Slowing Aging Could Transform Society As We Know It
People's lives have been getting longer for more than a century. In 1900, in even the wealthiest countries, life expectancy was under 50, according to the World Health Organization. By 2015, the worldwide average was 74, and a girl born in Japan that year could expect to live to 87. Most of that extra lifespan came from improvements in nutrition and sanitation, and the development of vaccines and antibiotics.
People's lives have been getting longer for more than a century. In 1900, in even the wealthiest countries, life expectancy was under 50, according to the World Health Organization. By 2015, the worldwide average was 74, and a girl born in Japan that year could expect to live to 87. Most of that extra lifespan came from improvements in nutrition and sanitation, and the development of vaccines and antibiotics.
The question is, how will slowing aging change society?
But now scientists are trying to move beyond just eliminating the diseases that kill us to actually slowing the aging process itself. By developing new drugs to tackle the underlying mechanisms that make our bodies grow old and frail, researchers hope to give people many more years of healthy life. The question is, how will that change society?
There are several biological mechanisms that affect aging. One involves how cells react when they're damaged. Some die, but others enter a state called senescence, in which they halt their normal growth and send out signals that something's gone wrong. That signaling causes inflammation at the sight of a wound, for instance, and triggers the body's repair processes. Once everything is back to normal, the senescent cells die off and the inflammation fades. But as we age, the machinery for clearing senescent cells becomes less efficient and they begin to pile up. Some researchers think that this accumulation of senescent cells is what causes chronic inflammation, which has been implicated in conditions such as heart disease and diabetes.
The first clinical trial in humans of senolytic drugs is happening now.
In 2015, researchers at the Mayo Clinic in Minnesota and the Scripps Research Institute in Florida tested the first so-called senolytic drugs, which cause senescent cells to die. After the scientists treated mice with a combination of an anti-cancer drug and a plant pigment that can act as an antioxidant, some of the senescent cells shrank away and caused the mouse's heart function to revert to that of a much younger mouse.
"That suggests that senescence isn't just a consequence of aging, it's actually a driver of aging," says Paul Robbins, a professor of molecular medicine at Scripps and one of the researchers involved. Other animal studies have found that reducing the number of senescent cells improves a variety of age-related conditions, such as frailty, diabetes, liver disease, pulmonary fibrosis, and osteoporosis.
Now the same researchers are moving those tests to humans in the first clinical trials of senolytic drugs. In July 2016, the Mayo Clinic launched what may be the first clinical trial of senolytic therapy, studying the effect of the two drugs, called dasatinib and quercetin, on people with chronic kidney disease, which they hope to complete in 2021. Meanwhile Mayo and Scripps researchers have identified six different biochemical pathways that give rise to senescence, along with several drug candidates that target those pathways. Robbins says it's likely that different drugs will work better for different cells in the body.
Would radical life extension lead to moral deterioration, risk aversion, and an abandonment of creativity?
In Robbins' work, treating mice with senolytic drugs has extended their median lifespan—the age at which half the animals in his experiment have died—by about 30 percent, but hasn't extended the maximum lifespan. In other words, the oldest mice treated with the drugs died at the same age as mice who hadn't been treated, but more of the mice who received senolytics lived to that ripe old age. The same may turn out to be true for humans, with more people living to the limits of the lifespan—estimated by some to be about 115—but no one living much longer. On the other hand, Robbins says, it's early days for these therapies, and it may turn out that delaying aging actually does push the limit of life farther out.
Others expect more radical extensions of human life; British gerontologist Aubrey DeGray talks about people living for 1000 years, and people who call themselves transhumanists imagine replacing body parts as they wear out, or merging our minds with computers to make us essentially immortal. Brian Green, an ethicist at Santa Clara University in California, finds that concept horrifying. He fears it would make people value their own lives too highly, demoting other moral goods such as self-sacrifice or concern for the environment. "It kind of lends itself to a moral myopia," he says. "Humans work better if they have a goal beyond their own survival." And people who live for centuries might become averse to risk, because with longer lives they have more to lose if they were to accidentally die, and might be resistant to change, draining the world of creativity.
Most researchers are focused on "extending the 'healthspan,' so that the people who live into their 90s are vigorous and disease-free."
