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The first unified theory of aging might be the key to humans living forever.
Nick Saraev is 25 years old, far too young, it would seem, to be thinking about death. And yet, since he turned 21, he has taken steps to prevent the infirmities of old age. Every day, he takes 2,000 mg of fish oil and 4,000 IU of vitamin D to help prevent heart disease and other ailments. He steams or pressure-cooks most of his meals because, he says, charring meats creates chemicals that may increase the risk of cancer. And in the winter, he keeps the humidity of his home at 35 percent, because dry air chaps his skin and makes him cough, both of which he considers manifestations of chronic inflammation, which may be bad for longevity.
Based on the life expectancies of young men in North America, Saraev, a freelance software engineer based near Vancouver, believes he has about 55 years before he really has to think about aging. Given the exponential advances in microprocessors and smartphones in his lifetime, he insists the biotech industry will figure out a solution by then. For this reason, Saraev, like any number of young, optimistic, tech-associated men, believes that if he takes the correct preventative steps now, he might well live forever. Saraev’s plan is to keep his body in good enough shape to hit “Longevity Escape Velocity,” a term coined by English gerontologist Aubrey de Grey to denote slowing down your aging enough to reach each new medical advance as it arrives. If you delay your death by 10 years, for example, that’s 10 more years scientists have to come up with a drug, computer program, or robot assist that can make you live even longer. Keep up this game of reverse leapfrog, and eventually death can’t catch you. The term is reminiscent of “planetary escape velocity,” the speed an object needs to move in order to break free of gravity.
The science required to break free of death, unfortunately, is still at ground level. According to Nir Barzilai, M.D., director of the Institute for Aging Research at Albert Einstein College of Medicine in New York City, scientists currently understand aging as a function of seven to nine biological hallmarks, factors that change as we grow older and seem to have an anti-aging effect when reversed. You can imagine these as knobs you can turn up or down to increase or decrease the likelihood of illness and frailty. Some of these you may have heard of, including how well cells remove waste, called proteostasis; how well cells create energy, or mitochondrial function; how well cells implement their genetic instructions, or epigenetics; and how well cells maintain their DNA’s integrity, called DNA repair or telomere erosion.
Saraev doesn’t think he, personally, will figure out how to fiddle with these anti-aging knobs to make humans live longer. He is not a doctor (though he once considered it). He’s just noticed that more and more people—researchers, scientists, podcasters, denizens of Reddit—are talking about human lifespan as a number that could change dramatically in the next century. Just three years ago, after much lobbying by research and industry groups, the World Health Organization added a distinction that characterizes aging as a disease—one that humanity might cure eventually. So Saraev’s question is the same one we all have, one that intensifies as the years slide by:
ONE COMMONALITY AMONG PEOPLE who advocate for longer human lifespans is an intolerance of death even as a concept. Many proponents of super longevity remember the moment they first learned that a family member would die, and will tell you their refusal to accept it has led to a lifetime searching for a solution. Whereas many of us hoard money, amass achievements, or have children in search of surrogate immortality, longevity enthusiasts are determined to bring about the real thing, whatever it takes.
James Strole, for example, considers himself a warrior against a “deathist” paradigm. At 72, he doesn’t have Nick Saraev’s luxury of time to wait for science to solve aging. Instead, he is trying to bring about the solution himself. After a career in real- estate investing, Strole cofounded People Unlimited, a community to inspire people to live infinite lifespans, in 1995, then added the nonprofit Coalition for Radical Life Extension (CRLE) in 2016. A major goal of both organizations is to introduce the public to anti-aging developments so that when innovations come, they can be integrated into society as naturally as possible. CRLE now hosts an annual scientific conference and festival called RAADFest, which stands for Revolution Against Aging and Death. Strole calls it “Woodstock for radical life extension.” RAADFest seems wild. Prior to the 2020 festivities, which went online because of Covid, the annual event took place in Las Vegas. Sizzle reels of previous years intersperse panel discussions with on-stage exercise classes, rock and vocal performances, flamenco dance exhibitions, and a guy in a leopard-print hat playing a flute next to what looks like the android from Ex Machina. Suzanne Somers showed up. People did squats in businesswear. A speaker informed the audience that they were between “the last mortal generation and the first immortal human generation,” which might be true, depending on how you define “between.”
