exercise have positive health effects, it’s high-intensity interval training (HIIT) — the sort that significantly raises your heart and respiration rates — that engages the greatest number of health — promoting genes, and more of them in older exercisers.

You’ll know you are doing vigorous activity when it feels challenging. Your breathing should be deep and rapid at 70 to 85 percent of your maximum heart rate. You should sweat and be unable to say more than a few words without pausing for breath. This is the hypoxic response, and it’s great for inducing just enough stress to activate your body’s defenses against aging without doing permanent harm.”

“Many of the longevity genes that are turned on by exercise are responsible for the health benefits of exercise, such as extending telomeres, growing new microvessels that deliver oxygen to cells, and boosting the activity of mitochondria, which burn oxygen to make chemical energy. We’ve known for a long time that these bodily activities fall as we age. What we also know now is that the genes most impacted by exercise-induced stress can bring them back to the levels associated with youth. In other words: exercise turns on the genes to make us young again at a cellular level.”

Temperature

“Exposing your body to less-than-comfortable temperatures is another very effective way to turn on your longevity genes.

When the world takes us out of the thermoneutral zone — the small range of temperatures that don’t require our bodies to do any extra work to stay warm or cool off — all sorts of things happen. Our breathing patterns shift. The blood flow to and through our skin — the largest organ in our body — changes. Our heart rates speed up or slow down. These reactions aren’t happening just “because.” All of these reactions have genetic roots dating back to M. superstes’s fight for survival all those billions of years ago.

Homeostasis, the tendency for living things to seek a stable equilibrium, is a universal biological principle. Indeed, it is the guiding force of the survival circuit. And thus we see it everywhere we look — especially on the low end of the thermometer. As scientists have increasingly turned their attention to the impacts of reduced food intake on the human body, it has quickly become clear that calorie restriction has the effect of reducing core body temperature. It wasn’t at first clear whether this contributed to prolonged vitality or was simply a by-product of all of the changes happening in the bodies of organisms exposed to this particular sort of stress.

Back in 2006, though, a team from the Scripps Research Institute genetically engineered some lab mice to live their lives a half degree cooler than normal-a feat they accomplished by playing a trick on the mice’s biological thermostat. The team inserted copies of the mouse UCP2 gene into the mice’s hypothalamus, which regulates the skin, sweat glands, and blood vessels. UCP2 short-circuited mitochondria in the hypothalamus so they produced less energy but more heat. That, in turn, caused the mice to cool down about half a degree Celsius. The result was a 20 percent longer life for female mice, the equivalent of about seven additional healthy human years, while male mice got an extension of 12 percent.”

“Not only could UCP2 make mice “run cold,” the Canadian team demonstrated, but colder temperatures could change the way the gene operated, too — through its ability to rev up brown adipose tissue.

Also known as “brown fat,” this mitochondria-rich substance was, until recently, thought to exist only in infants. Now we know that it is found in adults, too, although the amount of it decreases as we age. Over time, it becomes harder and harder to find; it mingles with white fat and is spread out even more unevenly across the body. It “hangs out” in different areas in different people, sometimes in the abdomen, sometimes across the upper back.”

“One study of genetically-engineered mice, for instance, demonstrated that the function of brown fat is enhanced in these remarkably long-lived animals. Other studies have shown that animals with abundant brown fat or subjected to shivering cold for 3 hours a day have much more of the mitochondrial, UCP-boosting sirtuin, SIRT3, and experience significantly reduced rates of diabetes, obesity, and Alzheimer’s.”

“Another thing you can try is activating the mitochondria in your brown fat by being a bit cold. The best way to do this might be the simplest — a brisk walk in a T-shirt on a winter day in a city such as Boston will do the trick. Exercising in the cold, in particular, appears to turbocharge the creation of brown adipose tissue. Leaving a window open overnight or not using a heavy blanket while you sleep could help too.”

“A 2018 study conducted in Helsinki found that “physical function, vitality, social functioning, and general health were significantly better among sauna users than non-users,” although the researchers were correct to point out that part of the effect could be due to the fact that those who are sick or disabled don’t go to the sauna.

A more convincing study followed a group of more than 2,300 middle-aged men from eastern Finland for more than twenty years. Those who used a sauna with great frequency — up to seven times a week — enjoyed a twofold drop in heart disease, fatal hearts attacks, and all-cause mortality events over those who heat bathed once per week.”

Hazards

“The levels of DNA-damaging aromatic amines in cigarette smoke are about fifty to sixty times as high in secondhand as in firsthand smoke.”

“It would also be wise to be wary of the PCBs and other chemicals found in plastics, including many plastic bottles and take-out containers. (Avoid microwaving these; it releases even more PCBs.) Exposure to azo dyes, such as aniline yellow, which is used in everything from fireworks to the yellow ink in home printers, can also damage our DNA. And or-ganohalides — compounds that contain substituted halogen atoms and are used in solvents, degreasers, pesticides, and hydraulic fluid — can also wreak havoc on our genomes.”

“We’ve known for more than half a century that N-nitroso compounds are present in food treated with sodium nitrite, including some beers, most cured meats, and especially cooked bacon. In the decades since, we’ve learned that these compounds are potent carcinogens. What we’ve also come to understand is that cancer is just the start of our nitrate-treated woes, because nitroso compounds can inflict DNA breakage as well — sending those overworked sirtuins back to work some more.