He's not too worried, though, that that's where studies such as the Mayo Clinic's are headed, and supports that sort of research. "Hopefully these things will work, and they'll help us live a little bit longer," Green says, "but the idea of radical life extension where we're going to live indefinitely longer, I think that is very unrealistic."
Most of the researchers working on combatting aging don't, in fact, talk of unlimited lifespans. Rather, they talk about extending the "healthspan," so that the people who live into their 90s are vigorous and disease-free up until nearly the end of their lives.
If scientists can lengthen life while reducing the number of years people suffer with dementia or infirmity, that could be beneficial, says Stephen Post, a professor of medicine and director of the Center for Medical Humanities, Compassionate Care, and Bioethics at Stony Brook University in New York. But even increasing the population of vigorous 90-somethings might have negative implications for society. "What would we do with all these people who are living so long?" he asks. "Would we stop having children? Would we never retire?"
Adding 2.2 healthy years to the U.S. life by delaying aging could benefit the economy by $7.1 trillion over 50 years.
If people keep working well past their 60s, that could mean there would be fewer jobs available for younger people, says Maxwell Mehlman, professor of bioethics at Case Western Reserve University's School of Law in Ohio. Mehlman says society may have to rethink age discrimination laws, which bar firing or refusing to hire people over a certain age, to make room for younger workers. On the other hand, those who choose to retire and live another two or three decades could strain pension and entitlement systems.
But a longer healthspan could reduce costs in the healthcare system, which now are driven disproportionately by older people. Jay Olshansky, an epidemiologist at the University of Illinois at Chicago School of Public Health, has estimated that adding 2.2 healthy years to the U.S. life by delaying aging would benefit the economy by $7.1 trillion over 50 years, as spending on illnesses such as cancer and heart disease drop.
For his part, Robbins says that the scientific conferences in the anti-aging field, which tend to focus on the technical research, should hold more sessions on social and economic impacts. If anti-aging therapies start extending healthy lifespans, as he and other researchers hope they will within a decade or so, society will need to adjust.
Ultimately, it's an extension of health, not just of longevity, that will benefit us. Extra decades of senescence do nobody any good. As Green says, "Nobody wants to live in a nursing home for 1000 years."
In the 1966 movie "Fantastic Voyage," actress Raquel Welch and her submarine were shrunk to the size of a cell in order to eliminate a blood clot in a scientist's brain. Now, 55 years later, the scenario is becoming closer to reality.
California-based startup Bionaut Labs has developed a nanobot about the size of a grain of rice that's designed to transport medication to the exact location in the body where it's needed. If you think about it, the conventional way to deliver medicine makes little sense: A painkiller affects the entire body instead of just the arm that's hurting, and chemotherapy is flushed through all the veins instead of precisely targeting the tumor.
"Chemotherapy is delivered systemically," Bionaut-founder and CEO Michael Shpigelmacher says. "Often only a small percentage arrives at the location where it is actually needed."
But what if it was possible to send a tiny robot through the body to attack a tumor or deliver a drug at exactly the right location?
Several startups and academic institutes worldwide are working to develop such a solution but Bionaut Labs seems the furthest along in advancing its invention. "You can think of the Bionaut as a tiny screw that moves through the veins as if steered by an invisible screwdriver until it arrives at the tumor," Shpigelmacher explains. Via Zoom, he shares the screen of an X-ray machine in his Culver City lab to demonstrate how the half-transparent, yellowish device winds its way along the spine in the body. The nanobot contains a tiny but powerful magnet. The "invisible screwdriver" is an external magnetic field that rotates that magnet inside the device and gets it to move and change directions.
The current model has a diameter of less than a millimeter. Shpigelmacher's engineers could build the miniature vehicle even smaller but the current size has the advantage of being big enough to see with bare eyes. It can also deliver more medicine than a tinier version. In the Zoom demonstration, the micorobot is injected into the spine, not unlike an epidural, and pulled along the spine through an outside magnet until the Bionaut reaches the brainstem. Depending which organ it needs to reach, it could be inserted elsewhere, for instance through a catheter.
"The hope is that we can develop a vehicle to transport medication deep into the body," says Max Planck scientist Tian Qiu.
