SIX
BIG STEPS AHEAD
TO THE EXTENT WE THOUGHT about it—and we seldom did—we used to think aging would be a very complicated thing to change, if we could change it at all.
For most of human history, of course, we simply saw aging like the coming of the seasons; indeed, the shift from spring to summer to fall to winter was a common analogy we used to describe the movement from childhood to young adulthood to middle age to our “golden years.” More recently, we figured that aging was inexorable but we might be able to deal with some of the diseases that made it a less appealing process. Later still, we figured that we might be able to attack each of the hallmarks and perhaps we could treat a few of the symptoms at a time. Even then, it seemed as though it would be a huge endeavor.
But here’s the thing: it’s really not.
Once you recognize that there are universal regulators of aging in everything from yeast to roundworms to mice to humans . . .
. . . and once you understand that those regulators can be changed with a molecule such as NMN or a few hours of vigorous exercise or a few less meals . . .
. . . and once you realize that it’s all just one disease . . .
. . . it all becomes clear:
Aging is going to be remarkably easy to tackle.
Easier than cancer.
I know how that sounds. It sounds crazy.
But so did the idea of microorganisms before an amateur scientist named Antonie van Leeuwenhoek first described the world of the “small little animals” he saw under his homemade microscope in 1671; for hundreds of years to come, doctors rebelled against the idea that they needed to wash their hands before surgery. Now infections, one of the chief reasons patients used to die after surgery, have become the very thing hospital personnel are most fastidiously attentive to preventing in the operating room. Just by washing up before surgery, we have profoundly improved the rates at which patients survive. Once we understood what the problem was, it was an easy problem to solve.
For goodness’ sake, we solved it with soap.
The idea of vaccines would also have sounded crazy to most people before the English physician Edward Jenner successfully used fluid he had gathered from a cowpox blister to inoculate an eight-year-old boy named James Phipps in what today would be an egregiously unethical experiment but at the time sparked a new era in immunological medicine. Indeed, the idea of giving a patient a little bit of a disease in order to prevent a lot of disease would have been seen as insane—even potentially homicidal—to many people until Jenner did it in 1796. We now know that vaccines are the single most effective medical intervention in human history in terms of saving and extending lifespans. So again, once we understood what the problem was, it was an easy one to solve.
The successes of STACs, AMPK activators, and mTOR inhibitors are a tremendously powerful indicator that we’re working in an area of our biology that is upstream of every major aging-associated disease. The fact that these molecules have been shown to extend the lifespan of virtually every organism they’ve been tested on is further evidence that we’re engaging with an ancient and powerful program to prolong life.1
But there is another pharmaceutical target that could increase our longevity, just a bit downstream from the processes we believe longevity molecules are impacting but still upstream of a lot of the symptoms of aging.
You might recall that one of the key hallmarks of aging is the accumulation of senescent cells. These are cells that have permanently ceased reproduction.
Young human cells taken out of the body and grown in a petri dish divide about forty to sixty times until their telomeres become critically short, a point discovered by the anatomist Leonard Hayflick that we now call the Hayflick limit. 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.
The other, safer solution to a short telomere is to shut the cell down. This happens, I believe, by permanently engaging the survival circuit. The exposed telomere, seen as a DNA break, causes epigenetic factors such as the sirtuins to leave their posts permanently in an attempt to repair the damage, but there is no other DNA end to ligate it to. This shuts cell replication down, similar to the way that broken DNA in old yeast distracts Sir2 from the mating genes and shuts down fertility.
Triggering of the DNA damage response and major alterations to the epigenome are well known to occur in human senescent cells—and when we introduce epigenetic noise into the ICE cells they go on to senesce earlier than untreated cells, so maybe this idea has merit. 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. In the petri dish and in frozen, thinly sliced tissue sections, we can stain zombie cells blue because they make a rare enzyme called beta-galactosidase, and when we do that, they light up clearly. The older the cells, the more blue we see. For example, a sample of white fat looks white when we are in our 20s, pale blue in middle age, and dark royal blue in old age. And that’s scary, because when we have lots of these senescent cells in our bodies, it’s a clear sign that aging is getting a strong grip on us.
