Category: Aging

Is Longevity Constrained by Nature or by Government Regulations?

I am a longevity optimist. If regulatory constraints are loosened, I believe entrepreneurs will bring us quicker progress.

(p. A12) S. Jay Olshansky, who studies the upper bounds of human longevity at the University of Illinois Chicago, believes people shouldn’t expect to live to 100.

. . .

Kaare Christensen, co-author of a paper predicting most newborns born in the 2000s would live to 100 if medical progress continued, said it is too soon to know who is right. Future advances could make up for stalled life expectancy gains.

“The setback could be temporary,” he said.

Christensen, who runs studies on very old people at the Danish Aging Research Center in Denmark, said people in their 90s have better cognitive function and healthier teeth over their lifetimes than counterparts of the same age born just 10 years earlier.

“I would say prepare for your 90s instead,” Christensen said.

Old-age debate

Olshansky’s foray into the limits of lifespan began in 1990 when he published a paper in Science stating that life expectancy wouldn’t rise dramatically even if diseases including cancer and heart disease are eliminated. He has been fighting about it ever since.

James Vaupel, a demographer, pushed back. In a 2021 paper, Vaupel pointed to statistics showing that since around 1840 life expectancy at birth has increased almost 2.5 years per decade in some countries.

Vaupel and Olshansky published dueling papers over the decades until Vaupel’s death at age 76 in 2022.

Steven Austad, a professor of biology at the University of Alabama at Birmingham, was asked at a 2001 scientific meeting when he thought the first person to live to 150 would be born. “I think that person is already alive,” Austad replied. Austad said he based his answer on optimism that scientists will figure out how to change the biology of aging.

When Olshansky heard about the exchange, he bet Austad that wasn’t true. In 150 years, he argued, there still wouldn’t be a person alive at 150. The men wagered $150 each, which they put in a fund to pay out in 150 years, with the winner’s heirs to reap the profit. A decade ago, they each added another $150 to the account.

Austad said he agreed with Olshansky that most newborns born now won’t live to 100. But he thinks his optimism that someone will live to 150 is justified. He pointed to a study showing the compound rapamycin extended the lifespan of mice, even if they start getting it later in life. Some longevity enthusiasts are taking rapamycin themselves. Studies on other potentially antiaging compounds are under way.

“If any turn out to work,” Austad said, “they will win my bet for me.”

For the full story see:

Amy Dockser Marcus. “Live Until 100? Our Chances Are Slim.” The Wall Street Journal (Wednesday, July 17, 2024): A12.

(Note: ellipsis added.)

(Note: the online version of the story has the date July 11, 2024, and has the title “Think You Will Live to 100? These Scientists Think You’re Wrong.”)

The paper co-authored by Christensen and mentioned above, is:

Christensen, Kaare, Gabriele Doblhammer, Roland Rau, and James W. Vaupel. “Ageing Populations: The Challenges Ahead.” Lancet 374, no. 9696 (Oct. 3, 2009): 1196-208.

The 2021 paper co-authored by Vaupel and mentioned above, is:

Vaupel, James W., Francisco Villavicencio, and Marie-Pier Bergeron-Boucher. “Demographic Perspectives on the Rise of Longevity.” Proceedings of the National Academy of Sciences 118, no. 9 (2021): e2019536118.

Diet Low in Fat and Sugar May Have Helped Morera Become Oldest Person in World

But at least it appears that she was able to keep drinking coffee. She also apparently embraced new technology and stayed intellectually sharp (maybe the coffee helped ;).

(p. A1) Maria Branyas Morera, an American-born Spanish woman believed to be the oldest person in the world, died on Monday [Aug. 19, 2024] in Olot, Spain. She was 117.

Her family wrote in a post on her X account that she had died in her sleep. She had been living in a nursing home.

“A few days ago she told us: ‘One day I will leave here. I will not try coffee again, nor eat yogurt, nor pet my dog,’” her family wrote in Catalan in the post. “‘I will also leave my memories, my reflections, and I will cease to exist in this body. One day I don’t know, but it’s very close, this long journey will be over.’”

. . .

Having been born before the emergence of the telephone, Ms. Branyas came to embrace the digital revolution, fashioning herself on social media as “Super Àvia Catalana,” or “Super Catalan Grandma.” She posted bite-size pieces of life advice, observations and jokes to thousands of followers.

