A company uses AI to fight muscle loss and unhealthy aging
There’s a growing need to slow down the aging process. The world’s population is getting older and, according to one estimate, 80 million Americans will be 65 or older by 2040. As we age, the risk of many chronic diseases goes up, from cancer to heart disease to Alzheimer’s.
BioAge Labs, a company based in California, is using genetic data to help people stay healthy for longer. CEO Kristen Fortney was inspired by the genetics of people who live long lives and resist many age-related diseases. In 2015, she started BioAge to study them and develop drug therapies based on the company’s learnings.
The team works with special biobanks that have been collecting blood samples and health data from individuals for up to 45 years. Using artificial intelligence, BioAge is able to find the distinctive molecular features that distinguish those who have healthy longevity from those who don’t.
In December 2022, BioAge published findings on a drug that worked to prevent muscular atrophy, or the loss of muscle strength and mass, in older people. Much of the research on aging has been in worms and mice, but BioAge is focused on human data, Fortney says. “This boosts our chances of developing drugs that will be safe and effective in human patients.”
How it works
With assistance from AI, BioAge measures more than 100,000 molecules in each blood sample, looking at proteins, RNA and metabolites, or small molecules that are produced through chemical processes. The company uses many techniques to identify these molecules, some of which convert the molecules into charged atoms and then separating them according to their weight and charge. The resulting data is very complex, with many thousands of data points from patients being followed over the decades.
BioAge validates its targets by examining whether a pathway going awry is actually linked to the development of diseases, based on the company’s analysis of biobank health records and blood samples. The team uses AI and machine learning to identify these pathways, and the key proteins in the unhealthy pathways become their main drug targets. “The approach taken by BioAge is an excellent example of how we can harness the power of big data and advances in AI technology to identify new drugs and therapeutic targets,” says Lorna Harries, a professor of molecular genetics at the University of Exeter Medical School.
Martin Borch Jensen is the founder of Gordian Biotechnology, a company focused on using gene therapy to treat aging. He says BioAge’s use of AI allows them to speed up the process of finding promising drug candidates. However, it remains a challenge to separate pathologies from aspects of the natural aging process that aren’t necessarily bad. “Some of the changes are likely protective responses to things going wrong,” Jensen says. “Their data doesn’t…distinguish that so they’ll need to validate and be clever.”
Developing a drug for muscle loss
BioAge decided to focus on muscular atrophy because it affects many elderly people, making it difficult to perform everyday activities and increasing the risk of falls. Using the biobank samples, the team modeled different pathways that looked like they could improve muscle health. They found that people who had faster walking speeds, better grip strength and lived longer had higher levels of a protein called apelin.
Apelin is a peptide, or a small protein, that circulates in the blood. It is involved in the process by which exercise increases and preserves muscle mass. BioAge wondered if they could prevent muscular atrophy by increasing the amount of signaling in the apelin pathway. Instead of the long process of designing a drug, they decided to repurpose an existing drug made by another biotech company. This company, called Amgen, had explored the drug as a way to treat heart failure. It didn’t end up working for that purpose, but BioAge took note that the drug did seem to activate the apelin pathway.
BioAge tested its new, repurposed drug, BGE-105, and, in a phase 1 clinical trial, it protected subjects from getting muscular atrophy compared to a placebo group that didn’t receive the drug. Healthy volunteers over age 65 received infusions of the drug during 10 days spent in bed, as if they were on bed rest while recovering from an illness or injury; the elderly are especially vulnerable to muscle loss in this situation. The 11 people taking BGE-105 showed a 100 percent improvement in thigh circumference compared to 10 people taking the placebo. Ultrasound observations also revealed that the group taking the durg had enhanced muscle quality and a 73 percent increase in muscle thickness. One volunteer taking BGE-105 did have muscle loss compared to the the placebo group.
Heather Whitson, the director of the Duke University Centre for the study of aging and human development, says that, overall, the results are encouraging. “The clinical findings so far support the premise that AI can help us sort through enormous amounts of data and identify the most promising points for beneficial interventions.”
