research on longevity

Scientists Have Reached a Key Milestone in Learning How to Reverse Aging

I t’s been 13 years in the making, but Dr. David Sinclair and his colleagues have finally answered the question of what drives aging. In a study published Jan. 12 in Cell , Sinclair, a professor of genetics and co-director of the Paul F. Glenn Center for Biology of Aging Research at Harvard Medical School, describes a groundbreaking aging clock that can speed up or reverse the aging of cells.

Scientists studying aging have debated what drives the process of senescence in cells—and primarily focused on mutations in DNA that can, over time, mess up a cell’s normal operations and trigger the process of cell death. But that theory wasn’t supported by the fact that older people’s cells often were not riddled with mutations, and that animals or people harboring a higher burden of mutated cells don’t seem to age prematurely .

Sinclair therefore focused on another part of the genome, called the epigenome. Since all cells have the same DNA blueprint, the epigenome is what makes skin cells turn into skin cells and brain cells into brain cells. It does this by providing different instructions to different cells for which genes to turn on, and which to keep silent. Epigenetics is similar to the instructions dressmakers rely on from patterns to create shirts, pants, or jackets. The starting fabric is the same, but the pattern determines what shape and function the final article of clothing takes. With cells, the epigenetic instructions lead to cells with different physical structures and functions in a process called differentiation.

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In the Cell paper, Sinclair and his team report that not only can they age mice on an accelerated timeline, but they can also reverse the effects of that aging and restore some of the biological signs of youthfulness to the animals. That reversibility makes a strong case for the fact that the main drivers of aging aren’t mutations to the DNA, but miscues in the epigenetic instructions that somehow go awry. Sinclair has long proposed that aging is the result of losing critical instructions that cells need to continue functioning, in what he calls the Information Theory of Aging. “Underlying aging is information that is lost in cells, not just the accumulation of damage,” he says. “That’s a paradigm shift in how to think about aging. “

His latest results seem to support that theory. It’s similar to the way software programs operate off hardware, but sometimes become corrupt and need a reboot, says Sinclair. “If the cause of aging was because a cell became full of mutations, then age reversal would not be possible,” he says. “But by showing that we can reverse the aging process, that shows that the system is intact, that there is a backup copy and the software needs to be rebooted.”

In the mice, he and his team developed a way to reboot cells to restart the backup copy of epigenetic instructions, essentially erasing the corrupted signals that put the cells on the path toward aging. They mimicked the effects of aging on the epigenome by introducing breaks in the DNA of young mice. (Outside of the lab, epigenetic changes can be driven by a number of things, including smoking, exposure to pollution and chemicals.) Once “aged” in this way, within a matter of weeks Sinclair saw that the mice began to show signs of older age—including grey fur, lower body weight despite unaltered diet, reduced activity, and increased frailty.

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The rebooting came in the form of a gene therapy involving three genes that instruct cells to reprogram themselves—in the case of the mice, the instructions guided the cells to restart the epigenetic changes that defined their identity as, for example, kidney and skin cells, two cell types that are prone to the effects of aging. These genes came from the suite of so-called Yamanaka stem cells factors—a set of four genes that Nobel scientist Shinya Yamanaka in 2006 discovered can turn back the clock on adult cells to their embryonic, stem cell state so they can start their development, or differentiation process, all over again. Sinclair didn’t want to completely erase the cells’ epigenetic history, just reboot it enough to reset the epigenetic instructions. Using three of the four factors turned back the clock about 57%, enough to make the mice youthful again.

“We’re not making stem cells, but turning back the clock so they can regain their identity,” says Sinclair. “I’ve been really surprised by how universally it works. We haven’t found a cell type yet that we can’t age forward and backward.”

Read More: The Best Anti-Aging Serums, Tested and Reviewed

Rejuvenating cells in mice is one thing, but will the process work in humans? That’s Sinclair’s next step, and his team is already testing the system in non-human primates. The researchers are attaching a biological switch that would allow them to turn the clock on and off by tying the activation of the reprogramming genes to an antibiotic, doxycycline. Giving the animals doxycycline would start reversing the clock, and stopping the drug would halt the process. Sinclair is currently lab-testing the system with human neurons, skin, and fibroblast cells, which contribute to connective tissue.

In 2020, Sinclair reported that in mice, the process restored vision in older animals; the current results show that the system can apply to not just one tissue or organ, but the entire animal. He anticipates eye diseases will be the first condition used to test this aging reversal in people, since the gene therapy can be injected directly into the eye area.

“We think of the processes behind aging, and diseases related to aging, as irreversible,” says Sinclair. “In the case of the eye, there is the misconception that you need to regrow new nerves. But in some cases the existing cells are just not functioning, so if you reboot them, they are fine. It’s a new way to think about medicine.”

That could mean that a host of diseases—including chronic conditions such as heart disease and even neurodegenerative disorders like Alzheimer’s —could be treated in large part by reversing the aging process that leads to them. Even before that happens, the process could be an important new tool for researchers studying these diseases. In most cases, scientists rely on young animals or tissues to model diseases of aging, which doesn’t always faithfully reproduce the condition of aging. The new system “makes the mice very old rapidly, so we can, for example, make human brain tissue the equivalent of what you would find in a 70 year old and use those in the mouse model to study Alzheimer’s disease that way,” Sinclair says.

Beyond that, the implications of being able to age and rejuvenate tissues, organs, or even entire animals or people are mind-bending. Sinclair has rejuvenated the eye nerves multiple times, which raises the more existential question for bioethicists and society of considering what it would mean to continually rewind the clock on aging.

This study is just the first step in redefining what it means to age, and Sinclair is the first to acknowledge that it raises more questions than answers. “We don’t understand how rejuvenation really works, but we know it works,” he says. “We can use it to rejuvenate parts of the body and hopefully make medicines that will be revolutionary. Now, when I see an older person, I don’t look at them as old, I just look at them as someone whose system needs to be rebooted. It’s no longer a question of if rejuvenation is possible, but a question of when.”

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The Great Read The Health Issue

How Long Can We Live?

New research is intensifying the debate — with profound implications for the future of the planet.

Credit... Photo illustration by Maurizio Cattelan and Pierpaolo Ferrari

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By Ferris Jabr

• Published April 28, 2021 Updated June 15, 2023

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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?

The Business of Longevity: DealBook/Dialogue

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.”

Ferris Jabr is a contributing writer for the magazine. His January 2019 cover story on the evolution of beauty is featured in the latest edition of The Best American Science and Nature Writing. Maurizio Cattelan is an Italian artist whose work has been the subject of numerous solo exhibitions, including shows at the Guggenheim Museum in New York and the Pompidou Center in Paris. Pierpaolo Ferrari is an Italian photographer and, along with Cattelan, is a co-founder of the magazine Toiletpaper, known for its surreal and humorous imagery.

