Genflow Bioscience


How Long Can We Live?

In 1990, not long after Jean-Marie Robine and Michel Allard began conducting a nationwide study of French centenarians, one of their software programs spat out an error message. An individual in the study was marked as 115 years old, a number outside the program’s range of acceptable age values. They called their collaborators in Arles, where the subject lived, and asked them to double-check the information they had provided, recalls Allard, who was then the director of the IPSEN Foundation, a nonprofit research organization. Perhaps they made a mistake when transcribing her birth date? Maybe this Jeanne Calment was actually born in 1885, not 1875? No, the collaborators said. We’ve seen her birth certificate. The data is correct.

Calment was already well known in her hometown. Over the next few years, as rumors of her longevity spread, she became a celebrity. Her birthdays, which had been local holidays for a while, inspired national and, eventually, international news stories. Journalists, doctors and scientists began crowding her nursing-home room, eager to meet la doyenne de l’humanité. Everyone wanted to know her story.

Calment lived her entire life in the sunburned clay-and-cobble city of Arles in the South of France, where she married a second cousin and moved into a spacious apartment above the store he owned. She never needed to work, instead filling her days with leisurely pursuits: bicycling, painting, roller skating and hunting. She enjoyed a glass of port, a cigarette and some chocolate nearly every day. In town, she was known for her optimism, good humor and wit. (“I’ve never had but one wrinkle,” she once said, “and I’m sitting on it.”)

By age 88, Calment had outlived her parents, husband, only child, son-in-law and grandson. As she approached her 110th birthday, she was still living alone in her cherished apartment. One day, during a particularly severe winter, the pipes froze. She tried to thaw them with a flame, accidentally igniting the insulating material. Neighbors noticed the smoke and summoned the fire brigade, which rushed her to a hospital. Following the incident, Calment moved into La Maison du Lac, the nursing home situated on the hospital’s campus, where she would live until her death at age 122 in 1997.

In 1992, as Calment’s fame bloomed, Robine and Allard returned to her file. Clearly, here was someone special — someone who merited a case study. Arles was just an hour’s drive from the village where Robine, a demographer at the French National Institute of Health and Medical Research, lived at the time. He decided to arrange a visit. At La Maison du Lac, he introduced himself to the medical director, Victor Lèbre, and explained that he wanted to interview Calment. Lèbre replied that it was too late; Calment, he said, was completely deaf. But he agreed to let him meet the grande dame anyway. They walked down a long concrete corridor and into a small and spare room.

“Hello, Madame Calment,” Lèbre said.

“Good morning, doctor,” she answered without hesitation.

Lèbre was so shocked that he grabbed Robine by the arm and rushed him down the corridor back to his office, where he interrogated the nurses about Calment’s hearing. Apparently she could hear quite well at times, but experienced periods of near deafness; Lèbre had most likely mistaken one of those interludes for a permanent condition. Upon returning to Calment’s room, Robine saw her properly for the first time. She was sitting by the window in an armchair that dwarfed her shrunken frame. Her eyes, milky with cataracts, could distinguish light from dark, but did not focus on any place in particular. Her plain gray clothes appeared to be several decades old.

During that first meeting, Robine and Calment mostly exchanged pleasantries and idle chatter. Over the next few years, however, Robine and Allard, in collaboration with several other researchers and archivists, interviewed Calment dozens of times and thoroughly documented her life history, verifying her age and cementing her reputation as the oldest person who ever lived. Since then, Calment has become something of an emblem of the ongoing quest to answer one of history’s most controversial questions: What exactly is the limit on the human life span?

As medical and social advances mitigate diseases of old age and prolong life, the number of exceptionally long-lived people is increasing sharply. The United Nations estimates that there were about 95,000 centenarians in 1990 and more than 450,000 in 2015. By 2100, there will be 25 million. Although the proportion of people who live beyond their 110th birthday is far smaller, this once-fabled milestone is also increasingly common in many wealthy nations. The first validated cases of such “supercentenarians” emerged in the 1960s. Since then, their global numbers have multiplied by a factor of at least 10, though no one knows precisely how many there are. In Japan alone, the population of supercentenarians grew to 146 from 22 between 2005 and 2015, a nearly sevenfold increase.

Given these statistics, you might expect that the record for longest life span would be increasing, too. Yet nearly a quarter-century after Calment’s death, no one is known to have matched, let alone surpassed, her 122 years. The closest was an American named Sarah Knauss, who died at age 119, two years after Calment. The oldest living person is Kane Tanaka, 118, who resides in Fukuoka, Japan. Very few people make it past 115. (A few researchers have even questioned whether Calment really lived as long as she claimed, though most accept her record as legitimate based on the weight of biographical evidence.)

