Gene Therapies for Eternal Youth
Longevity startups are riding high as a wave of gene therapies advance through clinical trials. Can they actually turn back the clock?
Imagine a not-so-distant future, when a 60-year-old man named John Doe goes to the doctor to replace a faulty gene or insert a whole new gene into his body — something that cures his diabetes, for instance. This is no pipe dream.
So far, gene therapy has been approved by the U.S. Food and Drug Administration (FDA) for only a couple of applications like rare inherited diseases and blood cancer. That said, more than 2,000 clinical trials are taking place in 2023, with 200 of them having already reached phase 3 clinical trials. A slew of upcoming gene therapies could be approved — possibly in the months to come — in the United States and Europe, targeting everything from sickle cell disease and hemophilia to metastatic skin cancer. In this future, gene therapy will be approved for everything we can imagine — and many things we can’t.
Now fast forward 10 more years. That same man and his peers will have counted 70 circles round the sun. But John will remain biologically 60. At the same time, someone who is 30 years old in the year 2033 could theoretically begin the therapy at age 30, and stick at a biological age of 30 for the next 30 years, when their calendar would call them 60. That’s what gene therapies for longevity could do.
Some scientists dream of pushing this technology even further, including Yuri Deigin, a longevity drug developer and activist, and co-founder and director of YouthBio Therapeutics. The Seattle-based longevity startup utilizes a technique called partial reprogramming to develop gene therapies aimed at helping people remain young. Building on work first done in David Sinclair’s lab at Harvard, “The most incredible thing would be for a 60-year-old to take these therapies and start aging in reverse,” Deigin says. “Maybe we will do this in the years to come.”
And, unlike Benjamin Button, the Brad Pitt character who aged backward in the movie and died as a helpless baby, this novel scientific approach is all about creating multiple Benjamin Buttons — without the drama.
Stem-cell state of youthfulness
Partial reprogramming uses a group of proteins called Yamanaka factors to convert any given cell of the body into a pluripotent stem cell, essentially a group of embryonic cells that are undifferentiated, meaning that they have no specialized function yet and can renew themselves. The modality Deigin’s startup envisions involves injecting a vector carrying a gene into key organs of the body, such as [an aging] brain, which becomes highly susceptible to neurodegenerative disorders like Parkinson’s, Alzheimer’s, or glaucoma after the age of 65. A monthly or bi-monthly administration of a small molecule, probably a pill, would theoretically trigger the gene expression and set the target organ in rejuvenation mode.
“If you want to cure cancer, you really should be trying to cure aging.”
To force an adult cell into a stem-cell state of youthfulness, scientists take a stretch of DNA carrying the reprogramming instructions and package it with a solution of lipids that help it fuse into the membrane of the cell. Once the Yamanaka factors bind to the targeted region, the genes that trigger the stem cell expression are switched on and the genes that make the cell specialized are switched off. After about a month, the colonies that ideally match the morphology of the desired pluripotent stem cells are tested for safety and accuracy and to make sure they are now “identity-less” and able to become any specialized type of cell. Then, over the next few weeks, the cell colonies are fed molecules that turn them into astonishingly close proxies for nerve cells, heart cells, muscle cells, or kidney cells.
Deigin says they are currently using Yamanaka genes to set off this rejuvenating gene expression, but they are also actively seeking novel rejuvenating genes. “These are the genes we are, and will be, delivering as a payload in our gene therapies to be regularly activated by the small-molecule activator,” he says. Ultimately, he’s hoping for approval as a longevity enhancing drug however, “Initially,” he says, “we have to show their efficacy in the context of some disease to get them approved by the FDA. So we are developing our brain-specific therapy for preventing and treating Alzheimer’s,” he says. The big picture, though, is for YouthBio to use a combination therapy targeting key multiple organs of a healthy person — basically, an entire systemic rejuvenation.
Deigin’s longevity quest started when he was a drug developer for Alzheimer’s disease. “I soon understood that if I had to make a meaningful dent in Alzheimer’s or other age-related diseases, I had to get to the root of the problem,” he says. “The causal factor in all age-related diseases is aging. If you want to cure cancer, you really should be trying to cure aging,” he says.
