Could epigenetic reprogramming reverse aging?
Ten thousand years ago, the average human spent a maximum of 30 years on Earth. Despite the glory of Ancient Greece and the Roman Empire, most of their inhabitants didn’t surpass the age of 35. Between the 1500s and 1800, life expectancy (at least in Europe) fluctuated between 30 and 40 years.
Public health advancements like control of infectious diseases, better diet and clean sanitation, as well as social improvements have made it possible for human lifespans to double since 1800. Although lifespan differs widely today from country to country according to socioeconomic health, the average has soared to 73.2 years.
But this may turn out to be on the low side if epigenetic rejuvenation fulfills its great promise: to reverse aging, perhaps even completely. Epigenetic rejuvenation, or partial reprogramming, is the process by which a set of therapies are trying to manipulate epigenetics – how various changes can affect our genes – and the Yamanaka factors. These Yamanaka factors are a group of proteins that can convert any cell of the body into pluripotent stem cells, a group of cells that can turn into brand new cells, such as those of the brain or skin. At least in theory, it could be a recipe for self-renewal.
“Partial reprogramming tries to knock a few years off of people’s biological age, while preserving their original cell identity and function,” says Yuri Deigin, cofounder and director of YouthBio Therapeutics, a longevity startup utilizing partial reprogramming to develop gene therapies aimed at the renewal of epigenetic profiles. YouthBio plans to experiment with injecting these gene therapies into target organs. Once the cargo is delivered, a specific small molecule will trigger gene expression and rejuvenate those organs.
“Our ultimate mission is to find the minimal number of tissues we would need to target to achieve significant systemic rejuvenation,” Deigin says. Initially, YouthBio will apply these therapies to treat age-related conditions. Down the road, though, their goal is for everyone to get younger. “We want to use them for prophylaxis, which is rejuvenation that would lower disease risk,” Deigin says.
Epigenetics has swept the realm of biology off its feet over the last decade. We now know that we can switch genes on and off by tweaking the chemical status quo of the DNA’s local environment. "Epigenetics is a fascinating and important phenomenon in biology,’’ says Henry Greely, a bioethicist at Stanford Law School. Greely is quick to stress that this kind of modulation (turning genes on and off and not the entire DNA) happens all the time. “When you eat and your blood sugar goes up, the gene in the beta cells of your pancreas that makes insulin is turned on or up. Almost all medications are going to have effects on epigenetics, but so will things like exercise, food, and sunshine.”
Can intentional control over epigenetic mechanisms lead to novel and useful therapies? “It is a very plausible scenario,” Greely says, though a great deal of basic research into epigenetics is required before it becomes a well-trodden way to stay healthy or treat disease. Whether these therapies could cause older cells to become younger in ways that have observable effects is “far from clear,” he says. “Historically, betting on someone’s new ‘fountain of youth’ has been a losing strategy.”
The road to de-differentiation, the process by which cells return to an earlier state, is not paved with roses; de-differentiate too much and you may cause pathology and even death.
In 2003 researchers finished sequencing the roughly 3 billion letters of DNA that make up the human genome. The human genome sequencing was hailed as a vast step ahead in our understanding of how genetics contribute to diseases like cancer or to developmental disorders. But for Josephine Johnston, director of research and research scholar at the Hastings Center, the hype has not lived up to its initial promise. “Other than some quite effective tests to diagnose certain genetic conditions, there isn't a radical intervention that reverses things yet,” Johnston says. For her, this is a testament to the complexity of biology or at least to our tendency to keep underestimating it. And when it comes to epigenetics specifically, Johnston believes there are some hard questions we need to answer before we can safely administer relevant therapies to the population.
“You'd need to do longitudinal studies. You can't do a study and look at someone and say they’re safe only six months later,” Johnston says. You can’t know long-term side effects this way, and how will companies position their therapies on the market? Are we talking about interventions that target health problems, or life enhancements? “If you describe something as a medical intervention, it is more likely to be socially acceptable, to attract funding from governments and ensure medical insurance, and to become a legitimate part of medicine,” she says.
