Lifespan: The Revolutionary Science of Why We Age—and Why We Don't Have To

by David A. Sinclair

On my quest, I’ve wound my way left and right and had days when I wanted to give up. But I’ve persevered. Along the way, I have seen a lot of tributaries, but I’ve also found what may be the spring. In the coming pages, I will present a new idea about why aging evolved and how it fits into what I call the Information Theory of Aging. I will also tell you why I have come to see aging as a disease—the most common disease—one that not only can but should be aggressively treated. That’s part I.

In part II, I will introduce you to the steps that can be taken right now—and new therapies in development—that may slow, stop, or reverse aging, bringing an end to aging as we know it. And yes, I fully recognize the implications of the words “bringing an end to aging as we know it,” so, in part III, I will acknowledge the many possible futures these actions could create and propose a path to a future that we can look forward to, a world in which the way we can get to an increased lifespan is through an ever-rising healthspan, the portion of our lives spent without disease or disability.

Sure, little by little, millennia by millennia, we’ve been adding years to the average human life, they will say. Most of us didn’t get to 40, and then we did. Most of us didn’t get to 50, and then we did. Most of us didn’t get to 60, and then we did.12 By and large, these increases in life expectancy came as more of us gained access to stable food sources and clean water. And largely the average was pushed upward from the bottom; deaths during infancy and childhood fell, and life expectancy rose. This is the simple math of human mortality.

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One of the most promising breakthroughs in the past decade has been immune checkpoint therapy, or simply “immunotherapy.” Immune T-cells continually patrol our body, looking for rogue cells to identify and kill before they can multiply into a tumor. If it weren’t for T-cells, we’d all develop cancer in our twenties. But rogue cancer cells evolve ways to fool cancer-detecting T-cells so they can go on happily multiplying. The latest and most effective immunotherapies bind to proteins on the cancer cells’ surface. It is the equivalent of taking the invisible cloak off cancer cells so T-cells can recognize and kill them. Although fewer than 10 percent of all cancer patients currently benefit from immunotherapy, that number should increase thanks to the hundreds of trials currently in progress.

We continue to rail against a disease we once accepted as fate, pouring billions of dollars into research each year, and the effort is paying off. Survival rates for once lethal cancers are increasing dramatically. Thanks to a combination of a BRAF inhibitor and immunotherapy, survival of melanoma brain metastases, one of the deadliest types of cancer, has increased by 91 percent since 2011. Between 1991 and 2016, overall deaths from cancer in the United States declined by 27 percent and continue to fall.3 That’s a victory measured in millions of lives.

Aging research today is at a similar stage as cancer research was in the 1960s. We have a robust understanding of what aging looks like and what it does to us and an emerging agreement about what causes it and what keeps it at bay. From the looks of it, aging ...

Up until the second half of the twentieth century, it was generally accepted that organisms grow old and die “for the good of the species”—an idea that dates back to Aristotle, if not further. This idea feels quite intuitive. It is the explanation proffered by most people at parties...

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 proteostasis 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.

Aging, quite simply, is a loss of information. You might recognize that loss of information was a big part of the ideas that Szilard and Medawar independently espoused, but it was wrong because it focused on a loss of genetic information. But there are two types of information in biology, and they are encoded entirely differently. The first type of information—the type my esteemed predecessors understood—is digital. Digital information, as you likely know, is based on a finite set of possible values—in this instance, not in base 2 or binary, coded as 0s and 1s, but the sort that is quaternary or base 4, coded as adenine, thymine, cytosine, and guanine, the nucleotides A, T, C, G of DNA.

Because DNA is digital, it is a reliable way to store and copy information. Indeed, it can be copied again and again with tremendous accuracy, no different in principle from digital information stored in computer memory or on a DVD. DNA is also robust. When I first worked in a lab, I was shocked by how this “molecule of life” could survive for hours in boiling water and thrilled that it was recoverable from Neanderthal remains at least 40,000 years old.23 The advantages of digital storage explain why chains of nucleic acids have remained the go-to biological storage molecule for the past 4 billion years.

The other type of information in the body is analog. We don’t hear as much about analog information in the body. That’s in part because it’s newer to science, and in part because it’s rarely described in terms of information, even though that’s how it was first described when geneticists noticed strange nongenetic effects in plants they were breeding. Today, analog information is more commonly r...

In the same way that genetic information is stored as DNA, epigenetic information is stored in a structure called chromatin. DNA in the cell isn’t flailing around disorganized, it is wrapped around tiny balls of protein called histones.

Epigenetic information is what orchestrates the assembly of a human newborn made up of 26 billion cells from a single fertilized egg and what allows the genetically identical cells in our bodies to assume thousands of different modalities.