In her biography on X, she wrote, “I’m old, very old, but not an idiot.”

. . .

Like many supercentenarians, Ms. Branyas became the subject of scientific fascination. Dr. Esteller, the researcher who studied her genetics and lifestyle, found that her genes were protective against DNA damage, and that she had low levels of fat and sugar in her blood — all of which he said was helpful for living a long life. His research also found that her cells aged much slower than she did, meaning that she had a lower “biological age” than her actual age.

The Catalan diet, which is similar to the Mediterranean diet and includes a lot of olive oil, has also been linked to longer survival, he said. He added that Ms. Branyas liked to eat yogurt.

“What do you expect from life?” a doctor once asked Ms. Branyas while retrieving blood samples for study, according to El País.

Ms. Branyas, unmoved, answered simply: “Death.”

For the full obituary see:

Ali Watkins. “Maria Branyas Morera, 117; Was Oldest Person in the World.” The New York Times (Friday, August 23, 2024): B11.

(Note: ellipses, and bracketed date, added.)

(Note: the online version of the obituary was updated Aug. 22, 2024, and has the title “Maria Branyas Morera, World’s Oldest Person, Dies at 117.”)

The “Innovative Approach” of the Dog Aging Project May Have Hurt Its Odds for Renewed Funding

Veterinary medicine is less regulated than human medicine, and so trial and error experiments may allow faster innovation that would benefit both dogs and humans.

(p. D3) In late 2019, scientists began searching for 10,000 Americans willing to enroll their pets in an ambitious new study of health and longevity in dogs. The researchers planned to track the dogs over the course of their lives, collecting detailed information about their bodies, lifestyles and home environments. Over time, the scientists hoped to identify the biological and environmental factors that kept some dogs healthy in their golden years — and uncover insights about aging that could help both dogs and humans lead longer, healthier lives.

Today, the Dog Aging Project has enrolled 47,000 canines and counting, and the data are starting to stream in. The scientists say that they are just getting started.

“We think of the Dog Aging Project as a forever project, so recruitment is ongoing,” said Daniel Promislow, a biogerontologist at the University of Washington and a co-director of the project. “There will always be new questions to ask. We want to always have dogs of all ages participating.”

But Dr. Promislow and his colleagues are now facing the prospect that the Dog Aging Project might have its own life cut short. About 90 percent of the study’s funding comes from the National Institute on Aging, a part of the National Institutes of Health, which has provided more than $28 million since 2018. But that money will run out in June, and the institute does not seem likely to approve the researchers’ recent application for a five-year grant renewal, the scientists say.

“We have been told informally that the grant is not going to be funded,” said Matt Kaeberlein, the other director of the Dog Aging Project and a former biogerontology researcher at the University of Washington. (Dr. Kaeberlein is now the chief executive of Optispan, a health technology company.)

. . .

Steven Austad, a biogerontologist at the University of Alabama at Birmingham who is not part of the research team, said he was surprised that the researchers’ grant might not be renewed. “The importance of the things they publish and the depth of detail will increase over time, but I thought they got off to a really good start,” he said. “A large study like this really deserves a chance to mature.”

Dr. Austad’s miniature dachshund, Emmylou, is enrolled in the Dog Aging Project. But at 2 years old, he noted, Emmylou is “not going to teach them a lot about aging for a long time yet.”

The project’s innovative approach might have worked against it, Dr. Austad added. Reviewers accustomed to evaluating short-term research on lab mice and long-term studies of humans may not have known what to make of an enormous epidemiological study of pet dogs.

Whatever the reason, the refusal to commit to more funding is “wrong,” Dr. Kaeberlein said. “It’s just really, really difficult to justify this decision, if you look at the productivity and the impact of the project.”

That impact extends beyond the findings themselves, he added. “This project has engaged almost 50,000 Americans in biomedical scientific research.”

Over the last few years, Shelley Carpenter, of Gulfport, Miss., has provided the researchers with regular updates on and medical records for her Pembroke Welsh corgi, Murfee. (She also collected a cheek swab for genomic sequencing.) Ms. Carpenter, whose previous corgi died from a neurodegenerative disease similar to A.L.S., hoped that the project might produce new medical knowledge that could help both dogs and people.

For the full story see:

Emily Anthes. “Scientists Scramble to Keep Dog Aging Project Alive.” The New York Times (Tuesday, January 16, 2024): D3.