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. Being chronically inflamed is unhealthy: just ask someone with multiple sclerosis, inflammatory bowel disease, or psoriasis. All these diseases are associated with excess cytokine proteins.2 Inflammation is also a driving force in heart disease, diabetes, and dementia. It is so central to the development of age-related diseases that scientists often refer to the process as “inflammaging.” And cytokines don’t just cause inflammation; they also cause other cells to become zombies, like a biological apocalypse. When this happens, they can even stimulate surrounding cells to become a tumor and spread.
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 resistance 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.3 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.
DELETING THE ZOMBIE SENESCENT CELLS IN OLD TISSUES. Thanks to the primordial survival circuit we’ve inherited from our ancestors, our cells eventually lose their identities and cease to divide, in some cases sitting in our tissues for decades. Zombie cells secrete factors that accelerate cancer, inflammation, and help turn other cells into zombies. Senescent cells are hard to reverse aging in, so the best thing to do is to kill them off. Drugs called senolytics are in development to do just that, and they could rapidly rejuvenate us.
Understanding why senescence evolved is not just an academic exercise; it could help us design better ways to prevent or kill senescent cells. Cellular senescence is a consequence of our inherited primordial survival circuits, which evolved to stop cell division and reproduction when DNA breaks were detected. Just as in old yeast cells, if DNA breaks happen too frequently or they overwhelm the circuit, human cells will stop dividing, then sit there in a panic, trying to repair the damage, messing up their epigenome, and secreting cytokines. This is the final stage of cellular aging—and it’s not pretty.
If zombie cells are so bad for our health, why doesn’t our body just kill them off? Why are senescent cells allowed to cause trouble for decades? Back in the 1950s, the evolutionary biologist George Williams was already on the case. His work, built upon by Judith Campisi from the Buck Institute for Research on Aging in California, proposes 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.
Consider the 15-million-year history of hominids, the great apes. In the vast majority of our family’s evolutionary journey, the forces of predation, starvation, disease, maternal mortality, infection, catastrophic weather events, and intraspecies violence meant that very few individuals saw more than a decade or two of life. Even in the relatively recent era of the Homo genus, what we now think of as “middle age” is an exceptionally new phenomenon.
A life expectancy of 50 and beyond was simply not a reality for most of our evolutionary history. Therefore, it didn’t matter if a mechanism for slowing the spread of cancer would eventually cause more cancer and other diseases, because it generally worked, as long as it allowed people to breed and rear some children. The saber-toothed tigers took things from there.
These days, of course, few people have to worry about being picked off by hungry predators. Hunger and malnutrition are still far too common, but abject starvation is increasingly rare. We’re getting better and better at staving off childhood diseases and have eliminated some of them almost entirely. Childbirth is an increasingly safe affair (although that, too, is something that can be vastly improved upon, especially in the developing world). Modern sanitation has resulted in tremendous improvements in the rates at which we die of infectious diseases. Modern technology is helping to warn us of impending catastrophes such as hurricanes and volcanic eruptions. And although the world often seems to be a vicious and violent place, the worldwide homicide rate and the numbers of wars globally have been falling for decades.
So we live longer—and evolution hasn’t had a chance to catch up. We’re plagued by senescent cells, which might as well be radioactive waste. If you put a tiny dab of these cells under a young mouse’s skin, it won’t be long before inflammation spreads and the entire mouse is filled with zombie cells that cause premature signs of aging.
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.4 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.5)
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.
But there is another option, just a bit further upstream, that could be even better.
THE HITCHHIKER’S GUIDE
The selfish genes we discussed earlier, called LINE-1 retrotransposons, and their fossil remnants, make up about half of the human genome, what is often referred to as “junk DNA.”