Then there’s radiation. Any source of natural or human-inflicted radiation, such as UV light, X-rays, gamma rays, and radon in homes (which is the second most frequent cause of lung cancer besides smoking) can cause additional DNA damage, necessitating the call-up of an epigenetic fix-it team. As someone who flies a lot for work, I think about this quite a bit — every time I go through security, in fact. Most of the research on the current versions of airport scanners suggests that they probably don’t do tremendous damage to our DNA, but there’s been little attention given to their long-term impact on our epigenome and the aging process. No one has ever tested what a mouse looks like two years after being repeatedly exposed to these devices. The ICE mice tell us that chromosome tickling is all that’s needed to accelerate aging. I’m aware the radiation exposure from millimeter-wave scanners is lower than that from previous scanners. The security attendants at the machine tell travelers the exposure is about the “same as the flight.” But with millions of flight miles under my belt, why would I want to double the damage? Whenever possible, I take the pre-check line or ask for a pat down instead.”

Biology

“Life can potentially last forever, as long as it can preserve critical biological information and absorb energy from somewhere in the universe.”

“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 moi 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.”

“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. 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. 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.

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.”

“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 lifespan and in humans dramatically improved the immune responses of elderly people to a flu vaccine.”

“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.”

“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.

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. 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.

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. 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. 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.

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. 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.

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. 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.”

“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. 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.”

Research

“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?”

“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.”

“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.

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. 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. Ever wonder why organic foods, which are often grown under more stressful conditions, might be better for you?”

“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.

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. 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.”

“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.”

“Shin-ichiro mai 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, 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 Ima 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 ultra-marathoners; 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.”

“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.”

Fertility

“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.”

“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.”

“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.”

“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.

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. 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, while the same gene pathway plays an important role in male fertility, as a central player in the production and development of sperm.”

Senescence

“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.”

“Although the enzyme known as telomerase can extend telomeres — the discovery of which afforded Elizabeth Blackburn, Carol Greider, and Jack Szostak a Nobel Prize in 2009 — it is switched off to protect us from cancer, except in stem cells. In 1997, it was a remarkable finding that if you put telomerase into cultured skin cells, they don’t ever senesce.

Why short telomeres cause senescence has been mostly worked out. A very short telomere will lose its histone packaging, and, like a shoelace that’s lost an aglet, the DNA at the end of the chromosome becomes exposed. The cell detects the DNA end and thinks it’s a DNA break. It goes to work to try to repair the DNA end, sometimes fusing two ends of different chromosomes together, which leads to hypergenome instability as chromosomes are shredded during cell division and fused again, over and over, potentially becoming a cancer.”

“I suspect that senescence in nerve and muscle cells, which don’t divide much or at all, is the result of epigenetic noise that causes cells to lose their identity and shut down. This once-beneficial response, which evolved to help cells survive DNA damage, has a dark side: the permanently panicked cell sends out signals to surrounding cells, causing them to panic, too. Senescent cells are often referred to as “zombie cells,” because even though they should be dead, they refuse to die.”

“Small numbers of senescent cells can cause widespread havoc. Even though they stop dividing, they continue to release tiny proteins called cytokines that cause inflammation and attract immune cells called macrophages that then attack the tissue.”

“We already know that destroying senescent cells in mice can give them substantially healthier and significantly longer lives. It keeps their kidneys functioning better for longer. It makes their hearts more resistant to stress. Their lifespans, as a result, are 20 to 30 percent longer, according to research led by Mayo Clinic molecular biologists Darren Baker and Jan van Deursen. In animal models of disease, killing of senescent cells makes fibrotic lungs more pliable, slows the progression of glaucoma and osteoarthritis, and reduces the size of all sorts of tumors.”

“It’s proposed that we evolved senescence as a rather clever trick to prevent cancer when we are in our 30s and 40s. Senescent cells, after all, don’t divide, which means that cells with mutations aren’t able to spread and form tumors. But if senescence evolved to prevent cancer, why would it eventually promote cancer in adjacent tissue, not to mention a host of other aging-related symptoms?

This is where “antagonistic pleiotropy” comes into play: the idea that a survival mechanism that is good for us when we are young is kept through evolution because this far outweighs any problems it might cause when we get older. Yes, natural selection is callous, but it works.”

“A class of pharmaceuticals called senolytics may be the zombie killers we need to fight the battle against aging on this front. These small-molecule drugs are designed to specifically kill senescent cells by inducing the death program that should have happened in the first place.

That’s what the Mayo Clinic’s James Kirkland has done. He needed only a quick course of two senolytic molecules — quercetin, which is found in capers, kale, and red onions, and a drug called dasatinib, which is a standard chemotherapy treatment for leukemia — to eliminate the senescent cells in lab mice and extend their lifespan by 36 percent. The implications of this work cannot be overstated. If senolytics work, you could take a course of a medicine for a week, be rejuvenated, and come back ten years later for another course. Meanwhile, the same medicines could be injected into an osteoarthritic joint or an eye going blind, or inhaled into lungs made fibrotic and inflexible by chemotherapy, to give them an age-reversal boost, too. (Rapamycin, the Easter Island longevity molecule, is what’s known as a “senomorphic” molecule, in that it doesn’t kill senescent cells but does prevent them from releasing inflammatory molecules, which may be almost as good.)