More studies are needed to find out which patients benefit the most and whether there are side effects. “I think further studies will answer more questions,” Whitson says, noting that BGE-105 was designed to enhance only one aspect of physiology associated with exercise, muscle strength. But exercise itself has many other benefits on mood, sleep, bones and glucose metabolism. “We don’t know whether BGE-105 will impact these other outcomes,” she says.
The future
BioAge is planning phase 2 trials for muscular atrophy in patients with obesity and those who have been hospitalized in an intensive care unit. Using the data from biobanks, they’ve also developed another drug, BGE-100, to treat chronic inflammation in the brain, a condition that can worsen with age and contributes to neurodegenerative diseases. The team is currently testing the drug in animals to assess its effects and find the right dose.
BioAge envisions that its drugs will have broader implications for health than treating any one specific disease. “Ultimately, we hope to pioneer a paradigm shift in healthcare, from treatment to prevention, by targeting the root causes of aging itself,” Fortney says. “We foresee a future where healthy longevity is within reach for all.”
Silkworms with spider DNA spin silk stronger than Kevlar
Story by Freethink
The study and copying of nature’s models, systems, or elements to address complex human challenges is known as “biomimetics.” Five hundred years ago, an elderly Italian polymath spent months looking at the soaring flight of birds. The result was Leonardo da Vinci’s biomimetic Codex on the Flight of Birds, one of the foundational texts in the science of aerodynamics. It’s the science that elevated the Wright Brothers and has yet to peak.
Today, biomimetics is everywhere. Shark-inspired swimming trunks, gecko-inspired adhesives, and lotus-inspired water-repellents are all taken from observing the natural world. After millions of years of evolution, nature has quite a few tricks up its sleeve. They are tricks we can learn from. And now, thanks to some spider DNA and clever genetic engineering, we have another one to add to the list.
The elusive spider silk
We’ve known for a long time that spider silk is remarkable, in ways that synthetic fibers can’t emulate. Nylon is incredibly strong (it can support a lot of force), and Kevlar is incredibly tough (it can absorb a lot of force). But neither is both strong and tough. In all artificial polymeric fibers, strength and toughness are mutually exclusive, and so we pick the material best for the job and make do.
Spider silk, a natural polymeric fiber, breaks this rule. It is somehow both strong and tough. No surprise, then, that spider silk is a source of much study.The problem, though, is that spiders are incredibly hard to cultivate — let alone farm. If you put them together, they will attack and kill each other until only one or a few survive. If you put 100 spiders in an enclosed space, they will go about an aggressive, arachnocidal Hunger Games. You need to give each its own space and boundaries, and a spider hotel is hard and costly. Silkworms, on the other hand, are peaceful and productive. They’ll hang around all day to make the silk that has been used in textiles for centuries. But silkworm silk is fragile. It has very limited use.
The elusive – and lucrative – trick, then, would be to genetically engineer a silkworm to produce spider-quality silk. So far, efforts have been fruitless. That is, until now.
We can have silkworms creating silk six times as tough as Kevlar and ten times as strong as nylon.
Spider-silkworms
Junpeng Mi and his colleagues working at Donghua University, China, used CRISPR gene-editing technology to recode the silk-creating properties of a silkworm. First, they took genes from Araneus ventricosus, an East Asian orb-weaving spider known for its strong silk. Then they placed these complex genes – genes that involve more than 100 amino acids – into silkworm egg cells. (This description fails to capture how time-consuming, technical, and laborious this was; it’s a procedure that requires hundreds of thousands of microinjections.)
