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Steve Hill March 20, 2019
We have talked about the potential of partial cellular reprogramming in previous articles, and today, we want to draw attention to a new paper that promises to further refine reversal of epigenetic aging in cells.
As we age, our cells experience alterations to their epigenetic markers, and this changes gene expression, which is proposed to be a primary reason we age. Recently, there has been considerable interest in resetting these epigenetic markers to reverse cellular aging, and this paper builds on that.
Three of the study’s authors, Prof. Vittorio Sebastiano, Jay Sarkar, and Marco Quarta, have founded Turn.bio, a biotech company that is working to bring partial cellular reprogramming to humans. The company is also currently enjoying the leadership of Gary Hudson from Oisin Biotechnologies, who is standing in as CEO to help the company get off the ground and funded.
It is worth noting that this paper is a preprint, has not yet been peer reviewed, and is published in bioRxiv in the interest of sharing knowledge faster.
The birth of cellular reprogramming
Back in 2006, Drs. Takahashi and Yamanaka discovered that it was possible to change cells from one type to another by reprogramming them using just four master genes: Oct-4, Sox2, Klf4, and c-Myc (OSKM) . These four factors are commonly known as the Yamanaka factors.
Prior to this discovery, it was generally thought that cells, once specialized, could not change into a different cell type. However, once cells were exposed to the four reprogramming factors expressed by these genes, they reverted back to a younger developmental state and regained the potential to become any other cell type in the body. This state is known as pluripotency.
This is the basis of creating induced pluripotent stem cells (iPSCs), which are used in current stem cell therapies. This process allows cells such as skin cells to be taken from a patient and reprogrammed back into this flexible, pluripotent state; these cells are then guided using other chemical triggers to change into the cell type that the patient needs.
Another interesting aspect of cellular reprogramming is that cells also experience a reversal of the epigenetic markers that develop as we age, thereby reverting back to a younger state. In a very real sense, cells have their age reset and become functionally young again.
Partial cellular reprogramming
This discovery showed that it is possible to reprogram cells to become whatever cell type is needed and that cellular aging is not a one-way process, allowing for the rejuvenation of cells.
However, inducing pluripotency in the cells of a living person would be a very bad idea indeed; imagine if a heart cell forgot it was a heart cell and became a bone cell but was still in the heart! Also, making cells pluripotent in the body carries the risk of causing teratomas, which are tumors made up of multiple types of tissue, such as hair, muscle, or bone. Therefore, we need a solution that can rejuvenate our cells without them forgetting what jobs they are supposed to be doing and without promoting cancer.
One potential answer is partial cellular reprogramming.
In a nutshell, partial cellular reprogramming involves exposing aged cells to OSKM for just long enough that they reset the epigenetic markers that determine if they are young or old but not long enough that the cells forget what they are and become pluripotent. As of late 2016, this approach was successfully demonstrated in living animals .
Turn.bio is using transient messenger RNA (mRNA) that mimics the effects of OSKM but includes some factors that help to refine the reprogramming process. Messenger RNA (mRNA) is a family of RNA molecules that relay genetic information from the DNA to the ribosome, where they determine the amino acid sequences of the proteins that are produced as the end result of gene expression.
This approach emulates OSKM expression in that it changes the epigenetic aging markers of the target cells. In doing so, it reverses the age of the cells without the risk of changing their type or causing a teratoma to form.
Aging is characterized by a gradual loss of function occurring at the molecular, cellular, tissue and organismal levels. At the chromatin level, aging is associated with the progressive accumulation of epigenetic errors that eventually lead to aberrant gene regulation, stem cell exhaustion, senescence, and deregulated cell/tissue homeostasis. The technology of nuclear reprogramming to pluripotency, through over-expression of a small number of transcription factors, can revert both the age and the identity of any cell to that of an embryonic cell by driving epigenetic reprogramming. Recent evidence has shown that transient transgenic reprogramming can ameliorate age-associated hallmarks and extend lifespan in progeroid mice. However, it is unknown how this form of epigenetic rejuvenation would apply to physiologically aged cells and, importantly, how it might translate to human cells. Here we show that transient reprogramming, mediated by transient expression of mRNAs, promotes a rapid reversal of both cellular aging and of epigenetic clock in human fibroblasts and endothelial cells, reduces the inflammatory profile in human chondrocytes, and restores youthful regenerative response to aged, human muscle stem cells, in each case without abolishing cellular identity. Our method, that we named Epigenetic Reprogramming of Aging (ERA), paves the way to a novel, potentially translatable strategy for ex vivo cell rejuvenation treatment. In addition, ERA holds promise for in vivo tissue rejuvenation therapies to reverse the physiological manifestations of aging and the risk for the development of age-related diseases.
We have already seen partial cellular reprogramming used safely in living animals, and Turn.bio’s approach has the potential to further refine that process to make it safer and easier to translate to humans.
This approach has great potential given that epigenetic alterations are likely a primary reason we age, and reversing the epigenetic aging markers in our cells could rejuvenate our organs and tissues as it did in animal studies. That is not to suggest that reversing epigenetic aging is the only problem to solve, because the other hallmarks continue to accrue, but given that it is a primary aging process, some optimism is in order for this and similar approaches.
The key take-home from this paper is that their mixture of reprogramming factors can change the gene expression and function of aged cells back to those of younger cells while avoiding the loss of cell identity and cancer. The next step for these researchers will be to move their technique to animal studies, which is the first step towards bringing it to people.
 Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. cell, 126(4), 663-676.
 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.