Reversing age-related diseases in humans may only be a few years away. However, studies in mice have already begun to show promising discoveries. A new study out of Rejuvenate Bio found how partial reprogramming could be a potential treatment in the elderly to reverse age-associated diseases and potentially extend the human lifespan.
A new study found enhanced health and a 109% increase in the lifespan of mice over control.
Partial reprogramming shows efficacy in reversing age-related diseases in mice.
The antibiotic-induced system used in mice could not be used in larger animals or humans.
More studies are needed to investigate the ideal therapeutic for humans in terms of turning the Yamanaka factors on and off to maximize health benefits and avoid tumor formation.
Noah Davidsohn, Ph.D., chief scientific officer and co-founder at Rejuvenate Bio, told HealthNews that they’re hoping to be in the clinic for this type of next-generational therapy, age reversal with the intermittent pulsing of partial reprogramming factors very soon.
“We hope to be in the clinic for humans for a specific disease within the next five years,” Davidsohn said. “We’re working on a number of different angles in terms of which disease to address first.”
Whether it’d be decreased immunity, heart disease, or Alzheimer’s, his team is working toward utilizing their therapy, with efficacy and safety for a particular age-related disease first, then expanding to multiple different indications after that.
“We’re not focused on increasing lifespan,” Davidsohn explained, adding, “We’re focused on reversing disease states. As a consequence, you might end up with a longer lifespan, but you will be disease-free at that point.”
What is partial reprogramming?
Partial reprogramming refers to a type of gene therapy that leverages the power of the Yamanaka factors in a cyclical manner.
The Yamanaka factors, discovered in 2006 by Shinya Yamanaka, are four transcription factors (Oct4, Sox2, Klf4, C-Myc), also known as OSKM factors, that can transform any cell back into a stem cell.
Such a newfound discovery led many scientists down the path to test what would happen if the Yamanaka factors were fully induced. Unfortunately, they would find that while the impacted cells would show signs of rejuvenation during their dedifferentiation (turning into stem cells), there was also a high rate of cancer development.
Then in 2010, Prim Singh proposed the idea of turning on the Yamanaka factors only periodically to achieve rejuvenation but avoid tumor formation. Hence, partial reprogramming was born.
A study published in 2016 was one of the first to show how “short-term cyclic expression of Oct4, Sox2, Klf4, and c-Myc (OSKM) ameliorates cellular and physiological hallmarks of aging and prolongs lifespan in a mouse model of premature aging. Similarly, expression of OSKM in vivo improves recovery from metabolic disease and muscle injury in older wild-type mice.”
The sample size of the present study consisted of 20 mice in the control group and 20 in the group that got the treatment. The Rejuvenate Bio team used elderly 124-week-old mice, equivalent to about a 77-year-old human.
Instead of performing partial reprogramming on all four Yamanaka factors, they did one more slight tweak to their therapeutic approach. They only targeted three of the four (OCT4, SOX2, and KLF4).
The reason being, as Davidsohn explained, “c-Myc [M] is generally considered way more oncogenic than the others, and without using M, we just had OSK in our cassette that decreased tumorigenicity of this therapeutic.”
To periodically “switch on” those Yamanaka factors, they used cyclically induced doxycycline, an antibiotic derived from bacterial genes.
Such an antibiotic-induced system, however, couldn't be applied to larger animals and humans because the bacterial components would trigger an immune response. An inducer that can be considered is either a drug that's already been FDA-approved with minimal side effects or a so-called "GRAS" molecule, a substance generally recognized as safe by the FDA but has never been put through a trial, i.e., caffeine.
Their findings showed systemic effects that enhanced health parameters and more than doubled (109%) the remaining lifespan of mice over controls. “We also didn’t see any teratomas [tumors], so that was a nice positive checkmark in the box.”
To measure the therapeutics’ impact on healthspan, they looked at a couple of metrics, such as the frailty index, which included several phenotypic measurements (i.e., fur loss, gray fur, hunched back, and loss in mobility) as well as the epigenetic state. Davidsohn explained that while the epigenetic state is not yet a definite biomarker for aging, it’s starting to be accepted as a biomarker to quantify healthspan.
Beyond an increase in lifespan, the data showed a decrease in frailty and a reverse of the epigenetic state to a younger profile of health.
There’s more that’s yet to be done, though, as the team hasn’t done a complete pathology report or toxicology study. “We plan on doing such a study as we move into the clinic and onto mammals and humans,” Davidsohn said.
The study is currently in a preprint phase as the team is still performing additional data analysis before submitting it for review to a peer-reviewed journal.
The path from mice to humans
Many different factors contribute to aging, but we don’t yet have a complete model of exactly how it happens. While genetics play a role, epigenetics and one’s environment and lifestyle choices contribute to how certain genes are expressed and whether they get turned on or off.
A study out of Dr. David Sinclair’s lab recently published new findings answering the question, "What drives aging?"
Rejuvenate Bio’s goal to address age-related diseases comes at a time when as the aging population grows, there’s an increase in the number of people suffering from chronic diseases. According to the Centers for Disease Control and Prevention (CDC), by 2030, about one in five Americans will be 65 years and older. Additionally, older adults are at a higher risk for developing age-related diseases, such as heart disease, dementia, arthritis, kidney disease, diabetes, and cancer, which significantly reduce their quality of life. The CDC shows that approximately 85% of older adults have at least one chronic health condition, and 60% have at least two.
Instead of being in the field of longevity, extending one’s lifespan, Rejuvenate Bio is looking to focus on age reversal and getting rid of diseases associated with aging, so that people can have more years where they are present, active, and happy to be here.
There has been a lot of accumulated basic research over the decades, but being able to translate that research to therapeutics has been limited. Thus, the path to human trials still presents many unknowns.
Questions regarding an exact sequence, how long the Yamanaka factors should be turned on or turned off, and how often it has to be done are yet to be investigated in larger mammals before it reaches human clinical trials.
Being able to control the expression over time very specifically is key to making sure the system is only “turned on” for the right amount of time, so that would increase health and not cause problems, such as the formation of tumors.
The results seen in mice were systemic. In other words, the whole body was impacted, but Davidshon says when it comes to humans, they want to start with being tissue-specific first.
Their near-term goal is to focus on specific tissues and diseases in those tissues to narrow them down. This will help prove safety and control, and as the technology improves, it could evolve into a more systemic approach.
“I’m hoping that we, Rejuvenate Bio, as well as others, will start making in-roads to providing these general increasing-health therapeutics,” Davidshon said. “We don’t want to increase the number of years you have a problem. We want to get rid of the problem and give you years without a problem.”
- Journal of Biosciences. Nuclear reprogramming and epigenetic rejuvenation.
- Cell. In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming.
- FDA. Generally Recognized as Safe (GRAS).
- Cell. Loss of epigenetic information as a cause of mammalian aging.
- bioRxiv. Gene Therapy Mediated Partial Reprogramming Extends Lifespan and Reverses Age-Related Changes in Aged Mice.