This had all been done before, and this had failed before. Where Mi and his team succeeded was using a concept called “localization.” Localization involves narrowing in on a very specific location in a genome. For this experiment, the team from Donghua University developed a “minimal basic structure model” of silkworm silk, which guided the genetic modifications. They wanted to make sure they had the exactly right transgenic spider silk proteins. Mi said that combining localization with this basic structure model “represents a significant departure from previous research.” And, judging only from the results, he might be right. Their “fibers exhibited impressive tensile strength (1,299 MPa) and toughness (319 MJ/m3), surpassing Kevlar’s toughness 6-fold.”
A world of super-materials
Mi’s research represents the bursting of a barrier. It opens up hugely important avenues for future biomimetic materials. As Mi puts it, “This groundbreaking achievement effectively resolves the scientific, technical, and engineering challenges that have hindered the commercialization of spider silk, positioning it as a viable alternative to commercially synthesized fibers like nylon and contributing to the advancement of ecological civilization.”
Around 60 percent of our clothing is made from synthetic fibers like nylon, polyester, and acrylic. These plastics are useful, but often bad for the environment. They shed into our waterways and sometimes damage wildlife. The production of these fibers is a source of greenhouse gas emissions. Now, we have a “sustainable, eco-friendly high-strength and ultra-tough alternative.” We can have silkworms creating silk six times as tough as Kevlar and ten times as strong as nylon.
We shouldn’t get carried away. This isn’t going to transform the textiles industry overnight. Gene-edited silkworms are still only going to produce a comparatively small amount of silk – even if farmed in the millions. But, as Mi himself concedes, this is only the beginning. If Mi’s localization and structure-model techniques are as remarkable as they seem, then this opens up the door to a great many supermaterials.
Nature continues to inspire. We had the bird, the gecko, and the shark. Now we have the spider-silkworm. What new secrets will we unravel in the future? And in what exciting ways will it change the world?
Gene Transfer Leads to Longer Life and Healthspan
The naked mole rat won’t win any beauty contests, but it could possibly win in the talent category. Its superpower: fighting the aging process to live several times longer than other animals its size, in a state of youthful vigor.
It’s believed that naked mole rats experience all the normal processes of wear and tear over their lifespan, but that they’re exceptionally good at repairing the damage from oxygen free radicals and the DNA errors that accumulate over time. Even though they possess genes that make them vulnerable to cancer, they rarely develop the disease, or any other age-related disease, for that matter. Naked mole rats are known to live for over 40 years without any signs of aging, whereas mice live on average about two years and are highly prone to cancer.
Now, these remarkable animals may be able to share their superpower with other species. In August, a study provided what may be the first proof-of-principle that genetic material transferred from one species can increase both longevity and healthspan in a recipient animal.
There are several theories to explain the naked mole rat’s longevity, but the one explored in the study, published in Nature, is based on the abundance of large-molecule high-molecular mass hyaluronic acid (HMM-HA).
A small molecule version of hyaluronic acid is commonly added to skin moisturizers and cosmetics that are marketed as ways to keep skin youthful, but this version, just applied to the skin, won’t have a dramatic anti-aging effect. The naked mole rat has an abundance of the much-larger molecule, HMM-HA, in the chemical-rich solution between cells throughout its body. But does the HMM-HA actually govern the extraordinary longevity and healthspan of the naked mole rat?
To answer this question, Dr. Vera Gorbunova, a professor of biology and oncology at the University of Rochester, and her team created a mouse model containing the naked mole rat gene hyaluronic acid synthase 2, or nmrHas2. It turned out that the mice receiving this gene during their early developmental stage also expressed HMM-HA.
The researchers found that the effects of the HMM-HA molecule in the mice were marked and diverse, exceeding the expectations of the study’s co-authors. High-molecular mass hyaluronic acid was more abundant in kidneys, muscles and other organs of the Has2 mice compared to control mice.
In addition, the altered mice had a much lower incidence of cancer. Seventy percent of the control mice eventually developed cancer, compared to only 57 percent of the altered mice, even after several techniques were used to induce the disease. The biggest difference occurred in the oldest mice, where the cancer incidence for the Has2 mice and the controls was 47 percent and 83 percent, respectively.