It’s a lot of genetic baggage, and they are sneaky buggers. In young cells, these ancient “mobile DNA elements,” also known as retrotransposons, are prevented by chromatin from jumping out of the genome, then breaking DNA to reinsert themselves elsewhere. We and others have shown that LINE-1 genes are bundled up and rendered silent by sirtuins.6 But as mice age, and possibly as we do as well, these sirtuins become scattered all over the genome, having been recruited away to repair DNA breaks elsewhere, and many of them never find their way home. This loss is exacerbated by a drop in NAD levels—the same thing we first saw in old yeast. Without sirtuins to spool the chromatin and silence the transposon DNA, cells start to transcribe these endogenous viruses.
This is bad. And it only gets worse.
Over time, as mice age, the once silent LINE-1 prisoners are turned into RNA and the RNA is turned into DNA, which is reinserted into the genome at a different place. Besides creating genome instability and epigenomic noise that causes inflammation, LINE-1 DNA leaks from the nucleus into the cytoplasm, where it is recognized as a foreign invader. In response, the cells release even more immunostimulatory cytokines that cause inflammation throughout the body.
New work by John Sedivy at Brown University and Vera Gorbunova from the University of Rochester raises the possibility that one of the main reasons SIRT6 mutant mice age so rapidly is that these retroviral hellhounds have no leash, causing numerous DNA breaks and the epigenome to degrade rapidly instead of slowly. Convincing evidence has come from experiments showing that antiretrovirals, the same kinds used to fight HIV, extend the lifespan of SIRT6 mutant mice about twofold. It may turn out that, as NAD levels decline with age, sirtuins are rendered unable to silence retrotransposon DNA. Perhaps one day, safe antiretroviral drugs or NAD boosters will be used to keep these jumping genes silent.7 We would not have stopped aging completely at its source, but we would be fighting the battle before total anarchy ensues and the genie that is aging becomes even harder to put back in the bottle.
VAX TO THE FUTURE
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.8 Other immuno-oncological 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 (CAR-T) 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.
When people first hear that it may be possible to vaccinate against aging, rather than just treat its symptoms or slow it down, it’s not uncommon for them to immediately express worries that we are “playing God” or “interfering with Mother Nature.” Maybe we are, but if so, that’s not unique to people involved in the fight against aging. We fight diseases of all kinds that God or Mother Nature gave us. We’ve been doing so for a long time, and we’re going to keep doing so for a long time to come.
The world rightfully celebrated the eradication of smallpox in 1980. When malaria is likewise eradicated—and I believe it will be sometime in the coming decades—our global community will rejoice once again. And if I could offer the world a vaccine for HIV, right now, there wouldn’t be many people—no decent ones, at least—who would say that we should just “let nature run its course.” These are ailments we’ve long considered diseases, though, and I accept that it will take some time to convince people that aging is no different.
To this end, I’ve found this thought experiment to be helpful: imagine an Airbus A380, a double-decker “superjumbo” filled with six hundred people on board, on approach to Los Angeles. The plane does not have landing gear, only parachutes. And all but one of the doors is stuck, so when the passengers evacuate, one by one, they’ll be scattered across the most densely populated area of the country.
Oh, and one more thing: the passengers are sick. Really sick. The disease they carry is highly contagious; it starts with lethargy and sore joints, then develops into hearing and vision loss, bones as brittle as century-old teacups, excruciatingly painful heart failure, and brain signals so badly interrupted that many victims won’t even be able to remember who they are. No one survives this disease, and death is almost always agonizing.
After a life of faithful service to the United States, you have found yourself behind the Resolute Desk in the Oval Office of the White House. The phone rings. The deputy director for infectious diseases from the Centers for Disease Control and Prevention tells you that if even one of the passengers is permitted to parachute into the greater Los Angeles area, tens of thousands of people will catch the disease and die. Each additional parachuter will increase the projected death toll exponentially.
The moment you put the receiver down, the phone rings again. The chairperson of the Joint Chiefs of Staff tells you that six US Air Force F-22 Raptor fighters are tracking the plane as it circles over the Pacific Ocean. The pilots have it locked in; their missiles are ready. The plane is running out of gas. The fate of the passengers, and the entire United States, rests upon your orders.