The question of whether aging is a disease that can be cured is hotly debated. Deigin believes modern medicine, in a sense, can’t see the forest for the trees; physicians are preoccupied with administering drugs aimed at slowing down the progression of age-related diseases instead of addressing the very root cause of the problem: aging itself. And the fact that the medical establishment propagates the traditional view that aging is a natural process has created a disconnect among the general population, Deigin believes.
“The public very much supports curing cancer, the public supports curing Alzheimer’s or heart disease, but when you start talking about getting rid of the aging process altogether, people are much more reluctant to agree to that and support that idea,’’ Deigin says.
A look at nature might prove there is no hard and fast rule when it comes to how various species grow old.
“We already have examples of animals who live hundreds of years,” Deigin says, pointing to various sea creatures. Take the whale shark: It can live up to 130 years. The bowhead whale can surpass two centuries of life. Radiocarbon dating shows the oldest Greenland shark in the world was born in 1627 — sixteen years before Isaac Newton — and was between 272 and 512 years old when fishermen found it. Sea sponges have a lifespan of 11,000 years. And some species of the humble jellyfish can take a U-turn when old age appears and head back to infancy. Seeing how other creatures in nature have indeed managed to reverse the aging process, the advocates of longevity medicine wonder what’s to stop humans from doing the same — even if it takes some genetic engineering to assist the process.
Mass production of gene therapies
At the time of this writing, scientists at YouthBio report they are conducting animal studies for Alzheimer’s disease with their gene therapy, which is code named YB002. While success in the lab or in preclinical animal studies often poorly predicts whether or not a drug will be effective and ultimately make it to market, some therapies could potentially be available for human trials in the next three or four years, according to Deigin. “We want to bring these therapies to the market as quickly as possible,” he says.
A promising study involving gene therapy interventions for mice was published on the preprint server bioRXiv in early 2023. Researchers from the University of California, San Diego and the University of Chicago used a modified virus to deliver the genes “ordering” cells to introduce three of the Yamanaka factors into the bodies of 124-week-old mice (the mouse equivalent of a 77-year-old human). The treated mice then lived for a median of 18.5 more weeks, while the untreated controls only made it to a median of 9 more weeks. “We also reported improvements in markers of health in the treated mice, such as reduced frailty,’’ says Noah Davidsohn, one of the study’s authors and co-founder and chief scientific officer at Rejuvenate Bio, a gene therapy company pioneering novel therapies to treat aging and age-related diseases.
“Our initial pipeline products are based on three longevity genes [FGF21, sTGFβR2, and αKlotho] with proven efficacy and unprecedented safety profiles validated by big pharma,” continues Davidsohn. By delivering combinations of these three genes, he says they have treated multiple models of age-related disease, heart failure, kidney failure, diabetes and obesity in mice, and heart failure and obesity in large animals — and in an aggregate way.
“We will give these children a future, not just a decade or two of health before aging diseases take hold.”
“We deliver genes that holistically reverse aging pathways in the cells that make them better equipped to deal with age-related stressors. This plays out in a number of different diseases that get more prevalent or worse as you get older,” adds Davidsohn. Their first indications show this approach can tackle mitral valve disease in dogs, a common canine heart disease affecting approximately 30 percent of dogs over the age of 10, and arrhythmogenic cardiomyopathy in humans, a rare genetic condition in which the myocardium, the heart’s muscular wall, breaks down in time, leading to irregular palpitations, lightheadedness, breathlessness, swollen limbs or tummy, and often, sudden death.
In 2024, Rejuvenate Bio will secure its first human investigational new drug application (IND) according to Davidsohn. An IND is a request from a clinical study sponsor to obtain authorization from the FDA allowing them to administer the drug to people in a clinical trial. But dogs will come first. “We will bring our first product to market for the treatment of heart failure in dogs through a partnership with Phibro, a large animal health company,” says Davidsohn.
