Today, we are going to take a look at the companies working on resetting cellular aging through a reprogramming approach that directly targets a core reason we age.
Cellular reprogramming resets aging in cells
As we age, our cells experience alterations to their epigenetic markers, and this, in turn, changes gene expression; this process is a primary hallmark of aging. These age-related changes lead to a decline of function and ultimately contribute to the loss of homeostasis, or balance, which allows age-related diseases to develop.
Recently, there has been considerable interest in resetting these epigenetic markers to potentially reverse cellular aging and restore youthful function to tissues and organs. In 2006, Drs. Takahashi and Yamanaka showed that a cell’s age or type is not something set in stone; rather, it is flexible and can be manipulated.
The researchers demonstrated that it is possible to reprogram cells from one type to another using just four master genes: Oct4, Sox2, Klf4, and c-Myc (OSKM), which are also known as Yamanaka factors. Exposing cells to these factors appears to reset the aging clock, making these cells forget their roles and their age while reverting them to a youthful, flexible, and embryonic state from which they can become any cell type.
This discovery turned the scientific world upside down, as prior to this, it was believed that egg cells (oocytes) must contain a complex range of factors needed to turn a somatic cell into an embryonic cell. It became the basis of induced pluripotent stem cell (iPSC) therapy, which we use today to produce transplant cells of different types.
Some researchers suggest that it may be possible to expose aged cells to reprogramming factors for just long enough so that they reset their epigenetic state and work like young cells again — but not long enough to erase their cell identify and make them forget what cell type they are. This approach is known as partial cellular reprogramming, and it could keep tissues and organs free from many of the damages that aging causes and help us to stay healthy and free from age-related diseases for longer.
Researchers are now investigating if it might be plausible to separate the reversal of cell identity from the reversal of cell age, and recent animal studies suggest that it is. In December 2016, Professor Juan Carlos Izpisua Belmonte and his team of researchers at the Salk Institute reported the conclusion of their study, which showed for the first time that the cells and organs of a living animal could be rejuvenated using the Yamanaka factors .
This has created a surge of interest in developing therapies that use these reprogramming factors. There are a number of labs and companies now involved in exploring the exciting possibilities of this approach.
Turn.Bio is one of a number of companies working on resetting cellular aging using the partial cellular reprogramming approach. In March 2019, the Turn.Bio team published a study showing the potential of using transient mRNA to trigger partial cell reprogramming and has been busy building on that research since.
In their study, the researchers claim that the cellular memory erasure and the resetting of epigenetic aging markers can be separated because the reversal of aging markers happens first in the reprogramming process; in other words, they believe that if they can expose cells just long enough to the reprogramming factors, it should be possible to reverse their epigenetic aging without resetting their type, which would obviously be bad news inside your body.
The unique thing about their approach is that they have added two additional factors, LIN28 and Nanog, to the four reprogramming Yamanaka factors; the combined cocktail is called OSKMLN. According to their research, this combination is more effective and spurs greater cellular rejuvenation.
Additionally, LIN28 also reduces the activity of Let-7, an mRNA that facilitates cell differentiation. Reducing its presence helps to reinforce cellular identity and may also further boost the rejuvenation process.
We think that the direction Turn.Bio is taking is particularly fascinating, especially its decision to use six reprogramming factors. If you would like to learn more about Turn.Bio, we interviewed Professor Vittorio Sebastiano last year about the company and the exciting research that it is doing.
While Turn.Bio is using more than the usual four Yamanaka factors, Youthereum Genetics is doing the opposite; this company is taking a minimalist approach and plans to use just a single factor, Oct4, to partially reprogram cells. Indeed, a number of studies suggest that Oct4 is the initiating reprogramming factor that kickstarts the entire process of cellular reprogramming. It could be the case that just this single factor is enough to achieve the goal of resetting epigenetic aging markers.
The company believes this streamlined approach is the best course to ensure safety while still resetting cellular aging. The basis for this line of thinking is that while OSKM has been demonstrated to reverse cellular aging in living animals, it is not without risk. Youthereum thinks that with the Yamanaka factors, there is a narrow therapeutic window between erasing aging markers and potentially overstimulating them, which could invite cancer. In an experiment in which mice were engineered to express OSKM for more than three days or so, they start to develop teratomas and die.
Clearly, there is a line to walk between rejuvenation and out-of-control cells prone to becoming cancerous, which is why Youthereum is opting to take this route. The risks of using more than one factor could possibly be mitigated, but this company has chosen a single factor in order to reduce those risks.
We are intrigued to see if the use of one factor will be enough to reset epigenetic aging markers and are following this company’s work closely. If you are interested in learning more about the work of Youthereum Genetics, we interviewed its CEO, Yuri Deigin, last year.
Others to keep an eye on
Professor Juan Carlos Izpisua Belmonte and his team at the Salk institute are also continuing their research and we expect in due course that they will move to launching a startup biotech company based on their findings.
Dr. David Sinclair is also very interested in the potential of partial cellular reprogramming and is part of Life Biosciences, a group of companies that is working on aging therapeutics. Dr. Sinclair is both co-founder and chairman of the board at Life Biosciences, which is taking a systemic approach of tackling all the hallmarks of aging collectively. We anticipate we will be hearing more from this organization in the near future once it concludes its initial research.
The promise of partial cellular reprogramming is considerable, and if it can be successfully translated to people, it has the potential to keep tissues and organs functionally younger and free from the diseases of aging. We are likely a number of years away from this happening, but perhaps in the next decade or so, we will see these approaches arriving at the clinic as treatments for age-related diseases.
 Ocampo A, Reddy P, Martinez-Redondo P, Platero-Luengo A, Hatanaka F, Hishida T, Li M, Lam D, Kurita M, Beyret E, Araoka T, Vazquez-Ferrer E, Donoso D, Roman JLXJ, Rodriguez-Esteban C, Nuñez G, Nuñez Delicado E, Campistol JM, Guillen I, Guillen P, Izpisua Belmonte JC. In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell. 2016;167:1719–33.