What do you do?
This, of course, is a “trolley problem,” an ethical thought experiment, of the type popularized by the philosopher Philippa Foot, that pits our moral duty not to inflict harm on others against our social responsibility to save a greater number of lives. It’s also, however, a handy metaphor, because the highly contagious disease the passengers are carrying is, as you doubtless have noticed, nothing more than a faster-acting version of aging.
When presented with the idea of a disease that could infect and kill legions of people—with horrendous symptoms, no less—very few of us would not make the horrible but necessary call to shoot down the plane, taking the lives of hundreds of people to protect the lives of millions.
With that in mind, consider this question: If you would sacrifice hundreds of human lives to stop a fast-acting version of aging from infecting millions, what would you be willing to do to prevent the disease as it actually occurs in the lives of everyone on the planet?
Worry not: what I’m about to suggest won’t actually come at the cost of human lives. Not hundreds. Not dozens. Not even one. But it would require us to confront an idea that many people would find alarming: infecting ourselves with a virus that would quickly move into every cell in our body, turning us into genetically modified organisms. The virus wouldn’t kill; it would do the opposite.
GET WITH THE REPROGRAM
Vaccines against senescent cells, CR mimetics, and retrotransposon suppressors are possible pathways to prolonged vitality, and work is under way already in labs and clinics around the world. But what if we didn’t need any of that? What if we could reset the aging clock and prevent cells from ever losing their identity and becoming senescent in the first place?
Yes, the solution to aging could be cellular reprogramming, a resetting of the landscape—the way, for instance, that jellyfish have been shown to do by using small body fragments to regenerate polyps that spawn a dozen new jellies.
The DNA blueprint to be young, after all, is always there, even when we are old. So how can we make the cell reread the blueprint? Here it’s helpful to return to the DVD metaphor. Over time, thanks to use and perhaps misuse, the digital information encoded as pits in the top layer of aluminum becomes obscured by some deep and some fine scratches, making it hard for the DVD player to read the disk. A DVD has thirty miles of data spiraled around the disk from the edge to the center, so if the disc is scratched, finding the start of a particular song becomes extremely difficult.
It’s the same situation for old cells, but far worse. The DNA in our cells holds about the same amount of data as a DVD, but in six feet of DNA that’s packed into a cell a tenth the size of a speck of dust. Together, all the DNA in our body, if laid end to end, would stretch twice the diameter of the solar system. Unlike a simple DVD, though, the DNA in our cells is wet and vibrating in three dimensions. And there aren’t 50 songs, there are more than 20,000. No wonder gene reading becomes difficult the older we get; it’s miraculous that any cell finds the right genes in the first place.
There are two ways to play an old, scratched DVD with fidelity. You could buy a better DVD player, one with a more powerful laser that could reveal the data under the scratches. Or you could polish the disc to expose the information again, making the DVD as good as new. I’ve heard that a rag with toothpaste on it works just fine.
Restoring youth in an organism is never going to be as simple as polishing a disk with toothpaste, but the first approach, putting a scratched DVD into a new player, was. Oxford University professor John Gurdon first did this in 1958, when he removed the chromosomes from a frog’s egg and replaced them with some chromosomes from an adult frog and obtained living tadpoles. Then, in 1996, Ian Wilmut and his colleagues at the University of Edinburgh replaced the chromosomes of a sheep’s egg with those from an udder cell. The result was Dolly, whose birth was met with a heated public debate about the purported dangers of cloning. The debate overshadowed the most important point: that old DNA retains the information needed to be young again.
WE ARE ANALOG, THEREFORE WE AGE. According to the Information Theory of Aging, we become old and susceptible to diseases because our cells lose youthful information. DNA stores information digitally, a robust format, whereas the epigenome stores it in analog format, and is therefore prone to the introduction of epigenetic “noise.” An apt metaphor is a DVD player from the 1990s. The information is digital; the reader that moves around is analog. Aging is similar to the accumulation of scratches on the disc so the information can no longer be read correctly. Where’s the polish?
