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In 2011, Dr. Dena Dubal was hired by the University of California, San Francisco, as an assistant professor of neurology. She set up a new lab with one chief goal: to understand a mysterious hormone called Klotho.
Benedicte Muller
In 2011, Dr. Dena Dubal was hired by the University of California, San Francisco, as an assistant professor of neurology. She set up a new lab with one chief goal: to understand a mysterious hormone called Klotho.
Dr. Dubal wondered if it might be the key to finding effective treatments for dementia and other disorders of the aging brain. At the time, scientists only knew enough about Klotho to be fascinated by it.
Mice bred to make extra Klotho lived 30 percent longer, for instance. But scientists also had found Klotho in the brain, and so Dr. Dubal launched experiments to see whether it had any effect on how mice learn and remember.
The results were startling. In one study, she and her colleagues found that extra Klotho protects mice with symptoms of Alzheimer’s disease from cognitive decline. “Their thinking, in every way that we could measure them, was preserved,” said Dr. Dubal.
She and her colleagues also bred healthy mice to make extra Klotho. They did better than their fellow rodents on learning mazes and other cognitive tests.
Klotho didn’t just protect their brains, the researchers concluded — it enhanced them. Experiments on more mice turned up similar results.
“I just couldn’t believe it — was it true, or was it just a false positive?” Dr. Dubal recalled. “But here it is. It enhances cognition even in a young mouse. It makes them smarter.”
Five years have passed since Dr. Dubal and her colleagues began publishing these extraordinary results. Other researchers have discovered tantalizing findings of their own, suggesting that Klotho may protect against other neurological disorders, including multiple sclerosis and Parkinson’s disease.
Now Dr. Dubal and other researchers are trying to build treatments based on these results. Either by injecting Klotho into the body or by stimulating the brain to make more of the hormone, they hope to treat diseases like Alzheimer’s.
The researchers developing these treatments readily acknowledge that they may fail. And other Klotho experts think there’s a huge amount of work left to do first to figure out how Klotho affects the brain.
“You’ve got all of this amazing stuff showing a really major impact, but we can’t really explain why,” said Gwendalyn D. King, a neuroscientist at the University of Alabama at Birmingham. “That’s where we’re stuck.”
But what happens if scientists get unstuck? What if a drug that enhances cognition really were possible?
Eric Juengst, the director of the University of North Carolina Center for Bioethics, has been thinking about these questions for two decades — back when such drugs were little more than thought experiments.
We tend to think of drugs that enhance performance — say, sports doping — as bad. Drugs that cure or prevent diseases are good. “The scientific community and the public all draw that line,” said Dr. Juengst.
When it comes to Klotho, there may be no such line. In theory, such a drug might offer both a way to prevent diseases of the brain and to enhance it.
Recent research is giving these questions a sudden urgency, according to Dr. Juengst.
“It’s exciting for someone who’s been doing armchair work on this for a long time to see it happening in the real world,” he said. “But it also makes it all the more pressing that this conversation get started in earnest.”
Spinning a Thread
In 1991, a cardiologist in Japan named Dr. Makoto Kuro-o began to study high blood pressure. He inserted DNA into mouse embryos, hoping to create a line of rodents that suffered from the condition.
Instead, some of his mice seemed to get old too fast. “Usually mice live two years, but these mice were dying after two or three months,” said Dr. Kuro-o, now a professor at Jichi Medical University in Japan.
Dr. Kuro-o suspected he had accidentally shut down a gene that had something to do with life span. When he autopsied the mice, he was astonished to find atrophied muscles, brittle bones and atherosclerosis.
“It’s like accelerated aging,” he said. He spent the next few years searching for the gene. When he and his colleagues finally found it, they named it Klotho, in honor of one of the three fates of Greek mythology. Her job was to spin the thread of each person’s life.
The Klotho hormone is produced in a few organs, Dr. Kuro-o and his colleagues found, including the brain. When they studied mice that lacked the hormone, they found that cognition deteriorated far faster than in ordinary animals.
These dramatic results led Dr. Kuro-o and his colleagues to reverse their experiments. Instead of breeding mice without Klotho, they produced a strain that made twice as much as normal. In 2005 the scientists reported that the extra Klotho allowed the mice to live longer.
Dr. Dubal wondered if extra Klotho might keep the brain resilient in old age. In one experiment, she collaborated with Dr. Kuro-o and other experts to study its effect on Alzheimer’s disease.
They began with mice that display some of symptoms of Alzheimer’s.Like people, they develop clumps of proteins in the brain and suffer a steep cognitive decline.
Dr. Dubal and her colleagues bred these mice with Klotho-boosted mice. As the offspring aged, they made the protein clumps that their forebears did. But in terms of learning and memory, they tested as well as healthy mice.
When the researchers bred healthy mice to produce extra Klotho, they got an even more striking result. The mice weren’t just resilient — they did even better on learning tests than normal.
Scientists can’t run these kinds of experiments on humans to see if the hormone had the same effect, of course. But nature has run an experiment of its own.
Some people carry a genetic variation that causes them to produce higher levels of Klotho than average in their bodies. Dr. Dubal and her colleagues identified a group of healthy old people with the variant and tested their cognition.
They scored better than people who make an average level of Klotho. “It’s not like they didn’t undergo cognitive decline,” said Dr. Dubal. “It’s just that they started off higher.”