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At the Human Longevity Lab, studying methods to slow or reverse aging

• Feinberg School of Medicine

The Potocsnak Longevity Institute at Northwestern University Feinberg School of Medicine has launched the Human Longevity Laboratory, a longitudinal,  cross-sectional study that will investigate the relationship between chronological age and biological age across different organ systems and validate interventions that may reverse or slow down the processes of aging.

“The relationship between chronological age (how many years old you are) and biological age (how old your body appears in terms of your overall health), and how they may differ, is key to understanding human longevity,” said Dr. Douglas Vaughan, director of the Potocsnak Longevity Institute. “Knowledge gained from this research may allow scientists to develop methods to slow the process of aging and push back the onset of aging-related disease, hopefully extending the ‘healthspan.’”

Anyone is eligible to participate in the Northwestern research study, but the scientists are focused on studying people who are disadvantaged with respect to biological aging, including those with HIV.

Our primary aim is to find ways to slow down the rate of aging in people that are aging too quickly and provide them with an opportunity to extend their healthspan.”

“We are particularly interested in bringing in people who are at risk for accelerated aging — people with chronic HIV infections, patients with chronic kidney disease, people exposed to toxic substances regularly (smoke and chemicals) and others,” Vaughan said. “Our primary aim is to find ways to slow down the rate of aging in people that are aging too quickly and provide them with an opportunity to extend their healthspan.”

The comprehensive research protocol includes assessments across various systems (cardiovascular, respiratory, neurocognitive, metabolic, and musculoskeletal), and novel molecular profiling of the epigenome. The studies will be performed at no cost to participants at Northwestern Medicine.

Over the next year, the team plans to enroll a diverse cohort representing individuals of all ages, ethnicities and socioeconomic backgrounds to form a picture of how aging affects all members of the population.

A participant’s results will be reviewed with them after their testing is complete. “That is information that might motivate some participants to improve their lifestyle, exercise more, lose weight or change their diet,” said Dr. John Wilkins, associate director of the Human Longevity Laboratory. Wilkins is also an associate professor of medicine in cardiology and of preventive medicine at the Feinberg School of Medicine, as well as a Northwestern Medicine physician.

Ultimately, the Human Longevity Laboratory will launch clinical trials designed to test therapeutics or interventions that might slow the velocity of aging.

View this site for more information on the study.

Dr. Vaughan plans to develop a network of sites duplicating the Human Longevity Laboratory with partners in the U.S. and globally. 

“We hope to clone our laboratory in terms of basic equipment and the protocol,” Vaughan said. “We intend to build a large database that is the most diverse and comprehensive in the world that will contribute significantly to our research.” Potential collaborative partners and sites have already been identified in Asia, Brazil, the Netherlands and in West Africa.

The Human Longevity Laboratory is part of the multi-center Potocsnak Longevity Institute , whose goal is to foster new discoveries and build on Northwestern’s ongoing research in the rapidly advancing science of aging. The Institute is funded by a gift from Chicago industrialist John Potocsnak and family.

“Aging is a primary risk factor for every disease affecting adults — including diabetes, arthritis, dementia, heart disease, diabetes, aging-related cancer, hypertension and frailty,” Vaughan said. “The biological processes that drive aging may be malleable. We think we can slow that process down, delay it, even theoretically reverse it. The curtain is being pulled back on what drives aging. We want to contribute to that larger discovery process.”

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About Stanford Center on Longevity

L onger lives are, at once, among the most remarkable achievements in all of human history and the greatest challenges of the 21st century. Whereas most discussions about aging societies are premised on the assumption that older people are frail and infirm, our premise is that problems of older people demand solutions so that the substantial increase in life expectancy can ultimately benefit individuals and societies. Stanford Center on Longevity’s mission is to accelerate and implement scientific discoveries, technological advances, behavioral practices, and social norms so that century long lives are healthy and rewarding.

We are a center on  longevity , not old age, because building a world where the majority of people thrive in old age requires attention to the entire life span. Research shows clearly that education, exercise, nutritional habits, financial decisions, and social choices early in life have substantial implications for quality of life at advanced ages. Increased longevity demands that we reconsider traditional models of the life course which will necessitate new norms and practices for education, work and families that span multiple generations.

To inspire change on a grand scale, SCL works with more than 150 Stanford faculty, their students and research staffs, as well as leaders from industries that are poised to distribute innovative products and services to the public, thought leaders who help to shape the ideas that influence cultural change, and policy makers who target important challenges and opportunities for long lived societies.

By fostering dialogue and collaborations among typically disconnected worlds, the Center aims to develop workable solutions for urgent issues confronting the world as the population ages. With these collaborations, we aim to redesign how we live our lives so that the great potential of longer life is fully realized.

Stanford Center on Longevity was founded in 2007 by two of the world’s leading authorities on longevity and aging. Laura Carstensen PhD , is the founding director. A professor of psychology at Stanford, she has won numerous awards, including a Guggenheim Fellowship, and her research has been supported for more than 30 years by the National Institute on Aging. Thomas Rando MD, PhD , professor of neurology and neurological sciences, is deputy director. His research on aging has demonstrated that is possible to identify biochemical stimuli that can induce stem cells in old tissues to repair injuries as effectively as in young tissues. This work has broad implications for the fields of regenerative medicine and stem cell transplantation.

Both Carstensen and Rando were inducted into the National Academy of Medicine in 2017.

Faculty Affiliates

With over 150 faculty affiliates, SCL employs a cross-disciplinary approach to tackle problems associated with increased longevity in the US and worldwide, engaging faculty in collaborations that range in focus from cognitive health to physical well-being and financial security.

Affiliated Centers

• Stanford Distinguished Careers Institute (DCI)
• Paul F. Glenn Center for the Biology of Aging
• Stanford Lifestyle Medicine

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Human longevity: Genetics or Lifestyle? It takes two to tango

Giuseppe passarino.

Department of Biology, Ecology and Earth Science, University of Calabria, 87036 Rende, Italy

Francesco De Rango

Alberto montesanto.

