Global Longevity Labs aims to transform medicine through programmable cellular rejuvenation.
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A series of research papers released over the past year reinforces the potential of cellular reprogramming, particularly in the battle against aging and age-related disease. To understand why all of this research is gathering steam now, we need to take a trip back to 2007, when a Japanese scientist at Kyoto University made a breakthrough by unlocking the secret to turn the biological clock back within individual cells.
“You’re trying to almost reverse disease in a disease-agnostic fashion.”
Yamanaka discovered four genes that, when expressed together, reset a cell from its mature state back to a point where it had the same properties as an embryonic stem cell (an iPS stem cell). So for example, if you have a skin cell taken from an adult human, Yamanaka’s genetic switches could revert that skin cell to tabula rasa, then coaxed to perform a different function. These four genes were dubbed Yamanaka factors, and together, they opened a raft of new possibilities in medical science.
The Japanese scientist drew inspiration from two breakthroughs decades apart. In 1962, Sir John Gurdon, sometimes described as the godfather of cloning, created a new frog by transferring the nucleus of a tadpole’s intestine cell into the egg of a toad. The success of his project proved that mature cells like the intestine cell still contain the genetic information needed to achieve pluripotency. Otherwise, the egg would never have developed into an organism. This concept was further reinforced by an even more high-profile achievement — the cloning of Dolly the sheep in 1996. He believed there was a set of instructions in the cell, an expression of certain genes, that was able to instruct the cell to return to its pluripotent state.
Yamanaka aims to solve two issues: create a steady supply of stem cells that won’t fall foul of immune rejection, and avoid the ethical conundrums associated with extracting stem cells from embryos.
Yamanaka’s breakthrough caught the eye of aging researchers. According to Reik, aging expert Steve Horvath kicked things off with a key observation in 2013: He suggested the age of an iPS cell was effectively zero, meaning that aside from erasing a cell’s function, Yamanaka factors also reset its biological age to zero. The hypothesis formed: If scientists could better control the effects of the Yamanaka factors and minimize the risk of side-effects, they may be able to erase some of the effect of aging on the body.
“Would cells know how to become younger and healthier?”
In 2016, scientist Juan Carlos Izpisua Belmonte at the Salk Institute in California made the first major breakthrough in proving this hypothesis: He expressed the Yamanaka factors in mice with progeria, a genetic condition that causes the body to age at an alarmingly rapid rate. The treated animals lived 30 percent longer than a control group, and — crucially — didn’t develop any cancers, one of the biggest risks of using Yamanaka factors.
The iPS cells produced by the Yamanaka factors have all the exceptional properties of embryonic stem cells – able to grow, divide, and become any cell, whether it be a skin, blood, or brain cell. But if they are allowed to develop in the body unchecked, these pluripotent cells cause embryo-like tumors called teratomas. In fact, one of the four Yamanaka factors is a known oncogene, which means it can cause cancer.
Aging researchers like Belmonte discovered that the trick was to limit the capabilities of the Yamanaka factors so the cells don’t fully reach iPS form. This can be done by either expressing the genes for a certain amount of time, expressing only some of the genes and not others, or changing their expression level. In Belmonte’s case, his team switched the genes on for two days a week over several weeks. This has the effect of reversing damage over time, without fully resetting cells.
Pluripotent stem cells may be a tool for scientists to repair damaged tissue.
In the last three years, the science into Yamanaka factors has exploded. In 2020, a team led by David Sinclair used three of the four Yamanaka factors to restore lost sight in mice. Sinclair is a well-known figure in the longevity field who is outspoken in his enthusiasm for extending life beyond the norm. In this study, Sinclair and his team examined the epigenome, the chemical compounds that tell genes what to do and when and where to do it, for signs of aging. In this context, it’s easier to imagine the epigenome as an old-fashioned vinyl record carrying vital instructions. Over time, the record becomes scratched. If you could remove those scratches and restore the record, Sinclair and others believed, you could restore function to the genome and rejuvenate cells.