(Note: ellipses added.)

(Note: the online version of the story has the date Jan. 11, 2024, and has the same title as the print version.)

Techno-Optimist Claims AI Tools “Will Help Scientists Design Therapies Faster and Better”

(p. A13) It is said that triumphant Roman generals, to ensure that the rapture of victory didn’t go to their heads, would require a companion to whisper in their ear: “Remember, you are only a man.” Jamie Metzl worries that we may have learned all too well such lessons in humility. Given remarkable recent advances in technology—and the promise of more to come—we need to lean into our emerging godlike powers, he believes, and embrace the opportunity to shape the world into a better place. In “Superconvergence,” he sets out to show us how, after first helping us overcome our hesitations.

. . .

. . . the big advances will be in medicine—and indeed are already in evidence. Mr. Metzl points to the blisteringly fast development of the Covid-19 mRNA vaccine, from digital file to widespread immunization in less than a year; and to gene-editing technologies like Crispr. He cites the experience of Victoria Gray, a young woman from Mississippi who was suffering from sickle-cell disease until, in 2019, researchers in Nashville, Tenn., reinfused her with her own cells, which had been Crispr-edited; the treatment worked, liberating her from the disease’s tormenting pain and crippling fatigue. For Mr. Metzl, these are just the first intimations of a revolution to come. AI tools like DeepMind’s Alphafold, he says, will help scientists design therapies faster and better.

To get smarter about human health, though, AI will need more information, and here Mr. Metzl’s ebullience edges toward the willful suspension of disbelief. His imagined future of healthcare will require “collecting huge amounts of genetic and systems biology data in massive and searchable databases.” The details will include not only medical records and the results of laboratory tests but data from the sensors he anticipates will be everywhere—“bathrooms, bedrooms, and offices”—as information is hoovered up from “toilets, mirrors, computers, phones and other devices without the people even noticing.” While acknowledging that such a scenario sounds like “an authoritarian’s dream and a free person’s nightmare,” he suggests that the chance to catch disease early may offset the risks. This trade-off promises to be a tough sell.

More than many techno-optimists, Mr. Metzl seems to grasp the intricacy of biological systems; he notes that they are beyond our full understanding right now. Even so, a time will come when “the sophistication of our tools and understanding meets and then exceeds the complexity of biology.”

For the full review, see:

David A. Shaywitz. “Getting Better, Faster.” The Wall Street Journal (Thursday, July 11, 2024): A13.

(Note: the online version of the review has the date July 10, 2024, and has the title “‘Superconvergence’ Review: Getting Better, Faster.”)

The book under review is:

Metzl, Jamie. Superconvergence: How the Genetics, Biotech, and AI Revolutions Will Transform Our Lives, Work, and World. New York: Timber Press, 2024.

Some Variants of One Mitochondrial Gene Double Your Odds of Living to 100

(p. D3) . . . what made the great blooming of biodiversity possible? Dr. Lane, building on ideas developed with the evolutionary biologist William Martin, traces its origins to a freak accident billions of years ago, when one microbe took up residence inside another. This event was not a branching of the evolutionary tree but a fusion with, he argues, profound consequences.

The new tenant provided energy for its host, paying chemical rent in exchange for safe dwelling. With this additional income, the host cell could afford investments in more complex biological amenities. The pairing thrived, replicated and evolved.

Today we call these inner microbes mitochondria; nearly every cell in our body has thousands of these energy factories. Dr. Lane and Dr. Martin have argued that because of mitochondria, complex cells have nearly 200,000 times as much energy per gene, setting the stage for larger genomes and unfettered evolution.

. . .

With age, mitochondrial mutations accumulate. Elsewhere, Dr. Lane has pointed to research showing that variants in a single mitochondrial gene halved the prospect of being hospitalized for age-related disease in patients who have them, and doubled the prospect of living to 100. This finding, Dr. Lane believes, could lead to medical advances if we understood how to protect mitochondrial DNA.

“How can we hope to understand disease,” he asks, “if we have no idea why cells work the way they do?”

. . .

Whether research will bear him out remains to be seen, but Dr. Lane’s many predictions, however incredible they seem, are testable and could keep scientists busy for years. As Sherlock Holmes remarked, “When you have eliminated the impossible, then whatever remains, however improbable, must be the truth.”