If the genome were a computer, the epigenome would be the software.

information storage was also needed to record and respond to environmental conditions, and this was best stored in analog format. Analog data are superior for this job because they can be changed back and forth with relative ease whenever the environment within or outside the cell demands it, and they can store an almost unlimited number of possible values, even in response to conditions that have never been encountered before.25

The unlimited number of possible values is why many audiophiles still prefer the rich sounds of analog storage systems. But even though analog devices have their advantages, they have a major disadvantage. In fact, it’s the reason we’ve moved from analog to digital. Unlike digital, analog information degrades over time—falling victim to the conspiring forces of magnetic fields, gravity, cosmic rays, and oxygen. Worse still, information is lost as it’s copied.

The longevity genes I work on are called “sirtuins,” named after the yeast SIR2 gene, the first one to be discovered. There are seven sirtuins in mammals, SIRT1 to SIRT7, and they are made by almost every cell in the body.

Scientific observations that had previously made no sense to me were falling perfectly into a larger picture. Broken DNA causes genome instability, I wrote, which distracts the Sir2 protein, which changes the epigenome, causing the cells to lose their identity and become sterile while they fixed the damage. Those were the analog scratches on the digital DVDs. Epigenetic changes cause aging.

To understand the Information Theory of Aging, we need to pay another visit to the epigenome, the part of the cell that the sirtuins help control. Up close, the epigenome is more complex and wonderful than anything we humans have invented. It consists of strands of DNA wrapped around spooling proteins called histones, which are bound up into bigger loops called chromatin, which are bound up into even bigger loops called chromosomes.

Every one of our cells has the same DNA, of course, so what differentiates a nerve cell from a skin cell is the epigenome, the collective term for the control systems and cellular structures that tell the cell which genes should be turned on and which should remain off. And this, far more than our genes, is what actually controls much of our lives. One of the best ways to visualize this is to think of our genome as a grand piano.13 Each gene is a key. Each key produces a note. And from instrument to instrument, depending on the maker, the materials, and the circumstances of manufacturing, each will sound a bit different, even if played the exact same way. These are our genes. We have about 20,000 of them, give or take a few thousand.14 Each key can also be played pianissimo (soft) or forte (with force). The notes can be tenuto (held) or allegretto (played quickly). For master pianists, there are hundreds of ways to play each individual key and endless ways to play the keys together, in chords and combinations that create music we know as jazz, ragtime, rock, reggae, waltzes, whatever. The pianist that makes this happen is the epigenome. Through a process of revealing our DNA or bundling it up in tight protein packages, and by marking genes with chemical tags called methyls and acetyls composed of carbon, oxygen, and hydrogen, the epigenome uses our genome to make the music of our lives.

Epidewort is the maestro of the piano '

Yes, sometimes the size, shape, and condition of a piano dictate what a pianist can do with it. It’s tough to play a concerto on an eighteen-key toy piano, and it’s mighty hard to make beautiful music on an instrument that hasn’t been tuned in fifty years. Likewise, the genome certainly dictates what the epigenome can do. A caterpillar can’t become a human being, but it can become a butterfly by virtue of changes in epigenetic expression that occur during metamorphosis, even though its genome never changes. Similarly, the child of two parents from a long line of people with black hair and brown eyes isn’t likely to develop blond hair and blue eyes, but twin agouti mice in the lab can turn out brown or golden, depending on how much the Agouti gene is turned on during gestation by environmental influences on the epigenome, such as folic acid, vitamin B12, genistein from soy, or the toxin bisphenol A.

Similarly, among monozygotic human twins, epigenetic forces can drive two people with the same genome in vastly different directions. It can even cause them to age differently. You can see this clearly in side-by-side photographs of the faces of smoking and nonsmoking twins; their DNA is still largely the same, but the smokers have bigger bags under their eyes, deeper jowls below their chins, and more wrinkles around their eyes and mouths. They are not older, but they’ve clearly aged faster. Studies of identical twins place the...

Now imagine you’re in a concert hall. A virtuoso pianist is seated at a gorgeously polished Steinway grand. The concerto begins. The music is beautiful, breathtaking. Everything is perfect. But then, a few minutes into the piece, the pianist misses a key. The first time it happens, it’s almost unnoticeable—an extra D, perhaps, in a chord that doesn’t need that note. Embedded in so many perfectly played notes, hidden among an otherwise flawless chord in an otherwise perfect melody, it’s nothing to worry about. But then, a few minutes later, it happens again. And then, with increasing frequency, again and again and again. It’s important to remember that there is nothing wrong with the piano. And the pianist is playing most of the notes prescribed by the composer. She’s just also playing some extra notes. Initially, this is just annoying. Over time it becomes unsettling. Eventually it ruins the concerto. Indeed, we’d assume that there was something wrong with the pianist. Someone might even rush onto the stage to make sure she is all right. Epigenetic noise causes the same kind of chaos. It is driven in large part by highly disruptive insults to the cell, such as broken DNA, as it ...