In March, Dr. Dubal and her colleagues published a study suggesting that Klotho may also provide some protection from Alzheimer’s disease to people as well.
One of the biggest risk factors for Alzheimer’s disease is a genetic variant called APOE e4. Inheriting two copies of the gene can increase the risk more than eightfold.
Dr. Dubal and her colleagues found that many people with APOE e4 appeared to be on their way to Alzheimer’s disease even if they had no sign of dementia yet. They had markers indicating a buildup of clumps in their brains.
Then Dr. Dubal and her colleagues looked at the people with both APOE e4 and extra Klotho. They had no extra clumps.
It’s possible that in these people Klotho is slowing the effects of carrying APOE e4, Dr. Dubal speculated. “Maybe their brains are biologically younger,” she said.
A few other research groups have also found promising results in people, but all of the studies — Dr. Dubal’s included — are small. Nevertheless, the combination of results from people and mice have spurred some Klotho researchers to try to turn their knowledge into a treatment.
A Brain Protector?
In 2015, one of Dr. Dubal’s collaborators, Carmela Abraham of Boston University, decided it was time to form a company. She and her co-founders called it Klogene Therapeutics.
Based on her 15 years of research, Dr. Abraham reasoned that raising Klotho levels in the brain might shield people from degenerative disorders of the brain. Klogene has been developing a range of new techniques to manipulate the hormone.
In one line of experiments, they used the gene-editing technique called Crispr to alter the DNA of human neurons. The engineered cells make more Klotho.
Klogene also has been testing compounds that can raise the production of Klotho. “Our dream solution is that you take a pill a day, the way you take statins right now,” said Dr. Abraham.
Dr. Dubal is also collaborating on drug research: She’s investigating injecting Klotho into the body. The strategy comes out of a 2017 study that took her by surprise.
She was going to observe what happened to mice that got Klotho injections in the brain. But first she injected the hormone into the bellies of mice, to have a point of comparison. Within a few hours of the injection, the mice started doing better on cognition tests.
Dr. Dubal is now following up on that unexpected result with a biotech startup to see if injections can prevent Alzheimer’s disease.
“The vision would be a shot in the belly,” she said. “But we just don’t know until we test it.”
Earlier in her career, Dr. King helped Dr. Abraham search for compounds that spur the brain to make more Klotho. But these days, Dr. King is skeptical about the prospect of a drug: “I think it’s very early to be heading directly there.”
Dr. King doesn’t dispute the remarkable results of the Klotho experiments. It’s just that researchers can’t account for them.
When Dr. Dubal injects Klotho into mice, for example, the hormone doesn’t actually get into the brain. It must trigger some series of reactions in the body — but no one can say what they are.
For her part, Dr. King thinks the priority now is to take a close look at what Klotho does in individual cells.
“We’ve got a lot of really big observations, and we really need to understand what’s going on at the cell level that would explain them,” she said.
Dr. King and her colleagues have inspected cells taken from a region of the mouse brain called the hippocampus, which is vital for memory. Without Klotho, these neurons grow slowly and don’t sprout a healthy supply of branches. Dousing them with the hormone lets them multiply normally again.
Other studies suggest that Klotho can alter other types of neurons. But Dr. King doubts that one hormone can do lots of different things to lots of different kinds of cells.
“I wonder if there is something fundamental that Klotho is doing to support the brain,” she said. “If you have this helper around, they function better.”
Enhancement and Ethics
What would happen if Dr. Abraham found her dream solution and invented a pill to raise Klotho levels in the brain?
Perhaps people would respond like mice, gaining protection against disorders like Alzheimer’s disease. It’s also possible that healthy people would respond to such a pill the way healthy mice respond to extra Klotho — their minds would be enhanced.
For Dr. Juengst, the ethics of such a drug would be tricky to sort out. “Enhancement is not inherently evil,” he said. “We’d all have to give up coffee if it was.”
Yet we frown on performance-enhancing drugs because they offend our sense of fair play. Winning the Tour de France thanks to doping feels like a betrayal. If people could raise their SAT scores by taking a pill the night before an exam, that might not seem fair to many of us, either.
Dr. Juengst thinks that Klogene’s experiments with Crispr raise some particularly thorny questions. Would it be acceptable to use gene editing to alter people’s brains so that they made more of the hormone? Why not get an early start and alter Klotho in embryos?
Surveys about gene editing tend to reflect a traditional divide between diseases and enhancement. People are more inclined to approve gene editing to prevent a disease, and tend to say enhancement is wrong.
But if a Klotho-based treatment one day prevents dementia, there may be no way to enjoy those benefits without also accepting its use as a brain enhancement.
“I still struggle with it,” Dr. Dubal said. Despite the ethical complexities, she thinks that cognitive enhancement from Klotho could be a good thing — not just for individuals, but for society.
“If you were going into brain surgery, you’d want your neurosurgeon to be as sharp as possible,” she said. “Would it be wrong for her or him to take a shot of Klotho before your surgery? Probably not.”
But Dr. Dubal does see a risk of injustice if only some people are offered the benefits of a brain-enhancing drug. “Why couldn’t they be available to all?” she asked.
Ultimately, though, the most important factor for Dr. Dubal is whether the ethical concerns about enhancement prevent research into Klotho as a way to treat life-threatening diseases.
“We’re going to have 115 million people with Alzheimer’s disease by 2050,” she said. “If we can make this an effective treatment, then it is unethical not to do so.”
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