For the full review see:

Tim Requarth. “Rethinking the Textbook on Life.” The New York Times (Tuesday, July 21, 2015 [sic]): D3.

(Note: ellipses added.)

(Note: the online version of the review was updated July 20, 2015 [sic], and has the title “Book Review: Taking on ‘The Vital Question’ About Life.”)

The book under review is:

Lane, Nick. The Vital Question: Energy, Evolution, and the Origins of Complex Life. New York: W. W. Norton & Company, 2015.

In “An Entrenched Echo Chamber” the Highly Credentialed Slow Progress Toward an Alzheimer’s Cure

Centralized research funding (often centralized by government agencies) reduces the pluralism of ideas and methods that often lead to breakthrough innovations. The story of Alzheimer’s research, quoted below, is a dramatic case-in-point.

A secondary related lesson from the story quoted below is that Dr. Thambisetty, one of the outsiders struggling to make a difference, is trying to evade the enormous costs of mandated phase 3 clinical trials, by only investigating drugs that already have been approved by the FDA for use against other conditions. With his severely limited funding, and the huge costs of mandated phase 3 clinical trials, this may be a shrewd strategy for Thambisetty, but notice that by following it, he will never explore all the as-yet-unapproved chemicals that might include the best magic bullet against Alzheimer’s.)

(p. A25) What if a preposterous failed treatment for Covid-19 — the arthritis drug hydroxychloroquine — could successfully treat another dreaded disease, Alzheimer’s?

Dr. Madhav Thambisetty, a neurologist at the National Institute on Aging, thinks the drug’s suppression of inflammation, commonly associated with neurodegenerative disorders, might provide surprising benefits for dementia.

It’s an intriguing idea. Unfortunately, we won’t know for quite a while, if ever, whether Dr. Thambisetty is right. That’s because unconventional ideas that do not offer fealty to the dominant approach to study and treat Alzheimer’s — what’s known as the amyloid hypothesis — often find themselves starved for funds and scientific mind share.

Such shortsighted rigidity may have slowed progress toward a cure — a tragedy for a disease projected to affect more than 11 million people in the United States by 2040.

. . .

. . ., in 2006, an animal experiment published in the journal Nature identified a specific type of amyloid protein as the first substance found in brain tissue to directly cause symptoms associated with Alzheimer’s. Top scientists called it a breakthrough that provided a key target for treatments. The paper became one of the most cited in the field, and funds to explore similar proteins skyrocketed.

. . .

In 2022, my investigation in Science showed evidence that the famous 2006 experiment that helped push forward the amyloid hypothesis used falsified data. On June 24 [2024], after most of its authors conceded technical images were doctored, the paper was finally retracted.

. . .

In reporting for my forthcoming book about the disturbing state of play in Alzheimer’s research, I’ve spoken to many scientists pursuing alternatives. Dr. Thambisetty, for example, compares brain tissues from people who died in their 30s or 40s with and without genetic risk factors for Alzheimer’s. He then compares these findings to tissues from deceased Alzheimer’s patients and people who didn’t have the disease. Where changes overlap, drug targets might emerge. Rather than develop new drugs through lab and animal testing, followed by clinical trials that cost vast sums — a process that can take decades — he examines treatments already approved as reasonably safe and effective for other conditions. Patent protections have lapsed for many, making them inexpensive.

Experiments have also begun to test the weight-loss drug semaglutide (sold as Wegovy, among other brands). Researchers hope that results due in 2026 will show that its anti-inflammatory effects — like Dr. Thambisetty’s idea about hydroxychloroquine — slow cognitive decline.

Ruth Itzhaki, a research scientist at the University of Oxford, stirred curiosity in the 1990s when she shared evidence tying Alzheimer’s to herpesvirus — a scourge spread by oral or genital contact and often resulting in painful infections. For years, powerful promoters of the amyloid hypothesis ignored or dismissed the infection hypothesis for Alzheimer’s, effectively rendering it invisible, Dr. Itzhaki said with exasperation. Research suggests that viruses may hide undetected in organs, including the brain, for years, causing symptoms divergent from the original infection.

. . .

Sometimes a disease stems from a single clear-cut origin, such as genetic mutations that cause deadly sickle cell disease. “But very few diseases of aging have just one cause. It’s just not logical,” said Dr. Matthew Schrag, a neurologist at Vanderbilt University Medical Center. Working independently of his university, he discovered the 2006 research image manipulations.