LESSONS FROM YEAST CELLS ABOUT WHY WE AGE. In young yeast cells, male and female “mating-type information” (gene A) is kept in the “off” position by the Sir2 enzyme, the first sirtuin (encoded by a descendant of gene B). The highly repetitive ribosomal DNA (rDNA) is unstable, and toxic DNA circles form; these recombine and eventually accumulate to toxic levels in old cells, killing them. In response to DNA circles and the perceived genome instability, Sir2 moves away from silent mating-type genes to help stabilize the genome. Both male and female genes turn on, causing infertility, the main hallmark of yeast aging.

We don’t count the age of a single yeast cell with birthday candles. They simply don’t last that long. Instead, aging in yeast is measured by the number of times a mother cell divides to produce daughter cells. In most cases, a yeast cell gets to about 25 divisions before it dies. That, however, makes obtaining old yeast cells an exceptionally challenging task. Because by the time an average yeast cell expires, it is surrounded by 225, or 33 million, of its descendants. It took a week of work, a lot of sleepless nights, and a whole lot of caffeinated beverages to collect enough regular old cells. The next day, when I developed the film to visualize the rDNA, what I saw astounded me.17 Just like the mutants, the normal old yeast cells were packed with ERCs. That was a “Eureka!” moment. Not proof—a good scientist never has proof of anything—but the first substantial confirmation of a theory, the foundation upon which I and others would build more discoveries in the years to come. The first testable prediction was if we put an ERC into very young yeast cells—and we devised a genetic trick to do that—the ERCs would multiply and distract the sirtuins, and the yeast cells would age prematurely, go sterile, and die young—and they did. We published that work in December 1997 in the scientific journal Cell, and the news broke around the world: “Scientists figured out a cause of aging.”

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His first experiment was to insert an extra copy of SIR2 into the genome of yeast cells to see if it could stabilize the yeast genome and delay aging. When the extra SIR2 was added, ERCs were prevented, and he saw a 30 percent increase in the yeast cells’ lifespan, as we’d been hoping. Our hypothesis seemed to be standing up to scrutiny: the fundamental, upstream cause of sterility and aging in yeast was the inherent instability of the genome. What emerged from those initial results in yeast, and another decade of pondering and probing mammalian cells, was a completely new way to understand aging, an information theory that would reconcile seemingly disparate factors of aging into one universal model of life and death. It looked like this: 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.

We demonstrated that the redistribution of Sir2 to the nucleolus is a response to numerous DNA breakages, which happen as a result of ERCs multiplying and inserting back into the genome or joining together to form superlarge ERCs. When Sir2 moves to combat DNA instability, it causes sterility in old, bloated yeast cells. That was the first step of the survival circuit, though at the time we had no idea that it was as ancient and as essential to our very existence as it turned out to be.

We told the world that we could give yeast a Werner-like syndrome, causing exploded nucleoli.18 We described the ways in which mutants of SGS1, those we’d plagued with the yeast equivalent to the Werner syndrome mutation, accumulated ERCs more rapidly, leading to premature aging and a shortened lifespan.19 Crucially, by demonstrating that if you add an ERC to young cells they age prematurely, we had crucial evidence that ERCs don’t just happen during aging, they cause it. And by artificially breaking the DNA in the cell and watching the cellular response, we showed why sirtuins move—to help with DNA repair.20 That turned out to be the second step of the survival circuit.21 The DNA damage that gave rise to the ERCs was distracting Sir2 from the mating-type genes, causing them to become sterile, a hallmark of yeast aging. It was epigenomic noise in its purest form.

Eva Bober’s team at the Max Planck Institute for Heart and Lung Research in Bad Nauheim, Germany, reported that sirtuins stabilize human rDNA.23 Then, in 2018, Katrin Chua at Stanford University found that, by stabilizing human rDNA, sirtuins prevent cellular senescence—essentially the same antiaging function as we had found for sirtuins in yeast twenty years earlier.24 That was an astonishing revelation: over a billion years of separation between yeast and us, and, in essence, the circuit hadn’t changed.