Healthy aging and longevity in humans are modulated by a lucky combination of genetic and non-genetic factors. Family studies demonstrated that about 25 % of the variation in human longevity is due to genetic factors. The search for genetic and molecular basis of aging has led to the identification of genes correlated with the maintenance of the cell and of its basic metabolism as the main genetic factors affecting the individual variation of the aging phenotype. In addition, studies on calorie restriction and on the variability of genes associated with nutrient-sensing signaling, have shown that ipocaloric diet and/or a genetically efficient metabolism of nutrients, can modulate lifespan by promoting an efficient maintenance of the cell and of the organism. Recently, epigenetic studies have shown that epigenetic modifications, modulated by both genetic background and lifestyle, are very sensitive to the aging process and can either be a biomarker of the quality of aging or influence the rate and the quality of aging.

On the whole, current studies are showing that interventions modulating the interaction between genetic background and environment is essential to determine the individual chance to attain longevity.

The research on aging, and in particular the search for the determinants of successful aging and longevity, has been continuously growing in the last decades also due to the social and medical burden correlated to the continuous increase of lifespan in western countries and the consequent grow of the elderly population. One of the main questions in this field is the correlation between the genetic background and lifestyle in determining the individual chance of a delayed aging (possibly without age-related diseases and disabilities) and longevity. The results obtained by biogerontologists in these years, which highlighted most of the biological and biochemical mechanisms involved in the aging process, allowed to better understand such correlation. This has brought to elaborate important strategies focused on possible interventions to improve lifestyle in order to increase the chance to attain longevity by modulating the basic molecular mechanisms of aging.

The genetics of aging

Before the 1990ies it was largely spread the idea that aging is ineluctable and that genetics does not control it. It was important, in this view, the idea that aging occurs after reproduction, and then there is no need, but also no opportunity, for selection to act on genes that are expressed during this late period of life [ 1 ].

The researcher who pioneered the genetics of aging and longevity was Tom Johnson, who studied groups of C. elegans where he was able to separate long living individuals from short living subjects. The analysis of hybrids obtained from different strains of C. elegans, allowed to estimate that the heritability of life-span was between 20 and 50 % [ 2 , 3 ]. Subsequently, he started the analysis of different mutants and, with M. Klass, found a number of mutants with longer lifespan. Subsequently, Tom Johnson found out that most of the mutants with long lifespan had mutations in the age1 gene [ 4 ]. This gene turned out to be the catalytic subunit of class-I phosphatidylinositol 3-kinase (PI3K).

The studies of Johnson clearly demonstrated that genetic variability could indeed affect lifespan. This triggered many studies in model organisms in order to disentangle the different biochemical pathways which could affect lifespan, and to highlight the genes coding for the proteins involved in such pathways. In particular, yeast, C. elegans , drosophila and mice were analyzed and this highlighted numerous genes which could affect lifespan if mutated (for an updated list of these genes see http://genomics.senescence.info/genes/models.html ). Most of these genes are related to the maintenance of the integrity of the cell (especially the integrity of DNA). In C. elegans , however, some of the main genes which have been found to modulate lifespan ( daf2 , daf16 ) are related to the ability to enter the dauer status [ 5 , 6 ], that is a quiescent status (usually entered in case of nutrient deprivation) with a minimum energy expense, which causes an arrest of the reproduction process and allows the organism to live longer “expecting” for the availability of nutrients. This suggested that longevity can be attained by means of an efficient maintenance of the cell but also by diverting resources from reproduction to self maintenance, in line with previous findings that dietary restriction can extend lifespan. After the characterization of these genes in C. elegans , it was found that in mice the ortholog of daf16 (FOXO) could affect lifespan. In mammals, FOXO is correlated to the Insulin/IGF1 axis which is stimulated by nutrient availability and, through FOXO, promotes protein synthesis [ 7 – 11 ].

It is of note that some Authors suggested these molecular mechanisms modulating lifespan could be due to a pleiotropic effect of genes which have evolved for different purposes (such as the genes in the IGF-1 pathway which have evolved to face presence/absence of nutrients) but can, ultimately affect lifespan; others proposed that some genes may have evolved to program aging and avoid “immortality”, as this would hamper the continuous substitution of old subjects with new, younger, ones [ 12 , 13 ].

It was obviously inevitable that the research of the genetic basis of longevity turned to human beings and investigated whether the common genetic variability of human populations could affect inter individual differences in lifespan but also whether the genes found to prolong lifespan in model organisms, on turn, were correlated to human lifespan.

As to the first question (does common genetic variability affect lifespan, and in particular does it affect longevity?), this has been studied by two approaches. The first one was the reconstruction of the sibships of long-lived subjects [ 14 , 15 ] and the comparison of their survival curves with those of the birth cohorts born in the same geographical area. This approach demonstrated that brothers and sisters of the long-lived subjects had a clear survival advantage (at any age) with respect to the general population. The second approach, with intrafamily controls, was started in order to distinguish the genetic from the “familiar” effect. Montesanto et al. [ 15 ] compared the survival function of brothers of centenarians with those estimated for their brothers in law, that is with the men who married their sisters; these men were supposed to share with the brothers of the long lived subjects the familiar environment. By using this second approach, it has been found that the survival advantage of siblings of long-lived subjects was not completely shared by their brothers in law, despite they shared the same environment for most of their life. This suggested that beyond the family environment, there are genetic factors influencing survival and, consequently, lifespan. Interestingly, in this study, the survival curve of the sisters of long-lived subjects did not differ from the one of sisters in law, suggesting that the genetic component does explain lifespan in men more than in women. The genetic component of lifespan in humans has also been analyzed by comparing the age of death of monozygotic and dizygotic twins. This has allowed to estimate that about 25 % of the variation in human longevity can be due to genetic factors and indicated that this component is higher at older ages and is more important in males than in females [ 16 – 18 ].

In parallel to these studies, many researches have been carried out to search the genetic variants responsible of modulating human longevity. Most of them were carried out by a case/control approach, by comparing the frequency of specific polymorphisms in long-lived subjects and in younger geographically matched controls. The rationale of this study design is that as the population ages, alleles favorable for survival will be present at higher frequency among long-living people, while unfavorable alleles will be eliminated [ 19 – 21 ]. The candidate genes analyzed by this approach were either genes involved in age-related diseases (such as APOE, which had been observed to be involved in the predisposition to Alzheimer Disease and other age-related cognitive impairments), or genes implicated in pathways related to longevity in studies with model organisms (IGF-1, FOXO, Sirtuins) [ 22 – 25 ]. This study design has indeed led to find numerous polymorphic genes the variability of which affects longevity. However, each of these polymorphisms turned out to explain only a very small fraction of the longevity variability. Indeed high-throughput Genome-wide analyses, which have recently been carried out have identified many genes positively associated with longevity but only a very few ones could hold multiple test significance and successfully replicated in different studies and across different populations [ 26 – 29 ]. Population stratification and inadequate sample sizes are among the main plausible explanations [ 30 ]. The adoption of innovative study design and the development of new statistical and computational tools for effective processing of genetic data arising from high-throughput DNA technologies will help to better understand the complex genetic architecture underlying human longevity [ 31 , 32 ].