As the global population approaches eight billion, and science discovers increasingly promising ways to slow or reverse aging in the lab, the question of human longevity’s potential limits is more urgent than ever. When their work is examined closely, it’s clear that longevity scientists hold a wide range of nuanced perspectives on the future of humanity. Historically, however — and somewhat flippantly, according to many researchers — their outlooks have been divided into two broad camps, which some journalists and researchers call the pessimists and the optimists. Those in the first group view life span as a candle wick that can burn for only so long. They generally think that we are rapidly approaching, or have already reached, a ceiling on life span, and that we will not witness anyone older than Calment anytime soon.

In contrast, the optimists see life span as a supremely, maybe even infinitely elastic band. They anticipate considerable gains in life expectancy around the world, increasing numbers of extraordinarily long-lived people — and eventually, supercentenarians who outlive Calment, pushing the record to 125, 150, 200 and beyond. Though unresolved, the long-running debate has already inspired a much deeper understanding of what defines and constrains life span — and of the interventions that may one day significantly extend it.

The theoretical limits on the length of a human life have vexed scientists and philosophers for thousands of years, but for most of history their discussions were largely based on musings and personal observations. In 1825, however, the British actuary Benjamin Gompertz published a new mathematical model of mortality, which demonstrated that the risk of death increased exponentially with age. Were that risk to continue accelerating throughout life, people would eventually reach a point at which they had essentially no chance of surviving to the next year. In other words, they would hit an effective limit on life span.

Instead, Gompertz observed that as people entered old age, the risk of death plateaued. “The limit to the possible duration of life is a subject not likely ever to be determined,” he wrote, “even should it exist.” Since then, using new data and more sophisticated mathematics, other scientists around the world have uncovered further evidence of accelerating death rates followed by mortality plateaus not only in humans but also in numerous other species, including rats, mice, shrimp, nematodes, fruit flies and beetles.

In 2016, an especially provocative study in the prestigious research journal Nature strongly implied that the authors had found the limit to the human life span. Jan Vijg, a geneticist at the Albert Einstein College of Medicine, and two colleagues analyzed decades’ worth of mortality data from several countries and concluded that although the highest reported age at death in these countries increased rapidly between the 1970s and 1990s, it had failed to rise since then, stagnating at an average of 114.9 years. Human life span, it seemed, had arrived at its limit. Although some individuals, like Jeanne Calment, might reach staggering ages, they were outliers, not indicators of a continual lengthening of life.

‘Could someone run a two-minute mile? No. The human body is incapable of moving that fast based on anatomical limitations.’

While a few scientists from the more pessimistic tradition applauded the study, many researchers sternly critiqued its methods, in particular the bold generalization based on what one commentary called a “limited, noisy set of data.” Nearly a dozen rebuttals appeared in Nature and other journals. James Vaupel, the founding director of the Max Planck Institute for Demographic Research and a staunch critic of the idea that the human life span has reached its limit, called the study a travesty and told the science journalist Hester van Santen that the authors “just shoveled the data into their computer like you’d shovel food into a cow.”

Robine remembers the furor well. He was one of several peer reviewers whom Nature recruited to evaluate the study by Vijg and his co-authors before publication. The first draft did not satisfy Robine’s standards, because it focused only on the United States and relied on data he considered incomplete. Among other changes, he recommended using the more comprehensive International Database on Longevity, which he and Vaupel developed with colleagues. Van Santen reported in a peer-review post-mortem that, based on the substantial criticism by Robine and one of the other reviewers, Nature initially declined to publish the study. After Vijg and his co-authors sent Nature a thoroughly revised version, however, Robine conceded that the study was sound enough to publish, though he still disagreed with its conclusions. (Vijg stands by the methodology and conclusions of the study.)

Two years later, in 2018, the equally prestigious journal Science published a study that completely contradicted the one in Nature. The demographers Elisabetta Barbi of the University of Rome and Kenneth Wachter of the University of California, Berkeley, along with several colleagues, examined the survival trajectories of nearly 4,000 Italians and concluded that, while the risk of death increased exponentially up to age 80, it then slowed and eventually plateaued. Someone alive at 105 had about a 50 percent chance of living to the next year. The same was true at 106, 107, 108 and 109. Their findings, the authors wrote, “strongly suggest that longevity is continuing to increase over time, and that a limit, if any, has not been reached.”