With regard to longevity, Has2 males increased their lifespan by more than 16 percent and the females added 9 percent. “Somehow the effect is much more pronounced in male mice, and we don’t have a perfect answer as to why,” says Dr. Gorbunova. Another improvement was in the healthspan of the altered mice: the number of years they spent in a state of relative youth. There’s a frailty index for mice, which includes body weight, mobility, grip strength, vision and hearing, in addition to overall conditions such as the health of the coat and body temperature. The Has2 mice scored lower in frailty than the controls by all measures. They also performed better in tests of locomotion and coordination, and in bone density.
Gorbunova’s results show that a gene artificially transferred from one species can have a beneficial effect on another species for longevity, something that had never been demonstrated before. This finding is “quite spectacular,” said Steven Austad, a biologist at the University of Alabama at Birmingham, who was not involved in the study.
Just as in lifespan, the effects in various organs and systems varied between the sexes, a common occurrence in longevity research, according to Austad, who authored the book Methuselah’s Zoo and specializes in the biological differences between species. “We have ten drugs that we can give to mice to make them live longer,” he says, “and all of them work better in one sex than in the other.” This suggests that more attention needs to be paid to the different effects of anti-aging strategies between the sexes, as well as gender differences in healthspan.
According to the study authors, the HMM-HA molecule delivered these benefits by reducing inflammation and senescence (cell dysfunction and death). The molecule also caused a variety of other benefits, including an upregulation of genes involved in the function of mitochondria, the powerhouses of the cells. These mechanisms are implicated in the aging process, and in human disease. In humans, virtually all noncommunicable diseases entail an acceleration of the aging process.
So, would the gene that creates HMM-HA have similar benefits for longevity in humans? “We think about these questions a lot,” Gorbunova says. “It’s been done by injections in certain patients, but it has a local effect in the treatment of organs affected by disease,” which could offer some benefits, she added.
“Mice are very short-lived and cancer-prone, and the effects are small,” says Steven Austad, a biologist at the University of Alabama at Birmingham. “But they did live longer and stay healthy longer, which is remarkable.”
As for a gene therapy to introduce the nmrHas2 gene into humans to obtain a global result, she’s skeptical because of the complexity involved. Gorbunova notes that there are potential dangers in introducing an animal gene into humans, such as immune responses or allergic reactions.
Austad is equally cautious about a gene therapy. “What this study says is that you can take something a species does well and transfer at least some of that into a new species. It opens up the way, but you may need to transfer six or eight or ten genes into a human” to get the large effect desired. Humans are much more complex and contain many more genes than mice, and all systems in a biological organism are intricately connected. One naked mole rat gene may not make a big difference when it interacts with human genes, metabolism and physiology.
Still, Austad thinks the possibilities are tantalizing. “Mice are very short-lived and cancer-prone, and the effects are small,” he says. “But they did live longer and stay healthy longer, which is remarkable.”
As for further research, says Austad, “The first place to look is the skin” to see if the nmrHas2 gene and the HMM-HA it produces can reduce the chance of cancer. Austad added that it would be straightforward to use the gene to try to prevent cancer in skin cells in a dish to see if it prevents cancer. It would not be hard to do. “We don’t know of any downsides to hyaluronic acid in skin, because it’s already used in skin products, and you could look at this fairly quickly.”
“Aging mechanisms evolved over a long time,” says Gorbunova, “so in aging there are multiple mechanisms working together that affect each other.” All of these processes could play a part and almost certainly differ from one species to the next.
“HMM-HA molecules are large, but we’re now looking for a small-molecule drug that would slow it’s breakdown,” she says. “And we’re looking for inhibitors, now being tested in mice, that would hinder the breakdown of hyaluronic acid.” Gorbunova has found a natural, plant-based product that acts as an inhibitor and could potentially be taken as a supplement. Ultimately, though, she thinks that drug development will be the safest and most effective approach to delivering HMM-HA for anti-aging.