The first human trials of senolytics were started in 2018 to treat osteoarthritis and glaucoma, conditions in which senescent cells can accumulate. It will be a few more years before we know enough about the effects and safety of these drugs to provide them to everyone, but if they work, the potential is vast.”

“In 2018, scientists at Stanford University reported that they had developed an inoculation that significantly lowered the rates at which mice suffered from breast, lung, and skin cancer. By injecting the mice with stem cells inactivated by radiation and later adding a booster shot like those humans use for tetanus, hepatitis B, and whooping cough, the stem cells primed the immune system to attack cancers that normally would be invisible to the immune system. Other immunooncological approaches are making even greater strides. Therapies such as PD-1 and PD-L1 inhibitors, which expose cancer cells so they can be killed, and chimeric antigen receptors T-cell (CART) therapies, which modify the patient’s own immune T-cells and reinject them to go kill cancer cells, are saving lives of people who, just a few years before, have been told to go home and make funeral arrangements. Now, some of these patients are being given a new lease on life.

If we can use the immune system to kill cancer cells, it stands to reason that we can do that for senescent cells, too. And some scientists are on the case. Judith Campisi from the Buck Institute for Research on Aging and Manuel Serrano from Barcelona University believe that senescent cells, like cancers, remain invisible to the immune system by waving little protein signs that say, “No zombie cells here.”

If Campisi and Serrano are right, we should be able to take away those signs and give the immune system permission to go kill senescent cells. Perhaps a few decades from now a typical vaccine schedule that currently protects babies against polio, measles, mumps, and rubella might also include a shot to prevent senescence when they reach middle age.”

Cloning

“Cloning is now routinely done to produce farm animals, racehorses, and even pets. In 2017, you could order up a dog clone for the “bargain” price of $40,000 — or two of them, as Barbra Streisand did to replace her beloved Sammie, a curly haired Coton de Tu-lear.9 The fact that Sammie was 14 when she died and donated cells — that’s somewhere in the range of 75 in human years — didn’t impact the clones one bit. The implications of these experiments are profound.

What they show is that aging can be reset.”

“When an egg is fertilized, epigenetic information — biological “radio signals” — is sent out. It travels between dividing cells and across time. If all goes well, the egg develops into a healthy baby and eventually a healthy teenager. But with successive cell divisions and the overreaction of the survival circuit to DNA damage, the signal becomes increasingly noisy. Eventually, the receiver, your body when it is 80, has lost a lot of the original information.

We know that cloning a new tadpole or a mammal from an old one is possible. So even if a lot of the epigenetic information is lost in old age, obscured by epigenetic noise, there must be information that tells the cell how to reset. This fundamental information, laid down early in life, is able to tell the body how to be young again — the equivalent of a backup of the original data.”

The Future

“To end aging as we know it, we need to find three more things that Shannon knew were essential for a signal to be restored even if it is obscured by noise:

• An “observer” who records the original data
• The original “correction data”
• And a “correcting device” to restore the original signal

I believe we may have finally found the biological correcting device.

In 2006, the Japanese stem cell researcher Shinya Yamanaka announced to the world that after testing dozens of combinations of genes, he had discovered that a set of four — Oct4, KIf4, Sox2, and c-Myc — could induce adult cells to become pluripotent stem cells, or iPSCs, which are immature cells that can be coaxed into becoming any other cell type. These four genes code for powerful transcription factors that each controls entire sets of other genes that move cells around on the Waddington landscape during embryonic development.”

“I predict, and my students are now showing in the lab, that we can use these and other switches not just to reset our cells in petri dishes but to reset an entire body’s epigenetic landscape — to get the marbles back into the valleys where they belong — sending sirtuins back to where they came from, for instance. Cells that have lost their identity during aging can be led back to their true selves we’ve been looking for.”

“There are a rapidly increasing number of approved gene therapy products and hundreds of clinical trials under way. Patients with an RPE65 mutation that causes blindness, for example, can now be cured with a simple injection of a safe virus that infects the retina and delivers, forever, the functional RPE65 gene.

I predict that cellular reprogramming in the body will first be used to treat age-related diseases in the eye, such as glaucoma and macular degeneration (the eye is the organ of choice to trial gene therapies because it is immunologically isolated). But if the therapy is safe enough to deliver into the entire body — as the long-term mouse studies in my lab suggest they might one day be — this may be in our future:

At age 30, you would get a week’s course of three injections that introduce a specially engineered adeno-associated virus, or AAV, which causes a very mild immune response, less even than what is commonly caused by a flu shot. The virus, which has been known to scientists since the 1960s, has been modified so it doesn’t spread or cause illness. What this theoretical version of the virus would carry would be a small number of genes — some combination of Yamanaka factors, perhaps — and a fail-safe switch that could be turned on with a well-tolerated molecule such as doxycycline, an antibiotic that can be taken as a tablet, or, even better, one that’s completely inert.

Nothing, at that point, would change in the way your genes work. But when you began to see and feel the effects of aging, likely sometime in your mid-40s, you would be prescribed a month’s course of doxycycline. With that, the reprogramming genes would be switched on.