. . .

“There is an entrenched echo chamber that involves a lot of big names,” Dr. Schrag said. “It’s time for the field to move on.”

For the full commentary see:

Charles Piller. “All the Alzheimer’s Research We Didn’t Do.” The New York Times (Friday, July 12, 2024): A25.

(Note: ellipses, and bracketed year, added.)

(Note: the online version of the commentary has the date July 7, 2024, and has the same title as the print version. Where there are a couple of small differences in wording, the passages quoted above follow the online version.)

Piller’s paper in Science, mentioned above, is:

Piller, Charles. “Blots on a Field?” Science 377, no. 6604 (July 2022): 358-63.

Piller’s commentary is related to his forthcoming book:

Piller, Charles. Doctored: Fraud, Arrogance, and Tragedy in the Quest to Cure Alzheimer’s. New York: Atria/One Signal Publishers, Forthcoming on February 4, 2025.

“Large Citizen Science Projects” Use Data Mining to Explore Risk Factors for Canine Cancers

(p. 2) Every dog has its day, and July 14, 2004, belonged to a boxer named Tasha. On that date, the National Institutes of Health announced that the barrel-chested, generously jowled canine had become the first dog to have her complete genome sequenced. “And everything has kind of exploded since then,” said Elaine Ostrander, a canine genomics expert at the National Human Genome Research Institute, who was part of the research team.

. . .

In the 2000s, scientists identified the genetic underpinnings of a variety of canine traits, including curly coats and bobbed tails. They pinpointed mutations that could explain why white boxers were prone to deafness. And they found that corgis, basset hounds and dachshunds owed their stubby legs to a genetic aberration in a family of genes that also regulates bone development in humans.

These early studies “highlighted both the potential that we could learn from dogs, but also that we were going to need bigger sample sizes to do it really well,” said Elinor Karlsson, a geneticist at UMass Chan Medical School and the Broad Institute. And so, researchers began creating large citizen science projects, seeking DNA samples and data from dogs across the United States.

Pet owners rose to the challenge. The Golden Retriever Lifetime Study, which began recruiting in 2012, has been following more than 3,000 dogs in an effort to identify genetic and environmental risk factors for cancer, which is especially common in the breed. Since 2019, the Dog Aging Project, a long-term study of health and longevity, has enrolled nearly 50,000 dogs.

Dr. Karlsson’s own project, Darwin’s Dogs, is at 44,000 canines and counting. (Some 4,000 have had their genomes sequenced.) Researchers are mining the data for clues about bone cancer, compulsive behavior and other traits.

For the full story see:

Emily Anthes. “Scientists’ New Best Friends.” The New York Times, Pets Special Section (Sunday, June 30, 2024): 2.

(Note: ellipsis added.)

(Note: the online version of the story has the same date as the print version, and has the title “How Science Went to the Dogs (and Cats).”)

With Metformin Patent Expired, No Firm Has Incentive to Fund $50 Million Randomized Clinical Trial to Show It Aids Longevity

The article quoted below was published eight years ago. Dr. Barzilai and his team are still, even now, trying to raise the (probably higher) funds to conduct the metformin clinical trial. Firms have no incentive to conduct the clinical trial. Since the patent for metformin (originally issued for its efficacy against diabetes) expired in the year 2000, even if the clinical trial succeeded, no firm would be able to recover in revenue the $50 cost of conducting the clinical trial. Clinical trials are so hugely expensive largely due to the large and long Phase 3 component, intended to prove efficacy. That is why I salute Milton Friedman’s suggestion that a step in the right direction would be for the FDA to only mandate the smaller and quicker Phase 1 and Phase 2 components, mainly intended to prove safety. If the total cost of the clinical trial was much lower, it might be easier to find non-profit or academic funding. (It’s hard to raise $50 million on a GoFundMe page!)

The system is set up so that cheap (off-patent) drugs like metformin do not get tested, and so do not get FDA approval for off-label uses. So the system is set up to reduce the use of low cost, but possibly effective, medicines.

(p. D5) “Aging is by far the best predictor of whether people will develop a chronic disease like atherosclerotic heart disease, stroke, cancer, dementia or osteoarthritis,” Dr. James L. Kirkland, director of the Kogod Center on Aging at the Mayo Clinic, said in an interview. “Aging way outstrips all other risk factors.”