That debate has since died down; the world today has other concerns. 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 Tulear.9 The fact that Sammie was 14 when she died and donated cells—that’s somewhere in the range of 75 in dog years—didn’t impact the clones one bit.
The implications of these experiments are profound. What they show is that aging can be reset. The scratches on the DVD can be removed, and the original information can be recovered. Epigenomic noise is not a one-way street.
But how might we reset the body without becoming a clone?
In his 1948 publications about the preservation of information during data transmissions, Claude Shannon provided a valuable clue.10
In an abstract sense, he proposed that information loss is simply an increase in entropy, or the uncertainty of resolving a message, and provided brilliant equations to back his ideas up. His work stemmed from the mathematics of Harry Nyquist and Ralph Hartley, two other engineers at Bell Labs who, in the 1920s, revolutionized our understanding of information transmission. Their notions of an “ideal code” were important for Shannon’s development of his communication theory.
In the 1940s, Shannon became obsessed with communications over a noisy channel, in which information is simply a set of possible messages that needs to be reconstructed by the recipient of the message—the receiver.
As Shannon brilliantly showed in his “noisy-channel coding theorem,” it is possible to communicate information nearly error free as long as you don’t exceed the channel capacity. But if the data exceeds the channel capacity or is subject to noise, which is often the case with analog data, the best way to ensure it makes it to the receiver is to store a backup set of data. That way, even if some primary data are lost, an “observer” can send this “correcting data” to a “correcting device” to recover the original message. This is how the internet works. If data packets are lost, they are recovered and resent moments later, all thanks to Transmission Control Protocol/Internet Protocol (TCP/IP).
As Shannon put it, “This observer notes the errors in the recovered message and transmits data to the receiving point over a ‘correction channel’ to enable the receiver to correct the errors.”
Though it may sound like esoteric language from the 1940s, what dawned on me in 2014 is that Shannon’s “A Mathematical Theory of Communication” is relevant to the Information Theory of Aging.
In Shannon’s drawing, there are three different components that have analogs in biology:
• The “source” of the information is the egg and sperm, from your parents.
• The “transmitter” is the epigenome, transmitting analog information through space and time.
• The “receiver” is your body in the future.
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.
CLAUDE SHANNON’S 1948 SOLUTION TO RECOVERING LOST INFORMATION DURING DATA TRANSMISSIONS LED TO CELL PHONES AND THE INTERNET. It may also be the solution to reversing aging.
Source: C. E. Shannon, “A Mathematical Theory of Communication,” Bell System Technical Journal 27, no. 3 (July 1948): 379–423 and 27, no. 4 (October 1948): 623–66.
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, Klf4, 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. These genes are found in most multicellular species, including chimpanzees, monkeys, dogs, cows, mice, rats, chickens, fish, and frogs. For his discovery, essentially showing that complete cellular age reversal was possible in a petri dish, Yamanaka won the Nobel Prize in Physiology or Medicine along with John Gurdon in 2012. We now call these four genes Yamanaka factors.
At first blush, Yamanaka’s experiments might sound like a nifty laboratory parlor trick. But the implications for aging are profound, and not only because he paved the way for us to grow entirely new populations of blood cells, tissues, and organs in the dish that can be and are being transplanted into patients.
What he identified, I believe, is the reset switch responsible for Gurdon’s tadpoles—the biological correcting device.
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. This is the DVD polish we’ve been looking for.
We are making progress every week in restoring the youthful epigenome of mice by delivering reprogramming factors. The pace of discovery is mind spinning. A full night of sleep for me and my lab members is increasingly rare.
In the 1990s, there were major concerns about the safety of delivering genes to humans. But 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 silent. Biologically, physically, and mentally, you would be a couple of decades younger, but you’d retain all your knowledge, 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.11 He’s shown that the skin and kidneys of regular old mice heal more quickly, too.