A new way of looking at the genetic data has been proposed by Raule et al. [ 33 ] who analyzed the complete sequences of mitochondrial DNA from long-lived subjects coming from different areas of Europe. The availability of complete sequences allowed to evaluate for the first time the cumulative effects of specific, concomitant mitochondrial DNA (mtDNA) mutations, including those that per se have a low, or very low, impact. The analysis indicated that the presence of single mutations on mtDNA complex I may be beneficial for longevity, while the co-occurrence of mutations on both complexes I and III or on both I and V might lower the individual’s chances for longevity. Previous analyses on single mutations falling on complex I (either specific mutations or mutations defining groups of haplotypes) had given contrasting results, showing association with longevity in some cases but not in others. It is likely that positive results were obtained in populations were mutations on complex I were not associated with mutations on complex III or V, while negative results were obtained in populations with high prevalence of mtDNA haplotypes carrying mutations on complex I in association with mutations in complex III and V. This approach confirmed that most of the genetic variants have a very limited effect on longevity, and that only their cumulative effect can give a consistent appreciable effect and suggests that a limit of previous analyses has been to search for single mutations instead of cumulative effects. On the other hand, it is very difficult to think of using such approach, which has been successful for mitochondrial DNA, on genomic DNA unless small fractions (or specific regions harboring genes involved in relevant pathways) are analyzed.

On the whole, the genetic association studies suggested that, also in humans, mutations in genes correlated with the maintenance of the cell and of its basic metabolism are essential in modulating lifespan. Indeed, genes involved in DNA repair [ 34 ], telomere conservation [ 35 – 37 ], heat shock response [ 38 , 39 ], and the management of free radicals’ levels [ 33 , 40 ] were found to contribute to longevity or, in case of reduced functionality, to accelerated senescence (cellular aging) and the consequent organism aging. In addition, as suggested by the studies in mice, the pathways involved in nutrient-sensing signaling and in regulating transcription, such as IGF-1/insulin axis [ 41 ] and TOR (target of rapamycin) [ 42 ] showed to be involved in modulating human longevity. Besides these genes involved in cellular maintenance/metabolism and senescence, concurrent efforts, especially from clinical studies, also showed that genes implicated in important organismal process may have a strong impact on aging and longevity. For instance genes involved in lipoprotein metabolism (especially APOE), cardiovascular homeostasis, immunity, and inflammation have been found to play an important role in aging, age-related disorders, and organism longevity [ 43 – 46 ].

Human longevity and life style

Life expectancy at birth has been increasing for most of the last century in western societies, thanks to the continuous amelioration of medical assistance, to the improvement of the environment (in particular clean, safe water and food), and to the improvement of nutrients. For instance, in Italy life expectancy went from 29 years in 1861 to 82 in 2011 (Table  1 reports the evolution of this data in women and men). Similarly, the extreme longevity has been growing in these years. Indeed, the number of centenarians (still in Italy) remarkably increased from 165 in 1951 to more than 15000 in 2011. These results have been attained first by a dramatic reduction of infectious diseases, which, on turn, has dramatically reduced infantile mortality, but also mortality in adult age. In fact, in 2011 less than 10 % of deaths occurred in subjects under 60 years of age, while the corresponding figures were 74 % in 1872, 56 % in 1901 and 25 % in 1951. However, in the last decades, the continuous extension of lifespan was mainly due to the improvement of medical assistance with respect to age-related diseases, especially Cardiovascular Diseases and Cancer, which allowed to increase lifespan of 5 years in the last 2 decades and of 2 years in the last 10 years (data from www.mortality.org and www.istat.it ).

Evolution of lifespan expectancy in Italy from 1861

These data clearly show that environmental factors have a very strong impact on lifespan and on longevity in humans. However, the extension of lifespan that there has been in the last decades have not been accompanied by a similar extension of healthy lifespan. Indeed, in most cases this lifespan extension is due to the chronicit of the age-related diseases. This has brought the community of biogerontologists to study interventions, possibly modulated on the knowledge emerged from the studies on the genetic and biomolecular basis of longevity, to extend not only lifespan but also healthy lifespan, or, with a new word, “healthspan”. In fact, model organisms with mutations that extend lifespan have a healthy life also when they are old. This suggested that health span extension could be attained by targeting (stimulating or silencing) the genes, which had been highlighted to be involved in life extension in both model organisms and humans [ 47 ]. In support of this hypothesis, it has been reported that dietary restricted mice, which live much longer and show a very delayed aging phenotype than mice fed at libitum , at old age have an expression pattern very different from mice of the same age for a number of genes correlated with life extension, such as those related to DNA repair, stress response, immune response and others [ 48 , 49 ]. Thus, dietary restriction can trigger a molecular-genetic response which postpones aging and age-related phenotypes. This has brought to search for drugs or interventions which may act on these mechanisms without the side effects of calorie restriction. Among the most important interventions which have been considered in this context, we may name the protein restriction, the use of drugs targeting different genes of IGF-1 axis or of the FOXO/TOR pathway [ 47 ]. In addition, these studies have allowed to reconsider previous data on some areas characterized by exceptional longevity (such as Okinawa, Sardinia and Calabria) which are characterized by traditional ipoproteic diets, such as the “Mediterranean diet” [ 50 – 53 ]. In these cases, then, the environment, that is the traditional diet, has allowed to stimulate the molecular mechanisms which can increase life span.

Among the several changes that occur with the aging process, in the last decade Epigenomics has attracted the interest of many researchers. This was mainly due to the fact that epigenetic modifications summarizing, at least in part, the interaction between the individual genetic background and lifestyle characteristics, should be potentially able to capture part of the unexplained susceptibility observed today for complex diseases (the so-called missing heritability problem).

Starting from the pioneeristic observations that epigenetic modifications affect not only the aging process but also its quality (successful aging) [ 54 ], EpiGenome-Wide Association Studies identified hundreds of sites spread along the entire genome in which methylation levels change between oldest old and younger subjects. In particular, Horwat and co-workers, on the basis of the methylation levels of 353 CpG units, formulated a mathematical model, the so-called epigenetic clock, that showed some important properties [ 55 ]. First, it was able predict the chronological age of a subject starting from the methylation level of several cells and tissues of his body. Second, it represents one of the most accurate biomarker of age (also superior to the estimates obtained from the telomere length). Third, using methylation levels of blood and brain tissues from subjects affected by Down syndrome, it showed that an accelerated aging occur in such a syndrome [ 56 ]. Fourth, it was able to predict all-cause mortality also after adjusting for traditional risk factors [ 57 ]. Finally, when it was used to estimate the biological age of several tissues from supercentenarians, it has been demonstrated that brain and muscle represent the youngest tissues of these exceptional individuals [ 58 ].