In some ways, Strole’s views are progressive, even refreshing. He stands against ageism, and believes that people should act without concern for whether their choices, behavior, or clothing are age-appropriate. But some RAADFest vendors could induce a bout of skepticism in even the most credulous consumer. Vendors and sponsors include supplement suppliers, biohackers, purveyors of eye creams, mystic oils, and an $8,500 air filtration system. There’s a group that hawks a pendant to protect the body from electromagnetic radiation, and another advertising a mat that beams electromagnetic radiation at the body to reduce age. (One hopes these antithetical booths aren’t located across from one another at RAADFest.) Some companies associated with RAADFest parrot wild claims about the threats of 5G networks—a common conspiracy theory—while Quantum Cellular Medicine, a “gold sponsor,” promotes misinformation about the coronavirus vaccine. It’s hard not to look at some of the products, in their hyperbolic packaging, and compare them to 1800s newspaper ads for Dr. You-Can-Trust-Me’s life-extending potions. Or worse.
RAADFest presents some potentially compelling innovations in longevity. We asked Nir Barzilai, M.D., director of the Institute for Aging Research at the Albert Einstein College of Medicine, which ones might be too good to be true.
Vibranz Orion Series Mystic Oils: Inhaling drops of these plant-based essential oils will balance your mind and body, Vibranz attests. The oils supposedly harmonize with the frequencies of your cells. Dr. Barzilai says: “Bullshit. Cells are not synchronized in any way that you could just breathe oil [and see results].”
Defytime Aging Care Cream: Activated molecules within this face and neck cream detect telomeres in your skin to vanish wrinkles and inhibit shortening, a key cause of aging. The price tag is steep: $1,500. Dr. Barzilai says: “Elongating telomeres or overexpressing telomerase can be harmful and possibly cause cancer, and having nice skin doesn’t mean you won’t die.”
AgelessRX NAD+ Injection: One injection can drive up to 100 mg NAD+ into the bloodstream via fatty tissue, boosting sirtuins to enhance your energy and slow down signs of aging. Dr. Barzilai says: “This is an OK dose, but sometimes, when you have an expensive, invasive treatment, you elicit a placebo effect because people want to believe in it.
Sedona Wellness Mat: Pulsed electromagnetic frequencies vibrate through the mat to heighten your circulation and oxygen supply, strengthening your cardiovascular and skeletal systems. Dr. Barzilai says: “Physics is an important part of our health, but there has to be more of a scientific connection than a mattress.”
Strole says in order to make strides in superlongevity, people will have to invest in anti-aging research the way they have in fighting cancer. That might be a more apt analogy than he realizes. The early, confusing days of cancer treatment were also bifurcated, with promising, incredible science on one side, and worthless nostrums on the other. Before the science matured, consumers had a hard time telling which was which.
That confusion hasn’t stopped Strole from experimenting on his own body. He’s bullish on senolytics, drugs that purge the body of deteriorating cells, and exosome treatments, which infuse the body with little packages of extracellular communication materials, usually from immortal stem cells. Neither is approved by the U.S. Food and Drug Administration, but Strole says he feels like a teenager, living and working in the retirement paradise of Scottsdale, Arizona.
But how long can that last? If you look at actuarial tables, the risk of death after age 30 doubles every eight years (a mathematical curiosity dubbed the Gompertz-Makeham Law of Mortality). The oldest humans have only made it to their 120s. Even if those stats start to change, it’s unlikely human lifespan will jump to that of Galapagos tortoises (~100+ years) or bowhead whales (~200 years) overnight, let alone approach infinity. Strole’s cofounder in People Unlimited, Charles Paul Brown, died in 2014 at the age of 79, of complications from Parkinson’s and heart disease. What happens if Strole doesn’t make it? If his doctor says he’s got six weeks?
“First I’d do everything to turn that around, but I would look then at staying alive on some level. I probably would look at Cryo[genic freezing]. That wasn’t my first choice, but I think that’s very noble work,” Strole says. He admits the question gives him pause. “It’s like when they asked [Mike Tyson] whether he had a plan when he went in the ring. And he said yeah, but the first punch in the face, it’s all over.”
DAVID SINCLAIR, PH.D., DOESN’T think any earthling is going to live forever in the next 500 years, which is bad news for the immortality-chasers, because David Sinclair is the guy in longevity. An impish, Australian 52-year-old, he runs sister genetics labs at Harvard and the University of New South Wales in Sydney, has published dozens of articles in publications as prestigious as Nature and Science, and was named one of Time magazine’s top 50 people in healthcare in 2018.