The Yamanaka treatment, however, was highly toxic. If Belmonte overdid it by giving the mice the antibiotic for a few more days, the mice died. Serrano had also shown that by pushing the marbles too far up the landscape, the four-gene combo could induce teratomas, which are particularly disgusting tumors made up of several types of tissue, such as hair, muscle, or bone. Clearly, this tech is not ready for prime time. At least not yet. But we’re getting closer every day to being able to control the Waddington marbles safely, making sure they land back precisely in their original valleys and not at the top of the mountain, where they could cause cancer.
While all this was going on, guided by the success of the ICE mouse experiments, my lab had been looking for ways to delay and reverse epigenetic aging. We’d tried many different approaches: the Notch gene, Wnt, the four Yamanaka factors. Some had worked a little, but most were turning into tumor cells.
One day in 2016, after failing consistently for two years to get old cells to age in reverse without turning into tumor cells, a brilliant graduate student named Yuancheng Lu came into my office to say he was close to quitting. As a final effort, he suggested he try leaving out the c-Myc gene that was the likely cause of the teratomas, and I encouraged him to do so.
He delivered a viral package to mice, but this time with only three of the Yamanaka factors, then turned them on using doxycycline and waited for all the mice to get sick or die. But none of them did. They were totally fine. And after months of monitoring, no tumors arose, either. It was a surprise to both of us—a great surprise.
Instead of waiting for another year to see if the mice lived longer, Yuancheng suggested he use a mouse’s optic nerve as a way to test age reversal and rejuvenation. I was skeptical.
“I’m not superoptimistic this will work,” I told him. “Optic nerves just don’t regenerate, unless you are a newborn.”
The intricate network of cells and fibers that transmit nervous signals across our bodies is divided into two parts: the peripheral system and the central system. We’ve known for a long time that peripheral nerves, like those in our arms and legs, can grow back, albeit very, very slowly. The nerves of the central system, though—optic nerves and the nerves of the spinal cord—never grow back. Even those scientists who bucked convention, proposing novel therapies that could regenerate some aspect of the central system, have generally been circumspect about the potential for significant regrowth. Decades of work aimed at reversing glaucoma in the eye and spinal cord injury has had almost no positive momentum.
“You’ve picked the hardest problem in biology to solve,” I told Yuancheng.
“But,” he replied, “if we could solve that problem . . .”
There might have been a thousand ways to measure the impact of age reversal in mice, but buoyed by his recent successes, he decided to “go big or go home.” I liked that.
“No one changes the world by not taking risks,” I told him. “Go test it.”
The images that came to me in a text message a few months later took my breath away—so much so that I needed to make sure that what I was seeing was real.
I called Yuancheng immediately. “Am I seeing what I think I am seeing?”
“Maybe,” he said. “What are you seeing?”
“The future,” I said.
Yuancheng let out a tremendous sigh of relief. “David,” he said, “an hour ago I thought I was going to fail.”
For researchers, doubt is no vice. Doubt is the very normal and very human consequence of pushing yourself to do audacious things without knowing how those things are going to work out.
But on that day, things sure did seem to be working out. The image Yuancheng first texted to me looked like an orange, glowing jellyfish; its head was at the top, where the eye of the mouse sits, with long tentacles flowing down toward the brain. Two weeks earlier, Yuancheng and our collaborators had squeezed the optic nerve a few millimeters from the back of the eye with a set of tweezers, causing almost all the nerve cell axons, the tentacles, to die back toward the brain. They injected an orange fluorescent dye into the eye that is taken up by living neurons. So when Yuancheng took a microscope and looked below the crush site, there were no glowing nerves, just a mass of dead cell remnants.
The next picture he sent was an example of one where the reprogramming virus had been turned on after the crush. Instead of dead cells, a network of long, healthy spindly tentacles was making its way to connect up with the brain. It was the greatest example of nerve generation in history, and Yuancheng was only just getting started.
No one had really expected the reprogramming to work so well. One-month-old mice were initially chosen for these experiments to give us the greatest chance of success and because that’s what everyone else does. But Yuancheng 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.