However, even if the cause-effect relationship between methylation process and aging is still not clear, the potential applications of this discovery are very wide, ranging from detailed monitoring of changes occurring with age within individual systems or organs (muscle, brain, etc.) to forensic purposes. For this and several other reasons, future advances in this field could help the understanding of the complex physiology of aging, lifespan and age-associated diseases.

Conclusions

On the whole, although the common variability accounts for only 25 % of human lifespan variability, the knowledge of the genetic basis modulating longevity may give significant hints on modulating lifestyle in order to attain longevity and extend healthspan. That is, a few subjects can attain longevity because a lucky combination of polymorphisms which allow them to have an efficient metabolism or an efficient response to different stress. Most of the others can attain a similar result by targeting the same pathways with appropriate life style or interventions. In this context, the importance of epigenetic factors, both as biomarkers of aging and target of interventions will certainly grow in the forthcoming future.

Acknowledgements

This work was partially supported by the European Union’s Seventh Framework Programme (FP7/2007–2011) [grant number 259679] and by funds from Programma Operativo Nazionale [01_00937] - MIUR“Modelli sperimentali biotecnologici integrati per lo sviluppo e la selezione di molecole di interesse per la salute dell’uomo”.

Abbreviations

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

The authors equally contributed to the drafting and finalization of the manuscript. All authors read and approved the final manuscript.

Season 2 of the Buck podcast is live! Learn more.

by Buck Institute

May 31, 2024 .  BLOG

Food is Medicine

Yes, we already know that, says buck professor pankaj kapahi, but what are we doing about it.

Hippocrates may or may not have actually said “‘let thy food be thy medicine and thy medicine be thy food,” but regardless, it sums up an inescapable concept: our bodies are machines, and how they run depends on the fuel we feed them.

The journal Nature ran a news feature last month summarizing some of the promise, and lack thereof, of clinical trials that demonstrate the connections between diet and health. Benefits have been shown for various dietary interventions to treat or delay some conditions, including cardiovascular disease, diabetes, cognitive decline, migraines and women’s health issues such as polycystic ovarian syndrome (PCOS). Common sense diets that include ample vegetables, fruits, whole grains and low fat dairy, with reductions in salt, saturated fat, and alcohol, fare well regarding health outcomes.

However, in what is becoming the refrain for anything related to diet and health, more research is needed; large-scale randomized trials of dietary interventions, difficult to conduct, are required to make more specific recommendations.

“The studies get done but nobody pays attention to the findings,” says Kapahi. “My big revelation after doing this for so long is that food literally can be medicine, like a pill with all the good stuff inside to make people healthier, but it has been made impossible for people to take.”

Even in clinical practice, where there are accepted clinical guidelines about dietary interventions, it is rarely implemented by healthcare professionals. Additionally, there are cost and access barriers. Kapahi and the experts interviewed in the Nature commentary agree that one of the biggest hurdles in reducing nutrition insecurity is the lack of access to healthy and affordable foods. “Yet our government is subsidizing the worst kind of food,” says Kapahi, including unhealthy fats and refined grains.

“Instead of the great news that certain ways of eating are good for you and can help you stay healthy, the market forces are such that there is no incentive to think like that,” he says. “The news is that we are so stuck that we can’t do anything about it to get out of this cycle.”

It’s all about the money, he says; there is no money to be made from incentivizing health.

“We are a ‘sickcare” society,” he says. First people must fall sick, then they have to be treated, that’s how money is made. Nutrition is important, but no one is making money out of improving people’s health with basic foods. The system is creating a cycle of disease, then providing a drug to fix the problem.

  “At the heart of it, the answer is very simple: we could solve diseases by improving nutrition,” he says. “Despite this being understood by experts, we are not moving at all toward policy change,” which dictates what studies are funded and what foods are subsidized. 

The only fix is political action, according to Kapahi.

“The longer I am in this field, I realize that unfortunately no one at the top seems to see the damage their decisions are making on people’s health,” he says, adding that much of their decision making is heavily influenced by lobbying. “If there is no willingness to change from the top, maybe people have to be social activists and make it happen for themselves.”

What does Kapahi recommend? He says that his thoughts resonate with what Michael Pollan has already said: “Eat food. Not too much. Mostly plants.” Get involved with politics and policymaking at any level. Agood example of civic pressure, he points out, are the bans of sugary drinks in schools. Discuss with doctors or nutritionists whether andwhat dietary changes could help you.

“All this scientific research is useless if the culture doesn’t change and we don't turn this around ourselves,” he says. “What is the point of finding 100 ways bad food makes you sick and good food makes you better” if nobody is taking advantage of the insight?

“Eating badly is worse than smoking, and just like smoking it is time to do something about bad food as well,” he says.

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David Sinclair is among a group of researchers collaborating on a new nonprofit academy to promote aging research and drug discovery.

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Longevity and anti-aging research: ‘Prime time for an impact on the globe’

Alvin Powell

Harvard Staff Writer

HMS’s Sinclair discusses new nonprofit academy for work on extending the human lifespan

Research into longevity and healthy aging has progressed rapidly in recent years, but intense interest from the public, corporations, and the media has created an environment in which unfounded claims can be hard to separate from scientific facts.

In February, a group of 16 researchers from Harvard, MIT, and other institutions around the U.S. and Europe launched the nonprofit Academy for Health and Lifespan Research  to promote future work, ease collaborations between scientists, and ensure that governments and corporations are making decisions based on the latest facts instead of rumor, speculation, or hype.

The Boston-based organization will form a nexus for work on extending the human health span, fighting the myriad diseases associated with aging, and fostering the work of junior researchers. Harvard Medical School Genetics Professor David Sinclair, one of the new academy’s founding members and director of the Paul F. Glenn Center for the Biology of Aging at HMS, spoke to the Gazette about the status of aging research and the mission of the academy.

David Sinclair

GAZETTE:  Tell me about the academy. Is it intended to be mainly an advocacy organization?

SINCLAIR: The academy has been formed because our field of aging and longevity research has reached a point of maturity where the leaders in the field believe that we can have — or will have — a big impact on the planet. That impact will be in medicine, in health span, and in its knock-on effect on [everything from] human productivity to Social Security.