During the process, you’d likely place a drop of blood in a home biotracker or pay a visit to the doctor to make sure the system was working as expected, but that’s about it. Over the next month, your body would undergo a rejuvenation process as Waddington’s marbles were sent back to where they once were when you were young. Gray hair would disappear. Wounds would heal faster. Wrinkles would fade. Organs would regenerate. You would think faster, hear higher-pitched sounds, and no longer need glasses to read a menu. Your body would feel young again.

Like Benjamin Button, you would feel 35 again. Then 30. Then 25.

But unlike Benjamin Button, that’s where you would stop. The prescription would be discontinued. The AAV would switch off. The Yamanaka factors would fall si-lent. Biologically, physically, and mentally, you would be a couple of decades younger, but you’d retain all your knowiedge, wisdom, and memories.

You would be young again, not just looking young but actually young, free to spend the next few decades of your life without the aches and pains of middle age, untroubled by the prospects of cancer and heart disease. Then, a few more decades down the road, when those gray hairs begin showing up again, you’d start another cycle of the prescribed trigger.

What’s more, with the pace at which biotech is advancing, and as we learn how to manipulate the factors that reset our cells, we may be able to move away from using viruses and simply take a month’s course of pills.

Does that sound like science fiction? Something that is very far out in the future? Let me be clear: it’s not.

Manuel Serrano, the leader of the Cellular Plasticity and Disease laboratory at the Institute for Research in Biomedicine in Barcelona, and Juan Carlos Izpisua Belmonte, at the Salk Institute for Biological Studies in San Diego, have already engineered mice that have all of the Yamanaka factors from birth; these can be turned on by injecting the mice with doxycycline. In a now-famous study from 2016, when Belmonte triggered the Yamanaka factors for just two days a week throughout the lifespan of a prematurely aging mouse breed called LMNA, the mice remained young compared to their untreated siblings and lived 40 percent longer.”

“Yancheng and our skilled collaborators in Professor Zhigang He’s lab at Children’s Hospital at Harvard Medical School have now tested our reprogramming regimen on the damaged optic nerves of middle-aged mice aged twelve months. Their nerves also regenerate.

As I write this, we have restored vision in regular old mice.”

“If adult cells in the body, even old nerves, can be reprogrammed to regain a youthful epigenome, the information to be young cannot all be lost. There must be a repository of correction data, a backup set of data or molecular beacons, that is retained through adulthood and can be accessed by the Yamanaka factors to reset the epigenome using the cellular equivalent of TCP/IP.”

“The future looks interesting, to say the least. If we can fix the toughest-to-fix and regenerate the toughest-to-regenerate cells in our body, there’s really no reason to suspect we cannot regrow any type of cells our bodies need. Yes, that could mean fixing fresh spinal cord injuries, but it also means regrowing any other kind of tissue in our body that has been damaged by age: from the liver to the kidney, from the heart to the brain. Nothing is off the table.”

“In late 2018, a Chinese researcher, He Jiankui, reported that he had helped create the world’s first genetically altered children — twin girls whose births sparked a debate in scientific circles about the ethics of using gene editing to make “designer babies.””

“Lawan did have an aggressive cancer but not the kind of cancer for which she was being treated. She didn’t have lung cancer; she had a solid form of leukemia growing in her lung.

In the vast majority of cases in which cancer is found where it was found in Lawan’s body, it is indeed lung cancer. But now that we can detect the genetic signature of specific forms of cancer, using the place where you find the cancer as the only guide for what treatment to use is as ridiculous as categorizing an animal species based on where you’ve located it. It is like saying a whale is a fish because they both live in water.

Once we have a better idea of what kind of cancer we’re dealing with, we can better apply emerging techniques for dealing with it. We can even design a therapy tailored to a patient’s specific tumor — killing it before it has a chance to grow or spread to another place in the body.

That’s the idea behind one of the cancer-fighting innovations we discussed earlier, CAR T-cell therapy, in which doctors remove immune system cells from a patient’s blood and add a gene that allows the cells to bind to proteins on the patient’s tumor. Grown en masse in a lab and then reinfused into the patient’s body, the CAR T-cells go to work, hunting down cancer cells and killing them by using the body’s own defenses.

Another immunooncology approach we discussed earlier, checkpoint blockade therapy, quashes the ability of cancerous cells to evade detection by our immune systems. Much of the early work on this technique was completed by Arlene Sharpe, whose lab is located on the floor above mine at Harvard Medical School. In this approach, drugs are used to block the ability of cancer cells to present themselves as regular cells, essentially confiscating their fake passports and thus making it easier for T-cells to discriminate between friend and foe. This is the approach that was used, along with radiation therapy, by former president Jimmy Carter’s doctors to help his immune system fight off the melanoma in his brain and liver. Prior to this innovation, a diagnosis like his was, without exception, fatal.

CAR-T therapy and checkpoint inhibition are less than a decade old. And there are hundreds of other immuno-oncology clinical trials under way. The results thus far are promising, with remission rates of greater than 80 percent in some studies. Doctors who have spent their entire careers fighting cancer say this is the revolution they’ve been waiting for.

