Category: Aging

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.

Private-Sector Experimentation Versus Washington Inertia in the Fight for Longer Life

(p. A15) Amid today’s technological wizardry, it’s easy to forget that several decades have passed since a single innovation has dramatically raised the quality of life for millions of people. Summoning a car with one’s phone is nifty, but it pales in comparison with discovering penicillin or electrifying cities. Artificial intelligence is being heralded as the next big thing, but a cluster of scientists, technologists and investors are aiming higher. In the vernacular of Silicon Valley, where many of them are based, their goal is nothing less than disrupting death, and their story is at the center of “Immortality, Inc.” by science journalist Chip Walter.

. . .

That is the backdrop to Mr. Walter’s absorbing story, which he begins with a visit to Alcor, the Arizona-based organization that says it preserves corpses at minus 124 degrees Celsius “in an attempt to maintain brain viability after the heart stops.” (Current “patients” include baseball legend Ted Williams.) While this life-extending strategy, known as “cryonics,” is often ridiculed, the individuals profiled in “Immortality, Inc.” are high-status, highly regarded figures whose initiatives can’t be easily dismissed. What links them, writes Mr. Walter, is that “they are all troublemakers at heart.” They believe that the “conventional approaches” of most medical researchers and practitioners are, “at the very least, misguided.”

. . .

While “Immortality, Inc.” is focused on aging and the efforts to defy it, the book is also a gripping chronicle of private-sector experimentation and ingenuity in the face of inertia in Washington. “As recently as five years ago,” Mr. Walter writes, “the great pashas at [the National Institutes of Health] . . . looked upon aging research as largely crackpot.” He faults the Food and Drug Administration for refusing to classify aging as a disease. As a result, clinical trials—the foundation of medical research—can’t be conducted.

For the full review, see:

Matthew Rees. “BOOKSHELF; Birthdays Without End.” The Wall Street Journal (Monday, Jan. 27, 2020 [sic]): A15.

(Note: ellipses between paragraphs, added; ellipsis within paragraph, in original.)

(Note: the online version of the review has the date Jan. 26, 2020 [sic], and has the title “BOOKSHELF; ‘Immortality, Inc.’ Review: Birthdays Without End.”)

The book under review is:

Walter, Chip. Immortality, Inc.: Renegade Science, Silicon Valley Billions, and the Quest to Live Forever. Washington, D.C.: National Geographic, 2020.

Bdelloids Frozen for 24,000 Years Return to Life and Reproduce

(p. D2) Bdelloids can . . . come back to life after tens of thousands of years in deep freeze, according to a study published Monday [June 7, 2021] in the journal Current Biology. Bdelloids are one of a handful of teensy creatures, including tardigrades, that are known to survive incredibly inhospitable conditions.

. . .

For the study, scientists collected samples by drilling about 11 feet below the surface of permafrost in northeastern Siberia. They discovered living bdelloid rotifers locked in the ancient permafrost, whose average temperature hovers around 14 degrees Fahrenheit.

. . .

Radiocarbon-dating revealed the bdelloids were 24,000 years old. They then bounced back and were still capable of reproducing once thawed.

For the full story see:

Marion Renault. “The Deepest Sleeper: It Makes Rip Van Winkle Look Like an Amateur.” The New York Times (Tuesday, June 15, 2021 [sic]): D2.

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

(Note: the online version of the story has the date June 7, 2021 [sic], and has the title “This Tiny Creature Survived 24,000 Years Frozen in Siberian Permafrost.” Where the versions differ, in the passages quoted above I follow the online version.)

The study mentioned above is:

Shmakova, Lyubov, Stas Malavin, Nataliia Iakovenko, Tatiana Vishnivetskaya, Daniel Shain, Michael Plewka, and Elizaveta Rivkina. “A Living Bdelloid Rotifer from 24,000-Year-Old Arctic Permafrost.” Current Biology 31, no. 11 (June 7, 2021): R712-R713.

“Terminal Lucidity” Is “the Light Before the End of the Tunnel”

(p. D6) . . . “terminal lucidity,” [is] a term coined by the biologist Michael Nahm in 2009 to describe the brief state of clarity and energy that sometimes precedes death. Alexander Batthyány, another contemporary expert on dying, calls it “the light before the end of the tunnel.”

A 5-year-old boy in a coma for three weeks suddenly regains consciousness. He thanks his family for letting him go and tells them he’ll be dying soon. The next day, he does.

A 26-year-old woman with severe mental disabilities hasn’t spoken a word for years. Suddenly, she sings, “Where does the soul find its home, its peace? Peace, peace, heavenly peace!” The year is 1922. She sings for half an hour and then she passes away. The episode is witnessed by two prominent physicians and later recounted by them separately, at least five times, with identical descriptions.

Early reports of terminal lucidity date back to Hippocrates, Plutarch and Galen. Dr. Nahm collected 83 accounts of terminal lucidity written over 250 years, most of which were witnessed by medical professionals. Nearly 90 percent of cases happened within a week of death and almost half occurred on the final day of life.

Terminal lucidity occurred irrespective of ailment, in patients with tumors, strokes, dementia and psychiatric disorders. Dr. Nahm suggested the mechanism of terminal lucidity may differ from one disease to another. For example, severe weight loss in patients with brain tumors could cause the brain to shrink, yielding fleeting relief of pressure on the brain that might allow for clearer thinking. Yet this theory doesn’t explain terminal lucidity in people dying from dementia, kidney failure or other diseases. Like death itself, terminal lucidity retains a screen of mystery.