Vision declines dramatically in a mouse by 12 months of age. Bruce Ksander and Meredith Gregory-Ksander, from Massachusetts Eye and Ear at Harvard, know this well. There is a loss of the nerve impulses in the retina, and old mice don’t move their heads as often when moving lines are displayed in front of them, because they simply don’t see them.
“David, I must admit,” Bruce said, “I never expected this reprogramming stuff to work on normal aged eyes. I was only testing your virus because you were so excited to try it.”
The result he had seen the morning before had been the most exciting day in his research life: our OSK reprogramming virus had restored vision.
A few weeks later, Meredith showed that reprogramming also works to reverse vision loss caused by internal eye pressure known as glaucoma.
“Do you know what we’ve discovered?” Bruce remarked. “Everyone else has been working to slow the progression of glaucoma. This treatment restores vision!”
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.
What those youth markers are, we’re still not sure. They are likely to involve methyl tags on DNA, which are used to estimate an organism’s age, the so-called Horvath clock. They likely also involve something else: a protein, an RNA, or even a novel chemical attached to DNA that we haven’t yet discovered. But whatever they are made of, they are important, for they would be the fundamental correcting data that cells retain over a lifetime that somehow direct a reboot.
EPIGENETIC REPROGRAMMING REGROWS OPTIC NERVES AND RESTORES EYESIGHT IN OLD MICE. The Information Theory of Aging predicts that it is a loss of epigenetic rather than genetic information in the form of mutations. By infecting mice with reprogramming genes called Oct4, Sox2, and Klf4, the age of cells is reversed by the TET enzymes, which remove just the right methyl tags on DNA, reversing the clock of aging and allowing the cells to survive and grow like a newborn’s. How the enzymes know which tags are the youthful ones is a mystery. Solving that mystery would be the equivalent of finding Claude Shannon’s “observer,” the person who holds the the original data.
We also need to find the observer, the one who records what the original signal is when we are young. It can’t just be DNA methylation, because that doesn’t explain how the reprogrammed cells know to focus on some of the youthful methyl marks and strip off the ones that accumulated during aging, the cell equivalent of the scratches on the DVD. Perhaps it is a specialized histone, or a transcription factor, or a protein that latches onto methylated DNA when we are developing in utero and stays there for eighty years waiting until a signal comes from the correcting device to restore the original information.
In Claude Shannon’s parlance, when the correcting device is switched on by infecting cells with OSK genes, the cell somehow knows how to contact the observer and use the correction data to restore the original signal to that of a young cell.
Growing new nerves and restoring eyesight wasn’t enough for Yuancheng. When the DNA of the damaged neurons was examined, they seemed to be going through a very rapid aging program, one that was countered by the reprogramming factors. The neurons that received the reprogramming factors didn’t age, and they didn’t die. This is a radical idea but one that makes a lot of sense: severe cellular injury overwhelms the survival circuit and accelerates aging of the cell, leading to death, unless the clock is somehow reversed.
With these discoveries, we may be on the verge of understanding what makes biological time tick and how to wind it back. We know from our experiments that the biological information correcting device requires enzymes called ten-eleven translocation enzymes, or TETs, which clip off methyl tags from DNA, the same chemical tags that mark the passage of the Horvath aging clock. This is no coincidence, and points to the DNA methylation clock as not just an indicator of age but a controller of it. It’s the difference between a wristwatch and physical time.
In their role as a component of the correcting device, the TETs cannot just strip off all the methyls from the genome, for that would turn a cell into a primordial stem cell. We would not have old mice that can see better: we would have blind mice with tumors. How the TETs know to remove only the more recent methyls while preserving the original ones is a complete mystery.
It will likely take another decade and many other labs’ work to know precisely what the biological equivalent of the TCP/IP information recovery system is. But whatever it is, eyesight that should not be able to be restored is being restored and cells that should not be able to regrow are regrowing.
Compared to the decades of research into how to slow down aging and age-related disease by a few percent, the reprogramming work has been relatively quick and easy. All it took was an intrepid idea and the courage to buck convention.
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.