He and fellow researchers, who call themselves “geroscientists,” are hardly hucksters hawking magic elixirs to extend life. Rather, they are university scientists joined together by the American Federation for Aging Research to promote a new approach to healthier aging, which may — or may not — be accompanied by a longer life. They plan to test one or more substances that have already been studied in animals, and which show initial promise in people, in hopes of finding one that will keep more of us healthier longer.

As Dr. Kirkland wrote in . . ., “Aging: The Longevity Dividend”: “By targeting fundamental aging processes, it may be possible to delay, prevent, alleviate or treat the major age-related chronic disorders as a group instead of one at a time.”

. . .

The team, which includes Dr. Nir Barzilai, director of the Institute for Aging Research at Albert Einstein College of Medicine in The Bronx, and Steven N. Austad, who heads the biology department at the University of Alabama at Birmingham, plans to study one promising compound, a generic drug called metformin already widely used in people with Type 2 diabetes. They will test the drug in a placebo-controlled trial involving 3,000 elderly people to see if it will delay the development or progression of a variety of age-related ailments, including heart disease, cancer and dementia. Their job now is to raise the $50 million or so needed to conduct the study for the five years they expect it will take to determine whether the concept has merit.

. . .

Several studies have . . . found that individuals with exceptional longevity experience a compression of morbidity and spend a smaller percentage of their life being ill, Dr. Barzilai and his colleague Dr. Sofiya Milman wrote in the “Aging” book.

For the full commentary see:

Jane E. Brody. “Pursuing the Dream of Healthy Aging.” The New York Times (Tuesday, February 2, 2016 [sic]): D5.

(Note: ellipses added.)

(Note: the online version of the commentary has the date February 1, 2016 [sic], and has the title “Finding a Drug for Healthy Aging.”)

Dr. Kirkland’s co-edited book mentioned above is:

Olshansky, S. Jay, George M. Martin, and James L. Kirkland, eds. Aging: The Longevity Dividend, A Subject Collection from Cold Spring Harbor Perspectives in Medicine. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, 2015.

One study that documents that those who live 107 or more years do not have more years of illness and morbidity (the “compression of morbidity hypothesis”) is:

Sebastiani, Paola, and Thomas T. Perls. “The Genetics of Extreme Longevity: Lessons from the New England Centenarian Study.” Frontiers in Genetics 3 (Nov. 30, 2012).

Non-Drug Treatments Are Under-Studied Because They Are Hard to Patent, and Hard to Test in Randomized Clinical Trials

(p. C3) In particular, decades of research show that mental, physical and social stimulation is one of the potential ways to ward off Alzheimer’s disease.

. . .

All of these findings come from observational studies that look at people’s existing lifestyle and cognitive health, as opposed to providing them with a “lifestyle treatment” and then assessing cognitive outcomes. The gold standard in modern medicine is randomized, blind, placebo-controlled trials, which are more quantifiable and objective, and there have been few such trials of lifestyle treatments for dementia and Alzheimer’s.

Those that exist have shown disparate results. For example, a study published in the journal Applied Neuropsychology in 2003 found that while mental drills could train people to do better on specific tasks like recalling words from a list, the effect didn’t translate into overall cognitive improvement. Clinical trials on social engagement are currently lacking.

One reason why the cognitive benefits of lifestyle enrichment haven’t been sufficiently studied is that nonpharmacological treatments such as physical exercise can’t be easily patented, so pharmaceutical companies aren’t interested in investing. It’s also difficult to use placebos. In drug trials, a look-alike sugar pill and a test drug are randomly assigned to participants, but there’s no equivalent of a sugar pill for enrichment activities. Instead, the control group either receives no intervention, a fact that can’t be easily hidden to avoid bias, or they receive some other interventions that may have effects of their own and muddle trial results.

For the full essay, see:

Han Yu. “An Active Lifestyle Can Help To Ward Off Alzheimer’s.” The Wall Street Journal (Saturday, Feb. 27, 2021 [sic]): C3.

(Note: ellipsis added.)

(Note: the online version of the essay has the date February 25, 2021 [sic], and has the title “Can an Active Lifestyle Help Ward Off Alzheimer’s?”)

The essay quoted above is adapted from Yu’s book is:

Yu, Han. Mind Thief: The Story of Alzheimer’s. New York: Columbia University Press, 2021.