Like Deigin, Davidsohn believes we should stop viewing aging in reverse as a dystopian theme stemming from the science fiction fandom, but as something “extremely feasible.” Of course, there is still a gap in our technology and tools before we’ll be able to realize the example of a 60-year-old turning 30. “The three key technological areas we need to advance are better genes, better gene delivery, and better control systems for their expression,” says Davidsohn. With those, a complete organismal age reversal could be a possibility.
“There are countless examples of drugs and genetic interventions showcasing the plasticity of aging and our ability to slow aging across various species,” Davidsohn notes. The plasticity of aging is a given for his startup. “Aging results from gene expression patterns,” Davidsohn says. By controlling the way these genes are expressed, we can turn back the clock, reversing multiple pathological states like heart failure, cognitive decline, and musculoskeletal health issues, and restoring the entire system to a youthful and healthy state before pathology got in the way.
“Gene therapy started in the rare and orphan disease space where a single gene mutation drives a disease. Now, several drugs are on the market for those patients,” says Elizabeth Parrish, CEO of BioViva Science, a Washington-based biotech company working to develop treatments to reverse the aging process. Parrish doesn’t just preach these therapies; she lives according to her own advice. She is the first known human recipient of in vivo gene therapy designed to extend longevity, having received injections introducing copies of genes believed to trigger lengthening of telomeres, the protective DNA–protein structures found at both ends of each chromosome that shrink as we age. She also took injections of genes BioViva scientists believe will help retain muscle mass and generally extend lifespan.
The next level
Parrish agrees with Deigin that we can fight aging. She says she is ready to take gene therapy to the next level, curing aging in one of the places where it starts, in the human genome. (It should be noted there may be 11 more hallmarks of aging, such as epigenetic alterations, stem cell exhaustion, chronic inflammation, and the gradual loss of the protective caps of our chromosomes knows as telomere attrition, and this hallmark number could rise even more.) “By curing aging with gene therapy, we will not only treat complex conditions like aging-associated diseases, but also remedy many childhood diseases. We will give these children a future, not just a decade or two of health before aging diseases take hold,” she says.
Xiaojing Yang, lead scientist at myDNAge, a startup offering biological age tests, also places herself in the aging-is-a-disease camp. “What’s the number one high risk factor for cancer? It’s your age. Older people have a higher chance of getting cancer,” Yang says. And when she says “old,” she means epigenetically old. Our chronological age is a rigid number denoting how much time has passed since the day we were born. Our biological or epigenetic age is determined by our genetics, lifestyle, diet, and comorbidities, and is thus more malleable. “Your biological age may be 10 or (potentially many) more years higher or lower than your chronological age,” Yang says.
It is precisely these new and fascinating insights showing how age is not just a number that make longevity activists like Parrish hopeful. “Finding a back-door, [a] small molecule to reset epigenetic drift will be a major step in health and life extension,” she says. Yang says we may need much more to fight aging than injecting ourselves with a miracle cure or taking one of the miracle drugs that are all the rage today, like rapamycin, metformin, or nicotinamide mono nucleotide. Yang champions an approach through which doctors take into account things like our DNA, the places we inhabit, our lifestyle, and how our specific anatomical features — like the way our brain is structured — influence our overall health before they proceed to personalized treatments. “Even epigenetic signatures of twins are totally different, depending on their lifestyle. We would need to take into account precision medicine to fight aging,” Yang concludes.
In any case, the giddiness around living healthier longer is admittedly infectious. So why then haven’t regulatory agencies moved faster? The FDA hasn’t approved a single longevity therapy, and there is still plenty of skepticism in the scientific community about the gains versus potential side effects of these treatments. A recent study that is not yet peer-reviewed found that reprogramming a mouse’s cells may cause premature death due to liver and intestinal problems. Other animal studies have also suggested partial reprogramming treatments may cause cancer. Yet, even with all the open research questions, the longevity startup ecosystem is expected to soar to high heavens in the next few years.
“This is because the market for things that purport to improve people’s health and lives, like nutritional supplements, is huge,” says Henry (Hank) Greely, a bioethicist at Stanford Law School. “Almost none of them have been proven to any reasonable degree to do anything beyond lighten the consumer’s bank account,” Greely is quick to add.