So far, the three-Yamanaka-gene combination seems safe in mice even when turned on for a year, but there is still plenty of work to be done. There are a lot of unanswered questions: Can we deliver the combination to all cells? Will it eventually cause cancer? Should we keep the genes on or turn them off to let the cells rest? Will this work in some tissues better than others? Can it be given to middle-aged people, before they become sick, the same way we take statins to keep cholesterol in check to prevent heart disease?
I have little doubt that cellular reprogramming is the next frontier in aging research. One day it might be possible to reprogram cells via pills that stimulate the activity of the OSK factors or the TETs. This may be simpler than it sounds. Natural molecules stimulate the TET enzymes, including vitamin C and alpha-ketoglutarate, a molecule made in mitochondria that is boosted by CR and, when given to nematode worms, extends their lifespan, too.
For now, though, the best bet is gene therapy.
Because it could be so impactful, we should start debating the ethics of this technology now, before it arrives on our doorstep. The first question is who should be allowed to use this technology. A select few? The rich? The very sick? Should doctors let people who have terminal illnesses try it for so-called compassionate use? How about people over 100? Or 80? Or 60? When does the reward outweigh the risk?
There is an army of people willing to “boldly go,” sound-minded volunteers in their 90s and 100s whose bodies have been broken by the disease of aging. I can assure you that there is no shortage of those who, having peered up the road at perhaps a few more years of life that is defined by ever-increasing frailty and pain, are ready to take a chance at a few more good years, if not for that, then for the chance to give their children, grandchildren, and great-grandchildren a longer, healthier life. What do they have to lose, after all?
The ethics of the technology become more difficult, though, if reprogramming becomes safe enough to use in a way that is preventive. At what age should it be given? Does a disease have to appear before an antibiotic activator of reprogramming is prescribed? If mainstream doctors refuse to help, will people head overseas? If the technology could significantly cut health care costs, should it be mandated?
And if we can help children live longer, healthier lives, do we have a moral obligation to do so? If reprogramming technology can help a child repair an eye or recover from a spinal injury, should the genes be delivered before an accident happens so they are ready to be switched on at a moment’s notice, starting perhaps with an antibiotic drip in the ambulance?
If smallpox were to return to our planet, after all, parents who refused to vaccinate their children would be pariahs of the lowest order. When safe and effective treatments are available for a common childhood disease, parents who refuse to save their children’s lives can have their guardianship overridden by the doctrine of parens patriae.
Should every human have a choice to suffer from aging? Or should that choice be made, as vaccine decisions are in most cases, for the good of both individuals and humankind? Will those who elect to be rejuvenated still have to pay for those who have decided not to? Is it morally wrong not to do so, knowing you will prematurely become a burden on family members?
These are theoretical questions today, but they probably won’t remain theoretical for long.
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.”
The side effects of inducing DNA damage in embryos and the accuracy of gene editing are not well understood yet, which is why the scientific community has had such a violent negative reaction. There is also a tacit reason: scientists are fearful that gene-editing technologies, if abused, will go the way of GMOs and be outlawed for political or irrational reasons before their true potential can be realized.
These fears may be unfounded. If news of the first genetically modified children had broken in the 2000s, it would have sparked global debate and dominated the news for months. Protesters would have stormed labs, and presidents would have banned this use of the technology on embryos. But how times have changed. With a news cycle of hours and politics dished out over the internet, the story lasted a few days; then the world moved on to other, more interesting topics.
He’s stated intention was to give the twins the ability to resist HIV. That may sound admirable, but if I do the numbers, the risk wasn’t worth it. The chance of contracting HIV in China is less than one in a thousand. If He was going to maximize health benefits to offset the risks of the procedure, why not edit a gene that causes heart disease, which has an almost one-in-two chance of killing them?12 Or aging, which has a 90 percent chance of killing them? HIV immunity was just the simplest edit, not the most impactful.
As these technologies become commonplace and parents ponder how to get the biggest bang for the buck, how long will it be before another rogue scientist teams up with the world’s most driven helicopter parent to create a genetically modified family with the capacity to resist the effects of aging?
It may not be long at all.