The Dubious Result of a Randomized Controlled Trial (RCT)

Randomized controlled trials are widely viewed as the “gold standard” of medical evidence. But RCTs can be flawed in a variety of ways. They can have too few participants, they can be improperly randomized for a variety of reasons (not all relevant variables may have been identified or the protocol may not have been properly implemented). Forgive me, but the results of the RCT described below seem highly implausible. I believe that something about the RCT was flawed. Who can believe the result that those who engage in moderate exercise live shorter lives than those who only engage in very modest exercise. Common sense and many observational studies say the opposite, and such evidence should not be cavalierly dismissed.

(p. D6) Scientists have known for some time, . . ., that active people tend also to be long-lived people. According to multiple past studies, regular exercise is strongly associated with greater longevity, even if the exercise amounts to only a few minutes a week.

But almost all of these studies have been observational, meaning they looked at people’s lives at a moment in time, determined how much they moved at that point, and later checked to see whether and when they passed away. Such studies can pinpoint associations between exercise and life spans, but they cannot prove that moving actually causes people to live longer, only that activity and longevity are linked.

To find out if exercise directly affects life spans, researchers would have to enroll volunteers in long-term, randomized controlled trials, with some people exercising, while others work out differently or not at all. The researchers then would have to follow all of these people for years, until a sufficiently large number died to allow for statistical comparisons of the groups.

Such studies, however, are dauntingly complicated and expensive, one reason they are rarely done. They may also be limited, since over the course of a typical experiment, few adults may die. This is providential for those who enroll in the study but problematic for the scientists hoping to study mortality; with scant deaths, they cannot tell if exercise is having a meaningful impact on life spans.

Those obstacles did not deter a group of exercise scientists at the Norwegian University of Science and Technology in Trondheim, Norway, however. With colleagues from other institutions, they had been studying the impacts of various types of exercise on heart disease and fitness and felt the obvious next step was to look at longevity. So, almost 10 years ago, they began planning the study that would be published in October [2020] in The BMJ.

. . .

The scientists tested everyone’s current aerobic fitness as well as their subjective feelings about the quality of their lives and then randomly assigned them to one of three groups. The first, as a control, agreed to follow standard activity guidelines and walk or otherwise remain in motion for half an hour most days. (The scientists did not feel they could ethically ask their control group to be sedentary for five years.)

Another group began exercising moderately for longer sessions of 50 minutes twice a week. And the third group started a program of twice-weekly high-intensity interval training, or H.I.I.T., during which they cycled or jogged at a strenuous pace for four minutes, followed by four minutes of rest, with that sequence repeated four times.

. . .

The men and women in the high-intensity-intervals group were about 2 percent less likely to have died than those in the control group, and 3 percent less likely to die than anyone in the longer, moderate-exercise group. People in the moderate group were, in fact, more likely to have passed away than people in the control group.

For the full story see:

Gretchen Reynolds. “Working Out With Intensity.” The New York Times (Tuesday, December 29, 2020 [sic]): D6.

(Note: ellipses, and bracketed year, added.)

(Note: the online version of the story was updated Nov. 10, 2021 [sic–yes 2021], and has the title “The Secret to Longevity? 4-Minute Bursts of Intense Exercise May Help.” Where the wording of the versions slightly differs, the passages quoted above follow the online version.)

The study published in The British Medical Journal (BMJ), and mentioned above, is:

Stensvold, Dorthe, Hallgeir Viken, Sigurd L. Steinshamn, Håvard Dalen, Asbjørn Støylen, Jan P. Loennechen, Line S. Reitlo, Nina Zisko, Fredrik H. Bækkerud, Atefe R. Tari, Silvana B. Sandbakk, Trude Carlsen, Jan E. Ingebrigtsen, Stian Lydersen, Erney Mattsson, Sigmund A. Anderssen, Maria A. Fiatarone Singh, Jeff S. Coombes, Eirik Skogvoll, Lars J. Vatten, Jorunn L. Helbostad, Øivind Rognmo, and Ulrik Wisløff. “Effect of Exercise Training for Five Years on All Cause Mortality in Older Adults—the Generation 100 Study: Randomised Controlled Trial.” BMJ 371 (2020): m3485.