Sinclair believes we will solve aging. But living forever is an ambitious project, and while Sinclair does not believe there is an upper limit on human lifespan, he is realistic about how quickly we can push the current average. It’s still not clear how, exactly, to tweak the knobs of longevity to increase our lifespan far past current levels, but Sinclair, at least, has an idea about which knobs are most important. His most substantial contribution to longevity is what he calls the first real unified theory of aging—a single mechanism he believes explains various types of cellular dysfunction (those hallmarks of aging we mentioned earlier). Sinclair says getting old is a problem of information loss, a dysfunction in the way DNA is read and implemented in cells. He’s basically putting all his money on the epigenome, a flexible DNA interpreter that turns genes on and off based on environmental conditions.
As we live, our DNA takes damage from stressors such as UV rays, stress hormones, and X-rays. Certain families of proteins (sirtuins, for example, a family of enzymes that manage the DNA reader) can repair damaged DNA, but while they are doing it, they are unavailable to perform their usual epigenetic work, protecting other genes and preventing unnecessary genes from being transcribed. When the proteins finish making the repairs, they sometimes don’t go back to the places they came from, leading to a progressive sloppiness in how genes are implemented all over the body.
Sinclair compares aging to a scratch on a CD (see above). “The genome is the music, the reader is the epigenome, and the scratch has stopped the reader from reading the music in the same way,” he says. “I think aging stops cells from reading the right genes to remember how to be a brain cell or a liver cell.”
In other words, according to Sinclair’s theory, cells that had mastered their roles as blood or bones or brain become less capable of performing those functions, even though the instructions are still right there. Some interesting evidence he puts forward for this idea comes from cloning. When you transfer old DNA from an animal into a new cloned cell, you don’t get an old clone, but a young one. Therefore the DNA itself must contain all the instructions it ever did. That leaves the operating system as the most likely offender.
Sinclair, it should be noted, is not immune to the mad optimism that seems to strike everyone who works on longevity. He takes vitamin D, vitamin K, aspirin, the diabetes drug metformin, the grape extract resveratrol, and the sirtuin booster NMN daily, and has recommended a similar plan to his 81-year-old father. Though he doesn’t officially endorse supplements or treatments, he has happily detailed his personal plan on The Joe Rogan Experience (it’s also in his book, Lifespan: Why We Age—and Why We Don’t Have To). Not everyone loves this: Scientists who worry about maintaining legitimacy in a field swarming with crystals and essential oils grind their teeth when they hear someone as respected as Sinclair talking up unproven treatments in the popular press.
Barzilai says that if he had to rank Sinclair’s theory among the ideas out there about old age and mortality, he would “rank it as first.” But he also says it doesn’t explain everything about aging. “There’s still radiation that’s going to change our DNA. There are still metabolic abnormalities that are independent of epigenetics and maybe related more to food…The problem is that all of those hallmarks of aging are not totally dependent on epigenetics,” he says.
None of this means Sinclair is wrong. In a recent study, his lab used gene expression to return vision cells in old mice to a younger epigenetic state (they used a CD cleaning solution to buff out the scratches, you could say). The researchers observed damaged optic-nerve cells in the mice regrow their connections, supposedly impossible in an aged nervous system. They also restored old mice’s vision in a model of mouse glaucoma. That study landed on the December 2020 cover of Nature. And anyway, Sinclair isn’t recommending gene therapies for humans right now. His preferred anti-aging methods include things like exercising, eating a lot of plants, and not smoking. It would be difficult to find a doctor on earth who disagrees with those ideas. He does, however, prefer to eat stressed plants—those that have been intentionally under-nourished as they’ve grown—reasoning that mild stress turns on anti-aging defenses in the plants that benefit humans who eat them. (One assumes he has the saddest-looking garden in his neighborhood.)
Much of Sinclair’s research focuses on sirtuins, whose levels in the body decrease as we age. Two of the drugs he takes daily, NMN and resveratrol, are purported to goose the sirtuin system. (NAD+, another sirtuin booster, is the main ingredient in the anti-aging supplement Basis, from the popular longevity company Elysium, helmed by Sinclair’s postdoctoral mentor Leonard Gaurente.) But even these promising molecules have little to no chance of making us immortal by themselves. Much of Sinclair’s practical advice is still limited to behavioral interventions: The most effective involve a concept called “hormesis,” when mild stress damages the body just enough to set off positive cellular changes. Exercise, for example, sweating in a sauna, and allowing yourself to get cold spur the body to protect itself.