We wanted to come together to speak with one voice, to be able to help corporations and governments understand what things they should be thinking about now and give realistic projections of what life is going to be like 10, 20, 50 years from now. Because it’s not a question of if there’s going to be an impact, it’s really a question of what kind of a future we want to build when this happens.

GAZETTE: What kind of impact are we talking about? When you think about 10, 20, 50 years in the future, how do you see aging being transformed in the U.S. and around the world?  

SINCLAIR: The 16 researchers in the academy have all been working on this for most, if not all, of our careers. So that spans — for many of us — over 25 years. When we started, research on aging at the molecular level was the backwater of biology, but in the last 25 years, aging has moved to the forefront of science. It’s actually rare to open a leading scientific journal and not see a new breakthrough in our understanding of the aging process.

Recently, we’ve moved from being able to extend health and lifespan of simple organisms like yeast and worms and flies to being able to do this quite easily in animals, in mice and monkeys. With that knowledge — how to keep the body younger and not develop diseases of aging — we think it’s now prime time for having an impact on the globe.

By impact, I mean that instead of tackling one disease at a time, which is the way 20th-century medicine and pharmaceutical development was practiced, we believe we can [develop] medicines that will treat aging at its source and thereby have a much greater impact on health and lifespan than drugs that target a single disease.

Heart disease medicine may keep your heart healthy for an extra five or 10 years, but does nothing for your brain. So, we’re ending up with a population of people who live longer but not better and who need a lot of help, if they’re not completely [in the grip of] dementia. We don’t think that’s necessarily the only or the best approach.

“We’re generally in denial that, for most of the diseases that we get these days, the root cause is aging. I don’t know 10-year-olds that get Alzheimer’s disease or heart disease.” David Sinclair

Now, we have the knowledge. We’re developing the technologies to not just delay these diseases of aging but actually reverse aspects of them. Imagine you have a treatment for heart disease, but as a side effect you’d also be protected against Alzheimer’s, cancer, and frailty. You’d live a longer and healthier life.

The reason we can extend the lifespan of animals is not because we can just make them live longer, but we keep them healthy. The animals don’t get heart disease, cancer, Alzheimer’s, until sometimes 20 percent later in their life. And so that’s 20 percent longer youth, not just 20 percent longer life.

GAZETTE: Are there regulatory hurdles? When we’ve spoken in the past, you’ve mentioned that the FDA considers aging a natural process and therefore won’t approve drugs to treat it. Are we at a point where that is becoming a hurdle in getting advances out to the people who need them?

SINCLAIR: Opinions are changing rapidly about whether aging should be a condition that a doctor can prescribe a medicine for. That’s essentially what a disease is. It’s something that a doctor can read the label that this medicine is for aging or age-related conditions. We’re not at that point yet.

We currently live in a world where aging is so common that it’s considered by most of the world, including the medical community, as something that’s natural and inevitable. And if something’s considered inevitable, typically you don’t focus on it in the same way as something you can treat. Cancer was a natural part of life at one time, in the same way that aging is today. A hundred years ago, doctors didn’t focus on treating cancer as much as we do now, because then you couldn’t do much, if anything, about it. As soon as you show you can modify the disease process, like we learned in the 1970s with the discovery of oncogenes that cause cancer — and increasingly so today — then there’s renewed hope, and views about the condition shift.

There are now dozens of companies working on therapies that could potentially extend overall human health and lifespan, but none of them are working specifically toward an approval for aging because the FDA wouldn’t even know where to start. But that may be changing quickly. I’ve been part of a group that talked with the FDA, and they are willing and also quite enthusiastic about considering a change that defines aging as a disease. They would like us, first, to show that it’s possible to change the rate of aging, which in my view is backward, but that’s what they want.

In Australia, the government is 100 percent behind this, at the FDA level and in the Ministry for Health. I’m hopeful that one country in the world — it may be Australia, it may be the U.S., it may be an Asian country — will change its definition of aging. Once one country changes its definition, then it will be a domino effect and the others will follow.

One of the biggest changes that happened last year was the World Health Organization, in their international disease codebook , declared aging a condition that is treatable. So now doctors and countries can report back to the World Health Organization how many people in their country are suffering from this condition known as “old age.”

We’re generally in denial that, for most of the diseases that we get these days, the root cause is aging. I don’t know 10-year-olds that get Alzheimer’s disease or heart disease. It’s aging that increases the risk 1,000-fold for cancer, while if you smoke, it goes up fivefold. Which is more important to be focused on?  

GAZETTE: What excites you most about the state of anti-aging and longevity research?

SINCLAIR: Well, I hate to pick favorite children. Someone will always be upset. I have my hands in a few pies, but the most recent one that I’m excited about is cellular reprogramming.

GAZETTE:  And how does that occur?

SINCLAIR: We introduce a combination of genes into the animal, or the cell, and we see that the tissue is rejuvenated as though it was young again. So it can heal, it can start new growth, like it was young. And if we can figure out how to deliver that to patients in a safe way, then it’s quite possible that aging is a reversible disease.

GAZETTE: What genes are we changing?

  SINCLAIR: We’re using a combination of Yamanaka factors [used to reprogram differentiated adult cells into induced pluripotent stem cells] that are used to make stem cells currently in a dish, but what we’re finding is that you can introduce them into the animal as well. They tolerate it well and tissues rejuvenate.

I haven’t published it yet, so I can’t say too much, but we’re writing up the paper now that shows that parts of the mouse’s body that we thought would not ever improve are able to be regenerated. So we’re licensing that technology and hoping that it will be tested in the clinic in the next two years.

David Sinclair shows off an evaporator device used in the lab.

  GAZETTE:  How likely do you think it will be that the broad public accepts a solution that involves changing themselves at a cellular level? Is that a high hurdle?

SINCLAIR: If you’re going blind, I think you’d be quite enthusiastic about it.

Clearly we need to make sure it’s safe, too.

You asked me what I’m most excited about and it’s that one that has the biggest potential. But the one that’s closest to reality are the NAD boosters that we’ve had in clinical trials for over a year now over at the Brigham and Women’s Hospital.

GAZETTE: There have been some trials completed on those already, right?

SINCLAIR: Yes, we’ve done two trials, but they’ve been safety trials.

We’re just getting approval now to test it in older people. Ultimately, we’re planning on treating particular inherited diseases. I can’t say which ones without permission, but these drugs will typically be for diseases that are rare or less common.

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In the future, if a molecule or a drug makes it onto the market for one particular disease, then doctors can test it on their particular disease of expertise. And, if it works there — just like the statin drugs — expand it from a small group of families with high cholesterol [in the case of statins] to the world. But that would only happen if the drug was really safe.