To Reduce the Huge Costs of Randomized Clinical Trials, Groups Are Excluded for Whom the Trials Matter Most

(p. D5) Geriatricians have complained for years that figuring out treatments for their patients becomes dramatically more difficult when older people are excluded from clinical trials and other research.

For an 83-year-old, what are the risks and benefits of a surgical procedure, drug or medical device tested primarily on those in their 50s? When a drug trial excludes those who have several diseases and take other drugs, how do the results pertain to older adults — most of whom have several diseases and take other drugs?

. . .

Critics of age exclusion had reason to celebrate in December, when the National Institutes of Health issued new policy guidelines for the research it funds.

Starting next January, grant applicants will have to explain how they intend to include people of all ages, providing acceptable justifications for any group they leave out. The agency will monitor investigators to make sure they comply.

“It’s the right starting point,” said Dr. Florence Bourgeois, a pediatrician at Harvard Medical School. (Children also wind up taking drugs tested only in adults.)

. . .

How often are old people left out of important medical research? In 2011, it looked like progress when Dr. Donna Zulman and her colleagues at the University of Michigan reviewed 109 clinical trials published in leading journals and found that just 20 percent set upper age limits for participation.

An earlier review of trials published from 1994 to 2006 had found that 39 percent shut out people over age 65.

But, as the University of Michigan team also pointed out, even without age limits, studies may bar participants who have multiple disorders or disabilities, or those with limited life expectancy or cognitive impairment. Some researchers won’t enroll nursing home residents.

Those restrictions, too, effectively push older people out of clinical trials and other studies.

Maddeningly, exclusion rates remain high even for studies of diseases particularly common at older ages. Dr. Bourgeois and her colleagues looked at clinical trials for heart disease medications, for instance — primarily blood thinners, cholesterol and blood pressure drugs.

More than half of the trials had upper age limits, usually 75 or 80, and only about 12 percent of participants were aged 75 or older. Yet nearly 40 percent of people hospitalized with heart attacks are over age 75.

For the full story see:

Paula Span. “The Clinical Trial Is Open. Older People Need Not Apply.” The New York Times (Tuesday, April 17, 2018 [sic]): D5.

(Note: ellipses added.)

(Note: the online version of the story has the date April 13, 2018 [sic], and has the title “The Clinical Trial Is Open. The Elderly Need Not Apply.”)

Some published academic articles supporting the points made in the passages quoted above are:

Bourgeois, Florence T., Liat Orenstein, Sarita Ballakur, Kenneth D. Mandl, and John P. A. Ioannidis. “Exclusion of Elderly People from Randomized Clinical Trials of Drugs for Ischemic Heart Disease.” Journal of the American Geriatrics Society 65, no. 11 (Nov. 2017): 2354-61.

Bourgeois, Florence T., Srinivas Murthy, Catia Pinto, Karen L. Olson, John P.A. Ioannidis, and Kenneth D. Mandl. “Pediatric Versus Adult Drug Trials for Conditions with High Pediatric Disease Burden.” Pediatrics 130, no. 2 (Aug. 2012): 285-92.

Cruz-Jentoft, Alfonso J., Marina Carpena-Ruiz, Beatriz Montero-Errasquín, Carmen Sánchez-Castellano, and Elisabet Sánchez-García. “Exclusion of Older Adults from Ongoing Clinical Trials About Type 2 Diabetes Mellitus.” Journal of the American Geriatrics Society 61, no. 5 (May 2013): 734-38.

Lewis, Joy H., Meredith L. Kilgore, Dana P. Goldman, Edward L. Trimble, Richard Kaplan, Michael J. Montello, Michael G. Housman, and José J. Escarce. “Participation of Patients 65 Years of Age or Older in Cancer Clinical Trials.” Journal of Clinical Oncology 21, no. 7 (April 2003): 1383-89.

McGarvey, Caoimhe, Tara Coughlan, and Desmond O’Neill. “Ageism in Studies on the Management of Osteoporosis.” Journal of the American Geriatrics Society 65, no. 7 (July 2017): 1566-68.

Zulman, Donna M., Jeremy B. Sussman, Xisui Chen, Christine T. Cigolle, Caroline S. Blaum, and Rodney A. Hayward. “Examining the Evidence: A Systematic Review of the Inclusion and Analysis of Older Adults in Randomized Controlled Trials.” Journal of General Internal Medicine 26, no. 7 (July 2011): 783-90.