Johnston’s greatest concerns are of the philosophical and ethical nature. If we’re able to use epigenetic reprogramming to double the human lifespan, how much of the planet’s resources will we take up during this long journey? She believes we have a moral obligation to make room for future generations. “We should also be honest about who's actually going to afford such interventions; they would be extraordinarily expensive and only available to certain people, and those are the people who would get to live longer, healthier lives, and the rest of us wouldn't.”
That said, Johnston agrees there is a place for epigenetic reprogramming. It could help people with diseases that are caused by epigenetic problems such as Fragile X syndrome, Prader-Willi syndrome and various cancers.
Zinaida Good, a postdoctoral fellow at Stanford Cancer Institute, says these problems are still far in the future. Any change will be incremental. “Thinking realistically, there’s not going to be a very large increase in lifespan anytime soon,” she says. “I would not expect something completely drastic to be invented in the next 5 to 10 years. ”
Good won’t get any such treatment for herself until it’s shown to be effective and safe. Nature has programmed our bodies to resist hacking, she says, in ways that could undermine any initial benefits to longevity. A preprint that is not yet peer-reviewed reports cellular reprogramming may lead to premature death due to liver and intestinal problems, and using the Yamanaka factors may have the potential to cause cancer, at least in animal studies.
“Side effects are an open research question that all partial reprogramming companies and labs are trying to address,” says Deigin. The road to de-differentiation, the process by which cells return to an earlier state, is not paved with roses; de-differentiate too much and you may cause pathology and even death. Deigin is exploring other, less risky approaches. “One way is to look for novel factors tailored toward rejuvenation rather than de-differentiation.” Unlike Yamanaka factors, such novel factors would never involve taking a given cell to a state in which it could turn cancerous, according to Deigin.
An example of a novel factor that could lower the risk of cancer is artificially introducing mRNA molecules, or molecules carrying the genetic information necessary to make proteins, by using electricity to penetrate the cell instead of a virus. There is also chemical-based reprogramming, in which chemicals are applied to convert regular cells into pluripotent cells. This approach is currently effective only for mice though.
“The search for novel factors tailored toward rejuvenation without de-differentiation is an ongoing research and development effort by several longevity companies, including ours,” says Deigin.
He isn't disclosing the details of his own company’s underlying approach to lowering the risk, but he’s hopeful that something will eventually end up working in humans. Yet another challenge is that, partly because of the uncertainties, the FDA hasn’t seen fit to approve a single longevity therapy. But with the longevity market projected to soar to $600 billion by 2025, Deigin says naysayers are clinging irrationally to the status quo. “Thankfully, scientific progress is moved forward by those who bet for something while disregarding the skeptics - who, in the end, are usually proven wrong.”
DNA- and RNA-based electronic implants may revolutionize healthcare
Implantable electronic devices can significantly improve patients’ quality of life. A pacemaker can encourage the heart to beat more regularly. A neural implant, usually placed at the back of the skull, can help brain function and encourage higher neural activity. Current research on neural implants finds them helpful to patients with Parkinson’s disease, vision loss, hearing loss, and other nerve damage problems. Several of these implants, such as Elon Musk’s Neuralink, have already been approved by the FDA for human use.
Yet, pacemakers, neural implants, and other such electronic devices are not without problems. They require constant electricity, limited through batteries that need replacements. They also cause scarring. “The problem with doing this with electronics is that scar tissue forms,” explains Kate Adamala, an assistant professor of cell biology at the University of Minnesota Twin Cities. “Anytime you have something hard interacting with something soft [like muscle, skin, or tissue], the soft thing will scar. That's why there are no long-term neural implants right now.” To overcome these challenges, scientists are turning to biocomputing processes that use organic materials like DNA and RNA. Other promised benefits include “diagnostics and possibly therapeutic action, operating as nanorobots in living organisms,” writes Evgeny Katz, a professor of bioelectronics at Clarkson University, in his book DNA- And RNA-Based Computing Systems.