GAZETTE:  Is it most likely that something like a NAD booster will be taken daily by many people, in the way that statins are today, or, given the greater promise of the engineering approach, something like that being used widely? Or is there a third that you think might actually surpass those two?

SINCLAIR: I think that this drug has the potential to be used widely, like a statin.

If you reach age 45 and your blood glucose has crept up, you’re losing muscle strength and volume, and your doctor may say, “Hey, I can see that you’re starting to age.” They could then actually measure your biological age now pretty accurately with a blood test. The doctor might then say, “There’s this drug, it seems pretty safe, there’s no downside that we can tell and it protects you from all age-related diseases. Start taking it now before it’s too late.”

That’s the trick. You get the biggest bang for the buck if you treat before you get sick. That’s true for most diseases and it’s certainly true for the mouse populations we study here in the lab.

But this cellular reprogramming is exciting because it seems to work even once you’ve lost function of tissues.

GAZETTE: Kind of turning back time?

SINCLAIR:  Right. It’s going to end up being a combination of treatments that are used, I think.

That’s why I’m trying to help other entrepreneurs with their own inventions, so that we can address different aspects of aging and ultimately keep people healthier for much longer than we currently can.  

GAZETTE: To go back to our initial point, how do you see the Academy for Health and Lifespan Research doing its work? Will there be staff here in Boston? Will investigators like yourself spend a particular amount of time there?

SINCLAIR: We have our own secure network that we communicate and collaborate on, so first of all, it’s been a great step forward just linking us together.

Also, it’ll be headquartered here in Boston by David Setboun, the president. He’s hiring staff now. And those staff will be similar to other nonprofit organizations. There will be a philanthropic side, raising money — and also distributing the money that’s being raised. The money will be used to bring scientists together. There’s an annual meeting.

We think we’ll be able to sponsor young scientists and help research that way; we professors want to be able to replace ourselves with even better talent. Also, we’re planning on putting out publications to separate what’s real from what’s not real. The public finds it very difficult to distinguish science from fake science right now.  

GAZETTE: Part of that may be intentional.

SINCLAIR: I’ve been successful in getting my name off a lot of websites, but the research, Harvard’s name, and my face are still used by companies to insinuate that I endorse their product, when I would never do that. My lab and I don’t receive any money from the sale of supplements.

That’s a problem we want to solve. By uniting, we can have a seal of approval, where we can say this is what’s real, this is what isn’t, this is what we believe, as scientists, and this is not what we believe. And we have a website with this information, that’s going to be populated with white papers, and I suspect we’ll also be putting out other publications.

As the field grows, with interest from the lay public and investors and the media, we want to make sure the conversation stays evidence-based.

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Researchers reveal secrets of aging beta cells and their ability to secrete insulin

by Hebrew University of Jerusalem

A new study reveals that aging human pancreatic beta cells display features of senescence while maintaining elevated levels of genes crucial for their function. Despite their aging status, these cells therefore exhibit an ability to release insulin in response to glucose, aiding in blood sugar regulation.

Additionally, these aged cells show increased activity of genes that can stimulate the immune system. This sheds light on the potential role of aging beta cells in immune regulation and their relevance to autoimmune reactions in type 1 diabetes.

The study, led by Dr. Milan Patra along with Professors Ittai Ben-Porath and Yuval Dor from the Faculty of Medicine of the Hebrew University, is published in Nucleic Acids Research .

The diabetes challenge

Diabetes, characterized by insulin deficiency or resistance, hinges on dysfunctional pancreatic beta cells , which are responsible for secreting insulin to remove glucose from the blood. Enhancing or preserving the function of these cells is pivotal for developing diabetes treatments.

Globally, an estimated 463 million adults, or roughly 1 in 11, grapple with this condition, a figure expected to balloon due to aging populations, urbanization, poor diets, and sedentary lifestyles. Projections indicate that by 2045, over 700 million could be afflicted, posing daunting challenges to health care, economies, and public health efforts. Urgent action is imperative to stem this tide, necessitating effective prevention strategies, better access to care, and innovative treatments.

Functionality and immune response

The study demonstrates that a significant portion of adult human pancreatic beta cells activate a gene called p16, which indicates that they are in an aging-like state, termed cellular senescence . Interestingly, these senescent cells , rather than showing signs of dysfunctionality, show elevated levels of genes that are important for their function.

Thus, these cells appear to possess a higher level of functionality and maturity compared to their non-senescent neighbors. This is surprising, as previously identified senescent cells in other tissues are generally thought to be dysfunctional and have harmful effects.

By analyzing the gene organization of senescent beta cells, the researchers discovered that they change the packaging of the genes—the chromatin, generating a reprogrammed organization that allows activation of functionality. Because of this, it appears that the aging beta cells have the ability to release insulin in response to glucose in even larger amounts, which helps regulate blood sugar levels effectively.

This study also found that senescent beta cells have elevated levels of genes that communicate with the immune system. This response, termed the "interferon response" normally acts to indicate a viral infection to immune cells, recruiting their attack. However, the senescence beta cells activate this pathway in the absence of such infection: it is molecular changes in the cells themselves simulate this response.

The potential consequence is increased stimulation of immune cells to attack beta cells, the fundamental process that drives type I diabetes. This means that aging beta cells might help regulate immune responses and could be important for understanding autoimmune reactions in type 1 diabetes. Potentially, blocking this response, or the process of senescence, could be used to prevent the progression of type I diabetes in its early stages.

Implications for diabetes treatment

The discovery that aging pancreatic beta cells can retain high functionality and respond to immune signals challenges the traditional view that senescent cells are purely detrimental. This new understanding opens the door to potential therapies aimed at preserving or enhancing the insulin-secreting function of beta cells in diabetic patients.

"These findings are pivotal because they suggest that senescent beta cells are not a liability, but may act, in a pre-designed manner, to improve insulin production as we age, countering other detrimental effects," said Professor Ittai Ben Porath. "Furthermore, if it will be further established that senescence of beta cells is a prominent feature of the early stages of type I diabetes, targeting of these cells through drug treatment could represent a novel approach for preventing autoimmune attack of beta cells."

Future research plans include delving deeper into the mechanisms driving the increased activity of functional-maturation programs in aging beta cells, influenced by chromatin dynamics. A comprehensive understanding of these processes holds promise for the development of targeted therapies aimed at enhancing beta-cell functionality and lifespan, thereby improving the quality of life for individuals grappling with diabetes. Understanding how the process of senescence affects the interaction of immune cells with beta cells, and whether this is indeed associated with diabetes , may open the door for new treatment approaches.