“The big question was, is there a reset button?” he told Science at the time. “Would cells know how to become younger and healthier?”
The study targeted retinal cells in mice with a harmless virus containing three Yamanaka factors in an attempt to fix a severed optic nerve. The gambit was at least partially successful in restoring function to the retinal cells.
Around the same time, a study co-published by scientists at biotech company Genentech and the Salk Institute showed that expressing the Yamanaka factors in mice in cycles over an extended period of time had no apparent negative health effects on the animals. The study, which was co-led by Heinrich Jasper, who works in immunology discovery at Genentech, also found that partially reprogrammed cells reduced age-related changes in typical, healthy mice, not just those with disease or injury.
“It’s almost easier to fix something that’s broken than it is to make something that’s good, better.”
In January of this year, the San Diego-based biotech company Rejuvenate Bio released results from another study on reprogramming effects on aging. The company injected elderly mice with a virus that activated three of the Yamanaka factors and found that the animals lived an extra 18 weeks on average, compared to nine weeks for the control group.
Noah Davidsohn, chief science officer and co-founder at Rejuvenate Bio, tells Inverse the paper was significant because it was the first to properly realize some of the potential of the Yamanaka factors. He explains that while previous research has addressed mice with diseases or damage, like progeria or severed optic nerves, this work attempted to make otherwise healthy mice live longer.
“We put it in wild type mice that are really old and are basically the same as really old humans and show that we could increase their life and health span,” he says. “So I think that sparked an ‘Oh wow, it actually does what everyone is promising it’s been doing but hasn’t been done yet.’”
“It’s almost easier to fix something that’s broken than it is to make something that’s good, better,” Davidsohn says.
These types of studies underline the potential of cell reprogramming in the fight against age-related disease, but there is still a lot of work to be done. First, the field needs to understand exactly what is happening on a molecular level when the Yamanaka factors are expressed. This can lead to better control over their expression and will speed up their potential use in humans.
“If you think about aging as a biological process that leads to changes in cells, and these changes actually contribute to the incidents and progression of a wide range of age-related, chronic, degenerative diseases, then you might really learn something if you’ re trying to address these age-related changes and try to modulate them so you have an impact on the progression of a disease, or even on the instances of the disease.”
The promise and potential of the reprogramming field, particularly in relation to aging, has led to increased investment in the area. Jasper estimates there are around 15 to 20 labs working on using the Yamanaka factors together with aging research, and more are emerging every month. “There’s a lot of excitement about potentially what can be done there”
The Yamanaka factors may never reverse aging in humans, but they could still play an important role in the fight against the multitude of vicious diseases that come with getting older. The number of people aged 80 years or older is expected to triple by 2050, up to 426 million, according to World Health Organization figures—and age-related disease will inevitably become more prevalent. As research continues at a steady pace, cellular reprogramming could hold the key to managing that tidal wave of disease looming on the horizon — even if it won’t be applied to making otherwise healthy humans cheat the march of biological time.
Cells in healthy, resilient states resist stressors that give rise to disease, but this diminishes with aging. Early experiments have shown that this ability to resist stressors can be restored.
What are the fundamentals of this biology? Which parts can be harnessed to help more people live free from disease or disability? Our work is to pursue answers to these questions and more, and to develop applications for what we discover, with the goal of reversing disease.
What we find could change the way we think about medicine.
His discovery was a breakthrough for biological research, enabling the creation of induced pluripotent (non-embryonic) stem cells and revealing an even more interesting possibility.
Global Longevity Labs builds on Yamanaka’s findings by showing that cells can be “partially” reprogrammed. Rather than reverting completely to stem cells, Global Longevity Labs found that cells can be “partially” reprogrammed to a state that is more resilient to stressors, while maintaining both their identity and the enhanced functions seen in younger cells.
In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming
We now have pre-clinical data suggesting that the dysfunction associated with aging and disease can be reversible. This knowledge means that it may, one day, be possible to transform patients’ lives by reversing disease, injury and the disabilities that can occur throughout life.”