While a computer gives these inputs in binary code or "bits," such as a 0 or 1, biocomputing uses DNA strands as inputs, whether double or single-stranded, and often uses fluorescent RNA as an output.
Adamala’s research focuses on developing such biocomputing systems using DNA, RNA, proteins, and lipids. Using these molecules in the biocomputing systems allows the latter to be biocompatible with the human body, resulting in a natural healing process. In a recent Nature Communications study, Adamala and her team created a new biocomputing platform called TRUMPET (Transcriptional RNA Universal Multi-Purpose GatE PlaTform) which acts like a DNA-powered computer chip. “These biological systems can heal if you design them correctly,” adds Adamala. “So you can imagine a computer that will eventually heal itself.”
The basics of biocomputing
Biocomputing and regular computing have many similarities. Like regular computing, biocomputing works by running information through a series of gates, usually logic gates. A logic gate works as a fork in the road for an electronic circuit. The input will travel one way or another, giving two different outputs. An example logic gate is the AND gate, which has two inputs (A and B) and two different results. If both A and B are 1, the AND gate output will be 1. If only A is 1 and B is 0, the output will be 0 and vice versa. If both A and B are 0, the result will be 0. While a computer gives these inputs in binary code or "bits," such as a 0 or 1, biocomputing uses DNA strands as inputs, whether double or single-stranded, and often uses fluorescent RNA as an output. In this case, the DNA enters the logic gate as a single or double strand.
If the DNA is double-stranded, the system “digests” the DNA or destroys it, which results in non-fluorescence or “0” output. Conversely, if the DNA is single-stranded, it won’t be digested and instead will be copied by several enzymes in the biocomputing system, resulting in fluorescent RNA or a “1” output. And the output for this type of binary system can be expanded beyond fluorescence or not. For example, a “1” output might be the production of the enzyme insulin, while a “0” may be that no insulin is produced. “This kind of synergy between biology and computation is the essence of biocomputing,” says Stephanie Forrest, a professor and the director of the Biodesign Center for Biocomputing, Security and Society at Arizona State University.
Biocomputing circles are made of DNA, RNA, proteins and even bacteria.
Evgeny Katz
The TRUMPET’s promise
Depending on whether the biocomputing system is placed directly inside a cell within the human body, or run in a test-tube, different environmental factors play a role. When an output is produced inside a cell, the cell's natural processes can amplify this output (for example, a specific protein or DNA strand), creating a solid signal. However, these cells can also be very leaky. “You want the cells to do the thing you ask them to do before they finish whatever their businesses, which is to grow, replicate, metabolize,” Adamala explains. “However, often the gate may be triggered without the right inputs, creating a false positive signal. So that's why natural logic gates are often leaky." While biocomputing outside a cell in a test tube can allow for tighter control over the logic gates, the outputs or signals cannot be amplified by a cell and are less potent.
TRUMPET, which is smaller than a cell, taps into both cellular and non-cellular biocomputing benefits. “At its core, it is a nonliving logic gate system,” Adamala states, “It's a DNA-based logic gate system. But because we use enzymes, and the readout is enzymatic [where an enzyme replicates the fluorescent RNA], we end up with signal amplification." This readout means that the output from the TRUMPET system, a fluorescent RNA strand, can be replicated by nearby enzymes in the platform, making the light signal stronger. "So it combines the best of both worlds,” Adamala adds.
These organic-based systems could detect cancer cells or low insulin levels inside a patient’s body.
The TRUMPET biocomputing process is relatively straightforward. “If the DNA [input] shows up as single-stranded, it will not be digested [by the logic gate], and you get this nice fluorescent output as the RNA is made from the single-stranded DNA, and that's a 1,” Adamala explains. "And if the DNA input is double-stranded, it gets digested by the enzymes in the logic gate, and there is no RNA created from the DNA, so there is no fluorescence, and the output is 0." On the story's leading image above, if the tube is "lit" with a purple color, that is a binary 1 signal for computing. If it's "off" it is a 0.