Just because there is no known law of science saying we can’t live longer, doesn’t mean we can. “We are not sharks, or whales — or bristlecone pine trees, or giant tortoises,” Greely says. “The fact that other species live for decades or centuries longer than humans is a point of evidence, but not a terribly convincing one,” he adds. “So many things in the human body can go wrong.”
And then there is the cost.
Who can afford it?
Today, the price of getting treated with an approved gene therapy is likely to be at least $1.5 million per person — but as with every new innovation, longevity evangelists believe the therapy will trickle down to the masses eventually.
Not surprisingly, Deigin predicts gene therapies will become much less expensive in the coming years. “Just like COVID-19 proved billions of doses of vaccines could be manufactured quickly and cheaply, so can we mass-produce gene therapies,” he says.
Others are less convinced. The argument that COVID-19 vaccines are cheap is not particularly strong because vaccines are not in any reasonable definition a gene therapy, Greely says. “One might as well call wine a gene therapy because both the grapes and the yeast that combine to make it are made by genes.”
“Techno-utopians [are] attempting to make immortality a reality here and now, [but] a heaven on Earth will most likely make hell on Earth.”
Finances aside, fundamental existential questions may trouble the mind when the body refuses to die.
“Techno-utopians [are] attempting to make immortality a reality here and now, [but] a heaven on Earth will most likely make hell on Earth,” says Omar Sultan Haque, a psychiatrist and social scientist investigating questions ranging across global health, anthropology, social psychology, and bioethics. Haque believes that extending — to some degree — a life that is flourishing, is admirable, but it is folly to think we can eliminate aging and death as if they are diseases.
“If we don’t think humans have a natural teleology, or purpose, and that a human life doesn’t have a normative rhythm, with stages of life like chapters in a book, and an unfolding narrative to be discovered, and we view aging as a disease to be eradicated, rather than a part of the human condition, we would be making an amoral, materialistic utopia that abolishes death and the body’s entropy; a new techno-utopian secular religion,” he says. In this new techno-utopia, Haque fears there will be no higher moral law, no inherent limits and constraints on what we can treat or erase in the human condition.
The techno-dystopia cometh
Having eliminated one of the most fundamental needs humans have had since the dawn of time — survival — would we find ourselves in a techno-dystopia instead? Would we lose the purpose of life itself, our human dignity, our sense of life as a gift to be cherished rather than mastered and controlled, and our ideas of good and evil… just to become some sort of self-sustaining sentient lizards? And will we end up squandering most of the planet’s resources during our ultra-long journeys, leaving almost nothing for those to come?
“The ‘make room for other people’ argument is not pressing — for now — but neither is it absurd,” says Greely. “Otherwise, as a 70-year-old, why should I care about climate change? And why should anyone ever plant a new oak tree?” he says.
Deigin finds similar arguments fallacious if not downright backward.
“Helping those who suffer from aging today is more valuable than the rights of the people who haven’t been born,” he says. To support our preventive belief that the unborn generations deserve life and land, we condemn existing people to suffering. “And, first of all, what land? The Earth has incredible reserves. Even if the world population right now is at its peak, the standard of living is also at its peak,” Deigin says.
Longevity activists can’t comprehend why people fear a techno Armageddon and a spiritual and emotional lessening of the human experience, when all they aspire to do is maintain the vehicle that offers this experience, the human body, in its best state possible for as long as possible. “Our therapy will not magically stop people from dying; it will simply slow down the aging process,” Deigin says.
What could possibly go wrong? Everything, according to outspoken opponents like Hague and Greely.
Perhaps it’s all a matter of perspective — but in this case, there are diametrically opposed perspectives that would not seem to happily coexist. Deigin’s vision is one of a society where a person who has lived for 70 chronological years on Earth nevertheless will have the health and stamina of a 30-year-old. For Haque, such a society will be messing with the rules of the game and fiddling with the fundamental settings and constants of humanity’s existential physics, perhaps to the point of no return. For Deigin, the same community will simply be one of people with younger and healthier bodies, who will, by default, be far happier and more productive.
Either way, there is a good chance we’ll find out relatively soon.
Originally published at https://proto.life.