DNA-sequencing technology has also offered us an opportunity to understand the evolution of a specific patient’s cancer. We can take single cells from a slice of a tumor, read every letter of the DNA in those cells, and look at the cells’ three-dimensional chromatin architecture. In doing so, we can see the ages of different parts of the tumor. We can see how it has grown, how it has continued to mutate, and how it has lost its identity over time. That’s important, because if you look at only one part of a tumor — an older part, for instance — you could be missing the most aggressive part. Accordingly, you might treat it with a less effective therapy.Through sequencing, we can even see what kinds of bacteria have managed to make their way into a tumor. Bacteria, it turns out, can protect tumors from anticancer drugs. Using genomics, we can identify which bacteria are present and predict which antibiotics will work against those single-celled tumor protectors.

We can do all of this. Right now. Yet in many hospitals around the world the if-it-is-here-it-must-be-this and if-the-symptoms-are-this-it-must-be-that modes of diagnosis are still practiced.”

“Those aren’t the only questions that our DNA can answer. Increasingly, it can also tell you what foods to eat, what microbiomes to cultivate in your gut and on your skin, and what therapies will work best to ensure that you reach your maximum potential lifespan.”

“Those who score in a certain range on a genetic test called Oncotyoe DX, it has been discovered, respond every bit as well to hormone treatments as they do to chemo, the latter of which has far more side effects. The tragedy of this discovery is that it didn’t come until 2015.”

“It won’t be long before prescribing a drug without first knowing a patient’s genome will seem medieval.

And vitally, with genomic information aiding in our doctors’ decisions, we won’t have to wait to become sick to know what treatments will work best to prevent those diseases from developing in the first place.

As Julie Johnson, the director of the University of Florida’s Personalized Medicine Program, has pointed out, we are about to enter a world in which our genomes will be sequenced, stored, and already red-lighted for treatments that have been demonstrated to have adverse effects on people with similar gene types and combinations as we have. Likewise, we’ll be green-lighted for treatments that are known to work for people with similar genes, even if those treatments don’t work for most other people most of the time. This will be particularly important in developing countries, where the local genetics and gut flora are wildly different from the local population the drug was tested on.”

“Our flawed, symptom-first approach to medicine is about to change. We’re going to get ahead of symptoms. Way ahead. We’re even going to get ahead of “feeling bad.” Many diseases, after all, are genetically detectable long before they are symptomatic. In the very near future, proactive personal DNA scanning is going to be as routine as brushing our teeth.”

“Rhonda Patrick, a longevity scientist turned health and fitness expert, has been using a continual blood glucose-sensing device to see what foods give her body a major sugar spike, something many of us believe is to be avoided if we are to give ourselves the greatest chance of a long life. She’s seen that, at least for her, white rice is bad and potatoes aren’t so bad. When I asked her what food had been the most surprising, she didn’t hesitate.

“Grapes!” she exclaimed. “Avoid grapes.””

“A few companies are developing handheld breath analyzers that can diagnose cancer, infectious diseases, and inflammatory diseases. Their mission: to save 100,000 lives and $1.5 billion in health care costs. Numerous other companies are working on designing clothing with sensors that can track biomarkers, and automotive engineers are exploring putting biosensors in car seats that would send an alert to your dashboard or doctor if there’s something amiss in your heart rate or breathing pattern.

As I write this, I am wearing a regular-sized ring that is monitoring my heart rate, body temperature, and movements. It tells me each morning if I slept well, how much I dreamed, and how alert I will be during the day.”

“The most critical daily decisions that affect how long we live are centered around the foods we eat. If your blood sugar is high at breakfast, you’ll know to avoid sugar in your morning coffee. If your body is low on iron at lunch, you’ll know it and can order a spinach salad to compensate. When you get home from work, if you’ve failed to go outside for your daily dose of vitamin D from the sun, you’ll know that, too, and you’ll be able to mix up a smoothie that will address the deficiency. If you’re on the road and you need X vitamin or Y mineral, you’ll know not only what you need but where to get it. Your personal virtual assistant — the same Al-driven being who answers your internet search queries and reminds you about your next meeting — will point you to the nearest restaurant that has what you need or offer to have it delivered by a drone to wherever you are. It could, quite literally, be dropped into your hands from the sky”.

“In the future, if you are experiencing a heart attack — even if it’s perceptible only as a slight pain in your arm — or a ministroke, which so often goes undiagnosed until it’s identified on a brain scan years later, you’ll be alerted, and so will those around you who need to know. In an emergency, a trusted neighbor, a best friend, or whatever doctor happens to be closest to you can also be alerted. An ambulance will be dispatched to your door. This time, the doctors at the nearest hospital will know exactly why you are coming in before you even arrive.

Do you know an emergency room doctor? Ask her about the value of a single minute of additional treatment time. Or a single blood test’s worth of additional information.”

“At a time in which the era of human flight was in its infancy and most people had never ridden in a car, the H1N1 virus found its way to some of the furthest reaches of our globe. It killed people on remote islands and in arctic villages. It killed without regard to race or national boundaries. It killed like a new Black Death. Average life expectancy in the United States plummeted from 55 to 40 years. It recovered, but not until more than 100 million people of all ages globally had had their lives cut short.”