Imagine moving a screw through a steak with a magnet — that's essentially how the device works. But of course, the Bionaut is considerably different from an ordinary screw: "At the right location, we give a magnetic signal, and it unloads its medicine package," Shpigelmacher says.
To start, Bionaut Labs wants to use its device to treat Parkinson's disease and brain stem gliomas, a type of cancer that largely affects children and teenagers. About 300 to 400 young people a year are diagnosed with this type of tumor. Radiation and brain surgery risk damaging sensitive brain tissue, and chemotherapy often doesn't work. Most children with these tumors live less than 18 months. A nanobot delivering targeted chemotherapy could be a gamechanger. "These patients really don't have any other hope," Shpigelmacher says.
Of course, the main challenge of the developing such a device is guaranteeing that it's safe. Because tissue is so sensitive, any mistake could risk disastrous results. In recent years, Bionaut has tested its technology in dozens of healthy sheep and pigs with no major adverse effects. Sheep make a good stand-in for humans because their brains and spines are similar to ours.
The Bionaut device is about the size of a grain of rice.
Bionaut Labs
"As the Bionaut moves through brain tissue, it creates a transient track that heals within a few weeks," Shpigelmacher says. The company is hoping to be the first to test a nanobot in humans. In December 2022, it announced that a recent round of funding drew $43.2 million, for a total of 63.2 million, enabling more research and, if all goes smoothly, human clinical trials by early next year.
Once the technique has been perfected, further applications could include addressing other kinds of brain disorders that are considered incurable now, such as Alzheimer's or Huntington's disease. "Microrobots could serve as a bridgehead, opening the gateway to the brain and facilitating precise access of deep brain structure – either to deliver medication, take cell samples or stimulate specific brain regions," Shpigelmacher says.
Robot-assisted hybrid surgery with artificial intelligence is already used in state-of-the-art surgery centers, and many medical experts believe that nanorobotics will be the instrument of the future. In 2016, three scientists were awarded the Nobel Prize in Chemistry for their development of "the world's smallest machines," nano "elevators" and minuscule motors. Since then, the scientific experiments have progressed to the point where applicable devices are moving closer to actually being implemented.
Bionaut's technology was initially developed by a research team lead by Peer Fischer, head of the independent Micro Nano and Molecular Systems Lab at the Max Planck Institute for Intelligent Systems in Stuttgart, Germany. Fischer is considered a pioneer in the research of nano systems, which he began at Harvard University more than a decade ago. He and his team are advising Bionaut Labs and have licensed their technology to the company.
"The hope is that we can develop a vehicle to transport medication deep into the body," says Max Planck scientist Tian Qiu, who leads the cooperation with Bionaut Labs. He agrees with Shpigelmacher that the Bionaut's size is perfect for transporting medication loads and is researching potential applications for even smaller nanorobots, especially in the eye, where the tissue is extremely sensitive. "Nanorobots can sneak through very fine tissue without causing damage."
In "Fantastic Voyage," Raquel Welch's adventures inside the body of a dissident scientist let her swim through his veins into his brain, but her shrunken miniature submarine is attacked by antibodies; she has to flee through the nerves into the scientist's eye where she escapes into freedom on a tear drop. In reality, the exit in the lab is much more mundane. The Bionaut simply leaves the body through the same port where it entered. But apart from the dramatization, the "Fantastic Voyage" was almost prophetic, or, as Shpigelmacher says, "Science fiction becomes science reality."
This article was first published by Leaps.org on April 12, 2021.
How the Human Brain Project Built a Mind of its Own
In 2009, neuroscientist Henry Markram gave an ambitious TED talk. “Our mission is to build a detailed, realistic computer model of the human brain,” he said, naming three reasons for this unmatched feat of engineering. One was because understanding the human brain was essential to get along in society. Another was because experimenting on animal brains could only get scientists so far in understanding the human ones. Third, medicines for mental disorders weren’t good enough. “There are two billion people on the planet that are affected by mental disorders, and the drugs that are used today are largely empirical,” Markram said. “I think that we can come up with very concrete solutions on how to treat disorders.”