Many of the disputes over human longevity studies center on the integrity of different data sets and the varying statistical methods researchers use to analyze them. Where one group of scientists perceives a clear trend, another suspects an illusion. Robine finds the debate exciting and essential. “I’m not convinced by my colleagues’ suggesting that life is or is not limited,” he told me. “I think the question is still here. We don’t yet know the best kind of analysis or study design to use to tackle this question. The most important thing to do today is to keep collecting the data.”

On their own, however, life-span statistics can tell us only so much. Such data have been available for centuries and have clearly not settled the debate. The number of supercentenarians may still be too small to support unequivocal conclusions about mortality rates in extreme old age. But in more recent decades, scientists have made considerable progress toward understanding the evolutionary origins of longevity and the biology of aging. Instead of fixating on human demographics, this research considers all species on the planet and tries to derive general principles about duration of life and timing of death.

“I’m a little surprised that anyone today would question whether or not there is a limit,” S. Jay Olshansky, an expert on longevity and a professor in the School of Public Health at the University of Illinois at Chicago, told me. “It doesn’t really matter whether there is a plateau of mortality or not in extreme old age. There are so few people that make it up there, and the risk of death at that point is so high, that most people aren’t going to live much beyond the limits we see today.”

Olshansky, 67, has argued for decades that life span is obviously limited and that the mathematical models of feuding demographers are secondary to the biological realities of aging. He likes to make an analogy to athletics: “Could someone run a two-minute mile? No. The human body is incapable of moving that fast based on anatomical limitations. The same thing applies to human longevity.”

He is so thoroughly convinced of his position that he has backed it with an investment that may eventually grow to a sizable fortune for him or his heirs. In 2000, Steven Austad, a biologist now at the University of Alabama, Birmingham, told Scientific American, “The first 150-year-old person is probably alive right now.” When Olshansky disagreed, the two struck up a friendly bet: Each put $150 in an investment fund and signed a contract stipulating that the winner or his descendants would claim the returns in 2150. After the Vijg paper was published, they doubled their contributions. Olshansky originally invested the funds in gold and later in Tesla. He estimates the value will be well over $1 billion when it’s time to collect. “Oh, I am going to win,” Olshansky said when I asked him how he currently feels about the wager. “Ultimately, biology will determine which one of us is right. That’s why I’m so confident.”

Embedded in the question of the human life span’s limits is a more fundamental enigma: Why do we — why does any organism — get old and die in the first place? As the eminent physicist Richard Feynman put it in a 1964 lecture, “There is nothing in biology yet found that indicates the inevitability of death.”

Some organisms seem to be living proof of this claim. Scientists recently drilled into sediments deep beneath the seafloor and unearthed microbes that had probably survived “in a metabolically active form” for more than 100 million years. Pando, a 106-acre clonal colony of genetically identical aspen trees connected by a single root system in Utah, is thought to have sustained itself for as long as 14,000 years and counting.

A few creatures are so ageless that some scientists regard them as biologically immortal. Hydra, tiny relatives of jellyfish and corals, do not appear to age at all and can regenerate whole new bodies when sliced into pieces. When injured or threatened, a sexually mature Turritopsis dohrnii, the immortal jellyfish, can revert to its juvenile stage, mature and revert again, potentially forever. Biologically immortal organisms are not impervious to death — they can still perish from predation, lethal injury or infection — but they do not seem to die of their own accord. Theoretically, any organism with a continual supply of energy, a sufficient capacity for self-maintenance and repair and the good fortune to evade all environmental hazards could survive until the end of the universe.

Why, then, do so many species expire so dependably? Most longevity researchers agree that aging, the set of physical processes of damage and decay that result in death, is not an adaptive trait shaped by natural selection. Rather, aging is a byproduct of selection’s waning power over the course of an organism’s life. Selection acts most strongly on genes and traits that help living creatures survive adolescence and reproduce. In many species, the few individuals who make it to old age are practically invisible to natural selection because they are no longer passing on their genes, nor helping raise their relatives’ progeny.

As the British biologist Peter Medawar observed in the 1950s, harmful genetic mutations that are not expressed until late in life could accumulate across generations because selection is too weak to remove them, eventually resulting in specieswide aging. The American biologist George C. Williams elaborated on Medawar’s ideas, adding that some genes may be beneficial in youth but detrimental later on, when selection would overlook their disadvantages. Similarly, in the 1970s, the British biologist Thomas Kirkwood proposed that aging was partly due to an evolutionary trade-off between growth and reproduction on the one hand and day-to-day maintenance on the other. Devoting resources to maintenance is advantageous only if an organism is likely to continue surviving and reproducing. For many organisms, external threats are too great and numerous to endure for very long, so there is not much evolutionary pressure to preserve their bodies in old age, resulting in their deterioration.