If you are skeptical, and you should be, you might assume these SIRT mutant mice could just be sick and, therefore, short lived. But adding in more copies of the sirtuin genes SIRT1 and SIRT6 does just the opposite: it increases the health and extends the lifespan of mice, just as adding extra copies of the yeast SIR2 gene does in yeast.29 Credit for these discoveries goes to two of my previous colleagues, Shin-ichiro Imai, my former drinking buddy at the Guarente lab, and Haim Cohen, my first postdoc at Harvard. In yeast, we had shown that DNA breaks cause sirtuins to relocalize away from silent mating-type genes, causing old cells to become sterile. That was a simple system, and we’d figured it out in a few years.

I’ve come to think of sirtuins as the directors of a multifaceted disaster response corps, sending out a variety of specialized emergency teams to address DNA stability, DNA repair, cell survivability, metabolism, and cell-to-cell communication. In a way, this is like the command center for the thousands of utility workers who descended upon Louisiana and Mississippi in the wake of Hurricane Katrina in 2005. Most of the workers weren’t from the Gulf Coast, but they came, did their level best to fix what was broken, and then went home. Some were working in the storm-ravaged communities for a few days and others for a few weeks before returning to their normal lives. And for most, it wasn’t the first or last time they had done something like that; anytime there’s a mass disaster that impacts utilities, they swoop in to help. 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 opti...

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. This is the epigenetic noise that is at the heart of our unified theory.

If the information theory is correct—that aging is caused by overworked epigenetic signalers responding to cellular insult and damage—it doesn’t so much matter where the damage occurs. What matters is that it is being damaged and that sirtuins are rushing all over the place to address that damage, leaving their typical responsibilities and sometimes returning to other places along the genome where they are silencing genes that aren’t supposed to be silenced. This is the cellular equivalent of distracting the cellular pianist.

Remember, we’d done nothing to change the genome. We’d simply broken the mice’s DNA in places where there aren’t any genes and forced the cell to paste, or “ligate,” them back together. Just to make sure, later we broke the DNA in other places, too, with the same results. Those breaks had induced a sirtuin response. When those fixers went to work, their absence from their normal duties and presence on other parts of the genome altered the ways in which lots of genes were being expressed at the wrong time.

THE MAKING OF THE ICE MOUSE TO TEST IF THE CAUSE OF AGING MIGHT BE INFORMATION LOSS. A gene from a slime mold that encodes an enzyme that cuts DNA at a specific place was inserted into a stem cell and injected into an embryo to generate the ICE mouse. Turning on the slime mold gene cut the DNA and distracted the sirtuins, causing the mouse to undergo aging.

In this way of thinking, cancer, heart disease, Alzheimer’s, and other conditions we commonly associate with getting old are not necessarily diseases themselves but symptoms of something greater. Or, put more simply and perhaps even more seditiously: aging itself is a disease.

To put yourself into an aged mind-set, try this little experiment. Using your nondominant hand, write your name, address, and phone number while circling your opposite foot counterclockwise. That’s a rough approximation of what it feels like.

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.

Physical changes happen to everyone. Our skin wrinkles. Our hair grays. Our joints ache. We start groaning when we get up. We begin to lose resilience, not just to diseases but to all of life’s bumps and bruises.

Fortunately, a hip fracture for a teenager is a very rare event that nearly everyone is expected to bounce back from. At 50, such an injury could be a life-altering event but generally not a fatal one. It’s not long after that, though, that the risk factor for people who suffer a broken hip becomes terrifyingly high. Some reports show that up to half of those over the age of 65 who suffer a hip fracture will die wit...

The older we get, the less it takes for an injury or illness to drive us to our deaths. We are pushed closer and closer to the precipice until it takes nothing more than a gentle wind to send us over. This is the very definition of frailty.

There’s a reason why hospitals and research institutions are organized in this way. Most of our modern medical culture has been built to address medical problems one by one—a segregation that owes itself in no small part to our obsession with classifying the specific pathologies leading to death.

what this approach ignores is that stopping the progression of one disease doesn’t make it any less likely that a person will die of another. 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.

The way doctors treat illness today “is simple,” wrote S. Jay Olshansky, a demographer at the University of Illinois. “As soon as a disease appears, attack that disease as if nothing else is present; beat the disease down, and once you succeed, push the patient out the door until he or she faces the next challenge; then beat that one down. Repeat until failure.”14

The United States spends hundreds of billions of dollars each year fighting cardiovascular disease.15 But 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.

WHY TREATING ONE DISEASE AT A TIME HAS LITTLE IMPACT ON LIFESPAN. The graph shows an exponential increase in disease as each year passes after the age of 20. It’s hard to appreciate exponential graphs. If I were to draw this graph with a linear Y-axis, it would be two stories tall. What this means is 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.