“Individually, of course, real-time monitoring of vitals and body chemicals offers incredible benefits for optimizing health and preventing emergencies. Collectively, though, it could help us get ahead of a global pandemic.”

“It’s even worse for patients in Japan, where the ability to get an organ transplant remains far below those of Western countries. The reasons are both cultural and legal. In 1968, the Buddhist belief that the body should not be divided after death fueled an emotion-laden firestorm in the media about whether the first Japanese heart donor had truly been “brain dead” when the heart was removed by Dr. Juro Wada. A strict law was immediately enacted that banned the removal of organs from a cadaver until the heart had stopped beating. The law was relaxed thirty years later, but the Japanese remain divided on the issue and good organs remain hard to come by.”

“The geneticist Luhan Yang and her former mentor Professor George Church in my department at Harvard Medical School had just discovered how to gene edit mammalian cells when they began working to edit out genes in pigs. To what end? They envisioned a world in which pig farmers raise animals specifically designed to produce organs for the millions of people who are on transplant waiting lists.”

“Ever since researchers discovered in the early 2000s that they could modify inkjet printers to lay down 3D layers of living cells, scientists around the world have been working toward the goal of printing living tissue. Today scientists have implanted printed ovaries into mice and spliced printed arteries into monkeys. Others are working on printing skeletal tissue to fix broken bones. And printed skin is likely to start being used for grafts in the next few years, with livers and kidneys coming soon after that and hearts — which are a bit more complicated — a few years behind.

Soon it won’t matter if the morbid pipeline for human organ transplantation ends. That pipeline never met the demand anyway. In the future, when we need body parts, we might very well print them, perhaps by using our own stem cells, which will be harvested and stored for just such an occasion, or even using reprogrammed cells taken from blood or a mouth swab.”

“Let’s make it conservative math. Let’s assume that each of these vastly different technologies emerging over the next fifty years independently contributes to a longer, healthier lifespan.

DNA monitoring will soon be alerting doctors to diseases long before they become acute. We will identify and begin to fight cancer years earlier. If you have an infection, it will be diagnosed within minutes. If your heartbeat is irregular, your car seat will let you know. A breath analyzer will detect an immune disease beginning to develop. Keystrokes on the keyboard will signal early Parkinson’s disease or multiple sclerosis. Doctors will have far more information about their patients — and they will have access to it long before patients arrive at a clinic or hospital. Medical errors and misdiagnoses will be slashed. The result of any one of these innovations could be decades of prolonged healthy life. Let’s say, though, that all of these developments together will give us a decade.

Once people begin to accept that aging is not an inevitable part of life, will they take better care of themselves? I certainly have. So, too, it seems, have most of my friends and family members. Even as we have all stepped forward to be early adopters of biomedical and technological interventions that reduce the noise in our epigenomes and keep watch over the biochemical systems that keep us alive and healthy, I’ve noticed a definite tendency to eat fewer calories, reduce animal-based aminos, engage in more exercise, and stoke the development of brown fat by embracing a life outside the thermoneutral zone.

These are remedies available to most people regardless of socioeconomic status, and the impact on vitality has been exceptionally well studied. Ten additional healthy years is not an unreasonable expectation for people who eat well and stay active. But let’s cut that by half. Let’s call it five.

That’s fifteen years.

Molecules that bolster our survival circuit, putting our longevity genes to work, have offered between 10 and 40 percent more healthy years in animal studies. But let’s go with 10 percent, which gives us another eight years.

That’s twenty-three years total.

How long will it be before we are able to reset our epigenome, either with molecules we ingest or by genetically modifying our bodies, as my student now does in mice? How long until we can destroy senescent cells, either by drugs or outright vaccination? How long until we can replace parts of organs, grow entire ones in genetically altered farm animals, or create them in a 3D printer? A couple of decades, perhaps. Maybe three. One or all of those innovations is coming well within the ever-increasing lifespans of most of us, though. And when that happens, how many more years will we get? The maximum potential could be centuries, but let’s say it’s only ten years.

That’s thirty-three years.

At the moment, life expectancy in the developed world is a tad over 80 years. Add 33 to that.

That’s 113 years, a conservative estimate of life expectancy in the future, as long as most people come along for the ride. And recall that this number means that over half the population will exceed that number. It’s true that not all of these advances will be additive, and not everyone will eat well and exercise. But also consider that the longer we live, the greater chance we have of benefiting from radical medical advances that we cannot foresee. And the advances we’ve already made are not going away.

That’s why, as we move faster and faster toward a Star Trek world, for every month you manage to stay alive, you gain another week of life. Forty years from now, it could be another two weeks. Eighty years from now, another three. Things could get really interesting around the end of the century if, for every month you are alive, you live another four weeks.”

“If the medical revolution happens and we continue on the linear path we’re already on, some estimates suggest half of all children born in Japan today will live past 107. In the United States the age is 104. Many researchers believe that those estimates are overly generous, but I don’t. They might be conservative. I have long said that if even a few of the therapies and treatments that are most promising come to fruition, it is not an unreasonable expectation for anyone who is alive and healthy today to reach 100 in good health — active and engaged at levels we’d expect of healthy 50-year-olds today. One hundred twenty is our known potential, but there is no reason to think that it needs to be for the outliers. And I am on record as saying, in part to make a statement and in part because I have a front-row seat on what’s around the corner, that we could be living with the world’s first sesquicentenarian. If cellular reprogramming reaches its potential, by century’s end 150 may not be out of reach.”