But that still leaves the question of why there is such huge variation in life span among species. Biologists think life span is largely determined by a species’ anatomy and lifestyle. Small and highly vulnerable animals tend to reproduce quickly and die not long after, whereas larger animals, and those with sophisticated defenses, usually reproduce later in life and live longer overall. Ground-dwelling birds, for instance, often have shorter life spans than strong-winged, tree-nesting species, which are less susceptible to predators. Naked mole rats, which enjoy the cooperative benefits of tight-knit social groups and the protection of subterranean chambers, live five to 10 times longer than other similarly sized mammals.

A few species, like stalwart clonal trees with resilient root systems, are so well protected against environmental hazards that they don’t have to prioritize early growth and reproduction over long-term maintenance, allowing them to live an extraordinarily long time. Others, like the immortal jellyfish and hydra, are potentially indefinite, because they have retained primordial powers of rejuvenation that have been relegated to pockets of stem cells in most adult vertebrates.

Humans have never belonged to the select society of the everlasting. We most likely inherited fairly long life spans from our last common ancestor with chimpanzees, which may have been a large, intelligent, social ape that lived in trees away from ground predators. But we never out-evolved the eventual senescence that is part of being a complex animal with all manner of metabolically costly adaptations and embellishments.

As the years pass, our chromosomes contract and fracture, genes turn on and off haphazardly, mitochondria break down, proteins unravel or clump together, reserves of regenerative stem cells dwindle, bodily cells stop dividing, bones thin, muscles shrivel, neurons wither, organs become sluggish and dysfunctional, the immune system weakens and self-repair mechanisms fail. There is no programmed death clock ticking away inside us — no precise expiration date hard-wired into our species — but, eventually, the human body just can’t keep going.

Social advances and improving public health may further increase life expectancy and lift some supercentenarians well beyond Calment’s record. Even the most optimistic longevity scientists admit, however, that at some point these environmentally induced gains will run up against human biology’s limits — unless, that is, we fundamentally alter our biology.

Many scientists who study aging think that biomedical breakthroughs are the only way to substantially increase the human life span, but some doubt that anyone alive today will witness such radical interventions; a few doubt they are even possible. In any case, longevity scientists agree, significantly elongating life without sustaining well-being is pointless, and enhancing vitality in old age is valuable regardless of gains in maximum life span.

One of the many obstacles to these goals is the overwhelming complexity of aging in mammals and other vertebrates. Researchers have achieved astonishing results by tweaking the genome of the roundworm C. elegans, extending its life span nearly 10 times — the equivalent of a person’s living 1,000 years. Although scientists have used caloric restriction, genetic engineering and various drugs to stretch life span in more complex species, including fish, rodents and monkeys, the gains have never been as sharp as in roundworms, and the precise mechanisms underlying these changes remain unclear.

‘Cells can clean themselves up, they can get rid of old proteins, they can rejuvenate, if you turn on the youthful genes through this reset process.’

More recently, however, researchers have tested particularly innovative techniques for reversing and postponing some aspects of aging, with tentative but promising results. James Kirkland, an expert on aging at the Mayo Clinic in Rochester, Minn., has demonstrated with colleagues that certain drug cocktails purge old mice of senescent cells, granting them more than a month of additional healthy living. Their research has already inspired numerous human clinical trials.

At the same time, at the University of California, Berkeley, the married bioengineers Irina and Michael Conboy are investigating ways to filter or dilute aged blood in rodents to remove molecules that inhibit healing, which in turn stimulates cellular regeneration and the production of revitalizing compounds.

In a study published in Nature in December 2020, David Sinclair, a director of the Paul F. Glenn Center for the Biology of Aging Research at Harvard Medical School, along with colleagues, partly restored vision in middle-aged and ailing mice by reprogramming their gene expression. The researchers injected the mice’s eyes with a benign virus carrying genes that revert mature cells to a more supple, stem-cell-like state, which allowed their neurons to regenerate — an ability that mammals usually lose after infancy. “Aging is far more reversible than we thought,” Sinclair told me. “Cells can clean themselves up, they can get rid of old proteins, they can rejuvenate, if you turn on the youthful genes through this reset process.”

Known for his boyish features and sanguine predictions, Sinclair, 51, and several of his family members (including his dogs) follow versions of his life-prolonging regimen, which has, over the years, included regular exercise, sauna steams and ice baths, a two-meal-a-day mostly vegetarian diet, the diabetes drug metformin (which is purported to have anti-aging properties) and several vitamins and supplements, like the once-hyped but ultimately disappointing red-wine miracle molecule resveratrol. Sinclair has also founded at least 12 biotech companies and serves on the boards of several more, one of which is already pursuing human clinical trials of a gene therapy based on his recent Nature study.