My grandfather talked to us for 10 minutes the day before he died. He hadn’t spoken coherently in days. His hands had become baby-like, grasping our fingers or the bed railing reflexively. The weight of his eyelids had become too heavy to lift.

Suddenly, he was back. “What’s the good word?” he asked, as if that day was the same as all the days before. He marched down the line of grandchildren at his bedside, asking for the latest news in our lives. He asked if they ever finished building the Waldorf Astoria in Jerusalem. He made a joke, one I can’t remember except for the way he smiled out of the right side of his mouth, tilted his head from side to side, and held up his hands in jest.

And then, again, he was gone.

For the full commentary see:

Sara Manning Peskin, M.D. “The Gentler Symptoms of Dying.” The New York Times (Tuesday, July 18, 2017 [sic]): D6.

(Note: ellipsis and bracketed word added.)

(Note: the online version of the commentary has the date July 11, 2017 [sic], and the same title as the print version.)

“Terminal Rage” May Be “Rage Against the Dying of the Light”

The quotation below from Dylan Thomas is his first line and title for one of my favorite, albeit sad, poems. It is the first line, but my favorite line is: “Rage, rage against the dying of the light.”

(p. D4) Terminal Agitation

“Do not go gentle into that good night” (Dylan Thomas)

My grandfather screamed two days before he died. “Open that door and let me out! Right now! It’s a travesty! Open that door!”

It was the scream of a lost child. My grandfather’s eyebrows, which had been lost over the years from the outside inward so that only a centimeter of long gray hairs near the middle remained, tilted toward each other.

Until then, we were preparing for missing and absence. Not for an agitated delirium. Not for rage.

. . .

Instead of peacefully floating off, the dying person may cry out and try to get out of bed. Their muscles might twitch or spasm. The body can appear tormented.

. . .

People who witness terminal agitation often believe it is the dying person’s existential response to death’s approach. Intense agitation may be the most visceral way that the human body can react to the shattering of inertia. We squirm and cry out coming into the world, and sometimes we do the same leaving it.

For the full commentary see:

Sara Manning Peskin, M.D. “The Symptoms of Dying.” The New York Times (Tuesday, June 20, 2017 [sic]): D4.

(Note: ellipses added. In the original, the line of Dylan Thomas’s poem, and his name, appear in italics.)

(Note: the online version of the commentary has the same date and title as the print version.)

Elephants Have Backup or “Resurrected” Copies of Cancer-Killing Genes

(p. D3) Elephants ought to get a lot of cancer. They’re huge animals, weighing as much as eight tons. It takes a lot of cells to make up that much elephant.

All of those cells arose from a single fertilized egg, and each time a cell divides, there’s a chance that it will gain a mutation — one that may lead to cancer.

Strangely, however, elephants aren’t more prone to cancer than smaller animals. Some research even suggests they get less cancer than humans do.

On Tuesday [Aug. 14, 2018 [sic]], a team of researchers reported what may be a partial solution to that mystery: Elephants protect themselves with a unique gene that aggressively kills off cells whose DNA has been damaged.

Somewhere in the course of evolution, the gene had become dormant. But somehow it was resurrected, a bit of zombie DNA that has proved particularly useful.

Vincent J. Lynch, an evolutionary biologist at the University of Chicago and a co-author of the paper, published in Cell Reports, said that understanding how elephants fight cancer may provide inspiration for developing new drugs.

. . .

In 2015, Dr. Lynch and his colleagues discovered that elephants have evolved unusual p53 genes. While we only have one copy of the gene, elephants have 20 copies. Researchers at the University of Utah independently made the same discovery.

. . .

Dr. Lynch and his colleagues continued their search for cancer-fighting genes, and they soon encountered another one, called LIF6, that only elephants seem to possess.

In response to DNA damage, p53 proteins in elephants switch on LIF6. The cell makes LIF6 proteins, which then wreak havoc.

Dr. Lynch’s experiments indicate that LIF6 proteins make their way to the cell’s tiny fuel-generating factories, called mitochondria.

The proteins pry open holes in the mitochondria, allowing molecules to pour out. The molecules from mitochondria are toxic, causing the cell to die.

. . .

After the ancestors of elephants evolved ten LIF genes, however, something remarkable happened: One of these dead genes came back to life. That gene is LIF6.

Somewhere in the course of elephant evolution, a cellular mutation inserted a genetic switch next to LIF6, enabling the gene to be activated by p53. The resurrected gene now made a protein that could do something new: attack mitochondria and kill damaged cells.

For the full commentary see:

Carl Zimmer. “MATTER; A Resurrected Cancer Fighter.” The New York Times (Tuesday, August 21, 2018 [sic]): D3.

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

(Note: the online version of the commentary has the date Aug. 14, 2018 [sic], and has the title “MATTER; The ‘Zombie Gene’ That May Protect Elephants From Cancer.” Where there is a small difference in wording between the versions, the passages quoted above follow the online version.)

The paper published in Cell Reports and mentioned above is:

Vazquez, Juan Manuel, Michael Sulak, Sravanthi Chigurupati, and Vincent J. Lynch. “A Zombie LIF Gene in Elephants Is Upregulated by TP53 to Induce Apoptosis in Response to DNA Damage.” Cell Reports 24 (2018): 1765–76.