Markram's arguments were very persuasive. In 2013, the European Commission launched the Human Brain Project, or HBP, as part of its Future and Emerging Technologies program. Viewed as Europe’s chance to try to win the “brain race” between the U.S., China, Japan, and other countries, the project received about a billion euros in funding with the goal to simulate the entire human brain on a supercomputer, or in silico, by 2023.
Now, after 10 years of dedicated neuroscience research, the HBP is coming to an end. As its many critics warned, it did not manage to build an entire human brain in silico. Instead, it achieved a multifaceted array of different goals, some of them unexpected.
Scholars have found that the project did help advance neuroscience more than some detractors initially expected, specifically in the area of brain simulations and virtual models. Using an interdisciplinary approach of combining technology, such as AI and digital simulations, with neuroscience, the HBP worked to gain a deeper understanding of the human brain’s complicated structure and functions, which in some cases led to novel treatments for brain disorders. Lastly, through online platforms, the HBP spearheaded a previously unmatched level of global neuroscience collaborations.
Simulating a human brain stirs up controversy
Right from the start, the project was plagued with controversy and condemnation. One of its prominent critics was Yves Fregnac, a professor in cognitive science at the Polytechnic Institute of Paris and research director at the French National Centre for Scientific Research. Fregnac argued in numerous articles that the HBP was overfunded based on proposals with unrealistic goals. “This new way of over-selling scientific targets, deeply aligned with what modern society expects from mega-sciences in the broad sense (big investment, big return), has been observed on several occasions in different scientific sub-fields,” he wrote in one of his articles, “before invading the field of brain sciences and neuromarketing.”
"A human brain model can simulate an experiment a million times for many different conditions, but the actual human experiment can be performed only once or a few times," said Viktor Jirsa, a professor at Aix-Marseille University.
Responding to such critiques, the HBP worked to restructure the effort in its early days with new leadership, organization, and goals that were more flexible and attainable. “The HBP got a more versatile, pluralistic approach,” said Viktor Jirsa, a professor at Aix-Marseille University and one of the HBP lead scientists. He believes that these changes fixed at least some of HBP’s issues. “The project has been on a very productive and scientifically fruitful course since then.”
After restructuring, the HBP became a European hub on brain research, with hundreds of scientists joining its growing network. The HBP created projects focused on various brain topics, from consciousness to neurodegenerative diseases. HBP scientists worked on complex subjects, such as mapping out the brain, combining neuroscience and robotics, and experimenting with neuromorphic computing, a computational technique inspired by the human brain structure and function—to name just a few.
Simulations advance knowledge and treatment options
In 2013, it seemed that bringing neuroscience into a digital age would be farfetched, but research within the HBP has made this achievable. The virtual maps and simulations various HBP teams create through brain imaging data make it easier for neuroscientists to understand brain developments and functions. The teams publish these models on the HBP’s EBRAINS online platform—one of the first to offer access to such data to neuroscientists worldwide via an open-source online site. “This digital infrastructure is backed by high-performance computers, with large datasets and various computational tools,” said Lucy Xiaolu Wang, an assistant professor in the Resource Economics Department at the University of Massachusetts Amherst, who studies the economics of the HBP. That means it can be used in place of many different types of human experimentation.
Jirsa’s team is one of many within the project that works on virtual brain models and brain simulations. Compiling patient data, Jirsa and his team can create digital simulations of different brain activities—and repeat these experiments many times, which isn’t often possible in surgeries on real brains. “A human brain model can simulate an experiment a million times for many different conditions,” Jirsa explained, “but the actual human experiment can be performed only once or a few times.” Using simulations also saves scientists and doctors time and money when looking at ways to diagnose and treat patients with brain disorders.
Compiling patient data, scientists can create digital simulations of different brain activities—and repeat these experiments many times.
The Human Brain Project
Simulations can help scientists get a full picture that otherwise is unattainable. “Another benefit is data completion,” added Jirsa, “in which incomplete data can be complemented by the model. In clinical settings, we can often measure only certain brain areas, but when linked to the brain model, we can enlarge the range of accessible brain regions and make better diagnostic predictions.”