“It is not at all extravagant to expect that someday living to 150 will be standard. And if the Information Theory of Aging is sound, there may be no upward limit; we could potentially reset the epigenome in perpetuity.”

“On average, Americans consume more than three times the amount of food they need to survive and about 250 times as much water. In return, they produce 4.4 pounds of trash each day, recycling or composting only about of a third of it.”

“There is no one single factor that can explain all of these movements, but the economist Harun Onder is among those who have made a demographic observation: nationalist arguments tend to resonate with older people. Therefore, it is likely that the antiglobalist wave will be with us for some time to come. “Virtually every country in the world,” the United Nations reported in 2015, “is experiencing growth in the number and proportion of older persons in their population.” Europe and North America already have the largest per capita share of older persons; by 2030, according to the report, those over the age of 60 will account for more than a quarter of the population on both of these continents, and that proportion will continue to grow for decades to come. Once again, these are estimates based on ridiculously low pros jections for lengthened lifespans.

Older constituencies support older politicians. As it is now, politicians seem steadfastly opposed to stepping down in their 70s and 80s. More than half of the US senators running for reelection in 2018 were 65 or older. Democratic leader Nancy Pelosi was 78 that year. Dianne Feinstein and Chuck Grassley, two powerful senators, were 85. On average, members of the US Congress are 20 years older than their constituents.

At the time of his death in 2003, Strom Thurmond was 100 years old and had served 48 years as a US senator. That Thurmond was a centenarian in Congress is no vice — we want our leaders to have experience and wisdom, as long as they aren’t stuck in the past. The travesty was that Thurmond somehow managed to keep his seat in spite of a long record of supporting segregation and opposing civil rights, including basic voting rights. At the age of 99, he voted to use military force in Irag, opposed legislation to make pharmaceuticals more affordable, and helped kill a bill that would have added sexual orientation, gender, and disability to a list of categories covered by hate crimes legislation. After his death, the “family values” politician was revealed to have had a daughter with his family’s teenage African American housekeeper when he was 22, which was almost certainly an act of statutory rape under South Carolina law. Though he knew about the child, he never publicly acknowledged her. Thurmond lived in retirement only six months.”

“If you were a member of the American upper middle class in the 1970s, you weren’t just enjoying a more affluent life, you had a longer one, too. Those in the top half of the economy were living an average of 1.2 more years than those in the bottom half.

By the early 2000s, the difference had increased dramatically. Those in the upper half of the income spectrum could expect nearly six additional years of life, and by 2018, the divide had widened, with the richest 10 percent of Americans living thirteen more years of life than the poorest 10 percent.”

“Most countries tax people when they die as a way to limit wealth accumulation over generations, but it’s a little-known fact that, in the United States, estate taxes weren’t initially designed to limit multigenerational wealth; they were imposed to finance wars. In 1797, a federal tax was imposed to build a navy to fend off a possible French invasion; in 1862, an inheritance tax was instituted to finance the Civil War. The 1916 estate tax, which was similar to present-day estate taxes, helped pay for World War I.

In recent times, the burden of paying for wars has shifted to the rest of the population. Thanks to tax loopholes, the percentage of rich American families who pay what were cleverly branded as “death taxes” decreased fivefold, providing the lowest cost for “dying rich” in modern times.

All this means that the children of the wealthy are faring extremely well. Unless there is an upward revision to the tax code, they will continue to do better, both in how much money they inherit and in how much longer they will live than others do.

Remember, too, that aging is not yet considered a disease by any nation. Insurance companies don’t cover pharmaceuticals to treat diseases that aren’t recognized by government regulators, even if it would benefit humanity and the nation’s bottom line. Without such a designation, unless you are already suffering from a specific disease, such as diabetes in the case of metformin ongevity drugs will have to be paid for out of pocket.”

“An almost equal number of estimates-thirty-two of them — concluded that the number is somewhere above 8 billion. Eighteen of those estimates suggested that the carrying capacity is at least 16 billion. And a few estimates suggested that our planet has the potential to sustain more than 100 billion people.”

“If we were to stop all deaths — every single one around the globe-right now, we would add about 150,000 people to our planet each day. That would be 55 million people each year. That might sound like a lot, but it would be less than a single percentage point. At that rate, we would add a billion people to our ranks every eighteen years, which is still considerably slower than the rate at which the last few billion people have come along and easily countered by the global decline in family sizes.”

“In Europe, most workers are forced to retire in their mid-60s, including professors, who are just getting good at what they do. The best ones move to the United States so they can keep on innovating.”

“Treatments that once cost hundreds of thousands of dollars could be rendered obsolete by pills eventually costing pennies to make. People will spend the last days of their lives at home with their families instead of racking up huge bills in centers intended for nothing more than “aging in place.” The idea that we once spent trillions of dollars trying to eke out a few more weeks of life from people who were already teetering on the edge of death will be anathema.

The “peace dividend” we will receive from ending our long war on individual diseases will be huge. Over fifty years, Goldman estimated, the potential economic benefits of delayed aging would add up to more than $7 trillion in the United States alone. And that’s a conservative estimate, based on modest improvements in the percentages of older people living without a disease or disability.”