While still in research, TRUMPET and other biocomputing systems promise significant benefits to personalized healthcare and medicine. These organic-based systems could detect cancer cells or low insulin levels inside a patient’s body. The study’s lead author and graduate student Judee Sharon is already beginning to research TRUMPET's ability for earlier cancer diagnoses. Because the inputs for TRUMPET are single or double-stranded DNA, any mutated or cancerous DNA could theoretically be detected from the platform through the biocomputing process. Theoretically, devices like TRUMPET could be used to detect cancer and other diseases earlier.
Adamala sees TRUMPET not only as a detection system but also as a potential cancer drug delivery system. “Ideally, you would like the drug only to turn on when it senses the presence of a cancer cell. And that's how we use the logic gates, which work in response to inputs like cancerous DNA. Then the output can be the production of a small molecule or the release of a small molecule that can then go and kill what needs killing, in this case, a cancer cell. So we would like to develop applications that use this technology to control the logic gate response of a drug’s delivery to a cell.”
Although platforms like TRUMPET are making progress, a lot more work must be done before they can be used commercially. “The process of translating mechanisms and architecture from biology to computing and vice versa is still an art rather than a science,” says Forrest. “It requires deep computer science and biology knowledge,” she adds. “Some people have compared interdisciplinary science to fusion restaurants—not all combinations are successful, but when they are, the results are remarkable.”
In today’s podcast episode, Leaps.org Deputy Editor Lina Zeldovich speaks about the health and ecological benefits of farming crickets for human consumption with Bicky Nguyen, who joins Lina from Vietnam. Bicky and her business partner Nam Dang operate an insect farm named CricketOne. Motivated by the idea of sustainable and healthy protein production, they started their unconventional endeavor a few years ago, despite numerous naysayers who didn’t believe that humans would ever consider munching on bugs.
Yet, making creepy crawlers part of our diet offers many health and planetary advantages. Food production needs to match the rise in global population, estimated to reach 10 billion by 2050. One challenge is that some of our current practices are inefficient, polluting and wasteful. According to nonprofit EarthSave.org, it takes 2,500 gallons of water, 12 pounds of grain, 35 pounds of topsoil and the energy equivalent of one gallon of gasoline to produce one pound of feedlot beef, although exact statistics vary between sources.
Meanwhile, insects are easy to grow, high on protein and low on fat. When roasted with salt, they make crunchy snacks. When chopped up, they transform into delicious pâtes, says Bicky, who invents her own cricket recipes and serves them at industry and public events. Maybe that’s why some research predicts that edible insects market may grow to almost $10 billion by 2030. Tune in for a delectable chat on this alternative and sustainable protein.
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Further reading:
More info on Bicky Nguyen
https://yseali.fulbright.edu.vn/en/faculty/bicky-n...
The environmental footprint of beef production
https://www.earthsave.org/environment.htm
https://www.watercalculator.org/news/articles/beef-king-big-water-footprints/
https://www.frontiersin.org/articles/10.3389/fsufs.2019.00005/full
https://ourworldindata.org/carbon-footprint-food-methane
Insect farming as a source of sustainable protein
https://www.insectgourmet.com/insect-farming-growing-bugs-for-protein/
https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/insect-farming
Cricket flour is taking the world by storm
https://www.cricketflours.com/
https://talk-commerce.com/blog/what-brands-use-cricket-flour-and-why/
Lina Zeldovich has written about science, medicine and technology for Popular Science, Smithsonian, National Geographic, Scientific American, Reader’s Digest, the New York Times and other major national and international publications. A Columbia J-School alumna, she has won several awards for her stories, including the ASJA Crisis Coverage Award for Covid reporting, and has been a contributing editor at Nautilus Magazine. In 2021, Zeldovich released her first book, The Other Dark Matter, published by the University of Chicago Press, about the science and business of turning waste into wealth and health. You can find her on http://linazeldovich.com/ and @linazeldovich.