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Amy Pasquinelli Selected for Grant to Study the Role of Toxic RNA in Aging

Funding will support research on the mechanisms behind changes in RNA quality control

Professor Amy Pasquinelli

May 29, 2024

By Mario Aguilera

UC San Diego School of Biological Sciences Professor Amy Pasquinelli has been awarded a grant from the Hevolution Foundation to support research on aging.

Pasquinelli, a scientist in the Department of Molecular Biology, conducts research on microRNAs, molecules that help control gene expression and influence a range of biological processes.

Pasquinelli’s lab and others have shown that changes in RNA regulation can reduce healthspan and longevity. Chemically damaged, or “toxic RNAs,” have been known to accumulate in aging tissue, yet their root causes and extent are not well understood. With support from the Hevolution Foundation, Pasquinelli will investigate the causes and consequences of aberrant RNA accumulation during organismal aging.

With science’s emerging capabilities to target specific RNAs and use RNA as a therapeutic tool, Pasquinelli believes the need to study the mechanisms of RNA quality control in the context of aging organisms is urgent. Under the new grant, her lab will study Caenorhabditis elegans (C. elegans), a tiny roundworm that serves as a model organism for human similarities.

“By identifying potentially toxic RNA species in aging C. elegans, we have the ability to investigate how they are generated, the impact on longevity and mechanisms to counteract their negative effects,” said Pasquinelli. “With our expertise in RNA biology, this new focus on toxic RNA aims to fill a knowledge gap in aging research and inspire new strategies to promote healthy aging.”

By 2050, reports indicate that the global population over 60 years old will double to 2 billion people. Pasquinelli’s grant is one of 49 awards bestowed under the Hevolution Foundation’s Geroscience Research Opportunities Program to institutions across the United States, Canada and Europe.

“These 49 important research projects represent a significant step forward in deepening our understanding of healthy aging,” said Dr. Felipe Sierra, Hevolution’s chief scientific officer. “Hevolution's prime objective is to mobilize greater investment around uncovering the foundational mechanisms behind biological aging. We are steadfast in our belief that by examining the root causes of aging, rather than solely focusing on its associated diseases, we can usher in a brighter future for humanity.”

— With information from the Hevolution Foundation

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Improving Quality of Care for Older Adults

A q&a with snigdha jain, snigdha jain, md, mhs.

When Snigdha Jain, MD, MHS , became an ICU physician, she found that two-thirds of the individuals she cared for in the ICU were older adults. She also found that illness did not end with survival and discharge from the hospital for these patients. The realization prompted her to better understand how the lives of older adults change after a critical illness.

Now committed to a career in aging research, Jain, an assistant professor of medicine in the Section of Pulmonary, Critical Care, and Sleep Medicine at Yale , recently won the American Geriatrics Society Health and Aging Foundation New Investigator Award. The honor recognizes individuals conducting new and relevant studies in geriatrics.

In an interview, Jain discusses the inspiration behind her research focus on older adults, the role of social factors in quality of care, and why people of all ages should strive to be active during hospital stays.

What inspired you to pursue research in aging?

I was interested in improving outcomes after critical illness, which matters to many older adults because they value independence and quality of life, not just survival. Older adults may be at higher risk of decline after hospitalization because of pre-existing issues such as cognitive impairment, frailty, or chronic conditions.

I didn't realize how the questions I was interested in were the mainstay of geriatric research until I was introduced to the geriatric epidemiology training program at Yale. Working with Drs. Thomas Gill and Lauren Ferrante showed me how function and cognition are measured and helped me gain the tools to ask research questions that addressed the clinical problems I was seeing.

How can we improve the quality of care for older people?

It’s important to listen to older adults, validate their concerns, and understand that they may have lingering symptoms and problems because of a critical illness. We need to provide them with all kinds of support, such as referral to a specialist or rehab. We also need to make sure that everyone, including low-income older adults, receives this support. For example, I might want a patient to go to an outpatient physical therapy center to strengthen their muscles, but the patient might not have the caregiver support or the transportation to do those things. Understanding how effective care processes, such as rehabilitation, are delivered across the continuum of care can help us design interventions to ensure equitable access and quality of care during and beyond hospitalization.

If patients are hospitalized in a skilled nursing facility or admitted to a nursing facility after staying in the ICU, as happens with a third of older adults, we need to ensure the quality of care they receive in skilled nursing can assist their recovery. It’s important to provide patients with support beyond the ICU and medical diagnostics to assist them in their journey to recovery.

What research discoveries have you made that you wish every person, regardless of age, knew?

One of my recent studies with Dr. Gill found that when many older adults leave the hospital after a critical illness, they still have symptoms like shortness of breath or fatigue within the first three months after hospitalization that restrict them to bed for more than half a day or that make them cut down their activities. We discovered that such symptoms are associated with downstream disability. How much dependence these adults develop over the next six months is linked to the symptoms that restrict their activity. If you're not moving around much, there is a possibility you’ll become more disabled down the road.

I encourage older adults and everybody who’s in the hospital to advocate for themselves about the need to be active. Being in the hospital should not mean inactivity. Studies support the value of mobilization in preserving downstream function and cognition in critically ill patients.

My research also shows that older adults with low income or limited English proficiency or those who live in rural areas are less likely to be mobilized or offered physical therapy. I hope to build on this work to advocate for systemic and policy changes to make sure everyone can get equitable access to therapy services. We need to take into account social vulnerability to improve outcomes for everyone, not just a select few.

The Section of Pulmonary, Critical Care and Sleep Medicine is one of the eleven sections within Yale School of Medicine’s Department of Internal Medicine. To learn more about Yale-PCCSM, visit PCCSM's website , or follow them on Facebook and Twitter .

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Featured in this article

• Snigdha Jain, MD, MHS Assistant Professor; Assistant Professor, Internal Medicine
• Thomas M. Gill, MD Humana Foundation Professor of Medicine (Geriatrics) and Professor of Epidemiology (Chronic Diseases) and of Investigative Medicine; Director, Yale Program on Aging; Director, Claude D. Pepper Older Americans Independence Center; Director, Yale Center for Disability and Disabling Disorders; Director, Yale Training Program in Geriatric Clinical Epidemiology and Aging-Related Research
• Lauren Ferrante, MD, MHS Assistant Professor of Medicine (Pulmonary, Critical Care and Sleep Medicine); Director, Operations Core, Yale Claude D. Pepper Older Americans Independence Center; Student Thesis Chair, Internal Medicine