“With the money saved by preventing expensive medical care, a retraining fellowship could be provided for a few years to allow people over 70 to go back to school and start the career they’d always wished they’d started but didn’t.”

“The first nations to define aging as a disease, both in custom and on paper, will change the course of the future. The first places to provide large amounts of public funding to augment the fast-growing private investments in this field will prosper in kind. It will be their citizens who benefit first. Doctors will feel comfortable prescribing medicines, such as metformin, to their patients before they become irreversibly frail. Jobs will be created. Scientists and drug makers will flock to that country, Industries will thrive. Their national budget will see a significant return on investment. Their leaders’ names will be in the history books.”

“After thousands of studies, the evidence is irrefutable: if you believe climate change is a threat, you can’t say that GMOs are because the evidence that GMOs are safe is stronger than the evidence that climate change is occurring.”

“Made with 99 percent less water, 93 percent less land, and 90 percent fewer greenhouse gases, innovations that are giving us damn-near-close-to-meat products — with plant “leghemoglobin” that ‘bleeds” and some good old-fashioned mad science — are booming and will need to continue to boom if we are to feed our appetite for tasty protein without further degrading our planet.”

“Cities such as Las Vegas have demonstrated that by marrying conservation and innovation, efficient water recycling is not only possible but profitable; whereas metro Vegas grew by half a million people between 2000 and 2016, its total water use fell by a third.”

“At the 2018 Global Climate Action Summit, for instance, it was announced that twenty-seven cities had reached peak emission levels. A peak, not a plateau. All of those places were seeing steep emission declines. Among that group of cities was Los Angeles, which was once definable by its ubiquitous smog. It had cut its emissions by 11 percent. In one year.”

“One of the best examples comes from a tiny town in South Australia. After the closure of the last coal-fired power station in the state in 2016, investors built Sundrop Farms on the barren coast, then hired 175 people who had recently become unemployed. The farm uses free energy from the sun and seawater to make 180 Olympic-sized swimming pools’ worth of freshwater per year, an effort that in the past would have burned a million gallons of diesel fuel. Today, 33 thousand pounds of fresh organic tomatoes are shipped each year from the port where coal used to come in.”

“On June 18, 2018, WHO released the eleventh edition of the International Classification of Diseases, known as ICD-11. It is a fairly unremarkable document, except that someone slipped in a new disease code. At first no one saw it. Here is the line, which you can find on the WHO website if you type in code MG2A. It reads:

MG2A Old age

• old age without mention of psychosis
• senescence without mention of psychosis
• senile debility

Every country in the entire world is encouraged to start reporting using ICD-11 on January 1, 2022. What this means is that it is now possible to be diagnosed with a condition called “old age.” Countries will have to report back to the WHO with their statistics on who dies from aging as a condition.

Will this lead to changes at the regulatory level, directing billions of dollars in investment to develop the medicines we deserve? Will federal regulators and doctors finally accept that it is ethically okay to prescribe medicines to slow aging and all the diseases that aging causes? Will they recognize it is indeed within a patient’s rights to receive them? Will insurance companies reimburse patients for the cost of antiaging treatments that will save money down the line?”

Tips

“• I take 1 gram (1,000 mg) of MN every morning, along with 1 gram of resveratrol (shaken into my homemade yogurt) and 1 gram of metformin,

• I take a daily dose of vitamin D, vitamin K2, and 83 mg of aspirin.

• I strive to keep my sugar, bread, and pasta intake as low as possible. I gave up desserts at age 40, though I do steal tastes.

• I try to skip one meal a day or at least make it really small. My busy schedule almost always means that I miss lunch most days of the week.

• Every few months, a phlebotomist comes to my home to draw my blood, which I have analyzed for dozens of biomarkers. When my levels of various markers are not optimal, I moderate them with food or exercise.

• I try to take a lot of steps each day and walk upstairs, and I go to the gym most weekends with my son, Ben; we lift weights, jog a bit, and hang out in the sauna before dunking in an ice-cold pool.

• I eat a lot of plants and try to avoid eating other mammals, even though they do taste good. If I work out, I will eat meat.

• I don’t smoke. I try to avoid microwaved plastic, excessive UV exposure, X-rays, and CT scans.

• I try to stay on the cool side during the day and when I sleep at night.

• I aim to keep my body weight or BMI in the optimal range for healthspan, which for me is 23 to 25.”

“If I do take a supplement, look for a large manufacturer with a good reputation, seek highly pure molecules (more than 98 percent is a good guide), and look for “GMP” on the label, which means the product was made under “good manufacturing practices.” Nicotinamide riboside, or NR, is converted to NMN, so some people take NR instead of NMN because it is cheaper. Cheaper still are niacin and nicotinamide, but they don’t seem to raise NAD levels as NMN and NR do.

Some people have suggested NAD boosters could be taken with a compound that provides cells with methyl groups, such as trimethylglycine, also known as betaine or methylfolate. Conceptually, this makes sense — the “N” in NR and NMN stands for nicotinamide, a version of vitamin B3 that the body methylates and excretes in urine when it is in excess, potentially depleting cells of methyls — but this remains a theory.”