In a talk at Google, he envisioned a future in which people receive similar treatments every decade or so to undo the effects of aging throughout the body. “We don’t know how many times you can reset,” he said. “It might be three, it might be 3,000. And if you can reset your body 3,000 times, then things get really interesting. I don’t know if any of you want to live for 1,000 years, but I also don’t know if it’s going to be possible, but these are the questions we have to start thinking about. Because it’s not a question of if — it’s now a question of when.”

Longevity scientists who favor the idea of living for centuries or longer tend to speak effusively of prosperity and possibility. As they see it, sustaining life and promoting health are intrinsically good and, therefore, so are any medical interventions that accomplish this. Biomedically extended longevity would not only revolutionize general well-being by minimizing or preventing diseases of aging, they say, it would also vastly enrich human experience. It would mean the chance for several fulfilling and diverse careers; the freedom to explore much more of the world; the joy of playing with your great-great-great-grandchildren; the satisfaction of actually sitting in the shade of the tree you planted so long ago. Imagine, some say, how wise our future elders could be. Imagine what the world’s most brilliant minds could accomplish with all that time.

‘We still don’t know how to avoid frailty.’

In sharp contrast, other experts argue that extending life span, even in the name of health, is a doomed pursuit. Perhaps the most common concern is the potential for overpopulation, especially considering humanity’s long history of hoarding and squandering resources and the tremendous socioeconomic inequalities that already divide a world of nearly eight billion. There are still dozens of countries where life expectancy is below 65, primarily because of problems like poverty, famine, limited education, disempowerment of women, poor public health and diseases like malaria and H.I.V./AIDS, which novel and expensive life-extending treatments will do nothing to solve.

Lingering multitudes of superseniors, some experts add, would stifle new generations and impede social progress. “There is a wisdom to the evolutionary process of letting the older generation disappear,” said Paul Root Wolpe, the director of the Center for Ethics at Emory University, during one public debate on life extension. “If the World War I generation and World War II generation and perhaps, you know, the Civil War generation were still alive, do you really think that we would have civil rights in this country? Gay marriage?”

In her final years at La Maison du Lac, the once-athletic Jeanne Calment was essentially immobile, confined to her bed and wheelchair. Her hearing continued to decline, she was virtually blind and she had trouble speaking. At times, it was not clear that she was fully aware of her surroundings.

By some accounts, those in charge of Calment’s care failed to shield her from undue commotion and questionable interactions as journalists, tourists and spectators bustled in and out of her room. Following the release of an investigative documentary, the hospital director barred all visitors. The last time Robine saw her was shortly after her 120th birthday. About two years later, in the midst of an especially hot summer, Jeanne Calment died alone in her nursing-home room from unknown causes and was quickly buried. Only a few people were permitted to attend her funeral. Robine and Allard were not among them. Neither was Calment’s family: All her close relatives had been dead for more than three decades.

“Today, more people are surviving the major diseases of old age and entering a new phase of their life in which they become very weak,” Robine said. “We still don’t know how to avoid frailty.”

Perhaps the most unpredictable consequence of uncoupling life span from our inherited biology is how it would alter our future psychology. All of human culture evolved with the understanding that earthly life is finite and, in the grand scheme, relatively brief. If we are one day born knowing that we can reasonably expect to live 200 years or longer, will our minds easily accommodate this unparalleled scope of life? Or is our neural architecture, which evolved amid the perils of the Pleistocene, inherently unsuited for such vast horizons?


Scientists, philosophers and writers have long feared that a surfeit of time would exhaust all meaningful experience, culminating in debilitating levels of melancholy and listlessness. Maybe the desire for all those extra years masks a deeper longing for something unattainable: not for a life that is simply longer, but for one that is long enough to feel utterly perfect and complete.

In Jorge Luis Borges’s short story “The Immortal,” a Roman military officer stumbles upon a “secret river that purifies men of death.” After drinking from it and spending eons in deep thought, he realizes that death imbues life with value, whereas, for immortals, “Nothing can occur but once, nothing is preciously in peril of being lost.” Determined to find the antidote to everlasting life, he wanders the planet for nearly a millennium. One day, he drinks from a spring of clear water on the Eritrean coast and shortly thereafter scratches the back of his hand on a thorny tree. Startled by an unfamiliar twinge of pain, he searches for a sign of injury. As a drop of blood slowly pools on his skin — proof of his restored mortality — he simply watches, “incredulous, speechless, and in joy.”

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