With time, Jirsa’s team was able to move into patient-specific simulations. “We advanced from generic brain models to the ability to use a specific patient’s brain data, from measurements like MRI and others, to create individualized predictive models and simulations,” Jirsa explained. He and his team are working on this personalization technique to treat patients with epilepsy. According to the World Health Organization, about 50 million people worldwide suffer from epilepsy, a disorder that causes recurring seizures. While some epilepsy causes are known others remain an enigma, and many are hard to treat. For some patients whose epilepsy doesn’t respond to medications, removing part of the brain where seizures occur may be the only option. Understanding where in the patients’ brains seizures arise can give scientists a better idea of how to treat them and whether to use surgery versus medications.
“We apply such personalized models…to precisely identify where in a patient’s brain seizures emerge,” Jirsa explained. “This guides individual surgery decisions for patients for which surgery is the only treatment option.” He credits the HBP for the opportunity to develop this novel approach. “The personalization of our epilepsy models was only made possible by the Human Brain Project, in which all the necessary tools have been developed. Without the HBP, the technology would not be in clinical trials today.”
Personalized simulations can significantly advance treatments, predict the outcome of specific medical procedures and optimize them before actually treating patients. Jirsa is watching this happen firsthand in his ongoing research. “Our technology for creating personalized brain models is now used in a large clinical trial for epilepsy, funded by the French state, where we collaborate with clinicians in hospitals,” he explained. “We have also founded a spinoff company called VB Tech (Virtual Brain Technologies) to commercialize our personalized brain model technology and make it available to all patients.”
The Human Brain Project created a level of interconnectedness within the neuroscience research community that never existed before—a network not unlike the brain’s own.
Other experts believe it’s too soon to tell whether brain simulations could change epilepsy treatments. “The life cycle of developing treatments applicable to patients often runs over a decade,” Wang stated. “It is still too early to draw a clear link between HBP’s various project areas with patient care.” However, she admits that some studies built on the HBP-collected knowledge are already showing promise. “Researchers have used neuroscientific atlases and computational tools to develop activity-specific stimulation programs that enabled paraplegic patients to move again in a small-size clinical trial,” Wang said. Another intriguing study looked at simulations of Alzheimer’s in the brain to understand how it evolves over time.
Some challenges remain hard to overcome even with computer simulations. “The major challenge has always been the parameter explosion, which means that many different model parameters can lead to the same result,” Jirsa explained. An example of this parameter explosion could be two different types of neurodegenerative conditions, such as Parkinson’s and Huntington’s diseases. Both afflict the same area of the brain, the basal ganglia, which can affect movement, but are caused by two different underlying mechanisms. “We face the same situation in the living brain, in which a large range of diverse mechanisms can produce the same behavior,” Jirsa said. The simulations still have to overcome the same challenge.
Understanding where in the patients’ brains seizures arise can give scientists a better idea of how to treat them and whether to use surgery versus medications.
The Human Brain Project
A network not unlike the brain’s own
Though the HBP will be closing this year, its legacy continues in various studies, spin-off companies, and its online platform, EBRAINS. “The HBP is one of the earliest brain initiatives in the world, and the 10-year long-term goal has united many researchers to collaborate on brain sciences with advanced computational tools,” Wang said. “Beyond the many research articles and projects collaborated on during the HBP, the online neuroscience research infrastructure EBRAINS will be left as a legacy even after the project ends.”
Those who worked within the HBP see the end of this project as the next step in neuroscience research. “Neuroscience has come closer to very meaningful applications through the systematic link with new digital technologies and collaborative work,” Jirsa stated. “In that way, the project really had a pioneering role.” It also created a level of interconnectedness within the neuroscience research community that never existed before—a network not unlike the brain’s own. “Interconnectedness is an important advance and prerequisite for progress,” Jirsa said. “The neuroscience community has in the past been rather fragmented and this has dramatically changed in recent years thanks to the Human Brain Project.”
According to its website, by 2023 HBP’s network counted over 500 scientists from over 123 institutions and 16 different countries, creating one of the largest multi-national research groups in the world. Even though the project hasn’t produced the in-silico brain as Markram envisioned it, the HBP created a communal mind with immense potential. “It has challenged us to think beyond the boundaries of our own laboratories,” Jirsa said, “and enabled us to go much further together than we could have ever conceived going by ourselves.”