Probably the most supported intervention for living a very long time is as simple as changing your diet. “If I could only give one recommendation, it would be to eat less often,” Sinclair says. Studies dating back to the 1930s have shown that reducing calories around 30 percent has improved the lifespan of mice and monkeys, and improved biomarkers of age in humans. The research is so convincing that Barzilai uses it as a control in his study of other methods, to see if anything else works as well. Both Sinclair and Barzilai (as well as a number of other researchers) do it personally. Sinclair practices intermittent fasting. Barzilai follows the 16:8 diet, in which he only eats during an eight-hour stretch.
But plenty of people fast for health reasons, and still no one has exceeded the human age limit of roughly 122 years. What needs to happen to get humanity from where we are now, floating in a sea of partial, mostly behavioral cures, to the point when living much longer, healthier lives becomes the norm?
The first challenge is education, Sinclair says. Most people still don’t think of aging as a disease. The U.S. Food and Drug Administration doesn’t. And as long as that remains the case, studying and prescribing drugs to treat aging will be difficult. Sinclair brings up metformin, a drug that is approved to treat diabetes, but which has also been shown to slow aging in animals and decrease neurodegenerative disease and cancer in humans. (A large, nationwide trial of metformin, called TAME: Targeting Aging with Metformin, was postponed due to Covid but will begin shortly.) It’s likely that, like metformin, the first potential anti-aging drugs will trickle down to the young and healthy from populations of people who need them to treat specific diseases. That will be easier if doctors don’t have to prescribe them off-label.
Another challenge: There’s no reliable test for the body’s cellular (as opposed to numerical) age, which makes it difficult to know whether a given treatment is working unless a research study follows people all the way to death. Sinclair says he is starting a company to build such a test, hoping the product will be cheap and easy enough to become ubiquitous. “Lowering the barrier to doing this test routinely…will get the public accustomed to the concept that you can measure aging and that how you live affects that rate,” he says. He is not alone in this belief: Alex Zhavoronkov, a founder at the company Deep Longevity (and a scientist involved in lobbying the WHO to name aging a disease), is also developing a test of true age. The anti-aging supplement company Elysium has one as well, called Index. It remains to be seen which test will capture the most users, and which will be the most accurate, but the fact remains that you can’t make people live longer until you know how they’re dying, and how quickly they’re dying.
Other concerns involved in creating a population of immortals go beyond the pay grade of a Harvard biologist. Who will be allowed to live forever? What will happen to the Earth when humans stop dying? Will any of this involve robots? These are the questions we ask of philosophers, ethicists, and artists—and also of Natasha Vita-More, executive director of the transhumanist nonprofit Humanity+.
Vita-More predicts that seriously extending human lifespan will require advanced technology, helpers such as nanorobots that can rove the body and continually repair cellular damage. She doesn’t worry about overpopulation, because birthrates have been plummeting (in wealthy countries, at least) for years. As for climate change, she believes some of the biotechnological wave that lifts human lifespan will be used to treat the breakdown of the Earth, “by repairing, renewing, and regenerating its ecology.”
But it won’t all be wine and roses. A society that lives indefinitely will have to find new things for people to do after our current retirement age, as well as reimagine the healthcare industry, once most older people are no longer spending their later years sick. There will need to be regulation to ensure corporations don’t sell fake anti-aging cures, or jack up prices to absurd heights, or engage in any number of other unethical practices. And we will still need to raise up the impoverished, secure an equitable physical and economic infrastructure, and agree politically on doing the right things. But Vita-More believes we can do it.
“Is this too hopeful? I do not think so,” she says. “I think that the idea of death will take on new defining factors and parameters and that people might become a new type of human that is not restricted by chronological age, gender, race, size, and all the other criteria used to normalize society.”
This is possibly a little optimistic in the short term. But it is true that the quest to live longer doesn’t have to be about vanity. “People who survive chemotherapy and radiation from cancer, they are aging rapidly. They need help. People with HIV get age-related diseases 10 years before they should,” Barzilai says. Sure, those of us who are young and healthy, like Nick Saraev, might seek a cure for mortality because dying sounds unpleasant, but effective anti-aging treatments could also create health equality among those of us who are living out vastly different lifespans right now—those who have to use wheelchairs, who can’t afford fresh vegetables, or who develop early onset Alzheimer’s because of bad genes. James Strole once characterized his dream of superlongevity as “heaven on earth.”
Is that what this is? Not exactly. But it’s a start.